Difference between revisions of "Urothelial carcinoma"

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! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Page editor'''
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! colspan="2" style="color:white; font-size:125%; background-color:#08519c" align="center" |'''Section editor'''
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[[#top|Back to Top]]
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| style="background-color:#F0F0F0" |[[File:RisaWong.jpg|frameless|upright=0.3|center]]
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{{#lst:Editorial board transclusions|bladder}}
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|<big>Risa L. Wong, MD<br>University of Washington<br>Fred Hutchinson Cancer Research Center<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/RisaWongMD RisaWongMD]
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''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Urothelial_carcinoma_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Urothelial carcinoma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''.
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| style="background-color:#F0F0F0" |[[File:Alikhaki.jpg|frameless|upright=0.3|center]]
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<br><big>'''Note: this page has recently been renamed from "Bladder cancer" to "Urothelial carcinoma" to reflect the fact that most regimens here are generic to urothelial cancer. For now, the page also has adjuvant and perioperative regimens specific to bladder cancer, but these will be moved to a dedicated bladder cancer page soon.'''
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| style="width:35%" |<big>[[User:Alikhaki|Ali Raza Khaki, MD]]<br>Stanford University<br>Palo Alto, CA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/arkhaki arkhaki]
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*See the [[Bladder cancer|'''bladder cancer page''']] for regimens specific to bladder cancer.
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|-
 
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|}
 
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''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Bladder_cancer_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Bladder cancer - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''.
 
−
<br><big>Note: the page has adjuvant and perioperative regimens specific to bladder cancer as well as systemic regimens for the more general category of urothelial cancer.  
 
 
*See the [[Upper tract urothelial carcinoma|'''upper tract urothelial carcinoma page''']] for regimens specific to UTUC.</big>
 
*See the [[Upper tract urothelial carcinoma|'''upper tract urothelial carcinoma page''']] for regimens specific to UTUC.</big>
 
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{{TOC limit|limit=3}}
 
{{TOC limit|limit=3}}
 
=Guidelines=
 
=Guidelines=
−
==AUA, ASCO, ASTRO, SUO==
+
'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
−
*'''2017:''' Chang et al. [http://www.auanet.org/guidelines/muscle-invasive-bladder-cancer-new-(2017) Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline] [https://pubmed.ncbi.nlm.nih.gov/28456635 PubMed]
+
==[https://www.esmo.org/ ESMO]==
−
==EAU-ESMO==
+
*'''2022:''' Powles et al. [https://doi.org/10.1016/j.annonc.2021.11.012 Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/34861372/ PubMed]
−
*'''2019:''' Horwich et al. [https://academic.oup.com/annonc/article/30/11/1697/5629133 EAU–ESMO consensus statements on the management of advanced and variant bladder cancer—an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees]
 
−
==[http://www.esmo.org/ ESMO]==
 
 
*'''2019:''' [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer/eUpdate-Bladder-Cancer-Treatment-Recommendations1 eUpdate – Bladder Cancer Treatment Recommendations]
 
*'''2019:''' [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer/eUpdate-Bladder-Cancer-Treatment-Recommendations1 eUpdate – Bladder Cancer Treatment Recommendations]
 
*'''2019:''' [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer/eUpdate-Bladder-Cancer-Treatment-Recommendations2 eUpdate – Bladder Cancer Treatment Recommendations - Subsequent treatments post-chemotherapy or immunotherapy]
 
*'''2019:''' [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer/eUpdate-Bladder-Cancer-Treatment-Recommendations2 eUpdate – Bladder Cancer Treatment Recommendations - Subsequent treatments post-chemotherapy or immunotherapy]
−
*'''2014:''' Bellmunt et al. [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer Bladder cancer: ESMO Clinical Practice Guidelines] [https://pubmed.ncbi.nlm.nih.gov/25096609 PubMed]
 
−
==[https://www.nccn.org/ NCCN]==
 
−
*[https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf NCCN Guidelines - Bladder Cancer]
 
−
=Nonmuscle invasive bladder cancer/Intravesical chemotherapy=
 
−
==Bacillus Calmette-Guérin (BCG) monotherapy {{#subobject:eojb2c|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen variant #1, low-dose (27 mg) {{#subobject:52ca75|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
| rowspan="2" |[https://doi.org/10.1016/j.eururo.2007.04.062 Ojea et al. 2007 (CUETO study 95011)]
 
−
| rowspan="2" |1995-1998
 
−
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|1. [[Bladder_cancer#Mitomycin_monotherapy|Mitomycin]]
 
−
| style="background-color:#1a9850" |Superior DFS
 
−
|-
 
−
|2. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]; very-low-dose
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[Surgery#TURBT|TURBT]], within 14 to 21 days
 
−
====Immunotherapy, induction====
 
−
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 27 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36
 
−
'''6-week course, then proceed to additional therapy'''
 
−
====Immunotherapy, continuation====
 
−
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 27 mg intravesicularly once on day 1
 
−
'''14-day cycle for 6 cycles'''
 
−
===Regimen variant #2, intravesical (81 mg) & percutaneous, with maintenance therapy {{#subobject:221dfe|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[http://www.auajournals.org/article/S0022-5347(05)67707-5/fulltext Lamm et al. 2000 (SWOG 8507)]
 
−
|1985-1988
 
−
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 
−
|[[#Bacillus_Calmette-Gu.C3.A9rin_.28BCG.29_monotherapy|BCG]]; Intravesical & percutaneous BCG, without maintenance therapy
 
−
| style="background-color:#1a9850" |Superior RFS
 
−
|-
 
−
|}
 
−
====Immunotherapy, induction====
 
−
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 81 mg in 50.5 mL saline suspension is created and administered as follows:
 
−
**50 mL (~80.2 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15, 22, 29, 36. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.
 
−
**0.5 mL (~0.8 mg) applied once per day on days 1, 8, 15, 22, 29, 36 to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).
 
−
'''6-week course, then proceed to maintenance therapy'''
 
−
====Immunotherapy, maintenance====
 
−
''The authors were a bit unclear about the schedule of maintenance therapy. This is our best interpretation of how the schedule was described.''
 
−
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 81 mg in 50.5 mL saline suspension is created and administered as follows:
 
−
**50 mL (~80.2 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.
 
−
**0.5 mL (~0.8 mg) applied once per day on days 1, 8, 15 to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).
 
−
'''3-week courses; each course is given at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, and 36 months after the start of induction therapy'''
 
−
===Regimen variant #3, intravesical (81 mg) & percutaneous, without maintenance therapy {{#subobject:f5c250|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[http://www.auajournals.org/article/S0022-5347(05)67707-5/fulltext Lamm et al. 2000 (SWOG 8507)]
 
−
|1985-1988
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Bacillus_Calmette-Gu.C3.A9rin_.28BCG.29_monotherapy|BCG]]; Intravesical & percutaneous BCG, with maintenance therapy
 
−
| style="background-color:#d73027" |Inferior RFS
 
−
|-
 
−
|}
 
−
====Immunotherapy====
 
−
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 81 mg in 50.5 mL saline suspension is created and administered as follows:
 
−
**50 mL (~80.2 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15, 22, 29, 36. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.
 
−
**0.5 mL (~0.8 mg) applied once per day on days 1, 8, 15, 22, 29, 36 to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).
 
−
'''6-week course'''
 
−
===Regimen variant #4, intravesical (120 mg) & percutaneous, with maintenance therapy {{#subobject:8e5276|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.nejm.org/doi/10.1056/NEJM199110243251703 Lamm et al. 1991 (SWOG 8216)]
 
−
|1983-1985
 
−
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 
−
|[[#Doxorubicin_monotherapy|Doxorubicin]]
 
−
| style="background-color:#91cf60" |Seems to have superior DFS
 
−
|-
 
−
|}
 
−
====Immunotherapy, induction====
 
−
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 120 mg (3 vials) in 50.5 mL saline suspension is created and administered as follows:
 
−
**50 mL (~120 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15, 22, 29, 36. Patients retain the BCG suspension for up to 2 hours if possible.
 
−
**0.5 mL (~1.2 mg) applied once per day on days 1, 8, 15, 22, 29, 36 to the upper part of the inner thigh
 
−
'''6-week course, then proceed to maintenance therapy'''
 
−
====Immunotherapy, maintenance====
 
−
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] 120 mg (3 vials) in 50.5 mL saline suspension is created and administered as follows:
 
−
**50 mL (~120 mg) intravesicularly once on day 1. Patients retain the BCG suspension for up to 2 hours if possible.
 
−
**0.5 mL (~1.2 mg) applied once on day 1 to the upper part of the inner thigh
 
−
'''Given at 3 months, 6 months, 12 months, 18 months, and 24 months'''
 
−
===Regimen variant #5, 150 mg {{#subobject:d04712|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1016/s0022-5347(17)40002-4 Martínez-Piñeiro et al. 1990]
 
−
| rowspan="2" |1980-1988
 
−
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 
−
|1. [[#Doxorubicin_monotherapy|Doxorubicin]]<br> 2. [[#Thiotepa_monotherapy|Thiotepa]]
 
−
| style="background-color:#1a9850" |Superior RFS
 
−
|-
 
−
|}
 
−
''Note: details are very sparse in the abstract and this is probably only of historic interest.''
 
−
====Immunotherapy====
 
−
*[[Bacillus Calmette-Guérin (BCG)]] 150 mg intravesicularly x 15 treatments
 
−
===References===
 
−
#Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. [https://doi.org/10.1016/s0022-5347(17)40002-4 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/2106041 PubMed]
 
−
#'''SWOG 8216:''' Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA Jr, Sullivan J, Sarosdy MF, Crissman JD, Coltman CA. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med. 1991 Oct 24;325(17):1205-9. [https://www.nejm.org/doi/10.1056/NEJM199110243251703 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1922207 PubMed]
 
−
#'''SWOG 8507:''' Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, Sarosdy MF, Bohl RD, Grossman HB, Beck TM, Leimert JT, Crawford ED. Maintenance bacillus Calmette-Guérin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000 Apr;163(4):1124-9. [http://www.auajournals.org/article/S0022-5347(05)67707-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/10737480 PubMed]
 
−
#'''Meta-analysis:''' Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guérin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol. 2002 Nov;168(5):1964-70. [http://www.auajournals.org/article/S0022-5347(05)64273-5/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/12394686 PubMed]
 
−
#'''CUETO study 95011:''' Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, Chantada V, Camacho JE, Piñeiro LM, Rodríguez RH, Isorna S, Blas M, Martínez-Piñeiro JA, Madero R; CUETO. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guérin (27 mg) versus very low-dose bacillus Calmette-Guérin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27. [https://doi.org/10.1016/j.eururo.2007.04.062 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17485161 PubMed]
 
−
==Doxorubicin monotherapy {{#subobject:8034b6|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:49ccdb|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
| rowspan="2" |[https://doi.org/10.1016/s0022-5347(17)40002-4 Martínez-Piñeiro et al. 1990]
 
−
| rowspan="2" |1980-1988
 
−
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 
−
|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]
 
−
| style="background-color:#d73027" |Inferior RFS
 
−
|-
 
−
|2. [[#Thiotepa_monotherapy|Thiotepa]]
 
−
| style="background-color:#d3d3d3" |Not reported
 
−
|-
 
−
|[https://www.nejm.org/doi/10.1056/NEJM199110243251703 Lamm et al. 1991 (SWOG 8216)]
 
−
|1983-1985
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]
 
−
| style="background-color:#fc8d59" |Seems to have inferior DFS
 
−
|-
 
−
|}
 
−
''Inferior to BCG, included for reference purposes only.''
 
−
====Chemotherapy====
 
−
*[[Doxorubicin (Adriamycin)]] 50 mg intravesicularly once on day 1
 
−
'''7-day cycle for 5 cycles, then 30-day cycle for 11 cycles (approximately 1 year)'''
 
−
===References===
 
−
#Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. [https://doi.org/10.1016/s0022-5347(17)40002-4 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/2106041 PubMed]
 
−
#'''SWOG 8216:''' Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA Jr, Sullivan J, Sarosdy MF, Crissman JD, Coltman CA. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med. 1991 Oct 24;325(17):1205-9. [https://www.nejm.org/doi/10.1056/NEJM199110243251703 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1922207 PubMed]
 
−
==Gemcitabine monotherapy {{#subobject:343fc9|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen variant #1, 1 treatment {{#subobject:170d3b|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://jamanetwork.com/journals/jama/fullarticle/2680547 Messing et al. 2018 (SWOG S0337)]
 
−
|2008-2012
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[#Placebo_88|Placebo (saline)]]
 
−
| style="background-color:#1a9850" |Superior TTR
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[Surgery#TURBT|TURBT]], up to 3 hours prior
 
−
====Chemotherapy====
 
−
*[[Gemcitabine (Gemzar)]] 2000 mg in 100 mL of saline instilled intravesicularly for up to 60 minutes
 
−
'''One treatment'''
 
−
===Regimen variant #2, 6 treatments {{#subobject:fa5bb2|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2008.20.8199 Addeo et al. 2009]
 
−
|2003-2005
 
−
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 
−
|[[#Mitomycin_monotherapy|Mitomycin]]
 
−
| style="background-color:#1a9850" |Superior DFS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Gemcitabine (Gemzar)]] 2000 mg in 50 mL of saline instilled intravesicularly for up to 60 minutes once per day on days 1, 8, 15, 22, 29, 36
 
−
'''6-week course'''
 
−
===References===
 
−
#Addeo R, Caraglia M, Bellini S, Abbruzzese A, Vincenzi B, Montella L, Miragliuolo A, Guarrasi R, Lanna M, Cennamo G, Faiola V, Del Prete S. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. J Clin Oncol. 2010 Feb 1;28(4):543-8. Epub 2009 Oct 19. [https://doi.org/10.1200/JCO.2008.20.8199 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19841330 PubMed]
 
−
#'''SWOG S0337:''' Messing EM, Tangen CM, Lerner SP, Sahasrabudhe DM, Koppie TM, Wood DP Jr, Mack PC, Svatek RS, Evans CP, Hafez KS, Culkin DJ, Brand TC, Karsh LI, Holzbeierlein JM, Wilson SS, Wu G, Plets M, Vogelzang NJ, Thompson IM Jr. Effect of intravesical instillation of gemcitabine vs saline immediately following resection of suspected low-grade non-muscle-invasive bladder cancer on tumor recurrence: SWOG S0337 randomized clinical trial. JAMA. 2018 May 8;319(18):1880-1888. [https://jamanetwork.com/journals/jama/fullarticle/2680547 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29801011 PubMed] NCT00445601
 
−
==Mitomycin monotherapy {{#subobject:2e5944|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen variant #1, 30 mg x 12 {{#subobject:347e3e|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
| rowspan="2" |[https://doi.org/10.1016/j.eururo.2007.04.062 Ojea et al. 2007 (CUETO study 95011)]
 
−
| rowspan="2" |1995-1998
 
−
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 
−
|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]; low-dose
 
−
| style="background-color:#d73027" |Inferior DFS
 
−
|-
 
−
|2. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]; very-low-dose
 
−
| style="background-color:#ffffbf" |Did not meet efficacy endpoints
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[Surgery#TURBT|TURBT]], 14 to 21 days prior
 
−
====Chemotherapy====
 
−
*[[Mitomycin (Mutamycin)]] as follows:
 
−
**Cycles 1 to 3: 30 mg intravesicularly once per day on days 1 & 8
 
−
**Cycles 4 to 9: 30 mg intravesicularly once on day 1
 
−
'''14-day cycle for 9 cycles'''
 
−
===Regimen variant #2, 40 mg x 11 {{#subobject:531377|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2011.39.2936 Lammers et al. 2012]
 
−
|2003-2007
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Keyhole_limpet_hemocyanin_monotherapy_77|KLH]]
 
−
| style="background-color:#1a9850" |Superior RFS
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[Surgery#TURBT|TURBT]]
 
−
====Chemotherapy====
 
−
*[[Mitomycin (Mutamycin)]] 40 mg intravesicularly once on day 1
 
−
'''7-day cycle for 4 cycles, then monthly cycle for 4 cycles, then 3-month cycle for 3 cycles'''
 
−
===References===
 
−
#'''CUETO study 95011:''' Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, Chantada V, Camacho JE, Piñeiro LM, Rodríguez RH, Isorna S, Blas M, Martínez-Piñeiro JA, Madero R; CUETO. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guérin (27 mg) versus very low-dose bacillus Calmette-Guérin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27. [https://doi.org/10.1016/j.eururo.2007.04.062 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17485161 PubMed]
 
−
#Lammers RJ, Witjes WP, Janzing-Pastors MH, Caris CT, Witjes JA. Intracutaneous and intravesical immunotherapy with keyhole limpet hemocyanin compared with intravesical mitomycin in patients with non-muscle-invasive bladder cancer: results from a prospective randomized phase III trial. J Clin Oncol. 2012 Jun 20;30(18):2273-9. Epub 2012 May 14. [https://doi.org/10.1200/JCO.2011.39.2936 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22585689 PubMed]
 
−
==Pembrolizumab monotherapy {{#subobject:3cb963|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:7ae9e3|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
! style="width: 33%" |Study
 
−
! style="width: 33%" |Years of enrollment
 
−
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2019.37.7_suppl.350 Balar et al. (KEYNOTE-057)]
 
−
|NR in abstract
 
−
| style="background-color:#91cf61" |Phase 2 (RT)
 
−
|-
 
−
|}
 
−
====Immunotherapy====
 
−
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 
−
'''21-day cycle for 35 cycles (2 years)'''
 
−
====References====
 
−
#'''Abstract:''' Keynote-057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guerin (BCG). Arjun Vasant Balar, Girish S. Kulkarni, Edward M. Uchio, Joost Boormans, Loic Mourey, Laurence Eliot Miles Krieger, Eric A. Singer, Dean F. Bajorin, Ashish M. Kamat, Petros Grivas, Ho Kyung Seo, Hiroyuki Nishiyama, Badrinath R. Konety, Kijoeng Nam, Ekta Kapadia, Tara L. Frenkl, Ronald De Wit. Journal of Clinical Oncology 2019 37:7_suppl, 350-350. [https://doi.org/10.1200/JCO.2019.37.7_suppl.350 link to abstract] NCT02625961
 
−
==Thiotepa monotherapy {{#subobject:5b9d6c|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:97d2e7|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
| rowspan="2" |[https://doi.org/10.1016/s0022-5347(17)40002-4 Martínez-Piñeiro et al. 1990]
 
−
| rowspan="2" |1980-1988
 
−
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 
−
|1. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]
 
−
| style="background-color:#d73027" |Inferior RFS
 
−
|-
 
−
|2. [[#Doxorubicin_monotherapy|Doxorubicin]]
 
−
| style="background-color:#d3d3d3" |Not reported
 
−
|-
 
−
|}
 
−
''Inferior to BCG, included for reference purposes only.''
 
−
====Chemotherapy====
 
−
*[[Thiotepa (Thioplex)]] 50 mg intravesicularly x 15 treatments
 
−
===References===
 
−
#Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. [https://doi.org/10.1016/s0022-5347(17)40002-4 link to original article] '''contains partial protocol''' [https://pubmed.ncbi.nlm.nih.gov/2106041 PubMed]
 
−
==Valrubicin monotherapy {{#subobject:58jgac|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:74j2e7|Variant=1}}===
 
−
{| class="wikitable" style="color:white; background-color:#404040"
 
−
|<small>'''FDA-recommended dose'''</small>
 
−
|-
 
−
|}
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
! style="width: 33%" |Study
 
−
! style="width: 33%" |Years of enrollment
 
−
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2967799-3 Steinberg et al. 2000]
 
−
|1993-1996
 
−
| style="background-color:#91cf61" |Non-randomized (RT)
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Valrubicin (Valstar)]] 800 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36
 
−
'''6-week course'''
 
−
===References===
 
−
#Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M; Valrubicin Study Group. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guérin refractory carcinoma in situ of the bladder. J Urol. 2000 Mar;163(3):761-7. Erratum in: J Urol. 2008 Jan;179(1):386. [https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805%2967799-3 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10687972 PubMed]
 
−
=Neoadjuvant chemotherapy=
 
−
==Atezolizumab monotherapy {{#subobject:3cb963|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:7ae9e3|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.nature.com/articles/s41591-019-0628-7 Powles et al. 2019 (ABACUS)]
 
−
|2016-2018
 
−
| style="background-color:#91cf61" |Phase 2
 
−
|-
 
−
|}
 
−
====Immunotherapy====
 
−
*[[Atezolizumab (Tecentriq)|Atezolizumab]] 1200 mg IV over 60 minutes once on day 1
 
−
'''21-day cycle for 2 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Surgery#Cystectomy|Radical cystectomy]] to be performed 4 to 8 weeks after completion of chemotherapy
 
−
===References===
 
−
#'''ABACUS:''' Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, Szabados B, Pous AF, Gravis G, Herranz UA, Protheroe A, Ravaud A, Maillet D, Mendez MJ, Suarez C, Linch M, Prendergast A, van Dam PJ, Stanoeva D, Daelemans S, Mariathasan S, Tea JS, Mousa K, Banchereau R, Castellano D. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019 Nov 4. [https://www.nature.com/articles/s41591-019-0628-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31686036 PubMed] NCT02662309
 
−
==Cisplatin & Gemcitabine (GC) {{#subobject:d08e11|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
GC: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin
 
−
===Regimen variant #1, single-dose cisplatin {{#subobject:dc99d5|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
! style="width: 25%" |Study
 
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585515/ Dash et al. 2008]
 
−
| style="background-color:#ffffbe" |Retrospective
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
'''21-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Surgery#Bladder_cancer_surgery|Surgery]]
 
−
===Regimen variant #2, split-dose cisplatin {{#subobject:be43aa|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
! style="width: 25%" |Study
 
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585515/ Dash et al. 2008]
 
−
| style="background-color:#ffffbe" |Retrospective
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
'''21-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Surgery#Bladder_cancer_surgery|Surgery]]
 
−
===Regimen variant #3, single-dose cisplatin & 1250mg/m2 gemcitabine {{#subobject:221dfe|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://ascopubs.org/doi/suppl/10.1200/JCO.21.02051 Pfister et al. 2022 (GETUG-AFU V05 VESPER)]
 
−
|2013-2018
 
−
| style="background-color:#1a9851" |Phase 3 (C-RT)
 
−
|[[Bladder cancer#MVAC.2C dose-dense|ddMVAC]], 6 cycles
 
−
| style="background-color:#fc8d59" |Seems to have inferior PFS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once per day on day 1
 
−
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
'''21-day cycle for 4 cycles'''
 
−
====Supportive medications====
 
−
*[[Filgrastim (Neupogen)]] 5 μg/kg/ day as a subcutaneous injection from day 3 to day 7 if febrile neutropenia or if cycle shift ≥ 7 days due to neutropenia.
 
  
−
*Antiemetics used included [[Aprepitant (Emend)]], [[Ondansetron (Zofran)]], and [[Methylprednisolone (Solumedrol)]].
+
*'''2014:''' Bellmunt et al. [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Bladder-Cancer Bladder cancer: ESMO Clinical Practice Guidelines] [https://pubmed.ncbi.nlm.nih.gov/25096609/ PubMed]
−
====Subsequent treatment====
+
 
−
*[[Surgery#Cystectomy|Cystectomy]] to be performed up to 8 weeks after completion of chemotherapy
+
==NCCN==
−
===References===
+
*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1417 NCCN Guidelines - Bladder Cancer]
−
#'''Retrospective:''' Dash A, Pettus JA 4th, Herr HW, Bochner BH, Dalbagni G, Donat SM, Russo P, Boyle MG, Milowsky MI, Bajorin DF. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer. 2008 Nov 1;113(9):2471-7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585515/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18823036 PubMed]
+
 
−
#'''GETUG-AFU V05 VESPER:''' Pfister C, Gravis G, Fléchon A, Chevreau C, Mahammedi H, Laguerre B, Guillot A, Joly F, Soulié M, Allory Y, Harter V, Culine S; VESPER Trial Investigators. Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol. 2022 Mar 7:JCO2102051. Epub ahead of print. [https://doi.org/10.1200/JCO.21.02051 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/35254888/ PubMed] NCT01812369
+
*'''2017:''' Spiess et al. [https://doi.org/10.6004/jnccn.2017.0156 Bladder Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology] [https://pubmed.ncbi.nlm.nih.gov/28982750/ PubMed]
−
#'''KEYNOTE-B15:''' NCT04700124
+
*'''2009:''' Montie et al. [https://doi.org/10.6004/jnccn.2009.0002 Bladder cancer] [https://pubmed.ncbi.nlm.nih.gov/19176203/ PubMed]
−
#'''KEYNOTE-866:''' NCT03924856
+
==SITC==
−
==Cisplatin & Gemcitabine (GC) & Pembrolizumab {{#subobject:hy2e11|Regimen=1}}==
+
*'''2021:''' Galsky et al. [https://dx.doi.org/10.1136/jitc-2021-002552 Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of urothelial cancer] [https://pubmed.ncbi.nlm.nih.gov/34266883/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
**'''2017:''' Kamat et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5557323/ Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma] [https://pubmed.ncbi.nlm.nih.gov/28807024/ PubMed]
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
GC & Pembrolizumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, Pembrolizumab
 
−
===Regimen {{#subobject:beyaba|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.21.01003 Rose et al. 2021 (LCCC 1520)]
 
−
|2016-2020
 
−
| style="background-color:#91cf61" |Phase 2
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
====Immunotherapy====
 
−
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 
−
'''21-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Surgery#Bladder_cancer_surgery|Radical cystectomy]]
 
−
===References===
 
−
#'''LCCC 1520:''' Rose TL, Harrison MR, Deal AM, Ramalingam S, Whang YE, Brower B, Dunn M, Osterman CK, Heiling HM, Bjurlin MA, Smith AB, Nielsen ME, Tan HJ, Wallen E, Woods ME, George D, Zhang T, Drier A, Kim WY, Milowsky MI. Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer. J Clin Oncol. 2021 Aug 24:JCO2101003. Epub ahead of print. [https://doi.org/10.1200/jco.21.01003 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/34428076/ PubMed] NCT02690558
 
−
#'''KEYNOTE-866:''' NCT03924856
 
−
==MCV {{#subobject:553fe2|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
MCV: '''<u>M</u>'''ethotrexate, '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine
 
−
<br>CMV: '''<u>C</u>'''isplatin, '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine
 
−
===Regimen variant #1, 2 cycles {{#subobject:450c9f|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.nejm.org/doi/10.1056/NEJM199311043291903 Kaufman et al. 1993]
 
−
|NR
 
−
| style="background-color:#91cf61" |Phase 2
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|[https://doi.org/10.1200/jco.1996.14.1.119 Tester et al. 1996 (RTOG 88-02)]
 
−
|1988-1990
 
−
| style="background-color:#91cf61" |Phase 2
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|[https://doi.org/10.1200/jco.1998.16.11.3576 Shipley et al. 1998 (RTOG 89-03)]
 
−
|1990-1993
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant chemotherapy]]
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
 
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
 
−
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22
 
−
'''28-day cycle for 2 cycles'''
 
−
====Subsequent treatment====
 
−
*Kaufman et al. 1993, CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]
 
−
*RTOG 88-02 & 89-03: [[#Cisplatin_.26_RT|Cisplatin & RT induction]]
 
−
===Regimen variant #2, 3 cycles {{#subobject:3d008f|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract Griffiths et al. 1999 (BA06 30894)]
 
−
|1989-1995
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]
 
−
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup>
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]
 
−
|1989-1997
 
−
| style="background-color:#91cf61" |Non-randomized
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|}
 
−
''<sup>1</sup>Reported efficacy for BA06 30894 is based on the 2011 update.''<br>
 
−
''Patients in Zapatero et al. 2000 had T2 to T4 Nx M0 disease.''
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8
 
−
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 2, before hydration
 
−
*[[Vinblastine (Velban)]] 4 mg/m<sup>2</sup> IV bolus once per day on days 1 & 8
 
−
====Supportive medications====
 
−
*'''BA06 30894:''' [[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> IV or PO every 6 hours on days 2 & 9, given after hydration, with the first dose 24 hours after the previous day's dose of [[Methotrexate (MTX)]] (total dose per cycle: 120 mg/m<sup>2</sup>)
 
−
'''21-day cycle for 3 cycles'''
 
−
====Subsequent treatment====
 
−
*Zapatero et al. 2000: after 3 cycles of chemotherapy, patients underwent cystoscopy, biopsy, and abdominal CT
 
−
**Patients with CR or who were not surgical candidates: [[#Radiation_therapy|RT consolidation]] which begins 4 to 6 weeks after completion of chemotherapy
 
−
**Otherwise, patients proceeded to [[Surgery#Cystectomy|cystectomy]]
 
−
===References===
 
−
#Kaufman DS, Shipley WU, Griffin PP, Heney NM, Althausen AF, Efird JT. Selective bladder preservation by combination treatment of invasive bladder cancer. N Engl J Med. 1993 Nov 4;329(19):1377-82. [https://www.nejm.org/doi/10.1056/NEJM199311043291903 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8413433 PubMed]
 
−
#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [https://doi.org/10.1200/jco.1996.14.1.119 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8558186 PubMed]
 
−
#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [https://doi.org/10.1200/jco.1998.16.11.3576 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9817278 PubMed]
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
#'''BA06 30894:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; CUETO; International Collaboration of Trialists. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. Lancet. 1999 Aug 14;354(9178):533-40. Erratum in: Lancet 1999 Nov 6;354(9190):1650. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02292-8/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/10470696 PubMed] ISRCTN82694463
 
−
##'''Update:''' Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); [[Study_Groups#EORTC|EORTC]] Genito-Urinary Tract Cancer Group; Australian Bladder Cancer Study Group; National Cancer Institute of Canada Clinical Trials Group; Finnbladder; Norwegian Bladder Cancer Study Group; Club Urologico Espanol de Tratamiento Oncologico Group. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011 Jun 1;29(16):2171-7. Epub 2011 Apr 18. [https://doi.org/10.1200/jco.2010.32.3139 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107740/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21502557 PubMed]
 
−
#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11091353 PubMed]
 
−
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]
 
−
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]
 
−
==MVAC {{#subobject:701fbe|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin
 
−
===Regimen variant #1, 2 cycles {{#subobject:0f1661|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1093/annonc/mdu126 Kitamura et al. 2014 (JCOG0209)]
 
−
|2003-2009
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]
 
−
| style="background-color:#d9ef8b" |Might have superior OS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
 
−
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2
 
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
 
−
'''28-day cycle for 2 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Surgery#Radical_cystectomy|Radical cystectomy]]
 
−
===Regimen variant #2, 3 cycles {{#subobject:dc2c80|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.nejm.org/doi/full/10.1056/NEJMoa022148 Grossman et al. 2003 (SWOG S8710)]
 
−
|1987-1998
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]
 
−
| style="background-color:#d9ef8b" |Might have superior OS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
 
−
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2
 
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
 
−
'''28-day cycle for 3 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Surgery#Radical_cystectomy|Radical cystectomy]]
 
−
===References===
 
−
#'''SWOG S8710:''' Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003 Aug 28;349(9):859-66. [https://www.nejm.org/doi/full/10.1056/NEJMoa022148 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12944571 PubMed]
 
−
#'''JCOG0209:''' Kitamura H, Tsukamoto T, Shibata T, Masumori N, Fujimoto H, Hirao Y, Fujimoto K, Kitamura Y, Tomita Y, Tobisu K, Niwakawa M, Naito S, Eto M, Kakehi Y; Urologic Oncology Study Group of the Japan Clinical Oncology Group. Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209. Ann Oncol. 2014 Jun;25(6):1192-8. [https://doi.org/10.1093/annonc/mdu126 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24669010 PubMed] UMIN C000000093
 
−
##'''HRQoL analysis:''' Kitamura H, Hinotsu S, Tsukamoto T, Shibata T, Mizusawa J, Kobayashi T, Miyake M, Nishiyama N, Kojima T, Nishiyama H; Urologic Oncology Study Group of the Japan Clinical Oncology Group. Effect of neoadjuvant chemotherapy on health-related quality of life in patients with muscle-invasive bladder cancer: results from JCOG0209, a randomized phase III study. Jpn J Clin Oncol. 2020 Dec 16;50(12):1464-1469. [https://doi.org/10.1093/jjco/hyaa123 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32699909 PubMed]
 
−
==MVAC, dose-dense {{#subobject:3cb963|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
ddMVAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin
 
−
<br>AMVAC: '''<u>A</u>'''ccelerated '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin
 
−
===Regimen variant #1 (AMVAC), 3 cycles {{#subobject:c4bf38|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050203/ Plimack et al. 2014 (FER-GU-026)]
 
−
|2009-2012
 
−
| style="background-color:#91cf61" |Phase 2
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV over 30 minutes once on day 1
 
−
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV push once on day 1
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV push once on day 1
 
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV in 1 liter normal saline once on day 1
 
−
**Split dose could be used at physician discretion for patients with CrCl less than 60 mL/min/1.73m<sup>2</sup>: 35 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
====Supportive medications====
 
−
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once, 24 to 48 hours after completion of chemotherapy
 
−
*Antiemetics used included [[Aprepitant (Emend)]], [[Ondansetron (Zofran)]], and [[Methylprednisolone (Solumedrol)]].
 
−
'''14-day cycle for 3 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Surgery#Radical_cystectomy|Radical cystectomy]] with bilateral [[Surgery#Lymphadenectomy|lymphadenectomy]], within 4 to 8 weeks after the last cycle of chemotherapy
 
−
===Regimen variant #2 (ddMVAC), 4 cycles {{#subobject:7ae9e3|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7057274/ Choueiri et al. 2014 (DFCI 08-208)]
 
−
|2008-2012
 
−
| style="background-color:#91cf61" |Phase 2
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV over 30 minutes once on day 1
 
−
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV push once on day 2
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV push once on day 2
 
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV in 1 liter normal saline once on day 2
 
−
====Supportive medications====
 
−
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 3 (approximately 24 hours after day 2 chemotherapy)
 
−
'''14-day cycle for 4 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Surgery#Cystectomy|Cystectomy]] to be performed 4 to 10 weeks after completion of chemotherapy
 
−
=== Regimen variant #3 (ddMVAC), 6 cycles {{#subobject:7ae9e3|Variant=1}} ===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |Comparative Efficacy
 
−
|-
 
−
|[https://ascopubs.org/doi/pdf/10.1200/JCO.21.02051 Pfister et al. 2022 (GETUG-AFU V05 VESPER)]
 
−
|2013-2018
 
−
| style="background-color:#1a9850" |Phase 3
 
−
|[[Bladder cancer#Cisplatin .26 Gemcitabine .28GC.29|Cisplatin and Gemcitabine (GC)]]
 
−
| style="background-color:#91cf60" | Seems to have superior PFS
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV over 30 minutes once on day 1
 
−
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV push once on day 2
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV push once on day 2
 
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV in 1 liter normal saline once on day 2
 
−
====Supportive medications====
 
−
*[[Filgrastim (Neupogen)]] 5 μg/kg/ day as a subcutaneous injection from day 3 to day 9
 
−
*Antiemetics used often included [[Aprepitant (Emend)]], [[Ondansetron (Zofran)]], and [[Dexamethasone (Decadron)]] but were not specified by the trial.
 
−
'''14-day cycle for 6 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Surgery#Cystectomy|Cystectomy]] to be performed 4 to 10 weeks after completion of chemotherapy
 
  
−
===References===
 
−
#'''DFCI 08-208:''' Choueiri TK, Jacobus S, Bellmunt J, Qu A, Appleman LJ, Tretter C, Bubley GJ, Stack EC, Signoretti S, Walsh M, Steele G, Hirsch M, Sweeney CJ, Taplin ME, Kibel AS, Krajewski KM, Kantoff PW, Ross RW, Rosenberg JE. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol. 2014 Jun 20;32(18):1889-94. Epub 2014 May 12. [https://doi.org/10.1200/jco.2013.52.4785 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7057274/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24821883 PubMed] NCT00808639
 
−
#'''FER-GU-026:''' Plimack ER, Hoffman-Censits JH, Viterbo R, Trabulsi EJ, Ross EA, Greenberg RE, Chen DY, Lallas CD, Wong YN, Lin J, Kutikov A, Dotan E, Brennan TA, Palma N, Dulaimi E, Mehrazin R, Boorjian SA, Kelly WK, Uzzo RG, Hudes GR. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol. 2014 Jun 20;32(18):1895-901. Epub 2014 May 12. [https://doi.org/10.1200/jco.2013.53.2465 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050203/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24821881 PubMed] NCT01031420
 
−
#'''GETUG-AFU V05 VESPER:''' Pfister C, Gravis G, Fléchon A, Chevreau C, Mahammedi H, Laguerre B, Guillot A, Joly F, Soulié M, Allory Y, Harter V, Culine S; VESPER Trial Investigators. Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol. 2022 Mar 7:JCO2102051. Epub ahead of print. [https://doi.org/10.1200/JCO.21.02051 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/35254888/ PubMed] NCT01812369
 
−
==Pembrolizumab monotherapy {{#subobject:3cfac3|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:c4bf38|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.18.01148 Necchi et al. 2018 (PURE-01)]
 
−
|2017-2018
 
−
| style="background-color:#91cf61" |Phase 2
 
−
|-
 
−
|}
 
−
====Immunotherapy====
 
−
*[[Pembrolizumab (Keytruda)|Pembrolizumab]] 200 mg IV over 30 minutes once on day 1
 
−
'''21-day cycle for 3 cycles'''
 
−
====Subsequent treatment====
 
−
*[[Surgery#Radical_cystectomy|Radical cystectomy]], within 1 to 3 weeks after the last cycle of chemotherapy
 
−
===References===
 
−
#'''PURE-01:''' Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucianò R, Colecchia M, Giannatempo P, Mortarini R, Bianchi M, Farè E, Monopoli F, Colombo R, Gallina A, Salonia A, Messina A, Ali SM, Madison R, Ross JS, Chung JH, Salvioni R, Mariani L, Montorsi F. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 2018 Oct 20. [https://doi.org/10.1200/jco.18.01148 Link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30343614 PubMed] NCT02736266
 
−
##'''Update:''' Necchi A, Raggi D, Gallina A, Madison R, Colecchia M, Lucianò R, Montironi R, Giannatempo P, Farè E, Pederzoli F, Bandini M, Bianchi M, Colombo R, Gandaglia G, Fossati N, Marandino L, Capitanio U, Dehò F, Ali SM, Chung JH, Ross JS, Salonia A, Briganti A, Montorsi F. Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies. Eur Urol. 2019 Nov 7. [https://doi.org/10.1016/j.eururo.2019.10.026 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31708296 PubMed]
 
−
=Induction chemoradiotherapy=
 
−
==Cisplatin & RT {{#subobject:ebb6e9|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 
−
===Regimen variant #1, cisplatin 40 mg/m<sup>2</sup> qwk x 3 {{#subobject:f782c3|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.urologiconcology.org/article/S1078-1439(09)00029-5/fulltext Zapatero et al. 2009]
 
−
|1990-2007
 
−
| style="background-color:#91cf61" |Non-randomized
 
−
|-
 
−
|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]
 
−
|1998-2000
 
−
| style="background-color:#91cf61" |Phase 1/2
 
−
|-
 
−
|}
 
−
''Patients in Zapatero et al. 2009 had T2 to T4 N0 M0 disease. Patients in RTOG 97-06 had T2 to T4a N0 M0 disease without hydronephrosis. Dosing is per Figure 1 of Zapatero et al. 2010.''
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2, '''given first'''
 
−
'''7-day cycle for 3 cycles'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:
 
−
**'''Both trials:''' Accelerated hyperfractionated RT (AHFRT) with twice per day radiation, consisting of 1.8 Gy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 1.6 Gy fraction x 12 fractions is given to the "bladder tumor plus wide margin." Radiation therapy given 5 days per week. Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy.
 
−
**'''Zapatero et al. 2000 only:''' Normo-fractionated concurrent radiation therapy, 1.8 to 2 Gy fractions, given 5 times per week. Total induction and consolidation bladder dose of 64 to 66 Gy; total induction and consolidation pelvic lymph node dose of 44 to 46 Gy. Zapatero, et al. 2010 & Zapatero, et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy, nor what adjustments, if any, were made to chemotherapy for this radiation schedule.
 
−
====Subsequent treatment====
 
−
*3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
 
−
**Patients with complete regression (R0): [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]
 
−
**Nonresponders: [[Surgery#Cystectomy|Cystectomy]]
 
−
===Regimen variant #2, cisplatin 70 mg/m<sup>2</sup> q3wk x 2 {{#subobject:2443a6|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.1996.14.1.119 Tester et al. 1996 (RTOG 88-02)]
 
−
|1988-1990
 
−
| style="background-color:#91cf61" |Phase 2
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[#MCV|MCV]] x 2
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
 
−
'''21-day cycle for 2 cycles'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)
 
−
'''4.5-week course'''
 
−
====Subsequent treatment====
 
−
''Patient is restaged 2 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, urinary cytology, and computed tomographic scan of pelvis."''
 
−
*Patients with CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]
 
−
*Patients without CR proceeded immediately to: [[Surgery#Cystectomy|cystectomy]]
 
−
===Regimen variant #3, cisplatin 100 mg/m<sup>2</sup> q3wk x 2 {{#subobject:9a3fd0|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://jamanetwork.com/journals/jama/article-abstract/367764 Shipley et al. 1988]
 
−
|1980-1985
 
−
| style="background-color:#91cf61" |Non-randomized
 
−
|-
 
−
|[https://doi.org/10.1200/jco.1998.16.11.3576 Shipley et al. 1998 (RTOG 89-03)]
 
−
|1990-1993
 
−
| style="background-color:#91cf61" |Non-randomized portion of phase III RCT
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*RTOG 89-03: [[#MCV|MCV]] versus [[Bladder_cancer_-_null_regimens#No_neoadjuvant_therapy|no neoadjuvant therapy]]
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1
 
−
'''21-day cycle for 2 cycles'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)
 
−
'''4.5-week course'''
 
−
====Subsequent treatment====
 
−
''RTOG 89-03: Patient is restaged 4 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, and urinary cytology." ''
 
−
*RTOG 89-03; Patients not in CR usually proceeded to: [[Surgery#Cystectomy|cystectomy]]
 
−
*RTOG 89-03; Patients in complete remission usually proceeded to: [[#Cisplatin_.26_RT_2|cisplatin & RT consolidation]]
 
−
===References===
 
−
#Shipley WU, Prout GR Jr, Einstein AB, Coombs LJ, Wajsman Z, Soloway MS, Englander L, Barton BA, Hafermann MD. Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery. JAMA. 1987 Aug 21;258(7):931-5. [https://jamanetwork.com/journals/jama/article-abstract/367764 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3613023 PubMed]
 
−
#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [https://doi.org/10.1200/jco.1996.14.1.119 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8558186 PubMed]
 
−
#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [https://doi.org/10.1200/jco.1998.16.11.3576 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9817278 PubMed]
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
#'''RTOG 97-06:''' Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14529770 PubMed]
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
#Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439(09)00029-5/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]
 
−
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]
 
−
#'''SunRISe-2:''' NCT04658862
 
−
#'''SWOG S1806:''' NCT03775265
 
−
==Cisplatin & Fluorouracil (CF) & RT {{#subobject:b5e26|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen variant #1, 90/2400/24 {{#subobject:598234|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1634/theoncologist.5-6-471 Kaufman et al. 2000 (RTOG 95-06)]
 
−
|1995-1997
 
−
| style="background-color:#91cf61" |Phase 1/2
 
−
|-
 
−
|}
 
−
''Patients in RTOG 95-06 had clinical T2 to T4a Nx M0 disease without hydronephrosis and CrCl of at least 60 mL/min/1.73m<sup>2</sup>.''
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3, '''given second, before radiation'''
 
−
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, '''given first'''
 
−
====Supportive medications====
 
−
*IV hydration at 500 mL/H (no total volume specified) prior to [[Fluorouracil (5-FU)]]
 
−
'''14-day cycle for 2 cycles'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 3 Gy fractions twice per day, with the first fraction of each day given 1 to 2 hours after completion of chemotherapy and at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total induction dose: 24 Gy), administered to the whole bladder, bladder tumor volume, and pelvic lymph nodes
 
−
'''17-day course'''
 
−
====Dose modifications====
 
−
*Patients with grade III hematologic toxicity, defined as platelets less than 50 x 10<sup>9</sup>/L or ANC less than 1800/uL, had chemotherapy and radiation therapy held for at least one week, with therapy resuming when platelets were at least 100 x 10<sup>9</sup>/L and ANC at least 1800/uL.
 
−
====Subsequent treatment====
 
−
*Treatment followed by repeat cystoscopy, biopsy, and urine cytology in week 7 or 8
 
−
**Patients with complete response: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT consolidation]] in week 9
 
−
**Incomplete responders were recommended to undergo [[Surgery#Radical_cystectomy|radical cystectomy]]
 
−
===Regimen variant #2, 135/2400/40.3 {{#subobject:6be392|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ Coen et al. 2018 (RTOG 0712)]
 
−
|2008-2014
 
−
| style="background-color:#1a9851" |Randomized Phase 2 (C)
 
−
|[[#Gemcitabine_.26_RT|Gemcitabine & RT]]
 
−
| style="background-color:#d3d3d3" |Not reported<sup>1</sup>
 
−
|-
 
−
|}
 
−
''<sup>1</sup>This trial was not statistically powered to compare regimens.''
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3, 8 to 10, 15 to 17
 
−
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, 15 to 17
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:
 
−
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
 
−
**1.5 Gy fractions to the bladder every evening on days 1 to 5
 
−
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
 
−
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
 
−
'''17-day course'''
 
−
====Subsequent treatment====
 
−
*Treatment followed by repeat cystoscopy & biopsy
 
−
**Patients with complete response: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT consolidation]]
 
−
**Incomplete responders: [[Surgery#Radical_cystectomy|Radical cystectomy]]
 
−
===Regimen variant #3, 135/3600/40.3 {{#subobject:6be39|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
 
−
|2002-2008
 
−
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 
−
|[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT]]
 
−
| style="background-color:#d3d3d3" |Not reported
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
'''7-day cycle for 3 cycles'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:
 
−
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
 
−
**1.5 Gy fractions to the bladder every evening on days 1 to 5
 
−
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
 
−
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
 
−
'''3-week course'''
 
−
====Subsequent treatment====
 
−
*On week 7, patients under reevaluation for response.
 
−
**Patients with less than stage T1 disease: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT consolidation]]
 
−
**Patients with at least stage T1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]] on week 9, then [[#PGC|adjuvant PGC]]
 
−
===References===
 
−
#'''RTOG 95-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Chetner MP, Souhami L, Zlotecki RA, Sause WT, True LD. The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response. Oncologist. 2000;5(6):471-6. [https://doi.org/10.1634/theoncologist.5-6-471 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11110598 PubMed]
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
#'''RTOG 0712:''' Coen JJ, Zhang P, Saylor PJ, Lee CT, Wu CL, Parker W, Lautenschlaeger T, Zietman AL, Efstathiou JA, Jani AB, Kucuk O, Souhami L, Rodgers JP, Sandler HM, Shipley WU. Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712-a randomized phase II trial. J Clin Oncol. 2019 Jan 1;37(1):44-51. Epub 2018 Nov 15. [https://doi.org/10.1200/JCO.18.00537 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30433852 PubMed] NCT00777491
 
−
==Cisplatin, Paclitaxel, RT {{#subobject:803f28|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen variant #1, 40/50 x 3 + 40.3 Gy {{#subobject:b7ec20|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]
 
−
|NR in abstract
 
−
| style="background-color:#91cf61" |Phase 1/2
 
−
|-
 
−
|}
 
−
''Note: the abstract of Kaufman et al. 2009 said that patients with "greater than Stage T1 disease" were recommended for cystectomy, but Figure 1 clarified that it was greater than or equal to ypT1 disease.''
 
−
====Preceding treatment====
 
−
*[[Surgery#TURBT|TURBT]], within 4 to 6 weeks
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1
 
−
'''7-day cycle for 3 cycles'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT on days 1 to 5, 8 to 12, 15 to 17; 4 to 6 hours between radiation sessions. Kaufman et al. 2009 (RTOG 99-06) was unclear about exact radiation treatment plan, but it appears to have been the same as described in Mitin et al. 2013 (RTOG 02-33), which used radiation as follows:
 
−
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
 
−
**1.5 Gy fractions to the bladder every evening on days 1 to 5
 
−
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
 
−
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
 
−
'''3-week course'''
 
−
====Subsequent treatment====
 
−
*On week 7, over 3 weeks after induction therapy, patients under reevaluation with exam under anesthesia, cystoscopy with tumor site biopsy, and urine cytology
 
−
**Patients with less than stage ypT1 disease: [[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, paclitaxel, RT consolidation]]
 
−
**Patients with at least stage ypT1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]], then [[#Cisplatin_.26_Gemcitabine_.28GC.29_2|adjuvant cisplatin & gemcitabine]]
 
−
===Regimen variant #2, 45/50 x 3 + 40.3 Gy {{#subobject:6ecd8b|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
 
−
|2002-2008
 
−
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 
−
|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|Cisplatin, Fluorouracil, RT]]
 
−
| style="background-color:#d3d3d3" |Not reported
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1
 
−
'''7-day cycle for 3 cycles'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]], with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:
 
−
**1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
 
−
**1.5 Gy fractions to the bladder every evening on days 1 to 5
 
−
**1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
 
−
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
 
−
'''3-week course'''
 
−
====Subsequent treatment====
 
−
*On week 7, patients under reevaluation for response
 
−
**Patients with less than stage ypT1 disease: [[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, paclitaxel, RT consolidation]]
 
−
**Patients with at least stage ypT1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]] on week 9, then [[#PGC|adjuvant PGC]]
 
−
===References===
 
−
#Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19100600 PubMed]
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
==Fluorouracil, Mitomycin, RT {{#subobject:5e89d1|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
Fluorouracil, Mitomycin, RT: Fluorouracil, Mitomycin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 
−
===Regimen {{#subobject:6a18dc|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 James et al. 2012 (BC2001)]
 
−
|2001-2008
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[#Radiation_therapy_2|Radiation therapy]]
 
−
| style="background-color:#91cf60" |Seems to have superior locoregional DFS<br>DFS24: 67% vs 54%<br>(HR 0.68, 95% CI 0.48-0.96)
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup>/day IV continuous infusion for 10 total days (total dose: 5000 mg/m<sup>2</sup>) during radiation fractions 1 to 5, 16 to 20
 
−
*[[Mitomycin (Mutamycin)]] 12 mg/m<sup>2</sup> IV bolus once on day 1
 
−
====Radiotherapy====
 
−
*[[External beam radiotherapy]] given according to one of the following plans:
 
−
**Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.75 Gy fractions x 20 fractions (total dose: 55 Gy)
 
−
**Concurrent [[External_beam_radiotherapy|radiation therapy]], 2 Gy fractions x 32 fractions (total dose: 64 Gy)
 
−
'''4- to 6.5-week course'''
 
−
===References===
 
−
#'''BC2001:''' James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. [https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1106106/suppl_file/nejmoa1106106_appendix.pdf link to supplementary index] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22512481 PubMed] NCT00024349
 
−
==Gemcitabine & RT {{#subobject:91c0ea|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:6333a7|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ Coen et al. 2018 (RTOG 0712)]
 
−
|2008-2014
 
−
| style="background-color:#1a9851" |Randomized Phase 2 (E-de-esc)
 
−
|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|CF & RT]]
 
−
| style="background-color:#d3d3d3" |Not reported<sup>1</sup>
 
−
|-
 
−
|}
 
−
''<sup>1</sup>This trial was not statistically powered to compare regimens.''
 
−
====Chemotherapy====
 
−
*[[Gemcitabine (Gemzar)]] 27 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11
 
−
'''14-day cycle for 2 cycles'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 2 Gy per day to the pelvis on days 1 to 10, then 2 Gy per day to the bladder on days 11 to 14, then 2 Gy per day to the bladder tumor on days 15 to 20
 
−
**Total doses: pelvis: 20 Gy; whole bladder: 28 Gy; bladder tumor volume 40 Gy
 
−
'''3-week course'''
 
−
====Subsequent treatment====
 
−
*Treatment followed by repeat cystoscopy & biopsy
 
−
**Patients with complete response: Gemcitabine & RT consolidation
 
−
**Incomplete responders: [[Surgery#Radical_cystectomy|Radical cystectomy]]
 
−
===References===
 
−
#'''RTOG 0712:''' Coen JJ, Zhang P, Saylor PJ, Lee CT, Wu CL, Parker W, Lautenschlaeger T, Zietman AL, Efstathiou JA, Jani AB, Kucuk O, Souhami L, Rodgers JP, Sandler HM, Shipley WU. Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712-a randomized phase II trial. J Clin Oncol. 2019 Jan 1;37(1):44-51. Epub 2018 Nov 15. [https://doi.org/10.1200/JCO.18.00537 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30433852 PubMed] NCT00777491
 
−
#'''SunRISe-2:''' NCT04658862
 
−
==Paclitaxel & RT {{#subobject:89c0ea|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen variant #1 {{#subobject:6222a7|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract Zapatero et al. 2012]
 
−
|1990-2010
 
−
| style="background-color:#ffffbe" |Non-randomized, <20 pts
 
−
|-
 
−
|}
 
−
''Patients who had "mild renal insufficiency" received paclitaxel instead of cisplatin and had T2 to T4 N0 M0 disease.''
 
−
====Chemotherapy====
 
−
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per week, '''given 6 hours before radiation therapy'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:
 
−
**Accelerated hyperfractionated RT (AHFRT) with twice per day radiation, consisting of 1.8 Gy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 1.6 Gy fraction x 12 fractions is given to the "bladder tumor plus wide margin." Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy. Zapatero et al. 2012 did not specify the precise schedule of radiation therapy.
 
−
**Normo-fractionated concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.
 
−
'''One course'''
 
−
====Subsequent treatment====
 
−
*3 weeks after finishing radiation and chemotherapy, patients underwent restaging [[Surgery#TURBT|TURBT]]
 
−
**Patients with complete regression (R0): [[#Paclitaxel_.26_RT_2|Paclitaxel & RT consolidation]]
 
−
**Nonresponders: [[Surgery#Cystectomy|Cystectomy]]
 
−
===Regimen variant #2 {{#subobject:6222a7|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5536836/ Michaelson et al. 2016 (RTOG 0524)]
 
−
|2005-2013
 
−
| style="background-color:#91cf61" |Phase 1/2, 47 pts
 
−
|-
 
−
|}
 
−
==== Chemotherapy ====
 
−
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per week for 7 weeks
 
−
====Radiotherapy====
 
−
*Concurrent daily [[External_beam_radiotherapy|radiation therapy]] 64.8 Gy total in 36 fractions
 
−
'''One course'''
 
−
===References===
 
−
#Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]
 
−
#'''RTOG 0524:''' Michaelson MD, Hu C, Pham HT, Dahl DM, Lee-Wu C, Swanson GP, Vuky J, Lee RJ, Souhami L, Chang B, George A, Sandler H, Shipley W. A Phase 1/2 Trial of a Combination of Paclitaxel and Trastuzumab With Daily Irradiation or Paclitaxel Alone With Daily Irradiation After Transurethral Surgery for Noncystectomy Candidates With Muscle-Invasive Bladder Cancer (Trial NRG Oncology RTOG 0524). Int J Radiat Oncol Biol Phys. 2017 Apr 1;97(5):995-1001. Epub 2016 Dec 19. [https://doi.org/10.1016/j.ijrobp.2016.12.018 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5536836/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28333021/ PubMed]
 
−
==Radiation therapy {{#subobject:1103c0|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:e0ed54|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]
 
−
|1989-1997
 
−
| style="background-color:#91cf61" |Non-randomized
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 James et al. 2012 (BC2001)]
 
−
|2001-2008
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Fluorouracil.2C_Mitomycin.2C_RT|Fluorouracil, Mitomycin, RT]]
 
−
| style="background-color:#fc8d59" |Seems to have inferior locoregional DFS
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*Depending on response, treatment in Zapatero et al. 2000 preceded by [[#MCV|MCV]] x 3 or [[Surgery#Cystectomy|cystectomy]]
 
−
====Radiotherapy====
 
−
*[[External beam radiotherapy]] by the following criteria:
 
−
**CR: 2 Gy fractions given 5 days per week, with total bladder dose of 60 Gy. Total dose to regional lymph nodes: 50 Gy.
 
−
**Less than CR: total dose to the bladder of 64 to 66 Gy. No further details given about fractionation, schedule, or dose to lymph nodes.
 
−
===References===
 
−
#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11091353 PubMed]
 
−
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]
 
−
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]
 
−
#'''BC2001:''' James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. [https://www.nejm.org/doi/full/10.1056/NEJMoa1106106 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22512481 PubMed] NCT00024349
 
−
=Consolidation chemoradiotherapy=
 
−
==Cisplatin & RT {{#subobject:308d11|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 
−
===Regimen variant #1, cisplatin 40 mg/m<sup>2</sup>/wk x 2 {{#subobject:dc2b84|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]
 
−
|1989-1997
 
−
| style="background-color:#91cf61" |Non-randomized
 
−
|-
 
−
|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]
 
−
|1998-2000
 
−
| style="background-color:#91cf61" |Phase 1/2
 
−
|-
 
−
|}
 
−
''Note: Dosing is per Figure 1 of Zapatero et al. 2010.''
 
−
====Preceding treatment====
 
−
*Depending on response: [[#Cisplatin_.26_RT|Cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2, '''given first'''
 
−
'''7-day cycle for 2 cycles'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:
 
−
**'''Both trials:''' Accelerated hyperfractionated RT (AHFRT), 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.
 
−
**'''Zapatero et al. 2000 only:''' Normo-fractionated concurrent radiation therapy, 1.8 to 2 Gy fractions, given 5 times per week. Total induction and consolidation bladder dose of 64 to 66 Gy; total induction and consolidation pelvic lymph node dose of 44 to 46 Gy. Zapatero, et al. 2010 & Zapatero, et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy, nor what adjustments, if any, were made to chemotherapy for this radiation schedule.
 
−
====Subsequent treatment====
 
−
*RTOG 97-06: [[#MCV_2|Adjuvant MCV]]
 
−
===Regimen variant #2, cisplatin 70 mg/m<sup>2</sup> x 1 {{#subobject:314189|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.1996.14.1.119 Tester et al. 1996 (RTOG 88-02)]
 
−
|1988-1990
 
−
| style="background-color:#91cf61" |Phase 2
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*Depending on response, treatment preceded by [[#Cisplatin_.26_RT|cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 14 fractions (total dose in consolidation phase: 25.2 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)
 
−
'''3-week course'''
 
−
===Regimen variant #3, cisplatin 100 mg/m<sup>2</sup> x 1 {{#subobject:7afeca|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.1998.16.11.3576 Shipley et al. 1998 (RTOG 89-03)]
 
−
|1990-1993
 
−
| style="background-color:#91cf61" |Non-randomized portion of phase III RCT
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*Depending on response, treatment preceded by [[#Cisplatin_.26_RT|cisplatin & RT induction]] or [[Surgery#Cystectomy|cystectomy]]
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 14 fractions (total dose in consolidation phase: 39.6 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)
 
−
'''3-week course'''
 
−
===References===
 
−
#'''RTOG 88-02:''' Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. [https://doi.org/10.1200/jco.1996.14.1.119 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/8558186 PubMed]
 
−
#'''RTOG 89-03:''' Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. [https://doi.org/10.1200/jco.1998.16.11.3576 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9817278 PubMed]
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
#Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. [https://onlinelibrary.wiley.com/doi/full/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11091353 PubMed]
 
−
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. [http://www.urologiconcology.org/article/S1078-1439%2809%2900029-5/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19362865 PubMed]
 
−
##'''Update:''' Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]
 
−
#'''RTOG 97-06:''' Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14529770 PubMed]
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
==Cisplatin & Fluorouracil (CF) & RT {{#subobject:fe2538|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen variant #1, 30/1200 x 2 + 64.3 Gy {{#subobject:a18497|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
 
−
|2002-2008
 
−
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 
−
|[[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, Paclitaxel, RT]]
 
−
| style="background-color:#d3d3d3" |Not reported
 
−
|-
 
−
|}
 
−
''Note: Consolidation starts starts on week 8.''
 
−
====Preceding treatment====
 
−
*[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|Cisplatin, 5-FU, RT induction]]
 
−
====Chemotherapy====
 
−
''Starts on week 8.''
 
−
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
'''7-day cycle for 2 cycles'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day x 8 days. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.
 
−
'''2-week course'''
 
−
====Subsequent treatment====
 
−
*[[#PGC|Adjuvant PGC]]
 
−
===Regimen variant #2, 45/1200 x 2 + 44 Gy {{#subobject:904a96|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1634/theoncologist.5-6-471 Kaufman et al. 2000 (RTOG 95-06)]
 
−
|1995-1997
 
−
| style="background-color:#91cf61" |Phase 1/2
 
−
|-
 
−
|}
 
−
''Treatment starts on week 9.''
 
−
====Preceding treatment====
 
−
*Depending on response, treatment preceded by [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|cisplatin, fluorouracil, RT induction]] or [[Surgery#Cystectomy|cystectomy]]
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3, '''given second'''
 
−
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, '''given first'''
 
−
'''14-day cycle for 2 cycles'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 2.5 Gy fractions twice per day, with at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total consolidation dose: 20 Gy), administered to the whole bladder and bladder tumor volume. The total dose to the whole bladder and bladder tumor volume was 44 Gy in 16 fractions; the total dose to the pelvic lymph nodes was 24 Gy in 8 fractions.
 
−
====Dose modifications====
 
−
*Patients with grade III hematologic toxicity, defined as platelets less than 50 x 10<sup>9</sup>/L or ANC less than 1800/uL, had chemotherapy and radiation therapy held for at least one week, with therapy resuming when platelets were at least 100 x 10<sup>9</sup>/L and ANC at least 1800/uL.
 
−
====Supportive medications====
 
−
*IV hydration at 500 mL/H (no total volume specified) prior to [[Fluorouracil (5-FU)]]
 
−
'''17-day course'''
 
−
===References===
 
−
#'''RTOG 95-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Chetner MP, Souhami L, Zlotecki RA, Sause WT, True LD. The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response. Oncologist. 2000;5(6):471-6. [https://doi.org/10.1634/theoncologist.5-6-471 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11110598 PubMed]
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
==Cisplatin, Paclitaxel, RT {{#subobject:4bc0dd|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen variant #1, 30/50 x 2 + 64.3 Gy {{#subobject:9fefbd|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
 
−
|2002-2008
 
−
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 
−
|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|Cisplatin, 5-FU, RT]]
 
−
| style="background-color:#d3d3d3" |Not reported
 
−
|-
 
−
|}
 
−
''Note: Consolidation starts starts on week 8.''
 
−
====Preceding treatment====
 
−
*[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT induction]]
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1
 
−
'''7-day cycle for 2 cycles'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day x 8 days. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.
 
−
'''2-week course'''
 
−
====Subsequent treatment====
 
−
*[[#PGC|Adjuvant PGC]]
 
−
===Regimen variant #2, 40/50 x 2 + 64.3 Gy {{#subobject:6bec62|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]
 
−
|NR in abstract
 
−
| style="background-color:#91cf61" |Phase 1/2
 
−
|-
 
−
|}
 
−
''Consolidation starts starts on week 8.''
 
−
====Preceding treatment====
 
−
*[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT induction]]
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once on day 1
 
−
'''7-day cycle for 2 cycles'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.5 Gy fractions x 16 fractions, given twice per day (4 to 6 hour interval between treatments) on days 1 to 5, 8 to 10. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.
 
−
'''2-week course'''
 
−
====Subsequent treatment====
 
−
*[[#Cisplatin_.26_Gemcitabine_.28GC.29_2|Adjuvant cisplatin & gemcitabine]]
 
−
===References===
 
−
#'''RTOG 99-06:''' Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19100600 PubMed]
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
==Paclitaxel & RT {{#subobject:039b5c|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:de252a|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract Zapatero et al. 2012]
 
−
|1990-2010
 
−
| style="background-color:#ffffbe" |Non-randomized, <20 pts
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*Depending on response, treatment preceded by [[#Paclitaxel_.26_RT|paclitaxel & RT induction]] or [[Surgery#Cystectomy|cystectomy]]
 
−
====Chemotherapy====
 
−
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per week, given 6 hours before radiation therapy
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] according to one of the following:
 
−
**Accelerated hyperfractionated RT (AHFRT), 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.
 
−
**Normo-fractionated concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.
 
−
'''One course'''
 
−
===References===
 
−
#Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. [http://www.goldjournal.net/article/S0090-4295%2812%2900867-9/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22999456 PubMed]
 
 
=Adjuvant therapy=
 
=Adjuvant therapy=
−
==Cisplatin & Gemcitabine (GC) {{#subobject:684e48|Regimen=1}}==
+
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:72a413|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract Kaufman et al. 2009 (RTOG 99-06)]
 
−
|NR in abstract
 
−
| style="background-color:#91cf61" |Phase 1/2
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*Depending on response to induction, treatment starts 12 weeks after [[#Cisplatin.2C_Paclitaxel.2C_RT_2|cisplatin, paclitaxel, RT consolidation]], or 8 weeks after [[Surgery#Cystectomy|cystectomy]]
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 
−
'''28-day cycle for 4 cycles'''
 
−
===References===
 
−
#Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. [http://www.goldjournal.net/article/S0090-4295%2808%2901658-0/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19100600 PubMed]
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
==Cisplatin & Methotrexate {{#subobject:684e48|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:72a413|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 17%"|Study
 
−
!style="width: 15%"|Years of enrollment
 
−
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 17%"|Comparator
 
−
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2005.11.094 Lehmann et al. 2005 (AUO-AB 05/95)]
 
−
|1994-2000
 
−
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 
−
|[[#MVEC_88|M-VEC]] x 3
 
−
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
 
−
| style="background-color:#1a9850" |Less toxic
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*[[Surgery#Cystectomy|Radical cystectomy]]
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]]
 
−
*[[Methotrexate (MTX)]]
 
−
===References===
 
−
#'''AUO-AB 05/95:''' Lehmann J, Retz M, Wiemers C, Beck J, Thüroff J, Weining C, Albers P, Frohneberg D, Becker T, Funke PJ, Walz P, Langbein S, Reiher F, Schiller M, Miller K, Roth S, Kälble T, Sternberg D, Wellek S, Stöckle M; AUO. Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial (AUO-AB 05/95). J Clin Oncol. 2005 Aug 1;23(22):4963-74. Epub 2005 Jun 6. [https://doi.org/10.1200/JCO.2005.11.094 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15939920 PubMed]
 
−
==MCV {{#subobject:8e6bb8|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
MCV: '''<u>M</u>'''ethotrexate, '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine
 
−
===Regimen {{#subobject:ca6708|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract Hagan et al. 2003 (RTOG 97-06)]
 
−
|1998-2000
 
−
| style="background-color:#91cf61" |Phase 1/2
 
−
|-
 
−
|}
 
−
''Begins 8 weeks after consolidation. Note that only 45% of patients in RTOG 97-06 were able to complete all 3 cycles of MCV.''
 
−
====Preceding treatment====
 
−
*[[#Cisplatin_.26_RT_2|Cisplatin & RT consolidation]]
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
 
−
*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 2 to 4
 
−
*[[Vinblastine (Velban)]] 3 mg/m<sup>2</sup> IV once per day on days 2, 15, 22
 
−
'''28-day cycle for 3 cycles'''
 
−
===References===
 
−
#Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. [http://www.redjournal.org/article/S0360-3016%2803%2900718-1/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14529770 PubMed]
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
 
==Nivolumab monotherapy {{#subobject:23ugd2|Regimen=1}}==
 
==Nivolumab monotherapy {{#subobject:23ugd2|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen variant #1, q2wks {{#subobject:gu17g8|Variant=1}}===
 
===Regimen variant #1, q2wks {{#subobject:gu17g8|Variant=1}}===
 
{| class="wikitable" style="color:white; background-color:#404040"
 
{| class="wikitable" style="color:white; background-color:#404040"
Line 1,482: Line 43:
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
Line 1,488: Line 49:
 
|-
 
|-
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215888/ Bajorin et al. 2021 (CheckMate 274)]
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215888/ Bajorin et al. 2021 (CheckMate 274)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-324-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
 +
|-
 +
|} -->
 
|2016-2020
 
|2016-2020
 
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
−
|[[Bladder_cancer_-_null_regimens#Placebo|Placebo]]
+
|[[Urothelial_carcinoma_-_null_regimens#Placebo|Placebo]]
−
| style="background-color:#1a9850" |Superior DFS<br>Median DFS: 20.8 vs 10.8 mo<br>(HR 0.70, 98.22% CI 0.55-0.90)
+
| style="background-color:#1a9850" |Superior DFS (co-primary endpoint)<br>Median DFS: 20.8 vs 10.8 mo<br>(HR 0.70, 98.22% CI 0.55-0.90)
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*Radical surgery
+
*CheckMate 274: [[Surgery#Radical_surgery|Radical surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunotherapy====
 
====Immunotherapy====
−
*[[Nivolumab (Opdivo)]] 240 mg IV once on day 1
+
*[[Nivolumab (Opdivo)]] 240 mg IV over 30 minutes once on day 1
 
'''14-day cycle for up to 26 cycles (1 year)'''
 
'''14-day cycle for up to 26 cycles (1 year)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #2, q4wks {{#subobject:hy27g8|Variant=1}}===
 
===Regimen variant #2, q4wks {{#subobject:hy27g8|Variant=1}}===
 
{| class="wikitable" style="color:white; background-color:#404040"
 
{| class="wikitable" style="color:white; background-color:#404040"
Line 1,505: Line 75:
 
|}
 
|}
 
''Note: this is not the dose that was used in the registration study, CheckMate 274.''
 
''Note: this is not the dose that was used in the registration study, CheckMate 274.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*Radical surgery
+
*CheckMate 274: [[Surgery#Radical_surgery|Radical surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunotherapy====
 
====Immunotherapy====
 
*[[Nivolumab (Opdivo)]] 480 mg IV once on day 1
 
*[[Nivolumab (Opdivo)]] 480 mg IV once on day 1
 
'''28-day cycle for up to 13 cycles (1 year)'''
 
'''28-day cycle for up to 13 cycles (1 year)'''
 +
</div></div>
 
===References===
 
===References===
−
#'''CheckMate 274:''' Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, Bamias A, Lebret T, Shariat SF, Park SH, Ye D, Agerbaek M, Enting D, McDermott R, Gajate P, Peer A, Milowsky MI, Nosov A, Neif Antonio J Jr, Tupikowski K, Toms L, Fischer BS, Qureshi A, Collette S, Unsal-Kacmaz K, Broughton E, Zardavas D, Koon HB, Galsky MD. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114. [https://doi.org/10.1056/nejmoa2034442 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215888/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34077643/ PubMed] NCT02632409
+
#'''CheckMate 274:''' Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, Bamias A, Lebret T, Shariat SF, Park SH, Ye D, Agerbaek M, Enting D, McDermott R, Gajate P, Peer A, Milowsky MI, Nosov A, Neif Antonio J Jr, Tupikowski K, Toms L, Fischer BS, Qureshi A, Collette S, Unsal-Kacmaz K, Broughton E, Zardavas D, Koon HB, Galsky MD. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114. [https://doi.org/10.1056/nejmoa2034442 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215888/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/34077643/ PubMed] [https://clinicaltrials.gov/study/NCT02632409 NCT02632409]
−
==PGC {{#subobject:22e1d2|Regimen=1}}==
+
##'''HRQoL analysis:''' Witjes JA, Galsky MD, Gschwend JE, Broughton E, Braverman J, Nasroulah F, Maira-Arce M, Ye X, Shi L, Guo S, Hamilton M, Bajorin DF. Health-related Quality of Life with Adjuvant Nivolumab After Radical Resection for High-risk Muscle-invasive Urothelial Carcinoma: Results from the Phase 3 CheckMate 274 Trial. Eur Urol Oncol. 2022 Oct;5(5):553-563. Epub 2022 Mar 11. [https://doi.org/10.1016/j.euo.2022.02.003 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10062393/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35288066/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
#'''VOLGA:''' [https://clinicaltrials.gov/study/NCT04960709 NCT04960709]
−
|-
+
 
−
|[[#top|back to top]]
+
=Locally advanced or metastatic disease, first-line, platinum-ineligible=
−
|}
+
==Gemcitabine monotherapy {{#subobject:7fgei3|Regimen=1}}==
−
PGC: '''<u>P</u>'''aclitaxel, '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin
+
<div class="toccolours" style="background-color:#eeeeee">
−
<br>PCG: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>G</u>'''emcitabine
+
===Regimen {{#subobject:oasdvc|Variant=1}}===
−
===Regimen variant #1 {{#subobject:ad1bc8|Variant=1}}===
 
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2010.28.18_suppl.lba4518 Paz-Ares et al 2010 (SOGUG 99/01)]
+
|[https://doi.org/10.1016/j.urolonc.2023.04.016 Heinzelbecker et al. 2023 (AUO-AB 22/00)]
−
|2000-2007
+
|2000-07 to 2008-12
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
+
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[Bladder_cancer_-_null_regimens#Observation_2|Observation]]
+
|[[Bladder_cancer#Gemcitabine_monotherapy_999|Gemcitabine]]; adjuvant
−
| style="background-color:#1a9850" |Superior OS
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
|-
 
|-
 
|}
 
|}
−
''Patients in SOGUG 99/01 had pT3-4 and/or pN positive disease with adequate renal function (CrCl greater than 50 mL/min/1.73m<sup>2</sup>). The study prematurely closed due to poor recruitment and lacks adequate power to make firm conclusions, and has never been published in manuscript format.''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
====Preceding treatment====
 
−
*[[Surgery#Cystectomy|Cystectomy]]; the median time treatment started post-cystectomy was 48 days
 
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 8
+
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
+
'''21-day cycle for up to 6 cycles'''
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
+
</div></div>
−
'''21-day cycle for 4 cycles'''
 
−
===Regimen variant #2 {{#subobject:29bee9|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
 
−
|2002-2008
 
−
| style="background-color:#91cf61" |Non-randomized portion of phase II RCT
 
−
|-
 
−
|}
 
−
====Preceding treatment====
 
−
*Depending on response, adjuvant chemotherapy began 12 weeks after [[#Cisplatin.2C_Paclitaxel.2C_RT_2|cisplatin, paclitaxel, RT]] versus [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|cisplatin, 5-FU, RT]] or 8 weeks after [[Surgery#Cystectomy|cystectomy]]
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
'''21-day cycle for 4 cycles'''
 
 
===References===
 
===References===
−
#'''Abstract:''' L. G. Paz-Ares, E. Solsona, E. Esteban, A. Saez, J. Gonzalez-Larriba, A. Anton, M. Hevia, F. de la Rosa, V. Guillem, and J. Bellmunt. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. ASCO MEETING ABSTRACTS Jun 22, 2010:LBA4518. [https://doi.org/10.1200/jco.2010.28.18_suppl.lba4518 link to abstract] '''contains verified protocol'''
+
#'''AUO-AB 22/00:''' Heinzelbecker J, Spieler N, Kuehn M, Fischer C, Volkmer B, von Rundstedt F, Albers P, Becht E, Bannowsky A, Weber HM, Hofmann R, Müller M, Langbein S, Steiner G, Retz M, Kamradt J, Wagenpfeil G, Wellek S, Lehmann J, Stoeckle M. Adjuvant vs progression-triggered treatment with gemcitabine in platinum-ineligible high-risk bladder cancer patients: Long-term follow-up of a randomized phase 3 trial. Urol Oncol. 2023 Aug;41(8):356.e19-356.e30. Epub 2023 May 16. [https://doi.org/10.1016/j.urolonc.2023.04.016 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37198025/ PubMed] [https://clinicaltrials.gov/study/NCT00146276 NCT00146276]
−
#'''RTOG 02-33:''' Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157 PubMed] NCT00055601
+
 
−
##'''Pooled Update:''' Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. [https://doi.org/10.1200/jco.2008.19.5776 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734419/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19636019 PubMed]
 
−
##'''Pooled Update:''' Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. [https://doi.org/10.1200/jco.2014.57.5548 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239302/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25366678 PubMed]
 
−
=Locally advanced or metastatic disease, first-line, platinum-ineligible=
 
−
==Atezolizumab monotherapy {{#subobject:1d9e29|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:764948|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|Years of enrollment
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568632/ Balar et al. 2016 (IMvigor210)]
 
−
|2014-2015
 
−
| style="background-color:#91cf61" |Phase 2 (RT)
 
−
| style="background-color:#88419d; color:white " |ORR: 23% (95% CI 16-31)
 
−
|-
 
−
|}
 
−
<big>'''On 8/16/2018 the FDA updated the prescribing information for atezolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible.'''</big>
 
−
====Immunotherapy====
 
−
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
 
−
'''21-day cycles'''
 
−
===References===
 
−
#'''IMvigor210:''' Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, Dawson NA, van der Heijden MS, Dreicer R, Srinivas S, Retz MM, Joseph RW, Drakaki A, Vaishampayan UN, Sridhar SS, Quinn DI, Durán I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE 3rd, Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thåström A, Abidoye OO, Fine GD, Bajorin DF; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017 Jan 7;389(10064):67-76. Epub 2016 Dec 8. [http://thelancet.com/journals/lancet/article/PIIS0140-6736(16)32455-2/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568632/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27939400 PubMed] NCT02951767
 
 
==Pembrolizumab monotherapy {{#subobject:7fc2f6|Regimen=1}}==
 
==Pembrolizumab monotherapy {{#subobject:7fc2f6|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen {{#subobject:946aec|Variant=1}}===
 
===Regimen {{#subobject:946aec|Variant=1}}===
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
−
!style="width: 25%"|Years of enrollment
+
!style="width: 25%"|Dates of enrollment
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30616-2/fulltext Balar et al. 2017 (KEYNOTE-052)]
+
|[https://doi.org/10.1016/S1470-2045(17)30616-2 Balar et al. 2017 (KEYNOTE-052)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-277-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 
|2015-2016
 
|2015-2016
 
| style="background-color:#91cf61" |Phase 2 (RT)
 
| style="background-color:#91cf61" |Phase 2 (RT)
Line 1,608: Line 134:
 
|-
 
|-
 
|}
 
|}
−
<big>'''On 5/18/2018 the FDA released a warning that patients in the monotherapy arms of the ongoing KEYNOTE-361 trial with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.'''</big>
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
 
−
<big>'''On 8/16/2018 the FDA updated the prescribing information for pembrolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible.'''</big>
 
 
====Immunotherapy====
 
====Immunotherapy====
 
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#'''KEYNOTE-052:''' Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. Epub 2017 Sep 26. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30616-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28967485 PubMed] NCT02335424
+
#'''KEYNOTE-052:''' Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. Epub 2017 Sep 26. [https://doi.org/10.1016/S1470-2045(17)30616-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28967485/ PubMed] [https://clinicaltrials.gov/study/NCT02335424 NCT02335424]
 +
##'''Update:''' Vuky J, Balar AV, Castellano D, O'Donnell PH, Grivas P, Bellmunt J, Powles T, Bajorin D, Hahn NM, Savage MJ, Fang X, Godwin JL, Frenkl TL, Homet Moreno B, de Wit R, Plimack ER. Long-Term Outcomes in KEYNOTE-052: Phase II Study Investigating First-Line Pembrolizumab in Cisplatin-Ineligible Patients With Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2020 Aug 10;38(23):2658-2666. Epub 2020 Jun 17. [https://doi.org/10.1200/jco.19.01213 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32552471/ PubMed]
 +
##'''Pooled update:''' Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. [https://doi.org/10.1016/j.annonc.2022.11.012 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36494006/ PubMed]
 +
#'''LEAP-011:''' [https://clinicaltrials.gov/study/NCT03898180 NCT03898180]
 +
 
 
=Locally advanced or metastatic disease, first-line, platinum-eligible=
 
=Locally advanced or metastatic disease, first-line, platinum-eligible=
−
==Atezolizumab monotherapy {{#subobject:1d9e29|Regimen=1}}==
+
==Carboplatin & Gemcitabine (GCb) {{#subobject:8855e5|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
GCb: '''<u>G</u>'''emcitabine & '''<u>C</u>'''ar'''<u>b</u>'''oplatin
−
|-
+
<div class="toccolours" style="background-color:#eeeeee">
−
|[[#top|back to top]]
+
===Regimen variant #1, AUC 4.5/1000 x 6 {{#subobject:5f00b7|Variant=1}}===
−
|}
 
−
===Regimen {{#subobject:764948|Variant=1}}===
 
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
! style="width: 20%" |Study
+
! style="width: 17%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 15%" |Dates of enrollment
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
! style="width: 20%" |Comparator
+
! style="width: 17%" |Comparator
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
|-
 
|-
−
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]
+
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]
−
| rowspan="2" |2016-2018
+
| rowspan="2" |2015-2017
−
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
+
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
−
|1. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]<br> 2. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]
+
|1. [[#Durvalumab_monotherapy_999|Durvalumab]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+
| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
 +
| style="background-color:#d73027" |More toxic
 
|-
 
|-
−
|3. [[#Carboplatin_.26_Gemcitabine_.28GCb.29_.26_Atezolizumab|GCb & Atezolizumab]]<br> 4. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]
+
|2. [[Urothelial_carcinoma_-_historical#Durvalumab_.26_Tremelimumab|Durvalumab & Tremelimumab]]
−
| style="background-color:#d3d3d3" |Not reported
+
| style="background-color:#fee08b" |Might have inferior OS
 +
| style="background-color:#ffffbf" |Not more toxic
 
|-
 
|-
−
|}
+
|[https://doi.org/10.1056/nejmoa2312117 Powles et al. 2024 (EV-302)]
−
====Immunotherapy====
+
|2020-2023
−
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
+
| style="background-color:#1a9851" |Phase 3 (C)
−
'''21-day cycles'''
+
|[[#Enfortumab_vedotin_.26_Pembrolizumab|Enfortumab vedotin & Pembrolizumab]]
−
===References===
+
| style="background-color:#d73027" |Inferior PFS/OS
−
#'''IMvigor130:''' Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636
+
|
−
==Carboplatin & Gemcitabine (GCb) {{#subobject:8855e5|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
−
GCb: '''<u>G</u>'''emcitabine & '''<u>C</u>'''ar'''<u>b</u>'''oplatin
+
''Note: this was the lower bound of AUC specified by DANUBE & EV-302.''
−
===Regimen variant #1, AUC 4.5/1000 {{#subobject:5f00b7|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Carboplatin (Paraplatin)]] AUC 4.5 IV over 60 minutes once on day 1, '''given second'''
 +
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given first'''
 +
'''21-day cycle for up to 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
 
 +
===Regimen variant #2, AUC 4.5/1000, indefinite {{#subobject:5f0in7|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 17%" |Study
 
! style="width: 17%" |Study
−
! style="width: 15%" |Years of enrollment
+
! style="width: 15%" |Dates of enrollment
 
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 17%" |Comparator
 
! style="width: 17%" |Comparator
 
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
−
![[Overall response rate|'''ORR''']]
 
−
!Comparator [[Overall response rate|'''ORR''']]
 
 
|-
 
|-
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792956 De Santis et al. 2009 (EORTC 30986)]
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792956 De Santis et al. 2009 (EORTC 30986)]
 
|2001-2005
 
|2001-2005
 
| style="background-color:#1a9851" |Randomized Phase 2/3 (E-de-esc)
 
| style="background-color:#1a9851" |Randomized Phase 2/3 (E-de-esc)
−
|[[#M-CAVI_88|M-CAVI]]
+
|[[#M-CAVI_999|M-CAVI]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<sup>1</sup><br>ORR: 30.3% vs 41.2%
 
| style="background-color:#1a9851" |Lower toxicity than M-CAVI
 
| style="background-color:#1a9851" |Lower toxicity than M-CAVI
−
|Intention to treat: <br>38% (2009)<br>41.2% (2012)
 
−
|Intention to treat: <br>20% (2009)<br>30.3% (2012)
 
−
|-
 
−
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]
 
−
| rowspan="2" |2015-2017
 
−
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 
−
|1. [[#Durvalumab_monotherapy_99|Durvalumab]]
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]])
 
−
| style="background-color:#d73027" |(Grouped with [[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]]) More toxic
 
−
|Intention to treat (Cisplatin-ineligible): 46%
 
−
|Intention to treat (Cisplatin-ineligible): 24%
 
−
|-
 
−
|2. [[#Durvalumab_.26_Tremelimumab_77|Durvalumab & Tremelimumab]], then [[#Durvalumab_monotherapy_99|Durvalumab maintenance]]
 
−
| style="background-color:#fee08b" |Might have inferior OS
 
−
| style="background-color:#ffffbf" |(Grouped with [[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]]) Not more toxic
 
−
|Intention to treat (Cisplatin-ineligible): 46%
 
−
|Intention to treat (Cisplatin-ineligible): 36%
 
 
|-
 
|-
 
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]
 
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]
 
| rowspan="2" |2016-2018
 
| rowspan="2" |2016-2018
 
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
−
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]
+
|1. [[Urothelial_carcinoma_-_historical#Atezolizumab_monotherapy_2|Atezolizumab]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+
| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
−
|
 
−
|
 
 
|
 
|
 
|-
 
|-
−
|2. [[#Carboplatin_.26_Gemcitabine_.28GCb.29_.26_Atezolizumab|GCb & Atezolizumab]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]
+
|2a. [[Urothelial_carcinoma_-_historical#Carboplatin_.26_Gemcitabine_.28GCb.29_.26_Atezolizumab|GCb & Atezolizumab]]<br>2b. [[Urothelial_carcinoma_-_historical#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]
−
| style="background-color:#fc8d59" |Seems to have inferior OS
+
| style="background-color:#fee08b" |Might have inferior OS<sup>2</sup>
−
|
 
−
|
 
 
|
 
|
 
|-
 
|-
 
|}
 
|}
−
''Note: this was the lower bound of AUC specified by DANUBE. Patients on the DANUBE trial received up to 6 cycles.''
+
''<sup>1</sup>Reported efficacy for EORTC 30986 is based on the 2011 update.''<br>
 +
''<sup>2</sup>Reported efficacy for IMvigor130 is based on the 2023 update.''<br>
 +
''Note: Patients in EORTC 30986 who achieved complete response were given two additional cycles of treatment.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Carboplatin (Paraplatin)]] AUC 4.5 IV over 60 minutes once on day 1, '''given second'''
 
*[[Carboplatin (Paraplatin)]] AUC 4.5 IV over 60 minutes once on day 1, '''given second'''
 
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given first'''
 
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given first'''
−
'''21-day cycles (see note)'''
+
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
''Patients who achieved complete response were given two additional cycles of treatment.''
+
===Regimen variant #3, AUC 5/1000 x 6 {{#subobject:4gua36|Variant=1}}===
−
===Regimen variant #2, AUC 5/1000 {{#subobject:4gua36|Variant=1}}===
 
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
−
!style="width: 20%"|Years of enrollment
+
!style="width: 20%"|Dates of enrollment
 
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 20%"|Comparator
 
!style="width: 20%"|Comparator
Line 1,719: Line 235:
 
|[https://doi.org/10.1159/000012132 Carles et al. 2000]
 
|[https://doi.org/10.1159/000012132 Carles et al. 2000]
 
|1997-1998
 
|1997-1998
−
| style="background-color:#ffffbe" |Phase 2, <20 pts
+
| style="background-color:#ffffbe" |Phase 2, fewer than 20 pts
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
Line 1,726: Line 242:
 
| rowspan="2" |2015-2017
 
| rowspan="2" |2015-2017
 
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
−
|1. [[#Durvalumab_monotherapy_99|Durvalumab]]
+
|1. [[#Durvalumab_monotherapy_999|Durvalumab]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]])
+
| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
 
|-
 
|-
−
|2. [[#Durvalumab_.26_Tremelimumab_77|Durvalumab & Tremelimumab]], then [[#Durvalumab_monotherapy_99|Durvalumab maintenance]]
+
|2. [[Urothelial_carcinoma_-_historical#Durvalumab_.26_Tremelimumab|Durvalumab & Tremelimumab]]
 
| style="background-color:#fee08b" |Might have inferior OS
 
| style="background-color:#fee08b" |Might have inferior OS
 
|-
 
|-
Line 1,735: Line 251:
 
|rowspan=2|2016-2018
 
|rowspan=2|2016-2018
 
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
−
|1. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Pembrolizumab_99|GC & Pembrolizumab]]<br> 2. [[#Carboplatin_.26_Gemcitabine_.28GC.29_.26_Pembrolizumab_99|GCb & Pembrolizumab]]
+
|1a. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Pembrolizumab_333|GC & Pembrolizumab]]<br>1b. [[#Carboplatin_.26_Gemcitabine_.28GCb.29_.26_Pembrolizumab_333|GCb & Pembrolizumab]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS
+
| style="background-color:#fee08b" |Might have inferior OS
 
|-
 
|-
−
|3. [[#Pembrolizumab_monotherapy_99|Pembrolizumab]]
+
|2. [[#Pembrolizumab_monotherapy_999|Pembrolizumab]]
 
| style="background-color:#d3d3d3" |Not reported
 
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2312117 Powles et al. 2024 (EV-302)]
 +
|2020-2023
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Enfortumab_vedotin_.26_Pembrolizumab|Enfortumab vedotin & Pembrolizumab]]
 +
| style="background-color:#d73027" |Inferior PFS/OS
 
|-
 
|-
 
|}
 
|}
−
''Note: this was the upper bound of AUC specified by DANUBE.''
+
''Note: this was the upper bound of AUC specified by DANUBE & EV-302.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
 
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
 
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
'''21-day cycle for up to 6 cycles'''
 
'''21-day cycle for up to 6 cycles'''
−
===Regimen variant #3, AUC 5/1250 {{#subobject:4f0596|Variant=1}}===
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, AUC 5/1250 {{#subobject:4f0596|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
!style="width: 17%"|Study
 
!style="width: 17%"|Study
−
!style="width: 15%"|Years of enrollment
+
!style="width: 15%"|Dates of enrollment
 
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 17%"|Comparator
 
!style="width: 17%"|Comparator
 
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
−
![[Overall response rate|'''ORR''']]
 
−
!Comparator [[Overall response rate|'''ORR''']]
 
 
|-
 
|-
−
|[https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext Dogliotti et al. 2006]
+
|[https://doi.org/10.1016/j.eururo.2006.12.029 Dogliotti et al. 2006]
 
|2000-2002
 
|2000-2002
 
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
Line 1,764: Line 287:
 
|
 
|
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of reduced toxicity
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of reduced toxicity
−
|Intention to treat: 40% (95% CI NR)<br>Evaluable patients only: 56%<br>(95% CI: 40–72)
 
−
|Intention to treat: 49% (95% CI NR)<br>Evaluable patients only: 66%<br>(95% CI: 49–80)
 
 
|-
 
|-
 
|}
 
|}
 +
''ORR for this arm: Intention to treat: 40% (95% CI NR)<br>Evaluable patients only: 56%<br>(95% CI: 40–72)''<br>
 +
''ORR for control arm: Intention to treat: 49% (95% CI NR)<br>Evaluable patients only: 66%<br>(95% CI: 49–80)''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 30 to 60 minutes once on day 2
 
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 30 to 60 minutes once on day 2
 
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8
 
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8
 
'''21-day cycle for up to 6 cycles'''
 
'''21-day cycle for up to 6 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#Carles J, Nogué M, Domènech M, Pérez C, Saigí E, Villadiego K, Guasch I, Ibeas R. Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function. Oncology. 2000 Jun;59(1):24-7. [https://doi.org/10.1159/000012132 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/10895062/ PubMed]
+
#Carles J, Nogué M, Domènech M, Pérez C, Saigí E, Villadiego K, Guasch I, Ibeas R. Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function. Oncology. 2000 Jun;59(1):24-7. [https://doi.org/10.1159/000012132 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10895062/ PubMed]
−
#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. [https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17207911 PubMed]
+
#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. [https://doi.org/10.1016/j.eururo.2006.12.029 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17207911/ PubMed]
−
#'''EORTC 30986:''' De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Skoneczna I, Marreaud S, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol. 2009 Nov 20;27(33):5634-9. [https://doi.org/10.1200/JCO.2008.21.4924 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792956/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19786668 PubMed] NCT00111787
+
#'''EORTC 30986:''' De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Skoneczna I, Marreaud S, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol. 2009 Nov 20;27(33):5634-9. Epub 2009 Sep 28. [https://doi.org/10.1200/JCO.2008.21.4924 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792956/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19786668/ PubMed] [https://clinicaltrials.gov/study/NCT00111787 NCT00111787]
−
##'''Update:''' De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Gil T, Marreaud S, Daugaard G, Skoneczna I, Collette S, Lorent J, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012 Jan 10;30(2):191-9. [https://doi.org/10.1200/JCO.2011.37.3571 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255563/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22162575 PubMed]
+
##'''Update:''' De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Gil T, Marreaud S, Daugaard G, Skoneczna I, Collette S, Lorent J, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012 Jan 10;30(2):191-9. Epub 2011 Dec 12. [https://doi.org/10.1200/JCO.2011.37.3571 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255563/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22162575/ PubMed]
−
#'''IMvigor130:''' Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636
+
#'''IMvigor130:''' Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32416780/ PubMed] [https://clinicaltrials.gov/study/NCT02807636 NCT02807636]
−
#'''DANUBE:''' Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Sep 21:S1470-2045(20)30541-6. Epub ahead of print. [https://doi.org/10.1016/s1470-2045(20)30541-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32971005 PubMed] NCT02516241
+
##'''Update:''' Grande E, Arranz JÁ, De Santis M, Bamias A, Kikuchi E, Del Muro XG, Park SH, De Giorgi U, Alekseev B, Mencinger M, Izumi K, Schutz FA, Puente J, Li JR, O'Donnell PH, Kalebasty AR, Ye D, Mariathasan S, Bene-Tchaleu F, Bernhard S, Lee C, Davis ID, Galsky MD. Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study. Lancet Oncol. 2024 Jan;25(1):29-45. Epub 2023 Dec 12. [https://doi.org/10.1016/s1470-2045(23)00540-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38101433/ PubMed]
−
#'''KEYNOTE-361:''' Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. [https://doi.org/10.1016/s1470-2045(21)00152-2 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/34051178/ PubMed] NCT02853305
+
#'''DANUBE:''' Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1574-1588. Epub 2020 Sep 21. [https://doi.org/10.1016/s1470-2045(20)30541-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32971005/ PubMed] [https://clinicaltrials.gov/study/NCT02516241 NCT02516241]
−
==Carboplatin & Gemcitabine (GCb) & Atezolizumab {{#subobject:8tqccz|Regimen=1}}==
+
#'''KEYNOTE-361:''' Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. [https://doi.org/10.1016/s1470-2045(21)00152-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34051178/ PubMed] [https://clinicaltrials.gov/study/NCT02853305 NCT02853305]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
#'''EV-302:''' Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. [https://doi.org/10.1056/nejmoa2312117 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/38446675/ PubMed] [https://clinicaltrials.gov/study/NCT04223856 NCT04223856]
 +
#'''NILE:''' [https://clinicaltrials.gov/study/NCT03682068 NCT03682068]
 +
#'''RC48-C016:''' [https://clinicaltrials.gov/study/NCT05302284 NCT05302284]
 +
 
 +
==Carboplatin & Gemcitabine (GCb) & Pembrolizumab {{#subobject:88gic5|Regimen=1}}==
 +
GCb & Pembrolizumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''ar'''<u>b</u>'''oplatin, Pembrolizumab
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:4iggca|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[[#top|back to top]]
+
|rowspan=2|[https://doi.org/10.1016/s1470-2045(21)00152-2 Powles et al. 2021 (KEYNOTE-361)]
−
|}
+
|rowspan=2|2016-2018
−
GCb & Atezolizumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''ar'''<u>b</u>'''oplatin, Atezolizumab
+
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-RT-esc)
−
===Regimen {{#subobject:8q1jx8|Variant=1}}===
+
|1a. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br>1b. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
+
| style="background-color:#d9ef8b" |Might have superior OS (co-primary endpoint)<br>Median OS: 17 vs 14.3 mo<br>(HR 0.86, 95% CI 0.72-1.02)<br><br>Might have superior PFS<sup>1</sup> (co-primary endpoint)<br>Median PFS: 8.3 vs 7.1 mo<br>(HR 0.78, 95% CI 0.65-0.3)
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]
+
|2. [[#Pembrolizumab_monotherapy_999|Pembrolizumab]]
−
| rowspan="2" |2016-2018
 
−
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 
−
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]
 
 
| style="background-color:#d3d3d3" |Not reported
 
| style="background-color:#d3d3d3" |Not reported
−
|-
 
−
|2. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]
 
−
| style="background-color:#91cf60" |Seems to have superior OS
 
 
|-
 
|-
 
|}
 
|}
 +
''<sup>1</sup>Reported efficacy did not meet the prespecified boundary for statistical significance.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Carboplatin (Paraplatin)]] AUC 4.5 IV once on day 1
+
*[[Carboplatin (Paraplatin)]] as follows:
−
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
+
**Cycles 1 up to 6: AUC 5 IV once on day 1
 +
*[[Gemcitabine (Gemzar)]] as follows:
 +
**Cycles 1 up to 6: 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
====Immunotherapy====
 
====Immunotherapy====
−
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
+
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
−
'''21-day cycles'''
+
'''21-day cycle for up to 35 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#'''IMvigor130:''' Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636
+
#'''KEYNOTE-361:''' Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. [https://doi.org/10.1016/s1470-2045(21)00152-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34051178/ PubMed] [https://clinicaltrials.gov/study/NCT02853305 NCT02853305]
 
==Carboplatin & Paclitaxel (CP) {{#subobject:b33fe7|Regimen=1}}==
 
==Carboplatin & Paclitaxel (CP) {{#subobject:b33fe7|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen {{#subobject:5d481c|Variant=1}}===
 
===Regimen {{#subobject:5d481c|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.10782/full Vaughn et al. 2002 (ECOG E2896)]
+
|[https://doi.org/10.1002/cncr.10782 Vaughn et al. 2002 (ECOG E2896)]
 
|1996-1999
 
|1996-1999
 
| style="background-color:#91cf61" |Phase 2
 
| style="background-color:#91cf61" |Phase 2
Line 1,839: Line 368:
 
|}
 
|}
 
''Note: ECOG E4897 was closed early due to poor accrual.''
 
''Note: ECOG E4897 was closed early due to poor accrual.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1
 
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1
 
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV over 3 hours once on day 1
 
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV over 3 hours once on day 1
 
'''21-day cycle for up to 6 cycles'''
 
'''21-day cycle for up to 6 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#'''ECOG E2896:''' Vaughn DJ, Manola J, Dreicer R, See W, Levitt R, Wilding G. Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group. Cancer. 2002 Sep 1;95(5):1022-7. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.10782/full link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12209686 PubMed]
+
#'''ECOG E2896:''' Vaughn DJ, Manola J, Dreicer R, See W, Levitt R, Wilding G. Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group. Cancer. 2002 Sep 1;95(5):1022-7. [https://doi.org/10.1002/cncr.10782 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12209686/ PubMed]
−
#'''ECOG E4897:''' Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. [https://doi.org/10.1002/cncr.20123 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15073851/ PubMed] NCT00003376
+
#'''ECOG E4897:''' Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. [https://doi.org/10.1002/cncr.20123 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15073851/ PubMed] [https://clinicaltrials.gov/study/NCT00003376 NCT00003376]
−
==CISCA {{#subobject:b60f2a|Regimen=1}}==
+
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
CISCA: '''<u>CIS</u>'''platin, '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin)
 
−
===Regimen {{#subobject:2d0b5e|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 20%" |Study
 
−
! style="width: 20%" |Years of enrollment
 
−
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 20%" |Comparator
 
−
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
![[Overall response rate|'''ORR''']]
 
−
!Comparator [[Overall response rate|'''ORR''']]
 
−
|-
 
−
|[https://jamanetwork.com/journals/jama/article-abstract/356753 Sternberg et al. 1977]
 
−
|1976-1977
 
−
| style="background-color:#ffffbe" |Non-randomized, <20 pts
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
|
 
−
|
 
−
|-
 
−
|[https://doi.org/10.1200/jco.1990.8.6.1050 Logothetis et al. 1990]
 
−
|1985-1989
 
−
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 
−
|[[#MVAC_2|MVAC]]
 
−
| style="background-color:#d73027" |Inferior OS
 
−
|46% (95% CI 32-62)
 
−
|65% (95% CI 52-77)
 
−
|-
 
−
|}
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 2
 
−
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 2
 
−
====Supportive medications====
 
−
*Forced mannitol diuresis with [[Cisplatin (Platinol)]]
 
−
'''21-day cycle for up to 6 cycles'''
 
−
===References===
 
−
#Sternberg JJ, Bracken RB, Handel PB, Johnson DE. Combination chemotherapy (CISCA) for advanced urinary tract carcinoma: a preliminary report. JAMA. 1977 Nov 21;238(21):2282-7. [https://jamanetwork.com/journals/jama/article-abstract/356753 link to original article] [https://pubmed.ncbi.nlm.nih.gov/578848 PubMed]
 
−
#Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. [https://doi.org/10.1200/jco.1990.8.6.1050 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2189954 PubMed]
 
 
==Cisplatin & Gemcitabine (GC) {{#subobject:5cbd83|Regimen=1}}==
 
==Cisplatin & Gemcitabine (GC) {{#subobject:5cbd83|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''isplatin
 +
<br>GP: '''<u>G</u>'''emcitabine & '''<u>P</u>'''latinol (Cisplatin)
 +
{| class="wikitable" style="color:white; background-color:#9e4244"
 +
|<small>'''AIM pathway regimen 2022-08-01'''</small>
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
−
GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''isplatin
+
<div class="toccolours" style="background-color:#eeeeee">
−
<br>GP: '''<u>G</u>'''emcitabine & '''<u>P</u>'''latinol (Cisplatin)
+
===Regimen variant #1, 70/2000; q3wk x 6 {{#subobject:69fea8|Variant=1}}===
−
===Regimen variant #1, 70/1000, q3wk {{#subobject:69fea8|Variant=1}}===
 
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1093/annonc/mdf186 Soto Parra et al. 2002]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8462587/ Rosenberg et al. 2021 (CALGB 90601)]
−
|1998-2000
 
−
| style="background-color:#ffffbe" |Randomized Phase 2, <20 pts in this subgroup (E-esc)
 
−
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]; q4wk
 
−
| style="background-color:#d3d3d3" |Not reported
 
−
|-
 
−
|[https://doi.org/10.1200/jco.21.00286 Rosenberg et al. 2021 (CALGB 90601)]
 
 
|2009-2014
 
|2009-2014
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Cisplatin_.26_Gemcitabine_.28GCb.29_.26_Bevacizumab|GC & Bevacizumab]]
+
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Bevacizumab|GC & Bevacizumab]]
 
| style="background-color:#fee08b" |Might have inferior OS
 
| style="background-color:#fee08b" |Might have inferior OS
 
|-
 
|-
Line 1,919: Line 403:
 
| rowspan="2" |2015-2017
 
| rowspan="2" |2015-2017
 
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
−
|1. [[#Durvalumab_monotherapy_99|Durvalumab]]
+
|1. [[#Durvalumab_monotherapy_999|Durvalumab]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])
+
| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
 
|-
 
|-
−
|2. [[#Durvalumab_.26_Tremelimumab_77|Durvalumab & Tremelimumab]], then [[#Durvalumab_monotherapy_99|Durvalumab maintenance]]
+
|2. [[Urothelial_carcinoma_-_historical#Durvalumab_.26_Tremelimumab|Durvalumab & Tremelimumab]]
−
| style="background-color:#fee08b" |Might have inferior OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])
+
| style="background-color:#fee08b" |Might have inferior OS
−
|-
 
−
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]
 
−
| rowspan="2" |2016-2018
 
−
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 
−
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
−
|-
 
−
|2. [[#Carboplatin_.26_Gemcitabine_.28GCb.29_.26_Atezolizumab|GCb & Atezolizumab]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]
 
−
| style="background-color:#fc8d59" |Seems to have inferior OS
 
 
|-
 
|-
 
|rowspan=2|[https://doi.org/10.1016/s1470-2045(21)00152-2 Powles et al. 2021 (KEYNOTE-361)]
 
|rowspan=2|[https://doi.org/10.1016/s1470-2045(21)00152-2 Powles et al. 2021 (KEYNOTE-361)]
 
|rowspan=2|2016-2018
 
|rowspan=2|2016-2018
 
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
−
|1. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Pembrolizumab_99|GC & Pembrolizumab]]<br> 2. [[#Carboplatin_.26_Gemcitabine_.28GC.29_.26_Pembrolizumab_99|GCb & Pembrolizumab]]
+
|1a. [[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Pembrolizumab_333|GC & Pembrolizumab]]<br>1b. [[#Carboplatin_.26_Gemcitabine_.28GCb.29_.26_Pembrolizumab_333|GCb & Pembrolizumab]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoints of PFS/OS
+
| style="background-color:#fee08b" |Might have inferior OS
 
|-
 
|-
−
|3. [[#Pembrolizumab_monotherapy_99|Pembrolizumab]]
+
|2. [[#Pembrolizumab_monotherapy_999|Pembrolizumab]]
 
| style="background-color:#d3d3d3" |Not reported
 
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2309863 van der Heijden et al. 2023 (CheckMate 901 part 1)]
 +
|2018-01-30 to 2022-09-28
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Nivolumab|GC & Nivolumab]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS (co-primary endpoint)
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2312117 Powles et al. 2024 (EV-302)]
 +
|2020-2023
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Enfortumab_vedotin_.26_Pembrolizumab|Enfortumab vedotin & Pembrolizumab]]
 +
| style="background-color:#d73027" |Inferior PFS/OS
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 1 or 2
+
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 1
 
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
====Supportive medications====
+
====Supportive therapy====
−
*2 liters of fluid and "appropriate antiemetic therapy" given with [[Cisplatin (Platinol)]]
+
*2 liters of [[:Category:Hydration|fluid]] and "appropriate antiemetic therapy" given with cisplatin
 
*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
 
*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
−
'''21-day cycles (up to 6 cycles in CALGB 90601, DANUBE, KEYNOTE-361)'''
+
'''21-day cycle for 6 cycles'''
−
===Regimen variant #2, 70/1000, q4wk {{#subobject:53ad73|Variant=1}}===
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 70/2000; q3wk, indefinite {{#subobject:69find|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
|-
 
−
|[https://doi.org/10.1200/jco.2000.18.17.3068 von der Maase et al. 2000]
 
−
|1996-1998
 
−
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 
−
|[[#MVAC_2|MVAC]]
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
 
|-
 
|-
 
|[https://doi.org/10.1093/annonc/mdf186 Soto Parra et al. 2002]
 
|[https://doi.org/10.1093/annonc/mdf186 Soto Parra et al. 2002]
 
|1998-2000
 
|1998-2000
−
| style="background-color:#ffffbe" |Randomized Phase 2, <20 pts in this subgroup (E-de-esc)
+
| style="background-color:#ffffbe" |Randomized Phase 2, fewer than 20 pts in this subgroup (E-esc)
−
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]; q3wk
+
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]; q4wk
 
| style="background-color:#d3d3d3" |Not reported
 
| style="background-color:#d3d3d3" |Not reported
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ Bellmunt et al. 2012 (EORTC 30987)]
+
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]
−
|2001-2004
+
| rowspan="2" |2016-2018
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#PGC_2|PCG]]
 
−
| style="background-color:#fee08b" |Might have inferior OS
 
−
|-
 
−
|[https://www.karger.com/Article/Abstract/354085 Sternberg et al. 2013 (CILAB)]
 
−
|2008-2010
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Cisplatin_.26_Larotaxel_77|Cisplatin & Larotaxel]]
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
−
|-
 
−
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]
 
−
| rowspan="2" |2015-2017
 
 
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
−
|1. [[#Durvalumab_monotherapy_99|Durvalumab]]
+
|1. [[Urothelial_carcinoma_-_historical#Atezolizumab_monotherapy_2|Atezolizumab]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])
+
| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
 
|-
 
|-
−
|2. [[#Durvalumab_.26_Tremelimumab_77|Durvalumab & Tremelimumab]], then [[#Durvalumab_monotherapy_99|Durvalumab maintenance]]
+
|2a. [[Urothelial_carcinoma_-_historical#Carboplatin_.26_Gemcitabine_.28GCb.29_.26_Atezolizumab|GCb & Atezolizumab]]<br>2b. [[Urothelial_carcinoma_-_historical#Cisplatin_.26_Gemcitabine_.28GC.29_.26_Atezolizumab|GC & Atezolizumab]]
−
| style="background-color:#fee08b" |Might have inferior OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])
+
| style="background-color:#fee08b" |Might have inferior OS<sup>1</sup>
 
|-
 
|-
 
|}
 
|}
−
''Only a minority of patients in Soto Parra et al. 2002 had bladder cancer. The majority of patients had [[non-small cell lung cancer]].''
+
''<sup>1</sup>Reported efficacy for IMvigor130 is based on the 2023 update.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 2
+
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 1 or 2
−
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1, 8, 15
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
====Supportive medications====
+
====Supportive therapy====
−
*Per Soto Parra et al. 2002:
+
*2 liters of [[:Category:Hydration|fluid]] and "appropriate antiemetic therapy" given with cisplatin
−
*2 liters of fluid and "appropriate antiemetic therapy" given with [[Cisplatin (Platinol)]]
 
 
*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
 
*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
−
'''28-day cycle for up to 6 cycles'''
+
'''21-day cycles'''
−
===Regimen variant #3, 70/1250, q3wk {{#subobject:44c03b|Variant=1}}===
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 70/2500; q3wk {{#subobject:44c03b|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 17%" |Study
 
! style="width: 17%" |Study
−
! style="width: 15%" |Years of enrollment
+
! style="width: 15%" |Dates of enrollment
 
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 17%" |Comparator
 
! style="width: 17%" |Comparator
Line 2,011: Line 485:
 
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
|-
 
|-
−
|[https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext Dogliotti et al. 2006]
+
|[https://doi.org/10.1016/j.eururo.2006.12.029 Dogliotti et al. 2006]
 
|2000-2002
 
|2000-2002
 
| style="background-color:#1a9851" |Randomized Phase 2 (C)
 
| style="background-color:#1a9851" |Randomized Phase 2 (C)
Line 2,021: Line 495:
 
| rowspan="2" |2015-2017
 
| rowspan="2" |2015-2017
 
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
−
|1. [[#Durvalumab_monotherapy_99|Durvalumab]]
+
|1. [[#Durvalumab_monotherapy_999|Durvalumab]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])
+
| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
−
| style="background-color:#d73027" |(Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]]) More toxic
+
| style="background-color:#d73027" |More toxic
 
|-
 
|-
−
|2. [[#Durvalumab_.26_Tremelimumab_77|Durvalumab & Tremelimumab]], then [[#Durvalumab_monotherapy_99|Durvalumab maintenance]]
+
|2. [[Urothelial_carcinoma_-_historical#Durvalumab_.26_Tremelimumab|Durvalumab & Tremelimumab]]
−
| style="background-color:#fee08b" |Might have inferior OS (Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]])
+
| style="background-color:#fee08b" |Might have inferior OS
−
| style="background-color:#ffffbf" |(Grouped with [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]]) Not more toxic
+
| style="background-color:#ffffbf" |Not more toxic
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
+
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1 or 2
−
**''In DANUBE, Cisplatin given on day 1.''
 
 
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8
 
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8
 
'''21-day cycle for up to 6 cycles'''
 
'''21-day cycle for up to 6 cycles'''
−
===References===
+
</div></div><br>
−
#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. [https://doi.org/10.1200/jco.2000.18.17.3068 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11001674 PubMed]
+
<div class="toccolours" style="background-color:#eeeeee">
−
##'''Update:''' von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. [https://doi.org/10.1200/JCO.2005.07.757 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16034041 PubMed]
+
===Regimen variant #4, 70/3000; q4wk {{#subobject:53ad73|Variant=1}}===
−
#Soto Parra H, Cavina R, Latteri F, Sala A, Dambrosio M, Antonelli G, Morenghi E, Alloisio M, Ravasi G, Santoro A. Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol. 2002 Jul;13(7):1080-6. [https://doi.org/10.1093/annonc/mdf186 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12176787 PubMed]
 
−
#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. [https://www.europeanurology.com/article/S0302-2838(06)01589-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17207911 PubMed]
 
−
#'''EORTC 30987:''' Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. [https://doi.org/10.1200/JCO.2011.38.6979 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22370319 PubMed] NCT00022191
 
−
#'''CILAB:''' Sternberg CN, Skoneczna IA, Castellano D, Theodore C, Blais N, Voog E, Bellmunt J, Peters F, Le-Guennec S, Cerbone L, Risse ML, Machiels JP. Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB). Oncology. 2013;85(4):208-15. Epub 2013 Sep 24. [https://www.karger.com/Article/Abstract/354085 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24080920 PubMed] NCT00625664
 
−
#'''IMvigor130:''' Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636
 
−
#'''DANUBE:''' Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Sep 21:S1470-2045(20)30541-6. Epub ahead of print. [https://doi.org/10.1016/s1470-2045(20)30541-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32971005 PubMed] NCT02516241
 
−
#'''KEYNOTE-361:''' Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. [https://doi.org/10.1016/s1470-2045(21)00152-2 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/34051178/ PubMed] NCT02853305
 
−
#'''CALGB 90601:''' Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, Stadler WM, Teply BA, Picus J, Tagawa ST, Katragadda S, Vaena D, Misleh J, Hoimes C, Plimack ER, Flaig TW, Dreicer R, Bajorin D, Hahn O, Small EJ, Morris MJ. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J Clin Oncol. 2021 Aug 1;39(22):2486-2496. Epub 2021 May 14. [https://doi.org/10.1200/jco.21.00286 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33989025/ PubMed] NCT00942331
 
−
==Cisplatin & Gemcitabine (GC) & Atezolizumab {{#subobject:8gajcz|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
GC & Atezolizumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, Atezolizumab
 
−
===Regimen {{#subobject:80ihjx8|Variant=1}}===
 
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30230-0 Galsky et al. 2020 (IMvigor130)]
+
|[https://doi.org/10.1200/jco.2000.18.17.3068 von der Maase et al. 2000]
−
| rowspan="2" |2016-2018
+
|1996-1998
−
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
−
|1. [[#Atezolizumab_monotherapy_2|Atezolizumab]]
+
|[[#MVAC_2|MVAC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdf186 Soto Parra et al. 2002]
 +
|1998-2000
 +
| style="background-color:#ffffbe" |Randomized Phase 2, fewer than 20 pts in this subgroup (E-de-esc)
 +
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]; q3wk
 
| style="background-color:#d3d3d3" |Not reported
 
| style="background-color:#d3d3d3" |Not reported
 
|-
 
|-
−
|2. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]<br> 3. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ Bellmunt et al. 2012 (EORTC 30987)]
−
| style="background-color:#91cf60" |Seems to have superior OS
+
|2001-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#PGC_2|PCG]]
 +
| style="background-color:#fee08b" |Might have inferior OS
 +
|-
 +
|[https://doi.org/10.1159/000354085 Sternberg et al. 2013 (CILAB)]
 +
|2008-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cisplatin_.26_Larotaxel_999|Cisplatin & Larotaxel]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1016/s1470-2045(20)30541-6 Powles et al. 2020 (DANUBE)]
 +
| rowspan="2" |2015-2017
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Durvalumab_monotherapy_999|Durvalumab]]
 +
| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
 +
|-
 +
|2. [[Urothelial_carcinoma_-_historical#Durvalumab_.26_Tremelimumab|Durvalumab & Tremelimumab]]
 +
| style="background-color:#fee08b" |Might have inferior OS
 
|-
 
|-
 
|}
 
|}
 +
''Note: Only a minority of patients in Soto Parra et al. 2002 had bladder cancer. The majority of patients had [[non-small cell lung cancer]].''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
+
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 2
−
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1, 8, 15
−
====Immunotherapy====
+
====Supportive therapy====
−
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
+
*Per Soto Parra et al. 2002:
−
'''21-day cycles'''
+
*2 liters of [[:Category:Hydration|fluid]] and "appropriate antiemetic therapy" given with cisplatin
 +
*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
 +
'''28-day cycle for up to 6 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#'''IMvigor130:''' Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32416780 PubMed] NCT02807636
+
#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. [https://doi.org/10.1200/jco.2000.18.17.3068 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11001674/ PubMed]
 +
##'''Update:''' von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. [https://doi.org/10.1200/JCO.2005.07.757 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16034041/ PubMed]
 +
#Soto Parra H, Cavina R, Latteri F, Sala A, Dambrosio M, Antonelli G, Morenghi E, Alloisio M, Ravasi G, Santoro A. Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol. 2002 Jul;13(7):1080-6. [https://doi.org/10.1093/annonc/mdf186 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12176787/ PubMed]
 +
#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. [https://doi.org/10.1016/j.eururo.2006.12.029 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17207911/ PubMed]
 +
#'''EORTC 30987:''' Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. [https://doi.org/10.1200/JCO.2011.38.6979 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22370319/ PubMed] [https://clinicaltrials.gov/study/NCT00022191 NCT00022191]
 +
#'''CILAB:''' Sternberg CN, Skoneczna IA, Castellano D, Theodore C, Blais N, Voog E, Bellmunt J, Peters F, Le-Guennec S, Cerbone L, Risse ML, Machiels JP. Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB). Oncology. 2013;85(4):208-15. Epub 2013 Sep 24. [https://doi.org/10.1159/000354085 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24080920/ PubMed] [https://clinicaltrials.gov/study/NCT00625664 NCT00625664]
 +
#'''IMvigor130:''' Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. [https://doi.org/10.1016/s0140-6736(20)30230-0 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32416780/ PubMed] [https://clinicaltrials.gov/study/NCT02807636 NCT02807636]
 +
##'''Update:''' Grande E, Arranz JÁ, De Santis M, Bamias A, Kikuchi E, Del Muro XG, Park SH, De Giorgi U, Alekseev B, Mencinger M, Izumi K, Schutz FA, Puente J, Li JR, O'Donnell PH, Kalebasty AR, Ye D, Mariathasan S, Bene-Tchaleu F, Bernhard S, Lee C, Davis ID, Galsky MD. Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study. Lancet Oncol. 2024 Jan;25(1):29-45. Epub 2023 Dec 12. [https://doi.org/10.1016/s1470-2045(23)00540-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38101433/ PubMed]
 +
#'''DANUBE:''' Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1574-1588. Epub 2020 Sep 21. [https://doi.org/10.1016/s1470-2045(20)30541-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32971005/ PubMed] [https://clinicaltrials.gov/study/NCT02516241 NCT02516241]
 +
#'''KEYNOTE-361:''' Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. [https://doi.org/10.1016/s1470-2045(21)00152-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34051178/ PubMed] [https://clinicaltrials.gov/study/NCT02853305 NCT02853305]
 +
#'''CALGB 90601:''' Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, Stadler WM, Teply BA, Picus J, Tagawa ST, Katragadda S, Vaena D, Misleh J, Hoimes C, Plimack ER, Flaig TW, Dreicer R, Bajorin D, Hahn O, Small EJ, Morris MJ. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J Clin Oncol. 2021 Aug 1;39(22):2486-2496. Epub 2021 May 14. [https://doi.org/10.1200/jco.21.00286 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8462587/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33989025/ PubMed] [https://clinicaltrials.gov/study/NCT00942331 NCT00942331]
 +
#'''CheckMate 901 part 1:''' van der Heijden MS, Sonpavde G, Powles T, Necchi A, Burotto M, Schenker M, Sade JP, Bamias A, Beuzeboc P, Bedke J, Oldenburg J, Chatta G, Ürün Y, Ye D, He Z, Valderrama BP, Ku JH, Tomita Y, Filian J, Wang L, Purcea D, Patel MY, Nasroulah F, Galsky MD; CheckMate 901 Trial Investigators. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023 Nov 9;389(19):1778-1789. Epub 2023 Oct 22. [https://doi.org/10.1056/nejmoa2309863 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/37870949/ PubMed] [https://clinicaltrials.gov/study/NCT03036098 NCT03036098]
 +
#'''EV-302:''' Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. [https://doi.org/10.1056/nejmoa2312117 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/38446675/ PubMed] [https://clinicaltrials.gov/study/NCT04223856 NCT04223856]
 +
#'''NILE:''' [https://clinicaltrials.gov/study/NCT03682068 NCT03682068]
 +
#'''RC48-C016:''' [https://clinicaltrials.gov/study/NCT05302284 NCT05302284]
 +
 
 
==Cisplatin & Gemcitabine (GC) & Bevacizumab {{#subobject:5ig13|Regimen=1}}==
 
==Cisplatin & Gemcitabine (GC) & Bevacizumab {{#subobject:5ig13|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
GCB: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, '''<u>B</u>'''evacizumab
 
GCB: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, '''<u>B</u>'''evacizumab
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:u5fea8|Variant=1}}===
 
===Regimen {{#subobject:u5fea8|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.21.00286 Rosenberg et al. 2021 (CALGB 90601)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8462587/ Rosenberg et al. 2021 (CALGB 90601)]
 
|2009-2014
 
|2009-2014
 
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]
 
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]
−
| style="background-color:#d9ef8b" |Might have superior OS<br>Median OS: 14.5 vs 14.3 mo<br>(HR 0.87, 95% CI 0.72-1.05)
+
| style="background-color:#d9ef8b" |Might have superior OS (primary endpoint)<br>Median OS: 14.5 vs 14.3 mo<br>(HR 0.87, 95% CI 0.72-1.05)
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Cisplatin (Platinol)]] as follows:
 
*[[Cisplatin (Platinol)]] as follows:
Line 2,107: Line 608:
 
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#'''CALGB 90601:''' Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, Stadler WM, Teply BA, Picus J, Tagawa ST, Katragadda S, Vaena D, Misleh J, Hoimes C, Plimack ER, Flaig TW, Dreicer R, Bajorin D, Hahn O, Small EJ, Morris MJ. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J Clin Oncol. 2021 Aug 1;39(22):2486-2496. Epub 2021 May 14. [https://doi.org/10.1200/jco.21.00286 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33989025/ PubMed] NCT00942331
+
#'''CALGB 90601:''' Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, Stadler WM, Teply BA, Picus J, Tagawa ST, Katragadda S, Vaena D, Misleh J, Hoimes C, Plimack ER, Flaig TW, Dreicer R, Bajorin D, Hahn O, Small EJ, Morris MJ. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J Clin Oncol. 2021 Aug 1;39(22):2486-2496. Epub 2021 May 14. [https://doi.org/10.1200/jco.21.00286 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8462587/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33989025/ PubMed] [https://clinicaltrials.gov/study/NCT00942331 NCT00942331]
−
==Gemcitabine & Paclitaxel {{#subobject:385447|Regimen=1}}==
+
==Cisplatin & Gemcitabine (GC) & Nivolumab {{#subobject:igniv5|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
GC & Nivolumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, Nivolumab
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:jo4c2a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2309863 van der Heijden et al. 2023 (CheckMate 901 part 1)]
 +
|2018-01-30 to 2022-09-28
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[#Cisplatin_.26_Gemcitabine_.28GC.29|GC]] x 6
 +
| style="background-color:#91cf60" |Seems to have superior OS (co-primary endpoint)<br>Median OS: 21.7 vs 18.9 mo<br>(HR 0.78, 95% CI 0.63-0.96)<br><br>Superior PFS (co-primary endpoint)<br>Median PFS: 7.9 vs 7.6 mo<br>(HR 0.72, 95% CI 0.59-0.88)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cisplatin (Platinol)]] as follows:
 +
**Cycles 1 to 6: 70 mg/m<sup>2</sup> IV once on day 1
 +
*[[Gemcitabine (Gemzar)]] as follows:
 +
**Cycles 1 to 6: 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
====Immunotherapy====
 +
*[[Nivolumab (Opdivo)]] as follows:
 +
**Cycles 1 to 6: 360 mg IV once on day 1
 +
**Cycle 7 up to 28: 480 mg IV once on day 1
 +
'''21-day cycle for 6 cycles, then 28-day cycle for up to 22 cycles (2 years)'''
 +
</div></div>
 +
===References===
 +
#'''CheckMate 901 part 1:''' van der Heijden MS, Sonpavde G, Powles T, Necchi A, Burotto M, Schenker M, Sade JP, Bamias A, Beuzeboc P, Bedke J, Oldenburg J, Chatta G, Ürün Y, Ye D, He Z, Valderrama BP, Ku JH, Tomita Y, Filian J, Wang L, Purcea D, Patel MY, Nasroulah F, Galsky MD; CheckMate 901 Trial Investigators. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023 Nov 9;389(19):1778-1789. Epub 2023 Oct 22. [https://doi.org/10.1056/nejmoa2309863 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/37870949/ PubMed] [https://clinicaltrials.gov/study/NCT03036098 NCT03036098]
 +
 
 +
==Cisplatin & Gemcitabine (GC) & Pembrolizumab {{#subobject:igccc5|Regimen=1}}==
 +
GC & Pembrolizumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, Pembrolizumab
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:jx642a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1016/s1470-2045(21)00152-2 Powles et al. 2021 (KEYNOTE-361)]
 +
|rowspan=2|2016-2018
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|1a. [[#Cisplatin_.26_Gemcitabine_.28GC.29_3|GC]]<br>1b. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]
 +
| style="background-color:#d9ef8b" |Might have superior OS (co-primary endpoint)<br>Median OS: 17 vs 14.3 mo<br>(HR 0.86, 95% CI 0.72-1.02)<br><br>Might have superior PFS<sup>1</sup> (co-primary endpoint)<br>Median PFS: 8.3 vs 7.1 mo<br>(HR 0.78, 95% CI 0.65-0.3)
 +
|-
 +
|2. [[#Pembrolizumab_monotherapy_999|Pembrolizumab]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy did not meet the prespecified boundary for statistical significance.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cisplatin (Platinol)]] as follows:
 +
**Cycles 1 up to 6: 70 mg/m<sup>2</sup> IV once on day 1
 +
*[[Gemcitabine (Gemzar)]] as follows:
 +
**Cycles 1 up to 6: 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
====Immunotherapy====
 +
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 +
'''21-day cycle for up to 35 cycles (2 years)'''
 +
</div></div>
 +
===References===
 +
#'''KEYNOTE-361:''' Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. [https://doi.org/10.1016/s1470-2045(21)00152-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34051178/ PubMed] [https://clinicaltrials.gov/study/NCT02853305 NCT02853305]
 +
==Enfortumab vedotin & Pembrolizumab {{#subobject:dbopfd|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, q3wk pembrolizumab {{#subobject:1cc557|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2312117 Powles et al. 2024 (EV-302)]
 +
|2020-2023
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 +
|1a. [[#Cisplatin_.26_Gemcitabine_.28GC.29|GC]]<br>1b. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]
 +
| style="background-color:#1a9850" |Superior OS (co-primary endpoint)<br>Median OS: 31.5 vs 16.1 mo<br>(HR 0.47, 95% CI 0.38-0.58)<br><br>Superior PFS (co-primary endpoint)<br>Median PFS: 12.5 vs 6.3 mo<br>(HR 0.45, 95% CI 0.38-0.54)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Antibody-drug conjugate therapy====
 +
*[[Enfortumab vedotin (Padcev)]] 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1 & 8
 +
 
 +
====Immunotherapy====
 +
*[[Pembrolizumab (Keytruda)]] as follows:
 +
**Cycles 1 to 35: 200 mg IV once on day 1
 +
 
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, q6wk pembrolizumab {{#subobject:1c7637|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2312117 Powles et al. 2024 (EV-302)]
 +
|2020-2023
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 +
|1a. [[#Cisplatin_.26_Gemcitabine_.28GC.29|GC]]<br>1b. [[#Carboplatin_.26_Gemcitabine_.28GCb.29|GCb]]
 +
| style="background-color:#1a9850" |Superior OS (co-primary endpoint)<br>Median OS: 31.5 vs 16.1 mo<br>(HR 0.47, 95% CI 0.38-0.58)<br><br>Superior PFS (co-primary endpoint)<br>Median PFS: 12.5 vs 6.3 mo<br>(HR 0.45, 95% CI 0.38-0.54)
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
 +
''Note: Dosing is as described in the FDA approval announcement; this dosing was not reported in Powles et al. 2024.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Antibody-drug conjugate therapy====
 +
*[[Enfortumab vedotin (Padcev)]] 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1, 8, 22, 29
 +
 +
====Immunotherapy====
 +
*[[Pembrolizumab (Keytruda)]] as follows:
 +
**Cycles 1 to 17: 200 mg IV once on day 1
 +
 +
'''42-day cycles'''
 +
</div></div>
 +
===References===
 +
#'''EV-302:''' Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. [https://doi.org/10.1056/nejmoa2312117 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/38446675/ PubMed] [https://clinicaltrials.gov/study/NCT04223856 NCT04223856]
 +
 +
==Gemcitabine & Paclitaxel {{#subobject:385447|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #1 {{#subobject:af7c37|Variant=1}}===
 
===Regimen variant #1 {{#subobject:af7c37|Variant=1}}===
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
−
!style="width: 25%"|Years of enrollment
+
!style="width: 25%"|Dates of enrollment
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.24313/full Calabrò et al. 2009]
+
|[https://doi.org/10.1002/cncr.24313 Calabrò et al. 2009]
 
|2003-2005
 
|2003-2005
 
| style="background-color:#91cf61" |Phase 2
 
| style="background-color:#91cf61" |Phase 2
Line 2,127: Line 758:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Gemcitabine (Gemzar)]] 2500 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given second'''
 
*[[Gemcitabine (Gemzar)]] 2500 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given second'''
 
*[[Paclitaxel (Taxol)]] 150 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
 
*[[Paclitaxel (Taxol)]] 150 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
 
'''14-day cycle for 6 to 12 cycles'''
 
'''14-day cycle for 6 to 12 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #2 {{#subobject:b840fe|Variant=1}}===
 
===Regimen variant #2 {{#subobject:b840fe|Variant=1}}===
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
−
!style="width: 25%"|Years of enrollment
+
!style="width: 25%"|Dates of enrollment
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
Line 2,144: Line 778:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1
 
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1
 
'''21-day cycle for up to 6 cycles'''
 
'''21-day cycle for up to 6 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. [https://doi.org/10.1200/jco.2001.19.12.3018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408496 PubMed]
+
#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. [https://doi.org/10.1200/jco.2001.19.12.3018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408496/ PubMed]
−
#Calabrò F, Lorusso V, Rosati G, Manzione L, Frassineti L, Sava T, Di Paula ED, Alonso S, Sternberg CN. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer. 2009 Jun 15;115(12):2652-9. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24313/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19396817 PubMed]
+
#Calabrò F, Lorusso V, Rosati G, Manzione L, Frassineti L, Sava T, Di Paula ED, Alonso S, Sternberg CN. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer. 2009 Jun 15;115(12):2652-9. [https://doi.org/10.1002/cncr.24313 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19396817/ PubMed]
 
==MVAC {{#subobject:d2ea09|Regimen=1}}==
 
==MVAC {{#subobject:d2ea09|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin
 
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #1, standard {{#subobject:33db41|Variant=1}}===
 
===Regimen variant #1, standard {{#subobject:33db41|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992]
+
|[https://doi.org/10.1200/JCO.1992.10.7.1066 Loehrer et al. 1992 (ECOG E5886)]
 
|1984-1989
 
|1984-1989
 
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|[[Bladder_cancer_-_historical#Cisplatin_monotherapy|Cisplatin]]
+
|[[Urothelial_carcinoma_-_historical#Cisplatin_monotherapy|Cisplatin]]
 
| style="background-color:#1a9850" |Superior OS
 
| style="background-color:#1a9850" |Superior OS
 
|-
 
|-
Line 2,174: Line 807:
 
|1985-1989
 
|1985-1989
 
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
−
|[[#CISCA|CISCA]]
+
|[[Urothelial_carcinoma_-_historical#CISCA|CISCA]]
 
| style="background-color:#1a9850" |Superior OS
 
| style="background-color:#1a9850" |Superior OS
 
|-
 
|-
Line 2,203: Line 836:
 
|}
 
|}
 
''<sup>1</sup>Reported efficacy for EORTC 30924 is based on the 2005 update.''
 
''<sup>1</sup>Reported efficacy for EORTC 30924 is based on the 2005 update.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
 
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
Line 2,209: Line 843:
 
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once over 120 minutes on day 1 or 2
 
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once over 120 minutes on day 1 or 2
 
'''28-day cycles''' (number of cycles and criteria to continue therapy varies depending on reference)
 
'''28-day cycles''' (number of cycles and criteria to continue therapy varies depending on reference)
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #2, with G-CSF support {{#subobject:72266e|Variant=1}}===
 
===Regimen variant #2, with G-CSF support {{#subobject:72266e|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
Line 2,220: Line 856:
 
|1997-2002
 
|1997-2002
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Cisplatin_.26_Docetaxel_.28DC.29_99|Cisplatin & Docetaxel]]
+
|[[#Cisplatin_.26_Docetaxel_.28DC.29_999|Cisplatin & Docetaxel]]
 
| style="background-color:#91cf60" |Seems to have superior OS
 
| style="background-color:#91cf60" |Seems to have superior OS
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
 
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
Line 2,229: Line 866:
 
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 1
 
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 1
 
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV over 60 minutes once on day 1
−
====Supportive medications====
+
====Supportive therapy====
 
*[[Filgrastim (Neupogen)]] (dose not specified) SC once per day on days 7, 8, 9, 25, 26
 
*[[Filgrastim (Neupogen)]] (dose not specified) SC once per day on days 7, 8, 9, 25, 26
 
'''28-day cycles'''
 
'''28-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. [https://doi.org/10.1200/jco.1990.8.6.1050 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2189954 PubMed]
+
#Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. [https://doi.org/10.1200/jco.1990.8.6.1050 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2189954/ PubMed]
−
#Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. [https://doi.org/10.1200/JCO.1992.10.7.1066 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/1607913 PubMed]
+
#'''ECOG E5886:''' Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. [https://doi.org/10.1200/JCO.1992.10.7.1066 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1607913/ PubMed]
−
##'''Update:''' Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. [https://doi.org/10.1200/JCO.1997.15.7.2564 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9215826 PubMed]
+
##'''Update:''' Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. [https://doi.org/10.1200/JCO.1997.15.7.2564 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9215826/ PubMed]
−
#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. [https://doi.org/10.1200/jco.2000.18.17.3068 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11001674 PubMed]
+
#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. [https://doi.org/10.1200/jco.2000.18.17.3068 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11001674/ PubMed]
−
##'''Update:''' von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. [https://doi.org/10.1200/JCO.2005.07.757 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16034041 PubMed]
+
##'''Update:''' von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. [https://doi.org/10.1200/JCO.2005.07.757 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16034041/ PubMed]
−
#'''EORTC 30924:''' Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [https://doi.org/10.1200/jco.2001.19.10.2638 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11352955 PubMed]
+
#'''EORTC 30924:''' Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [https://doi.org/10.1200/jco.2001.19.10.2638 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11352955/ PubMed]
−
##'''Update:''' Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. [https://www.ejcancer.com/article/S0959-8049(05)00874-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16330205 PubMed]
+
##'''Update:''' Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. [https://doi.org/10.1016/j.ejca.2005.08.032 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16330205/ PubMed]
−
#Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002 Mar 1;20(5):1361-7. [https://doi.org/10.1200/JCO.2002.20.5.1361 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11870180 PubMed]
+
#Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002 Mar 1;20(5):1361-7. [https://doi.org/10.1200/JCO.2002.20.5.1361 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11870180/ PubMed]
−
#Bamias A, Aravantinos G, Deliveliotis C, Bafaloukos D, Kalofonos C, Xiros N, Zervas A, Mitropoulos D, Samantas E, Pectasides D, Papakostas P, Gika D, Kourousis C, Koutras A, Papadimitriou C, Bamias C, Kosmidis P, Dimopoulos MA; Hellenic Cooperative Oncology Group. Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol. 2004 Jan 15;22(2):220-8. Epub 2003 Dec 9. Erratum in: J Clin Oncol. 2004 May 1;22(9):1771. [https://doi.org/10.1200/JCO.2004.02.152 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14665607 PubMed]
+
#Bamias A, Aravantinos G, Deliveliotis C, Bafaloukos D, Kalofonos C, Xiros N, Zervas A, Mitropoulos D, Samantas E, Pectasides D, Papakostas P, Gika D, Kourousis C, Koutras A, Papadimitriou C, Bamias C, Kosmidis P, Dimopoulos MA; Hellenic Cooperative Oncology Group. Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol. 2004 Jan 15;22(2):220-8. Epub 2003 Dec 9. Erratum in: J Clin Oncol. 2004 May 1;22(9):1771. [https://doi.org/10.1200/JCO.2004.02.152 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14665607/ PubMed]
−
#'''ECOG E4897:''' Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. [https://doi.org/10.1002/cncr.20123 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15073851/ PubMed] NCT00003376
+
#'''ECOG E4897:''' Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. [https://doi.org/10.1002/cncr.20123 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15073851/ PubMed] [https://clinicaltrials.gov/study/NCT00003376 NCT00003376]
 +
 
 
==MVAC, dose-dense {{#subobject:c9beb1|Regimen=1}}==
 
==MVAC, dose-dense {{#subobject:c9beb1|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
ddMVAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin
 
ddMVAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:daeb1c|Variant=1}}===
 
===Regimen {{#subobject:daeb1c|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
![[Overall response rate|'''ORR''']]
 
−
!Comparator [[Overall response rate|'''ORR''']]
 
 
|-
 
|-
 
|[https://doi.org/10.1200/jco.2001.19.10.2638 Sternberg et al. 2001 (EORTC 30924)]
 
|[https://doi.org/10.1200/jco.2001.19.10.2638 Sternberg et al. 2001 (EORTC 30924)]
Line 2,264: Line 898:
 
|[[#MVAC_2|MVAC]]
 
|[[#MVAC_2|MVAC]]
 
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup>
 
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup>
−
|62% (95% CI 54-70)
 
−
|50% (95% CI 42-59)
 
 
|-
 
|-
 
|[https://doi.org/10.1093/annonc/mds583 Bamias et al. 2012 (HE 16/03)]
 
|[https://doi.org/10.1093/annonc/mds583 Bamias et al. 2012 (HE 16/03)]
 
|2003-2008
 
|2003-2008
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Dose-dense_Gemcitabine_.26_Cisplatin_.28GC.29_99|DD-GC]]
+
|[[#Dose-dense_Gemcitabine_.26_Cisplatin_.28GC.29_999|DD-GC]]
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
−
|
 
−
|
 
 
|-
 
|-
 
|}
 
|}
 
''<sup>1</sup>Reported efficacy for EORTC 30924 is based on the 2005 update.''<br>
 
''<sup>1</sup>Reported efficacy for EORTC 30924 is based on the 2005 update.''<br>
−
''Note: In contrast to Sternberg et al. 2001, Sternberg et al. 2006 specified 15-day cycles.''
+
''Note: In contrast to Sternberg et al. 2001, Sternberg et al. 2006 specified 15-day cycles. ORR for this arm of EORTC 30924 was 62% (95% CI 54-70) versus 50% (95% CI 42-59) in the control arm.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once on day 1
 
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once on day 1
Line 2,283: Line 914:
 
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2
 
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2
 
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
 
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
−
====Supportive medications====
+
====Supportive therapy====
−
*[[:Category:Granulocyte colony-stimulating factors|G-CSF]] (type not specified) 240 mcg/m<sup>2</sup> SC once per day on days 4 to 10 (additional use up to a total of 14 consecutive days if needed), injected at alternating sites, discontinued if ANC greater than 30,000/uL.
+
*[[:Category:Granulocyte colony-stimulating factors|G-CSF]] (type not specified) 240 mcg/m<sup>2</sup> SC once per day on days 4 to 10 (additional use up to a total of 14 consecutive days if needed), injected at alternating sites, discontinued if ANC greater than 30,000/μL.
 
**''In contrast to Sternberg et al. 2001, Sternberg et al. 2006 said G-CSF was given on days 3 to 7.''
 
**''In contrast to Sternberg et al. 2001, Sternberg et al. 2006 said G-CSF was given on days 3 to 7.''
 
'''14-day cycles'''
 
'''14-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#'''EORTC 30924:''' Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [https://doi.org/10.1200/jco.2001.19.10.2638 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11352955 PubMed]
+
#'''EORTC 30924:''' Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. [https://doi.org/10.1200/jco.2001.19.10.2638 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11352955/ PubMed]
−
##'''Update:''' Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. [https://www.ejcancer.com/article/S0959-8049(05)00874-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16330205 PubMed]
+
##'''Update:''' Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; [[Study_Groups#EORTC|EORTC]] Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. [https://doi.org/10.1016/j.ejca.2005.08.032 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16330205/ PubMed]
−
#'''HE 16/03:''' Bamias A, Dafni U, Karadimou A, Timotheadou E, Aravantinos G, Psyrri A, Xanthakis I, Tsiatas M, Koutoulidis V, Constantinidis C, Hatzimouratidis C, Samantas E, Visvikis A, Chrisophos M, Stravodimos K, Deliveliotis C, Eleftheraki A, Pectasides D, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol. 2013 Apr;24(4):1011-7. Epub 2012 Nov 7. [https://doi.org/10.1093/annonc/mds583 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23136231 PubMed] ACTRN12610000845033
+
#'''HE 16/03:''' Bamias A, Dafni U, Karadimou A, Timotheadou E, Aravantinos G, Psyrri A, Xanthakis I, Tsiatas M, Koutoulidis V, Constantinidis C, Hatzimouratidis C, Samantas E, Visvikis A, Chrisophos M, Stravodimos K, Deliveliotis C, Eleftheraki A, Pectasides D, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol. 2013 Apr;24(4):1011-7. Epub 2012 Nov 7. [https://doi.org/10.1093/annonc/mds583 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/23136231/ PubMed] ACTRN12610000845033
 
==PGC {{#subobject:393eb6|Regimen=1}}==
 
==PGC {{#subobject:393eb6|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
PGC: '''<u>P</u>'''aclitaxel, '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin
 
PGC: '''<u>P</u>'''aclitaxel, '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin
 
<br>PCG: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>G</u>'''emcitabine
 
<br>PCG: '''<u>P</u>'''aclitaxel, '''<u>C</u>'''isplatin, '''<u>G</u>'''emcitabine
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:837446|Variant=1}}===
 
===Regimen {{#subobject:837446|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
![[Overall response rate|'''ORR''']]
 
−
!Comparator [[Overall response rate|'''ORR''']]
 
 
|-
 
|-
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ Bellmunt et al. 2012 (EORTC 30987)]
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ Bellmunt et al. 2012 (EORTC 30987)]
Line 2,312: Line 939:
 
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]
 
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_3|Cisplatin & Gemcitabine]]
−
| style="background-color:#d9ef8b" |Might have superior OS<br>Median OS: 15.8 vs 12.7 mo<br>(HR 0.85, 95% CI 0.72-1.02)
+
| style="background-color:#d9ef8b" |Might have superior OS (primary endpoint)<br>Median OS: 15.8 vs 12.7 mo<br>(HR 0.85, 95% CI 0.72-1.02)
−
|56% (95% CI NR)
 
−
|44% (95% CI NR)
 
 
|-
 
|-
 
|}
 
|}
 +
''Note: ORR for this arm of EORTC 30987 was 56% vs 44% in the control arm.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
 
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
Line 2,322: Line 949:
 
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 8, '''given first'''
 
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 8, '''given first'''
 
'''21-day cycle for up to 6 cycles'''
 
'''21-day cycle for up to 6 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#'''EORTC 30987:''' Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. [https://doi.org/10.1200/JCO.2011.38.6979 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22370319 PubMed] NCT00022191
+
#'''EORTC 30987:''' Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. [https://doi.org/10.1200/JCO.2011.38.6979 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341152/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22370319/ PubMed] [https://clinicaltrials.gov/study/NCT00022191 NCT00022191]
 +
 
 
=Locally advanced or metastatic disease, maintenance after platinum chemotherapy=
 
=Locally advanced or metastatic disease, maintenance after platinum chemotherapy=
 
==Avelumab monotherapy {{#subobject:efub4c|Regimen=1}}==
 
==Avelumab monotherapy {{#subobject:efub4c|Regimen=1}}==
−
{| class="wikitable sortable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen {{#subobject:913o9g|Variant=1}}===
 
===Regimen {{#subobject:913o9g|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 17%" |Study
 
! style="width: 17%" |Study
−
! style="width: 15%" |Years of enrollment
+
! style="width: 15%" |Dates of enrollment
 
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 17%" |Comparator
 
! style="width: 17%" |Comparator
Line 2,339: Line 965:
 
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
|-
 
|-
−
|[https://www.nejm.org/doi/full/10.1056/NEJMoa2002788 Powles et al. 2020 (JAVELIN Bladder 100)]
+
|[https://doi.org/10.1056/NEJMoa2002788 Powles et al. 2020 (JAVELIN Bladder 100)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-220-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
 +
|-
 +
|} -->
 
|2016-2019
 
|2016-2019
 
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
−
|[[Bladder_cancer_-_null_regimens#Best_supportive_care|Best supportive care]]
+
|[[Urothelial_carcinoma_-_null_regimens#Best_supportive_care|Best supportive care]]
−
| style="background-color:#1a9851" |Superior OS
+
| style="background-color:#1a9851" |Superior OS<sup>1</sup> (primary endpoint)<br>Median OS: 23.8 vs 15 mo<br>(HR 0.76, 95% CI 0.63-0.91)
 
| style="background-color:#d73027" |More toxic
 
| style="background-color:#d73027" |More toxic
 
|-
 
|-
 
|}
 
|}
 +
''<sup>1</sup>Reported efficacy is based on the 2023 update.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[Bladder_cancer#Cisplatin_.26_Gemcitabine_3 | Cisplatin & Gemcitabine]] x 4 to 6 or [[Bladder_cancer#Carboplatin_.26_Gemcitabine_.28GCb.29 | Carboplatin & Gemcitabine]] x 4 to 6 cycles
+
*First-line [[#Cisplatin_.26_Gemcitabine_.28GC.29|GC]] x 4 to 6 or [[Urothelial_carcinoma#Carboplatin_.26_Gemcitabine_.28GCb.29 |GCb]] x 4 to 6
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
 
 
====Immunotherapy====
 
====Immunotherapy====
 
*[[Avelumab (Bavencio)]] 10 mg/kg IV over 60 minutes once per day on days 1 & 15
 
*[[Avelumab (Bavencio)]] 10 mg/kg IV over 60 minutes once per day on days 1 & 15
−
====Supportive Medications====
+
====Supportive therapy====
 
Premedication with a histamine H1 receptor (H1) blocker and acetaminophen approximately 30 to 60 minutes prior to each dose of avelumab for the first 4 doses; for example:
 
Premedication with a histamine H1 receptor (H1) blocker and acetaminophen approximately 30 to 60 minutes prior to each dose of avelumab for the first 4 doses; for example:
 
*[[Diphenhydramine (Benadryl)]] 25 to 50 mg IV or PO equivalent
 
*[[Diphenhydramine (Benadryl)]] 25 to 50 mg IV or PO equivalent
 
*[[Acetaminophen (Tylenol)]] 500 to 650 mg IV or PO equivalent
 
*[[Acetaminophen (Tylenol)]] 500 to 650 mg IV or PO equivalent
 
'''28-day cycles'''
 
'''28-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#'''JAVELIN Bladder 100:''' Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. Epub 2020 Sep 18. [https://www.nejm.org/doi/full/10.1056/NEJMoa2002788 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32945632 PubMed] NCT02603432
+
#'''JAVELIN Bladder 100:''' Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. Epub 2020 Sep 18. [https://doi.org/10.1056/NEJMoa2002788 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32945632/ PubMed] [https://clinicaltrials.gov/study/NCT02603432 NCT02603432]
 +
##'''PRO analysis:''' Grivas P, Kopyltsov E, Su PJ, Parnis FX, Park SH, Yamamoto Y, Fong PC, Tournigand C, Climent Duran MA, Bamias A, Caserta C, Chang J, Cislo P, di Pietro A, Wang J, Powles T. Patient-reported Outcomes from JAVELIN Bladder 100: Avelumab First-line Maintenance Plus Best Supportive Care Versus Best Supportive Care Alone for Advanced Urothelial Carcinoma. Eur Urol. 2023 Apr;83(4):320-328. Epub 2022 May 30. [https://doi.org/10.1016/j.eururo.2022.04.016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35654659/ PubMed]
 +
##'''Update:''' Powles T, Park SH, Caserta C, Valderrama BP, Gurney H, Ullén A, Loriot Y, Sridhar SS, Sternberg CN, Bellmunt J, Aragon-Ching JB, Wang J, Huang B, Laliberte RJ, di Pietro A, Grivas P. Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up. J Clin Oncol. 2023 Jul 1;41(19):3486-3492. Epub 2023 Apr 18. [https://doi.org/10.1200/jco.22.01792 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10306435/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37071838/ PubMed]
 +
#'''MAIN-CAV:''' [https://clinicaltrials.gov/study/NCT05092958 NCT05092958]
 +
 
 
==Pembrolizumab monotherapy {{#subobject:gbzb4c|Regimen=1}}==
 
==Pembrolizumab monotherapy {{#subobject:gbzb4c|Regimen=1}}==
−
{| class="wikitable sortable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen {{#subobject:9gia9g|Variant=1}}===
 
===Regimen {{#subobject:9gia9g|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 17%" |Study
 
! style="width: 17%" |Study
−
! style="width: 15%" |Years of enrollment
+
! style="width: 15%" |Dates of enrollment
 
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 17%" |Comparator
 
! style="width: 17%" |Comparator
Line 2,375: Line 1,012:
 
|2015-2018
 
|2015-2018
 
| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 
| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
−
|[[#Placebo_88|Placebo]]
+
|[[#Placebo_888|Placebo]]
−
| style="background-color:#91cf60" |Seems to have superior PFS<br>Median PFS: 5.4 vs 3 mo<br>(HR 0.65, 95% CI 0.43-0.97)
+
| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 5.4 vs 3 mo<br>(HR 0.65, 95% CI 0.43-0.97)
 
| style="background-color:#d73027" |More toxic
 
| style="background-color:#d73027" |More toxic
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*First-line platinum-based combination chemotherapy for up to 8 cycles without progression of disease
+
*First-line [[Regimen_classes#Platinum-based_regimen|platinum-based combination chemotherapy]] for up to 8 cycles, without progression of disease
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunotherapy====
 
====Immunotherapy====
 
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 
'''21-day cycle for up to 35 cycles (2 years)'''
 
'''21-day cycle for up to 35 cycles (2 years)'''
 +
</div></div>
 
===References===
 
===References===
−
#'''HCRN GU14-182:''' Galsky MD, Mortazavi A, Milowsky MI, George S, Gupta S, Fleming MT, Dang LH, Geynisman DM, Walling R, Alter RS, Kassar M, Wang J, Gupta S, Davis N, Picus J, Philips G, Quinn DI, Haines GK 3rd, Hahn NM, Zhao Q, Yu M, Pal SK. Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer. J Clin Oncol. 2020 Jun 1;38(16):1797-1806. Epub 2020 Apr 9. [https://doi.org/10.1200/jco.19.03091 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255983/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32271672 PubMed] NCT02500121
+
#'''HCRN GU14-182:''' Galsky MD, Mortazavi A, Milowsky MI, George S, Gupta S, Fleming MT, Dang LH, Geynisman DM, Walling R, Alter RS, Kassar M, Wang J, Gupta S, Davis N, Picus J, Philips G, Quinn DI, Haines GK 3rd, Hahn NM, Zhao Q, Yu M, Pal SK. Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer. J Clin Oncol. 2020 Jun 1;38(16):1797-1806. Epub 2020 Apr 9. [https://doi.org/10.1200/jco.19.03091 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255983/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32271672/ PubMed] [https://clinicaltrials.gov/study/NCT02500121 NCT02500121]
−
=Locally advanced or metastatic disease, after platinum chemotherapy=
+
=Locally advanced or metastatic disease, refractory/intolerant to platinum chemotherapy=
 
==Avelumab monotherapy {{#subobject:6C1497|Regimen=1}}==
 
==Avelumab monotherapy {{#subobject:6C1497|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen {{#subobject:D9FB6C|Variant=1}}===
 
===Regimen {{#subobject:D9FB6C|Variant=1}}===
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
−
!style="width: 25%"|Years of enrollment
+
!style="width: 25%"|Dates of enrollment
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493051/ Apolo et al. 2017 (JAVELIN)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493051/ Apolo et al. 2017 (JAVELIN Solid Tumor)]
−
|2014
+
|2014-2016
−
| style="background-color:#ffffbe" |Phase 1b (RT)
+
| style="background-color:#91cf61" |Phase 1b (RT)
−
|18% (95% CI 8-33)
+
|ORR: 17% (95% CI 11-24)<sup>1</sup>
 
|-
 
|-
 
|}
 
|}
 +
''<sup>1</sup>Reported efficacy is based on the 2017 update.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunotherapy====
 
====Immunotherapy====
 
*[[Avelumab (Bavencio)]] 10 mg/kg IV over 60 minutes once on day 1
 
*[[Avelumab (Bavencio)]] 10 mg/kg IV over 60 minutes once on day 1
−
====Supportive medications====
+
====Supportive therapy====
−
''Per Apolo et al. 2017 (JAVELIN):''
+
''Per Apolo et al. 2017:''
 
*"All patients were premedicated with [[:Category:Antihistamines|an antihistamine]] and [[Acetaminophen (Tylenol)|acetaminophen]] (doses and routes not given)
 
*"All patients were premedicated with [[:Category:Antihistamines|an antihistamine]] and [[Acetaminophen (Tylenol)|acetaminophen]] (doses and routes not given)
 
*The avelumab package insert suggests "Premedicate with acetaminophen and an antihistamine for the first 4 infusions and subsequently as needed."
 
*The avelumab package insert suggests "Premedicate with acetaminophen and an antihistamine for the first 4 infusions and subsequently as needed."
 
'''14-day cycles'''
 
'''14-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#'''Phase 1:''' Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, Safran H, Stinchcombe TE, Srdanov M, Gelb AB, Schlichting M, Chin K, Gulley JL. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase Ib study. J Clin Oncol. 2017 Jul 1;35(19):2117-2124. Epub 2017 Apr 4. [https://doi.org/10.1200/JCO.2016.71.6795 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493051/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28375787 PubMed] NCT01772004
+
#'''JAVELIN Solid Tumor:''' Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, Safran H, Stinchcombe TE, Srdanov M, Gelb AB, Schlichting M, Chin K, Gulley JL. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase Ib study. J Clin Oncol. 2017 Jul 1;35(19):2117-2124. Epub 2017 Apr 4. [https://doi.org/10.1200/JCO.2016.71.6795 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493051/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28375787/ PubMed] [https://clinicaltrials.gov/study/NCT01772004 NCT01772004]
 +
##'''Update:''' Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Aljumaily R, Britten CD, Dirix L, Lee KW, Taylor M, Schöffski P, Wang D, Ravaud A, Gelb AB, Xiong J, Rosen G, Gulley JL, Apolo AB. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018 Jan;19(1):51-64. Epub 2017 Dec 5. Erratum in: Lancet Oncol. 2018 Jul;19(7):e335. [https://doi.org/10.1016/s1470-2045(17)30900-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7984727/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29217288/ PubMed]
 
==Docetaxel monotherapy {{#subobject:385447|Regimen=1}}==
 
==Docetaxel monotherapy {{#subobject:385447|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen {{#subobject:b840fe|Variant=1}}===
 
===Regimen {{#subobject:b840fe|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
Line 2,434: Line 1,073:
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ Choueiri et al. 2012 (DFCI 06-116)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ Choueiri et al. 2011 (DFCI 06-116)]
 
|2007-2010
 
|2007-2010
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Docetaxel_.26_Vandetanib_99|Docetaxel & Vandetanib]]
+
|[[#Docetaxel_.26_Vandetanib_999|Docetaxel & Vandetanib]]
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 
|-
 
|-
Line 2,443: Line 1,082:
 
| rowspan="2" |2011-2014
 
| rowspan="2" |2011-2014
 
| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (C)
 
| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (C)
−
|1. [[#Docetaxel_.26_Icrucumab_77|Docetaxel & Icrucumab]]
+
|1. [[#Docetaxel_.26_Icrucumab_999|Docetaxel & Icrucumab]]
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 
|-
 
|-
Line 2,449: Line 1,088:
 
| style="background-color:#d73027" |Inferior PFS
 
| style="background-color:#d73027" |Inferior PFS
 
|-
 
|-
−
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ Bellmunt et al. 2017 (KEYNOTE-045)]
−
|2014-2015
+
|2014-11-05 to 2015-11-13
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Pembrolizumab_monotherapy_5|Pembrolizumab]]
+
|[[#Pembrolizumab_monotherapy_3|Pembrolizumab]]
 
| style="background-color:#d73027" |Inferior OS
 
| style="background-color:#d73027" |Inferior OS
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]
+
|[https://doi.org/10.1016/S0140-6736(17)33297-X Powles et al. 2017 (IMvigor211)]
−
|2015-2016
+
|2015-01-13 to 2016-02-15
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[Bladder_cancer_-_historical#Atezolizumab_monotherapy|Atezolizumab]]
+
|[[Urothelial_carcinoma_-_historical#Atezolizumab_monotherapy|Atezolizumab]]
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]
+
|[https://doi.org/10.1016/S0140-6736(17)32365-6 Petrylak et al. 2017 (RANGE)]
 
|2015-2017
 
|2015-2017
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
 
|[[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]
 
|[[#Docetaxel_.26_Ramucirumab|Docetaxel & Ramucirumab]]
 
| style="background-color:#d73027" |Inferior PFS<sup>1</sup>
 
| style="background-color:#d73027" |Inferior PFS<sup>1</sup>
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ Powles et al. 2021 (EV-301)]
 +
|2018-2020
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Enfortumab_vedotin_monotherapy|Enfortumab vedotin]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2308849 Loriot et al. 2023 (THOR cohort 1)]
 +
|2018-08-06 to NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Erdafitinib_monotherapy|Erdafitinib]]
 +
| style="background-color:#d73027" |Inferior OS
 
|-
 
|-
 
|}
 
|}
 
''<sup>1</sup>Reported efficacy for RANGE is based on the 2019 update.''<br>
 
''<sup>1</sup>Reported efficacy for RANGE is based on the 2019 update.''<br>
 
''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.''
 
''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Biomarker eligibility criteria====
 +
*THOR cohort 1: Susceptible FGFR2 or FGFR3 alterations
 +
====Prior treatment criteria====
 +
*KEYNOTE-045: Exposure to platinum-based chemotherapy
 +
*EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
 +
*THOR cohort 1: Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
+
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. [https://doi.org/10.1200/JCO.1997.15.5.1853 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9164195 PubMed]
+
#McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. [https://doi.org/10.1200/JCO.1997.15.5.1853 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9164195/ PubMed]
−
#'''DFCI 06-116:''' Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012 Feb 10;30(5):507-12. [https://doi.org/10.1200/jco.2011.37.7002 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22184381 PubMed] NCT00880334
+
#'''DFCI 06-116:''' Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012 Feb 10;30(5):507-12. Epub 2011 Dec 19. [https://doi.org/10.1200/jco.2011.37.7002 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104290/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22184381/ PubMed] [https://clinicaltrials.gov/study/NCT00880334 NCT00880334]
−
#'''JCDC:''' Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. [https://doi.org/10.1200/JCO.2015.65.0218 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26926681 PubMed] NCT01282463
+
#'''JCDC:''' Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. [https://doi.org/10.1200/JCO.2015.65.0218 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26926681/ PubMed] [https://clinicaltrials.gov/study/NCT01282463 NCT01282463]
−
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436
+
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://doi.org/10.1056/NEJMoa1613683 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28212060/ PubMed] [https://clinicaltrials.gov/study/NCT02256436 NCT02256436]
−
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]
+
##'''HRQoL analysis:''' Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. [https://doi.org/10.1200/jco.2017.76.9562 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29590008/ PubMed]
−
#'''RANGE:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28916371 PubMed] NCT02426125
+
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707/ PubMed]
−
##'''Update:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30668-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31753727 PubMed]
+
##'''Pooled update:''' Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. [https://doi.org/10.1016/j.annonc.2022.11.012 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36494006/ PubMed]
−
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29268948 PubMed] NCT02302807
+
#'''RANGE:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. [https://doi.org/10.1016/S0140-6736(17)32365-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28916371/ PubMed] [https://clinicaltrials.gov/study/NCT02426125 NCT02426125]
−
#'''SWOG S1937:''' NCT04579224
+
##'''Update:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. [https://doi.org/10.1016/S1470-2045(19)30668-0 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31753727/ PubMed]
−
#'''TROPiCS-04:''' NCT04527991
+
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://doi.org/10.1016/S0140-6736(17)33297-X link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29268948/ PubMed] [https://clinicaltrials.gov/study/NCT02302807 NCT02302807]
 +
#'''EV-301:''' Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. [https://doi.org/10.1056/NEJMoa2035807 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33577729/ PubMed] [https://clinicaltrials.gov/study/NCT03474107 NCT03474107]
 +
##'''Update:''' Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. [https://doi.org/10.1016/j.annonc.2023.08.016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37678672/ PubMed]
 +
##'''HRQoL analysis:''' Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. [https://doi.org/10.1016/j.eururo.2024.01.007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38418343/ PubMed]
 +
#'''THOR cohort 1:''' Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. [https://doi.org/10.1056/nejmoa2308849 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37870920/ PubMed] [https://clinicaltrials.gov/study/NCT03390504 NCT03390504]
 +
#'''SWOG S1937:''' [https://clinicaltrials.gov/study/NCT04579224 NCT04579224]
 +
#'''TROPiCS-04:''' [https://clinicaltrials.gov/study/NCT04527991 NCT04527991]
 +
 
 
==Docetaxel & Ramucirumab {{#subobject:385447|Regimen=1}}==
 
==Docetaxel & Ramucirumab {{#subobject:385447|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen {{#subobject:b840fe|Variant=1}}===
 
===Regimen {{#subobject:b840fe|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2015.65.0218 Petrylak et al. 2016 (JCDC)]
+
|rowspan=2|[https://doi.org/10.1200/JCO.2015.65.0218 Petrylak et al. 2016 (JCDC)]
−
|2011-2014
+
|rowspan=2|2011-2014
−
| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
+
|rowspan=2 style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
−
|[[#Docetaxel_monotherapy|Docetaxel]]
+
|1. [[#Docetaxel_monotherapy|Docetaxel]]
−
| style="background-color:#1a9850" |Superior PFS
+
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 5.4 vs 2.8 mo<br>(sHR 0.39, 95% CI 0.235-0.64)
 +
|-
 +
|2. [[#Docetaxel_.26_Icrucumab_777|Docetaxel & Icrucumab]]
 +
| style="background-color:#d3d3d3" |Not reported
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext Petrylak et al. 2017 (RANGE)]
+
|[https://doi.org/10.1016/S0140-6736(17)32365-6 Petrylak et al. 2017 (RANGE)]
 
|2015-2017
 
|2015-2017
 
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
|[[#Docetaxel_monotherapy|Docetaxel]]
 
|[[#Docetaxel_monotherapy|Docetaxel]]
−
| style="background-color:#1a9850" |Superior PFS<sup>1</sup> <br>(HR 0.70, 95% CI 0.57-0.85)
+
| style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>(HR 0.70, 95% CI 0.57-0.85)
 
|-
 
|-
 
|}
 
|}
 
''<sup>1</sup>Reported efficacy for RANGE is based on the 2019 update.''
 
''<sup>1</sup>Reported efficacy for RANGE is based on the 2019 update.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
Line 2,516: Line 1,185:
 
*[[Ramucirumab (Cyramza)]] 10 mg/kg IV once on day 1
 
*[[Ramucirumab (Cyramza)]] 10 mg/kg IV once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#'''JCDC:''' Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. [https://doi.org/10.1200/JCO.2015.65.0218 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26926681 PubMed] NCT01282463
+
#'''JCDC:''' Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. [https://doi.org/10.1200/JCO.2015.65.0218 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26926681/ PubMed] [https://clinicaltrials.gov/study/NCT01282463 NCT01282463]
−
#'''RANGE:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32365-6/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28916371 PubMed] NCT02426125
+
#'''RANGE:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. [https://doi.org/10.1016/S0140-6736(17)32365-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28916371/ PubMed] [https://clinicaltrials.gov/study/NCT02426125 NCT02426125]
−
##'''Update:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30668-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31753727 PubMed]
+
##'''Update:''' Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. [https://doi.org/10.1016/S1470-2045(19)30668-0 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946880/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31753727/ PubMed]
−
==Erdafitinib monotherapy {{#subobject:dbc30d|Regimen=1}}==
+
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
==Enfortumab vedotin & Pembrolizumab {{#subobject:dbi8bd|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:jeq057|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 +
!style="width: 25%"|Study
 +
!style="width: 25%"|Dates of enrollment
 +
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[[#top|back to top]]
+
|[https://doi.org/10.1200/jco.22.01643 Hoimes et al. 2022 (EV-103)]
 +
|2017-2020
 +
| style="background-color:#91cf61" |Phase 1b/2 (RT)
 +
|ORR: 73.3%<br>CR: 15.6%
 
|}
 
|}
−
===Regimen {{#subobject:473057|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Antibody-drug conjugate therapy====
 +
*[[Enfortumab vedotin (Padcev)]] 1.25 mg/kg IV once per day on days 1 & 8
 +
 
 +
====Immunotherapy====
 +
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 +
 
 +
'''21-day cycles'''
 +
</div></div>
 +
===References===
 +
#'''EV-103:''' Hoimes CJ, Flaig TW, Milowsky MI, Friedlander TW, Bilen MA, Gupta S, Srinivas S, Merchan JR, McKay RR, Petrylak DP, Sasse C, Moreno BH, Yu Y, Carret AS, Rosenberg JE. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023 Jan 1;41(1):22-31. Epub 2022 Aug 30. [https://doi.org/10.1200/jco.22.01643 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36041086/ PubMed] [http://clinicaltrials.gov/show/NCT03288545 NCT03288545]
 +
 
 +
==Erdafitinib monotherapy {{#subobject:dbc30d|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:473057|Variant=1}}===
 
{| class="wikitable" style="color:white; background-color:#404040"
 
{| class="wikitable" style="color:white; background-color:#404040"
 
|<small>'''FDA-recommended dose'''</small>
 
|<small>'''FDA-recommended dose'''</small>
Line 2,532: Line 1,226:
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
−
!style="width: 25%"|Years of enrollment
+
!style="width: 25%"|Dates of enrollment
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1817323 Loriot et al. 2019 (BLC2001)]
+
|[https://doi.org/10.1056/NEJMoa1817323 Loriot et al. 2019 (BLC2001)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-276-1 <span style="color:white;">ESMO-MCBS (1)</span>]'''
 +
|-
 +
|} -->
 
|2015-2018
 
|2015-2018
 
| style="background-color:#91cf61" |Phase 2 (RT)
 
| style="background-color:#91cf61" |Phase 2 (RT)
Line 2,542: Line 1,240:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 
====Biomarker eligibility criteria====
 
====Biomarker eligibility criteria====
 
*Alterations: FGFR3 mutation, FGFR2 fusion, or FGFR3 fusion
 
*Alterations: FGFR3 mutation, FGFR2 fusion, or FGFR3 fusion
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Erdafitinib (Balversa)]] 8 mg PO once per day
+
*[[Erdafitinib (Balversa)]] as follows:
−
**If serum phosphorus level and tolerability are acceptable at days 14 to 21, increase to 9 mg PO once per day
+
**Cycle 1: 8 mg PO once per day on days 1 to 21, then 9 mg PO once per day on days 22 to 28 if serum phosphorus level and tolerability are acceptable
−
**Additional dose adjustments per package insert
+
**Cycle 2 onwards: 9 mg PO once per day on days 1 to 28
 
'''28-day cycles'''
 
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:47gh17|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2308849 Loriot et al. 2023 (THOR cohort 1)]
 +
|2018-08-06 to NR
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 +
|1a. [[#Docetaxel_monotherapy|Docetaxel]]<br>1b. [[#Vinflunine_monotherapy|Vinflunine]]
 +
| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 12.1 vs 7.8 mo<br>(HR 0.64, 95% CI 0.47-0.88)
 +
|-
 +
|}
 +
''Note: The details of pharmacodynamic guidance were not described in the manuscript.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Biomarker eligibility criteria====
 +
*Susceptible FGFR2 or FGFR3 alterations
 +
====Prior treatment criteria====
 +
*Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Erdafitinib (Balversa)]] as follows:
 +
**Cycle 1: 8 mg PO once per day on days 1 to 13, then 9 mg PO once per day on days 14 to 21, guided by pharmacodynamics
 +
**Cycle 2 onwards: 9 mg PO once per day on days 1 to 21
 +
'''21-day cycles'''
 +
</div></div>
 +
 
===References===
 
===References===
−
#'''BLC2001:''' Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Zhong B, Stuyckens K, Santiago-Walker A, De Porre P, O'Hagan A, Avadhani A, Siefker-Radtke AO; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348. [https://www.nejm.org/doi/full/10.1056/NEJMoa1817323 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31340094 PubMed] NCT02365597
+
#'''BLC2001:''' Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Zhong B, Stuyckens K, Santiago-Walker A, De Porre P, O'Hagan A, Avadhani A, Siefker-Radtke AO; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348. [https://doi.org/10.1056/NEJMoa1817323 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31340094/ PubMed] [https://clinicaltrials.gov/study/NCT02365597 NCT02365597]
−
==Gemcitabine & Paclitaxel {{#subobject:ecfc0d|Regimen=1}}==
+
##'''Update:''' Siefker-Radtke AO, Necchi A, Park SH, García-Donas J, Huddart RA, Burgess EF, Fleming MT, Rezazadeh Kalebasty A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Akapame S, Santiago-Walker AE, Monga M, O'Hagan A, Loriot Y; BLC2001 Study Group. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol. 2022 Feb;23(2):248-258. Epub 2022 Jan 11. [https://doi.org/10.1016/s1470-2045(21)00660-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35030333/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
#'''THOR cohort 1:''' Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. [https://doi.org/10.1056/nejmoa2308849 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37870920/ PubMed] [https://clinicaltrials.gov/study/NCT03390504 NCT03390504]
 +
#'''THOR cohort 2:''' Siefker-Radtke AO, Matsubara N, Park SH, Huddart RA, Burgess EF, Özgüroğlu M, Valderrama BP, Laguerre B, Basso U, Triantos S, Akapame S, Kean Y, Deprince K, Mukhopadhyay S, Loriot Y; THOR cohort 2 investigators. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Ann Oncol. 2024 Jan;35(1):107-117. Epub 2023 Oct 21. [https://doi.org/10.1016/j.annonc.2023.10.003 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37871702/ PubMed] [https://clinicaltrials.gov/study/NCT03390504 NCT03390504]
 +
 
 +
==Gemcitabine monotherapy {{#subobject:ec25gd|Regimen=1}}==
 +
{| class="wikitable" style="color:white; background-color:#9e4244"
 +
|<small>'''AIM pathway regimen 2022-08-01'''</small>
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:3gaen7|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1016/s0959-8049(98)00030-6 Lorusso et al. 1998]
 +
|NR in abstract
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15
 +
'''28-day cycles'''
 +
</div></div>
 +
===References===
 +
# Lorusso V, Pollera CF, Antimi M, Luporini G, Gridelli C, Frassineti GL, Oliva C, Pacini M, De Lena M; Italian Co-operative Group on Bladder Cancer. A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Eur J Cancer. 1998 Jul;34(8):1208-12. [https://doi.org/10.1016/s0959-8049(98)00030-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9849481/ PubMed]
 +
==Gemcitabine & Paclitaxel {{#subobject:ecfc0d|Regimen=1}}==
 
GP: '''<u>G</u>'''emcitabine & '''<u>P</u>'''aclitaxel
 
GP: '''<u>G</u>'''emcitabine & '''<u>P</u>'''aclitaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #1, gemcitabine 2 out of 3 weeks {{#subobject:384057|Variant=1}}===
 
===Regimen variant #1, gemcitabine 2 out of 3 weeks {{#subobject:384057|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
Line 2,572: Line 1,330:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8
 
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8
 
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
 
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
 
'''21-day cycle for up to 6 cycles'''
 
'''21-day cycle for up to 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #2, weekly gemcitabine {{#subobject:9aa3e0|Variant=1}}===
 
===Regimen variant #2, weekly gemcitabine {{#subobject:9aa3e0|Variant=1}}===
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
−
!style="width: 25%"|Years of enrollment
+
!style="width: 25%"|Dates of enrollment
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
Line 2,585: Line 1,346:
 
|[https://doi.org/10.1200/jco.2001.19.12.3018 Meluch et al. 2001]
 
|[https://doi.org/10.1200/jco.2001.19.12.3018 Meluch et al. 2001]
 
|1997-1999
 
|1997-1999
−
| style="background-color:#ffffbe" |Phase 2, <20 pts in this subgroup
+
| style="background-color:#ffffbe" |Phase 2, fewer than 20 pts in this subgroup
 
| style="background-color:#8c96c6" |ORR: 47%
 
| style="background-color:#8c96c6" |ORR: 47%
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1
 
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1
 
'''21-day cycle for up to 6 cycles'''
 
'''21-day cycle for up to 6 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. [https://doi.org/10.1200/jco.2001.19.12.3018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408496 PubMed]
+
#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. [https://doi.org/10.1200/jco.2001.19.12.3018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408496/ PubMed]
−
#'''AUO AB 20/99:''' Albers P, Park SI, Niegisch G, Fechner G, Steiner U, Lehmann J, Heimbach D, Heidenreich A, Fimmers R, Siener R; AUO Bladder Cancer Group. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Ann Oncol. 2011 Feb;22(2):288-94. Epub 2010 Aug 2. [https://doi.org/10.1093/annonc/mdq398 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20682548 PubMed]
+
#'''AUO AB 20/99:''' Albers P, Park SI, Niegisch G, Fechner G, Steiner U, Lehmann J, Heimbach D, Heidenreich A, Fimmers R, Siener R; AUO Bladder Cancer Group. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Ann Oncol. 2011 Feb;22(2):288-94. Epub 2010 Aug 2. [https://doi.org/10.1093/annonc/mdq398 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20682548/ PubMed]
 
==MVAC {{#subobject:373ed3|Regimen=1}}==
 
==MVAC {{#subobject:373ed3|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin
 
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin, '''<u>C</u>'''isplatin
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:af2e64|Variant=1}}===
 
===Regimen {{#subobject:af2e64|Variant=1}}===
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
−
!style="width: 25%"|Years of enrollment
+
!style="width: 25%"|Dates of enrollment
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
Line 2,615: Line 1,375:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
 
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 15, 22
Line 2,620: Line 1,381:
 
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2
 
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once on day 2
 
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
 
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 2
−
'''28-day cycles''' (number of cycles and criteria to continue therapy varies depending on reference)
+
'''28-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#Han KS, Joung JY, Kim TS, Jeong IG, Seo HK, Chung J, Lee KH. Methotrexate, vinblastine, doxorubicin and cisplatin combination regimen as salvage chemotherapy for patients with advanced or metastatic transitional cell carcinoma after failure of gemcitabine and cisplatin chemotherapy. Br J Cancer. 2008 Jan 15;98(1):86-90. Epub 2007 Dec 18. [https://doi.org/10.1038/sj.bjc.6604113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359702/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18087289 PubMed]
+
#Han KS, Joung JY, Kim TS, Jeong IG, Seo HK, Chung J, Lee KH. Methotrexate, vinblastine, doxorubicin and cisplatin combination regimen as salvage chemotherapy for patients with advanced or metastatic transitional cell carcinoma after failure of gemcitabine and cisplatin chemotherapy. Br J Cancer. 2008 Jan 15;98(1):86-90. Epub 2007 Dec 18. [https://doi.org/10.1038/sj.bjc.6604113 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359702/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18087289/ PubMed]
 +
 
 
==Nivolumab monotherapy {{#subobject:86b89c|Regimen=1}}==
 
==Nivolumab monotherapy {{#subobject:86b89c|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
+
===Regimen variant #1, weight-based {{#subobject:beb7fa|Variant=1}}===
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:beb7fa|Variant=1}}===
 
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
−
!style="width: 25%"|Years of enrollment
+
!style="width: 25%"|Dates of enrollment
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30065-7/fulltext Sharma et al. 2017 (CheckMate 275)]
+
|[https://doi.org/10.1016/S1470-2045(17)30065-7 Sharma et al. 2017 (CheckMate 275)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-240-1 <span style="color:white;">ESMO-MCBS (1)</span>]'''
 +
|-
 +
|} -->
 
|2015
 
|2015
 
| style="background-color:#91cf61" |Phase 2 (RT)
 
| style="background-color:#91cf61" |Phase 2 (RT)
−
|19.6% overall<br>PD-L1 expression ≥5%: 28.4%<br>PD-L1 expression ≥1%: 23.8%<br>PD-L1 expression <1%: 16.1%
+
|19.6% overall<br>PD-L1 expression at least 5%: 28.4%<br>PD-L1 expression at least 1%: 23.8%<br>PD-L1 expression less than 1%: 16.1%
 
|-
 
|-
 
|}
 
|}
−
====Preceding treatment====
+
''Note: this is the dosing used in the study but is not the FDA-recommended dose.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 
*At least one [[Regimen_classes#Platinum-based_regimen|platinum-based therapy]], with progression
 
*At least one [[Regimen_classes#Platinum-based_regimen|platinum-based therapy]], with progression
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunotherapy====
 
====Immunotherapy====
 
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
 
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
−
**''The FDA-approved dose which is listed in the package insert is 240 mg IV over 60 minutes once on day 1''
 
 
'''14-day cycles'''
 
'''14-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, flat dosing {{#subobject:beb6ea|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Nivolumab (Opdivo)]] 240 IV over 60 minutes once on day 1
 +
'''14-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#'''CheckMate 275:''' Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, Arranz JÁ, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017 Mar;18(3):312-322. Epub 2017 Jan 25. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30065-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/28131785 PubMed] NCT02387996
+
#'''CheckMate 275:''' Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, Arranz JÁ, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017 Mar;18(3):312-322. Epub 2017 Jan 25. [https://doi.org/10.1016/S1470-2045(17)30065-7 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28131785/ PubMed] [https://clinicaltrials.gov/study/NCT02387996 NCT02387996]
−
##'''Update:''' Galsky MD, Saci A, Szabo PM, Han GC, Grossfeld G, Collette S, Siefker-Radtke A, Necchi A, Sharma P. Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275. Clin Cancer Res. 2020 Jun 12. Epub ahead of print. [https://doi.org/10.1158/1078-0432.ccr-19-4162 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32532789 PubMed]
+
##'''Update:''' Galsky MD, Saci A, Szabo PM, Han GC, Grossfeld G, Collette S, Siefker-Radtke A, Necchi A, Sharma P. Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275. Clin Cancer Res. 2020 Oct 1;26(19):5120-5128. Epub 2020 Jun 12. [https://doi.org/10.1158/1078-0432.ccr-19-4162 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8166422/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32532789/ PubMed]
 +
 
 
==nab-Paclitaxel monotherapy {{#subobject:fec6dd|Regimen=1}}==
 
==nab-Paclitaxel monotherapy {{#subobject:fec6dd|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen {{#subobject:7dc525|Variant=1}}===
 
===Regimen {{#subobject:7dc525|Variant=1}}===
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
−
!style="width: 25%"|Years of enrollment
+
!style="width: 25%"|Dates of enrollment
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70162-1/fulltext Ko et al. 2013]
+
|[https://doi.org/10.1016/S1470-2045(13)70162-1 Ko et al. 2013 (ABX207-GU07CA)]
 
|2008-2010
 
|2008-2010
 
| style="background-color:#91cf61" |Phase 2
 
| style="background-color:#91cf61" |Phase 2
Line 2,668: Line 1,445:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 260 mg/m<sup>2</sup> IV once on day 1
 
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 260 mg/m<sup>2</sup> IV once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
−
====Dose modifications====
+
</div>
−
*"Two dose reductions were permitted, to 240 mg/m<sup>2</sup> and then to 180 mg/m<sup>2</sup>. When further dose reductions were required, study treatment was discontinued. Patients with febrile neutropenia, or delay of cycle because of persistent neutropenia, ANC of less than 500/uL for 1 week, or grade 3 or 4 thrombocytopenia required dose reductions. When sensory neuropathy of grade 2 or higher occurred, study drug was withheld until resolution to grade 2 or better, then reinstituted at the next lower dose. When mucositis or diarrhea of grade 3 or higher occurred, study drug was withheld until resolution to grade 1 or better, then reinstituted at the next lower dose. Patients with mucositis or diarrhea of grade 4 were removed from the trial."
+
<div class="toccolours" style="background-color:#fff2ae">
 +
====Dose and schedule modifications====
 +
*"Two dose reductions were permitted, to 240 mg/m<sup>2</sup> and then to 180 mg/m<sup>2</sup>. When further dose reductions were required, study treatment was discontinued. Patients with febrile neutropenia, or delay of cycle because of persistent neutropenia, ANC of less than 500/μL for 1 week, or grade 3 or 4 thrombocytopenia required dose reductions. When sensory neuropathy of grade 2 or higher occurred, study drug was withheld until resolution to grade 2 or better, then reinstituted at the next lower dose. When mucositis or diarrhea of grade 3 or higher occurred, study drug was withheld until resolution to grade 1 or better, then reinstituted at the next lower dose. Patients with mucositis or diarrhea of grade 4 were removed from the trial."
 +
</div></div>
 
===References===
 
===References===
−
#Ko YJ, Canil CM, Mukherjee SD, Winquist E, Elser C, Eisen A, Reaume MN, Zhang L, Sridhar SS. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 2013 Jul;14(8):769-76. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70162-1/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23706985 PubMed] NCT00683059
+
#'''ABX207-GU07CA:''' Ko YJ, Canil CM, Mukherjee SD, Winquist E, Elser C, Eisen A, Reaume MN, Zhang L, Sridhar SS. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 2013 Jul;14(8):769-76. Epub 2013 May 22. [https://doi.org/10.1016/S1470-2045(13)70162-1 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/23706985/ PubMed] [https://clinicaltrials.gov/study/NCT00683059 NCT00683059]
 
==Paclitaxel monotherapy {{#subobject:fec6dd|Regimen=1}}==
 
==Paclitaxel monotherapy {{#subobject:fec6dd|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable" style="color:white; background-color:#9e4244"
 +
|<small>'''AIM pathway regimen 2022-08-01'''</small>
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #1, q3wks {{#subobject:9fddc0|Variant=1}}===
 
===Regimen variant #1, q3wks {{#subobject:9fddc0|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ Bellmunt et al. 2017 (KEYNOTE-045)]
−
|2014-2015
+
|2014-11-05 to 2015-11-13
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Pembrolizumab_monotherapy_5|Pembrolizumab]]
+
|[[#Pembrolizumab_monotherapy_3|Pembrolizumab]]
 
| style="background-color:#d73027" |Inferior OS
 
| style="background-color:#d73027" |Inferior OS
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]
+
|[https://doi.org/10.1016/S0140-6736(17)33297-X Powles et al. 2017 (IMvigor211)]
−
|2015-2016
+
|2015-01-13 to 2016-02-15
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[Bladder_cancer_-_historical#Atezolizumab_monotherapy|Atezolizumab]]
+
|[[Urothelial_carcinoma_-_historical#Atezolizumab_monotherapy|Atezolizumab]]
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ Powles et al. 2021 (EV-301)]
 +
|2018-2020
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Enfortumab_vedotin_monotherapy|Enfortumab vedotin]]
 +
| style="background-color:#d73027" |Inferior OS
 
|-
 
|-
 
|}
 
|}
 
''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm. IMvigor211 allowed up to 2 prior lines of platinum-containing chemotherapy.''
 
''Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm. IMvigor211 allowed up to 2 prior lines of platinum-containing chemotherapy.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 +
*KEYNOTE-045: Exposure to platinum-based chemotherapy
 +
*EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
+
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #2, 3 out of 4 weeks {{#subobject:524ebf|Variant=1}}===
 
===Regimen variant #2, 3 out of 4 weeks {{#subobject:524ebf|Variant=1}}===
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
−
!style="width: 25%"|Years of enrollment
+
!style="width: 25%"|Dates of enrollment
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
Line 2,718: Line 1,514:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15
 
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15
 
'''28-day cycles'''
 
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, weekly {{#subobject:525ggf|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887921/ Sideris et al. 2016]
 +
|2004-2014
 +
| style="background-color:#ffffbe" |Retrospective
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. [https://doi.org/10.1200/jco.2002.20.4.937 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11844814 PubMed]
+
#Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. [https://doi.org/10.1200/jco.2002.20.4.937 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11844814/ PubMed]
−
#'''Retrospective:''' Sideris S, Aoun F, Zanaty M, Martinez NC, Latifyan S, Awada A, Gil T. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016 Jun;4(6):1063-1067. Epub 2016 Mar 17. [https://doi.org/10.3892/mco.2016.821 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887921/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27284445 PubMed]
+
#'''Retrospective:''' Sideris S, Aoun F, Zanaty M, Martinez NC, Latifyan S, Awada A, Gil T. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016 Jun;4(6):1063-1067. Epub 2016 Mar 17. [https://doi.org/10.3892/mco.2016.821 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887921/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27284445/ PubMed]
−
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436
+
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://doi.org/10.1056/NEJMoa1613683 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28212060/ PubMed] [https://clinicaltrials.gov/study/NCT02256436 NCT02256436]
−
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]
+
##'''HRQoL analysis:''' Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. [https://doi.org/10.1200/jco.2017.76.9562 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29590008/ PubMed]
−
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29268948 PubMed] NCT02302807
+
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707/ PubMed]
−
#'''TROPiCS-04:''' NCT04527991
+
##'''Pooled update:''' Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. [https://doi.org/10.1016/j.annonc.2022.11.012 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36494006/ PubMed]
 +
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://doi.org/10.1016/S0140-6736(17)33297-X link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29268948/ PubMed] [https://clinicaltrials.gov/study/NCT02302807 NCT02302807]
 +
#'''EV-301:''' Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. [https://doi.org/10.1056/NEJMoa2035807 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33577729/ PubMed] [https://clinicaltrials.gov/study/NCT03474107 NCT03474107]
 +
##'''Update:''' Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. [https://doi.org/10.1016/j.annonc.2023.08.016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37678672/ PubMed]
 +
##'''HRQoL analysis:''' Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. [https://doi.org/10.1016/j.eururo.2024.01.007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38418343/ PubMed]
 +
#'''TROPiCS-04:''' [https://clinicaltrials.gov/study/NCT04527991 NCT04527991]
 +
 
 
==Pembrolizumab monotherapy {{#subobject:b0cd2a|Regimen=1}}==
 
==Pembrolizumab monotherapy {{#subobject:b0cd2a|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable" style="color:white; background-color:#9e4244"
 +
|<small>'''AIM pathway regimen 2022-08-01'''</small>
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:8aec07|Variant=1}}===
 
===Regimen {{#subobject:8aec07|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ Bellmunt et al. 2017 (KEYNOTE-045)]
−
|2014-2015
+
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-278-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
 +
|-
 +
|} -->
 +
|2014-11-05 to 2015-11-13
 
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
−
|Investigator's choice of:<br> 1. [[#Docetaxel_monotherapy|Docetaxel]]<br> 2. [[#Paclitaxel_monotherapy|Paclitaxel]]<br> 3. [[#Vinflunine_monotherapy|Vinflunine]]
+
|Investigator's choice of:<br>1a. [[#Docetaxel_monotherapy|Docetaxel]]<br>1b. [[#Paclitaxel_monotherapy|Paclitaxel]]<br>1c. [[#Vinflunine_monotherapy|Vinflunine]]
−
| style="background-color:#1a9850" |Superior OS <br>Median OS: 10 mo vs 7 mo <br>(HR 0.73, 95% CI 0.59-0.91)
+
| style="background-color:#1a9850" |Superior OS (co-primary endpoint)<br>Median OS: 10 vs 7 mo <br>(HR 0.73, 95% CI 0.59-0.91)
 +
|-
 +
|[https://doi.org/10.1016/j.annonc.2023.10.003 Siefker-Radtke et al. 2023 (THOR cohort 2)]
 +
|2018-04-26 to NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Erdafitinib_monotherapy|Erdafitinib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 
====Biomarker eligibility criteria====
 
====Biomarker eligibility criteria====
−
For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.
+
*THOR cohort 2: Susceptible FGFR2 or FGFR3 alterations
 +
====Eligibility criteria====
 +
*KEYNOTE-045: For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) at least 10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.
 +
====Prior treatment criteria====
 +
*KEYNOTE-045: Exposure to platinum-based chemotherapy
 +
*THOR cohort 2: Exposure to one prior treatment that did NOT include an anti-PD-1 antibody or anti-PD-L1 antibody (anti-PD-(L)1-naive).
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunotherapy====
 
====Immunotherapy====
−
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+
*[[Pembrolizumab (Keytruda)]] 200 mg IV over 30 minutes once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div></div>
 +
 
===References===
 
===References===
−
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436
+
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://doi.org/10.1056/NEJMoa1613683 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28212060/ PubMed] [https://clinicaltrials.gov/study/NCT02256436 NCT02256436]
−
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]
+
##'''HRQoL analysis:''' Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. [https://doi.org/10.1200/jco.2017.76.9562 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29590008/ PubMed]
 +
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707/ PubMed]
 +
##'''Pooled update:''' Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. [https://doi.org/10.1016/j.annonc.2022.11.012 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36494006/ PubMed]
 +
#'''THOR cohort 2:''' Siefker-Radtke AO, Matsubara N, Park SH, Huddart RA, Burgess EF, Özgüroğlu M, Valderrama BP, Laguerre B, Basso U, Triantos S, Akapame S, Kean Y, Deprince K, Mukhopadhyay S, Loriot Y; THOR cohort 2 investigators. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Ann Oncol. 2024 Jan;35(1):107-117. Epub 2023 Oct 21. [https://doi.org/10.1016/j.annonc.2023.10.003 link to original article] '''cotains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37871702/ PubMed] [https://clinicaltrials.gov/study/NCT03390504 NCT03390504]
 +
 
 
==Pemetrexed monotherapy {{#subobject:fec6dd|Regimen=1}}==
 
==Pemetrexed monotherapy {{#subobject:fec6dd|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen {{#subobject:7dc525|Variant=1}}===
 
===Regimen {{#subobject:7dc525|Variant=1}}===
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
−
!style="width: 25%"|Years of enrollment
+
!style="width: 25%"|Dates of enrollment
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
Line 2,774: Line 1,617:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1
 
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006 Jul 20;24(21):3451-7. [https://doi.org/10.1200/jco.2005.03.6699 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16849761 PubMed]
+
#Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006 Jul 20;24(21):3451-7. [https://doi.org/10.1200/jco.2005.03.6699 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16849761/ PubMed]
−
==Vinflunine monotherapy {{#subobject:e40f4c|Regimen=1}}==
+
==Tislelizumab monotherapy {{#subobject:13vc7d|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:6klcv5|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://clinicaltrials.gov/study/NCT04004221 Awaiting publication (RATIONALE-204)]
 +
|2017-NR
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Tislelizumab (Baizean)]] 200 mg IV once on day 1
 +
'''21-day cycles'''
 +
</div></div>
 +
===References===
 +
# '''RATIONALE-204:''' [https://clinicaltrials.gov/study/NCT04004221 NCT04004221]
 +
==Toripalimab monotherapy {{#subobject:8ivc7d|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:6klko5|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://clinicaltrials.gov/study/NCT03113266 Awaiting publication (Junshi-JS001-009)]
 +
|2017-NR
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Toripalimab (Loqtorzi)]] 3 mg/kg IV once on day 1
 +
'''14-day cycles'''
 +
</div></div>
 +
===References===
 +
#'''Junshi-JS001-009:''' '''contains dosing details on CT.gov''' [https://clinicaltrials.gov/study/NCT03113266 NCT03113266]
 +
==Vinflunine monotherapy {{#subobject:e40f4c|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:b5b9b9|Variant=1}}===
 
===Regimen {{#subobject:b5b9b9|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 20%" |Study
 
! style="width: 20%" |Study
−
! style="width: 20%" |Years of enrollment
+
! style="width: 20%" |Dates of enrollment
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 20%" |Comparator
 
! style="width: 20%" |Comparator
Line 2,795: Line 1,677:
 
|2003-2006
 
|2003-2006
 
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|[[Bladder_cancer_-_null_regimens#Best_supportive_care_2|Best supportive care]]
+
|[[Urothelial_carcinoma_-_null_regimens#Best_supportive_care_2|Best supportive care]]
−
| style="background-color:#1a9850" |Superior OS<sup>1</sup> <br>(HR 0.72, 95% CI 0.57-0.91)
+
| style="background-color:#1a9850" |Superior OS<sup>1</sup> (primary endpoint)<br>Median OS: 6.9 vs 4.6 mo<br>(aHR 0.72, 95% CI 0.57-0.91)
 
|-
 
|-
−
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 Bellmunt et al. 2017 (KEYNOTE-045)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ Bellmunt et al. 2017 (KEYNOTE-045)]
−
|2014-2015
+
|2014-11-05 to 2015-11-13
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Pembrolizumab_monotherapy_5|Pembrolizumab]]
+
|[[#Pembrolizumab_monotherapy_3|Pembrolizumab]]
 
| style="background-color:#d73027" |Inferior OS
 
| style="background-color:#d73027" |Inferior OS
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext Powles et al. 2017 (IMvigor211)]
+
|[https://doi.org/10.1016/S0140-6736(17)33297-X Powles et al. 2017 (IMvigor211)]
−
|2015-2016
+
|2015-01-13 to 2016-02-15
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Urothelial_carcinoma_-_historical#Atezolizumab_monotherapy|Atezolizumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br>Median OS: 10.6 vs 11.1 mo<br>(HR 1.15, 95% CI 0.83-1.59)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ Powles et al. 2021 (EV-301)]
 +
|2018-2020
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Enfortumab_vedotin_monotherapy|Enfortumab vedotin]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2308849 Loriot et al. 2023 (THOR cohort 1)]
 +
|2018-08-06 to NR
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[Bladder_cancer_-_historical#Atezolizumab_monotherapy|Atezolizumab]]
+
|[[#Erdafitinib_monotherapy|Erdafitinib]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+
| style="background-color:#d73027" |Inferior OS
 
|-
 
|-
 
|}
 
|}
 
''<sup>1</sup>Reported efficacy for CA183004 is based on the 2013 update.''
 
''<sup>1</sup>Reported efficacy for CA183004 is based on the 2013 update.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Biomarker eligibility criteria====
 +
*THOR cohort 1: Susceptible FGFR2 or FGFR3 alterations
 +
====Prior treatment criteria====
 +
*KEYNOTE-045: Exposure to platinum-based chemotherapy
 +
*EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
 +
*THOR cohort 1: Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Vinflunine (Javlor)]] 320 mg/m<sup>2</sup> IV once on day 1
+
*[[Vinflunine (Javlor)]] 320 mg/m<sup>2</sup> IV over 20 minutes once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#'''CA183004:''' Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, Jagiello-Gruszfeld A, Karyakin O, Delgado FM, Hurteloup P, Winquist E, Morsli N, Salhi Y, Culine S, von der Maase H. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 20;27(27):4454-61. Epub 2009 Aug 17. Erratum in: J Clin Oncol. 2010 Jan 1;28(1):182. Winquist, Eric [added]. [https://doi.org/10.1200/JCO.2008.20.5534 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19687335 PubMed] NCT00315237
+
#'''CA183004:''' Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, Jagiello-Gruszfeld A, Karyakin O, Delgado FM, Hurteloup P, Winquist E, Morsli N, Salhi Y, Culine S, von der Maase H. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 20;27(27):4454-61. Epub 2009 Aug 17. Erratum in: J Clin Oncol. 2010 Jan 1;28(1):182. Winquist, Eric [added]. [https://doi.org/10.1200/JCO.2008.20.5534 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19687335/ PubMed] [https://clinicaltrials.gov/study/NCT00315237 NCT00315237]
−
##'''Update:''' Bellmunt J, Fougeray R, Rosenberg JE, von der Maase H, Schutz FA, Salhi Y, Culine S, Choueiri TK. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann Oncol. 2013 Jun;24(6):1466-72. Epub 2013 Feb 17. [https://doi.org/10.1093/annonc/mdt007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23419284 PubMed]
+
##'''Update:''' Bellmunt J, Fougeray R, Rosenberg JE, von der Maase H, Schutz FA, Salhi Y, Culine S, Choueiri TK. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann Oncol. 2013 Jun;24(6):1466-72. Epub 2013 Feb 17. [https://doi.org/10.1093/annonc/mdt007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23419284/ PubMed]
−
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1613683 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28212060 PubMed] NCT02256436
+
#'''KEYNOTE-045:''' Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. [https://doi.org/10.1056/NEJMoa1613683 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5635424/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28212060/ PubMed] [https://clinicaltrials.gov/study/NCT02256436 NCT02256436]
−
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707 PubMed]
+
##'''HRQoL analysis:''' Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. [https://doi.org/10.1200/jco.2017.76.9562 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29590008/ PubMed]
−
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33297-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29268948 PubMed] NCT02302807
+
##'''Update:''' Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. [https://doi.org/10.1093/annonc/mdz127 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31050707/ PubMed]
−
#'''TROPiCS-04:''' NCT04527991
+
##'''Pooled update:''' Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. [https://doi.org/10.1016/j.annonc.2022.11.012 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36494006/ PubMed]
−
=Locally advanced or metastatic disease, after platinum chemotherapy and/or immune checkpoint inhibitor=
+
#'''IMvigor211:''' Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. [https://doi.org/10.1016/S0140-6736(17)33297-X link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29268948/ PubMed] [https://clinicaltrials.gov/study/NCT02302807 NCT02302807]
 +
#'''EV-301:''' Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. [https://doi.org/10.1056/NEJMoa2035807 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33577729/ PubMed] [https://clinicaltrials.gov/study/NCT03474107 NCT03474107]
 +
##'''Update:''' Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. [https://doi.org/10.1016/j.annonc.2023.08.016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37678672/ PubMed]
 +
##'''HRQoL analysis:''' Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. [https://doi.org/10.1016/j.eururo.2024.01.007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38418343/ PubMed]
 +
#'''THOR cohort 1:''' Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. [https://doi.org/10.1056/nejmoa2308849 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37870920/ PubMed] [https://clinicaltrials.gov/study/NCT03390504 NCT03390504]
 +
#'''TROPiCS-04:''' [https://clinicaltrials.gov/study/NCT04527991 NCT04527991]
 +
 
 +
=Locally advanced or metastatic disease, refractory/intolerant to platinum chemotherapy and/or immune checkpoint inhibitor=
 
==Enfortumab vedotin monotherapy {{#subobject:dbdcad|Regimen=1}}==
 
==Enfortumab vedotin monotherapy {{#subobject:dbdcad|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable" style="color:white; background-color:#9e4244"
 +
|<small>'''AIM pathway regimen 2022-08-01'''</small>
 
|-
 
|-
−
|[[#top|back to top]]
 
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:415bc7|Variant=1}}===
 
===Regimen {{#subobject:415bc7|Variant=1}}===
 
{| class="wikitable" style="color:white; background-color:#404040"
 
{| class="wikitable" style="color:white; background-color:#404040"
Line 2,835: Line 1,747:
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
−
!style="width: 20%"|Years of enrollment
+
!style="width: 20%"|Dates of enrollment
 
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 20%"|Comparator
 
!style="width: 20%"|Comparator
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
![[Overall response rate|'''ORR''']]
 
−
!Comparator [[Overall response rate|'''ORR''']]
 
 
|-
 
|-
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784850/ Rosenberg et al. 2018 (EV-201)]
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784850/ Rosenberg et al. 2018 (EV-201)]
−
|2017-2018
+
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-275-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 +
|2017-10-08 to 2018-07-02
 
| style="background-color:#91cf61" |Phase 2 (RT)
 
| style="background-color:#91cf61" |Phase 2 (RT)
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
−
| style="background-color:#d3d3d3" |
+
|ORR: 44% (95% CI 35.2-53.2)
−
| style="background-color:#8c96c6" |44% (95% CI 35.2-53.2)
+
|-
−
| style="background-color:#d3d3d3" |
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ Powles et al. 2021 (EV-301)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-286-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJMoa2035807 Powles et al. 2021 (EV-301)]
+
|} -->
 
|2018-2020
 
|2018-2020
 
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
−
|Investigator-chosen chemotherapy:<br> 1. [[Bladder_cancer#Docetaxel_monotherapy | Docetaxel]]<br> 2. [[Bladder_cancer#Paclitaxel_monotherapy | Paclitaxel]]<br> 3. [[Bladder_cancer#Vinflunine_monotherapy | Vinflunine]]
+
|Investigator's choice of:<br>1a. [[Urothelial_carcinoma#Docetaxel_monotherapy | Docetaxel]]<br>1b. [[Urothelial_carcinoma#Paclitaxel_monotherapy | Paclitaxel]]<br>1c. [[Urothelial_carcinoma#Vinflunine_monotherapy | Vinflunine]]
−
| style="background-color:#1a9851" |Superior OS
+
| style="background-color:#1a9851" |Superior OS<sup>1</sup> (primary endpoint)<br>Median OS: 12.91 vs 8.94 mo<br>(HR 0.70, 95% CI 0.58-0.85)
−
|Intention to treat: 40.6%
 
−
|Intention to treat: 17.9%
 
 
|}
 
|}
 +
''<sup>1</sup>Reported efficacy for EV-301 is based on the 2023 update.''<br>
 +
''Note: ORR in this arm of EV-301 (ITT) was 40.6% vs 17.9 % in the control arm (ITT).''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 +
*Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Antibody-drug conjugate therapy====
 
====Antibody-drug conjugate therapy====
 
*[[Enfortumab vedotin (Padcev)]] 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1, 8, 15
 
*[[Enfortumab vedotin (Padcev)]] 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1, 8, 15
 
'''28-day cycles'''
 
'''28-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#'''EV-201:''' Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, Galsky MD, Hahn NM, Gartner EM, Pinelli JM, Liang SY, Melhem-Bertrandt A, Petrylak DP. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10;37(29): 2592-2600. Epub 2019 Jul 29. [https://doi.org/10.1200/JCO.19.01140 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784850/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31356140 Pubmed] NCT03219333
+
#'''EV-201:''' Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, Galsky MD, Hahn NM, Gartner EM, Pinelli JM, Liang SY, Melhem-Bertrandt A, Petrylak DP. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10;37(29): 2592-2600. Epub 2019 Jul 29. [https://doi.org/10.1200/JCO.19.01140 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784850/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31356140/ PubMed] [https://clinicaltrials.gov/study/NCT03219333 NCT03219333]
−
#'''EV-301:''' Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. [https://doi.org/10.1056/NEJMoa2035807 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33577729 Pubmed] NCT03474107
+
##'''Update:''' Yu EY, Petrylak DP, O'Donnell PH, Lee JL, van der Heijden MS, Loriot Y, Stein MN, Necchi A, Kojima T, Harrison MR, Hoon Park S, Quinn DI, Heath EI, Rosenberg JE, Steinberg J, Liang SY, Trowbridge J, Campbell M, McGregor B, Balar AV. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):872-882. Epub 2021 May 12. Erratum in: Lancet Oncol. 2021 Jun;22(6):e239. [https://doi.org/10.1016/s1470-2045(21)00094-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33991512/ PubMed]
 +
#'''EV-301:''' Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. [https://doi.org/10.1056/NEJMoa2035807 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8450892/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33577729/ PubMed] [https://clinicaltrials.gov/study/NCT03474107 NCT03474107]
 +
##'''Update:''' Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. [https://doi.org/10.1016/j.annonc.2023.08.016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37678672/ PubMed]
 +
##'''HRQoL analysis:''' Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. [https://doi.org/10.1016/j.eururo.2024.01.007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38418343/ PubMed]
 +
 
 
==Sacituzumab govitecan monotherapy {{#subobject:d9gacd|Regimen=1}}==
 
==Sacituzumab govitecan monotherapy {{#subobject:d9gacd|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen {{#subobject:417gu7|Variant=1}}===
 
===Regimen {{#subobject:417gu7|Variant=1}}===
 
{| class="wikitable sortable" style="color:white; background-color:#404040"
 
{| class="wikitable sortable" style="color:white; background-color:#404040"
Line 2,876: Line 1,799:
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
! style="width: 25%" |Study
 
! style="width: 25%" |Study
−
! style="width: 25%" |Years of enrollment
+
! style="width: 25%" |Dates of enrollment
 
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 
! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.20.03489 Tagawa et al. 2021 (TROPHY-U-01)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8315301/ Tagawa et al. 2021 (TROPHY-U-01)]
 
|2018-2019
 
|2018-2019
 
| style="background-color:#91cf61" |Phase 2 (RT)
 
| style="background-color:#91cf61" |Phase 2 (RT)
−
| style="background-color:#8c96c6" |ORR: 27% (95% CI 19.5-37)    
+
| style="background-color:#8c96c6" |ORR: 27% (95% CI 19.5-37)  
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 +
*Exposure to platinum-based therapy and checkpoint inhibitor, with progression
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Antibody-drug conjugate therapy====
 
====Antibody-drug conjugate therapy====
 
*[[Sacituzumab govitecan (Trodelvy)]] 10 mg/kg IV once per day on days 1 & 8
 
*[[Sacituzumab govitecan (Trodelvy)]] 10 mg/kg IV once per day on days 1 & 8
−
'''21-day cycles''' until unaccaptable toxicity or loss of clinical benefit
+
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
#'''TROPHY-U-01:''' Tagawa ST, Balar AV, Petrylak DP, Kalebasty AR, Loriot Y, Fléchon A, Jain RK, Agarwal N, Bupathi M, Barthelemy P, Beuzeboc P, Palmbos P, Kyriakopoulos CE, Pouessel D, Sternberg CN, Hong Q, Goswami T, Itri LM, Grivas P. TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. J Clin Oncol. 2021 Apr 30. Epub ahead of print. [https://doi.org/10.1200/jco.20.03489 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33929895/ Pubmed] NCT03547973
+
#'''TROPHY-U-01:''' Tagawa ST, Balar AV, Petrylak DP, Kalebasty AR, Loriot Y, Fléchon A, Jain RK, Agarwal N, Bupathi M, Barthelemy P, Beuzeboc P, Palmbos P, Kyriakopoulos CE, Pouessel D, Sternberg CN, Hong Q, Goswami T, Itri LM, Grivas P. TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. J Clin Oncol. 2021 Aug 1;39(22):2474-2485. Epub 2021 Apr 30. [https://doi.org/10.1200/jco.20.03489 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8315301/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33929895/ PubMed] [https://clinicaltrials.gov/study/NCT03547973 NCT03547973]
−
=Links=
+
##'''Update:''' Loriot Y, Petrylak DP, Rezazadeh Kalebasty A, Fléchon A, Jain RK, Gupta S, Bupathi M, Beuzeboc P, Palmbos P, Balar AV, Kyriakopoulos CE, Pouessel D, Sternberg CN, Tonelli J, Sierecki M, Zhou H, Grivas P, Barthélémy P, Tagawa ST. TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes. Ann Oncol. 2024 Apr;35(4):392-401. Epub 2024 Jan 18. [https://doi.org/10.1016/j.annonc.2024.01.002 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38244927/ PubMed]
−
*[http://www.eortc.be/tools/bladdercalculator/ EORTC Risk Tables for Predicting Recurrence and Progression in Individual Patients with Stage Ta T1 Bladder Cancer] - predicts probability of recurrence and progression in 1 to 5 years
+
#'''TROPiCs-04:''' [https://clinicaltrials.gov/study/NCT04527991 NCT04527991]
−
=Urine assays=
+
[[Category:Urothelial carcinoma regimens]]
−
''These are assays intended/being investigated as adjuncts to urine cytology and cystoscopy.''
 
−
*[https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=347921 Cxbladder (uRNA-2)], a "urine based bladder cancer test (uRNA-2) which detects RNA markers in urine."
 
−
*[http://www.scimedx.com/products/bladder_cancer/bladder_cancer.php ImmunoCyt™/uCyt+™], a cell-based detection assay which "uses fluorescent-labeled antibodies to 3 markers that are commonly found on malignant exfoliated urothelial cells."<ref>Greene KL, Berry A, Konety BR. Diagnostic Utility of the ImmunoCyt/uCyt+ Test in Bladder Cancer. Rev Urol. 2006 Fall;8(4):190-7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751037/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17192798 PubMed]</ref>
 
−
*[http://www.abbottmolecular.com/us/products/oncology/fish/bladder-cancer-urovysion.html UroVysion] (Abbott Molecular) "designed to detect aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus via fluorescence in situ hybridization (FISH) in urine specimens from persons with hematuria suspected of having bladder cancer."
 
−
=References=
 
−
<references />
 
−
[[Category:Bladder cancer regimens]]
 
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
 
[[Category:Genitourinary cancers]]
 
[[Category:Genitourinary cancers]]

Latest revision as of 17:48, 23 June 2024

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Page editor Section editor
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 Michael J. Glover, MD
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Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!.
Note: this page has recently been renamed from "Bladder cancer" to "Urothelial carcinoma" to reflect the fact that most regimens here are generic to urothelial cancer. For now, the page also has adjuvant and perioperative regimens specific to bladder cancer, but these will be moved to a dedicated bladder cancer page soon.

31 regimens on this page
47 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ESMO

NCCN

SITC

Adjuvant therapy

Nivolumab monotherapy

Regimen variant #1, q2wks

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bajorin et al. 2021 (CheckMate 274) 2016-2020 Phase 3 (E-RT-esc) Placebo Superior DFS (co-primary endpoint)
Median DFS: 20.8 vs 10.8 mo
(HR 0.70, 98.22% CI 0.55-0.90)

Preceding treatment

Immunotherapy

14-day cycle for up to 26 cycles (1 year)


Regimen variant #2, q4wks

FDA-recommended dose

Note: this is not the dose that was used in the registration study, CheckMate 274.

Preceding treatment

Immunotherapy

28-day cycle for up to 13 cycles (1 year)

References

  1. CheckMate 274: Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, Bamias A, Lebret T, Shariat SF, Park SH, Ye D, Agerbaek M, Enting D, McDermott R, Gajate P, Peer A, Milowsky MI, Nosov A, Neif Antonio J Jr, Tupikowski K, Toms L, Fischer BS, Qureshi A, Collette S, Unsal-Kacmaz K, Broughton E, Zardavas D, Koon HB, Galsky MD. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02632409
    1. HRQoL analysis: Witjes JA, Galsky MD, Gschwend JE, Broughton E, Braverman J, Nasroulah F, Maira-Arce M, Ye X, Shi L, Guo S, Hamilton M, Bajorin DF. Health-related Quality of Life with Adjuvant Nivolumab After Radical Resection for High-risk Muscle-invasive Urothelial Carcinoma: Results from the Phase 3 CheckMate 274 Trial. Eur Urol Oncol. 2022 Oct;5(5):553-563. Epub 2022 Mar 11. link to original article link to PMC article PubMed
  2. VOLGA: NCT04960709

Locally advanced or metastatic disease, first-line, platinum-ineligible

Gemcitabine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Heinzelbecker et al. 2023 (AUO-AB 22/00) 2000-07 to 2008-12 Phase 3 (C) Gemcitabine; adjuvant Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. AUO-AB 22/00: Heinzelbecker J, Spieler N, Kuehn M, Fischer C, Volkmer B, von Rundstedt F, Albers P, Becht E, Bannowsky A, Weber HM, Hofmann R, Müller M, Langbein S, Steiner G, Retz M, Kamradt J, Wagenpfeil G, Wellek S, Lehmann J, Stoeckle M. Adjuvant vs progression-triggered treatment with gemcitabine in platinum-ineligible high-risk bladder cancer patients: Long-term follow-up of a randomized phase 3 trial. Urol Oncol. 2023 Aug;41(8):356.e19-356.e30. Epub 2023 May 16. link to original article contains dosing details in manuscript PubMed NCT00146276

Pembrolizumab monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Balar et al. 2017 (KEYNOTE-052) 2015-2016 Phase 2 (RT) ORR: 24% (95% CI 20-29)

Immunotherapy

21-day cycles

References

  1. KEYNOTE-052: Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. Epub 2017 Sep 26. link to original article contains dosing details in abstract PubMed NCT02335424
    1. Update: Vuky J, Balar AV, Castellano D, O'Donnell PH, Grivas P, Bellmunt J, Powles T, Bajorin D, Hahn NM, Savage MJ, Fang X, Godwin JL, Frenkl TL, Homet Moreno B, de Wit R, Plimack ER. Long-Term Outcomes in KEYNOTE-052: Phase II Study Investigating First-Line Pembrolizumab in Cisplatin-Ineligible Patients With Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2020 Aug 10;38(23):2658-2666. Epub 2020 Jun 17. link to original article PubMed
    2. Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article PubMed
  2. LEAP-011: NCT03898180

Locally advanced or metastatic disease, first-line, platinum-eligible

Carboplatin & Gemcitabine (GCb)

GCb: Gemcitabine & Carboplatin

Regimen variant #1, AUC 4.5/1000 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Powles et al. 2020 (DANUBE) 2015-2017 Phase 3 (C) 1. Durvalumab Did not meet co-primary endpoint of OS More toxic
2. Durvalumab & Tremelimumab Might have inferior OS Not more toxic
Powles et al. 2024 (EV-302) 2020-2023 Phase 3 (C) Enfortumab vedotin & Pembrolizumab Inferior PFS/OS

Note: this was the lower bound of AUC specified by DANUBE & EV-302.

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #2, AUC 4.5/1000, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
De Santis et al. 2009 (EORTC 30986) 2001-2005 Randomized Phase 2/3 (E-de-esc) M-CAVI Did not meet primary endpoint of ORR1
ORR: 30.3% vs 41.2% 		Lower toxicity than M-CAVI
Galsky et al. 2020 (IMvigor130) 2016-2018 Phase 3 (C) 1. Atezolizumab Did not meet co-primary endpoint of OS
2a. GCb & Atezolizumab
2b. GC & Atezolizumab 		Might have inferior OS2

1Reported efficacy for EORTC 30986 is based on the 2011 update.
2Reported efficacy for IMvigor130 is based on the 2023 update.
Note: Patients in EORTC 30986 who achieved complete response were given two additional cycles of treatment.

Chemotherapy

21-day cycles


Regimen variant #3, AUC 5/1000 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Carles et al. 2000 1997-1998 Phase 2, fewer than 20 pts
Powles et al. 2020 (DANUBE) 2015-2017 Phase 3 (C) 1. Durvalumab Did not meet co-primary endpoint of OS
2. Durvalumab & Tremelimumab Might have inferior OS
Powles et al. 2021 (KEYNOTE-361) 2016-2018 Phase 3 (C) 1a. GC & Pembrolizumab
1b. GCb & Pembrolizumab 		Might have inferior OS
2. Pembrolizumab Not reported
Powles et al. 2024 (EV-302) 2020-2023 Phase 3 (C) Enfortumab vedotin & Pembrolizumab Inferior PFS/OS

Note: this was the upper bound of AUC specified by DANUBE & EV-302.

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #4, AUC 5/1250

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Dogliotti et al. 2006 2000-2002 Randomized Phase 2 (E-switch-ic) Cisplatin & Gemcitabine Did not meet primary endpoint of reduced toxicity

ORR for this arm: Intention to treat: 40% (95% CI NR)
Evaluable patients only: 56%
(95% CI: 40–72)
ORR for control arm: Intention to treat: 49% (95% CI NR)
Evaluable patients only: 66%
(95% CI: 49–80)

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. Carles J, Nogué M, Domènech M, Pérez C, Saigí E, Villadiego K, Guasch I, Ibeas R. Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function. Oncology. 2000 Jun;59(1):24-7. link to original article contains dosing details in abstract PubMed
  2. Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. link to original article contains dosing details in manuscript PubMed
  3. EORTC 30986: De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Skoneczna I, Marreaud S, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol. 2009 Nov 20;27(33):5634-9. Epub 2009 Sep 28. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00111787
    1. Update: De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Gil T, Marreaud S, Daugaard G, Skoneczna I, Collette S, Lorent J, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012 Jan 10;30(2):191-9. Epub 2011 Dec 12. link to original article link to PMC article contains dosing details in manuscript PubMed
  4. IMvigor130: Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. link to original article contains dosing details in manuscript PubMed NCT02807636
    1. Update: Grande E, Arranz JÁ, De Santis M, Bamias A, Kikuchi E, Del Muro XG, Park SH, De Giorgi U, Alekseev B, Mencinger M, Izumi K, Schutz FA, Puente J, Li JR, O'Donnell PH, Kalebasty AR, Ye D, Mariathasan S, Bene-Tchaleu F, Bernhard S, Lee C, Davis ID, Galsky MD. Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study. Lancet Oncol. 2024 Jan;25(1):29-45. Epub 2023 Dec 12. link to original article PubMed
  5. DANUBE: Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1574-1588. Epub 2020 Sep 21. link to original article PubMed NCT02516241
  6. KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article contains dosing details in abstract PubMed NCT02853305
  7. EV-302: Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. link to original article contains dosing details in manuscript PubMed NCT04223856
  8. NILE: NCT03682068
  9. RC48-C016: NCT05302284

Carboplatin & Gemcitabine (GCb) & Pembrolizumab

GCb & Pembrolizumab: Gemcitabine, Carboplatin, Pembrolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Powles et al. 2021 (KEYNOTE-361) 2016-2018 Phase 3 (E-RT-esc) 1a. GC
1b. GCb 		Might have superior OS (co-primary endpoint)
Median OS: 17 vs 14.3 mo
(HR 0.86, 95% CI 0.72-1.02)

Might have superior PFS1 (co-primary endpoint)
Median PFS: 8.3 vs 7.1 mo
(HR 0.78, 95% CI 0.65-0.3)
2. Pembrolizumab Not reported

1Reported efficacy did not meet the prespecified boundary for statistical significance.

Chemotherapy

Immunotherapy

21-day cycle for up to 35 cycles

References

  1. KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article contains dosing details in abstract PubMed NCT02853305

Carboplatin & Paclitaxel (CP)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Vaughn et al. 2002 (ECOG E2896) 1996-1999 Phase 2 ORR: 24% (95% CI 12-42)
Dreicer et al. 2004 (ECOG E4897) 1998-2001 Phase 3 (E-de-esc) MVAC Did not meet primary endpoint of OS

Note: ECOG E4897 was closed early due to poor accrual.

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. ECOG E2896: Vaughn DJ, Manola J, Dreicer R, See W, Levitt R, Wilding G. Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group. Cancer. 2002 Sep 1;95(5):1022-7. link to original article contains dosing details in abstract PubMed
  2. ECOG E4897: Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. link to original article contains dosing details in manuscript PubMed NCT00003376

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine & Cisplatin
GP: Gemcitabine & Platinol (Cisplatin)

AIM pathway regimen 2022-08-01

Regimen variant #1, 70/2000; q3wk x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rosenberg et al. 2021 (CALGB 90601) 2009-2014 Phase 3 (C) GC & Bevacizumab Might have inferior OS
Powles et al. 2020 (DANUBE) 2015-2017 Phase 3 (C) 1. Durvalumab Did not meet co-primary endpoint of OS
2. Durvalumab & Tremelimumab Might have inferior OS
Powles et al. 2021 (KEYNOTE-361) 2016-2018 Phase 3 (C) 1a. GC & Pembrolizumab
1b. GCb & Pembrolizumab 		Might have inferior OS
2. Pembrolizumab Not reported
van der Heijden et al. 2023 (CheckMate 901 part 1) 2018-01-30 to 2022-09-28 Phase 3 (C) GC & Nivolumab Seems to have inferior OS (co-primary endpoint)
Powles et al. 2024 (EV-302) 2020-2023 Phase 3 (C) Enfortumab vedotin & Pembrolizumab Inferior PFS/OS

Chemotherapy

Supportive therapy

  • 2 liters of fluid and "appropriate antiemetic therapy" given with cisplatin
  • "blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"

21-day cycle for 6 cycles


Regimen variant #2, 70/2000; q3wk, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Soto Parra et al. 2002 1998-2000 Randomized Phase 2, fewer than 20 pts in this subgroup (E-esc) Cisplatin & Gemcitabine; q4wk Not reported
Galsky et al. 2020 (IMvigor130) 2016-2018 Phase 3 (C) 1. Atezolizumab Did not meet co-primary endpoint of OS
2a. GCb & Atezolizumab
2b. GC & Atezolizumab 		Might have inferior OS1

1Reported efficacy for IMvigor130 is based on the 2023 update.

Chemotherapy

Supportive therapy

  • 2 liters of fluid and "appropriate antiemetic therapy" given with cisplatin
  • "blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"

21-day cycles


Regimen variant #3, 70/2500; q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Dogliotti et al. 2006 2000-2002 Randomized Phase 2 (C) Carboplatin & Gemcitabine Did not meet primary endpoint of reduced toxicity
Powles et al. 2020 (DANUBE) 2015-2017 Phase 3 (C) 1. Durvalumab Did not meet co-primary endpoint of OS More toxic
2. Durvalumab & Tremelimumab Might have inferior OS Not more toxic

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #4, 70/3000; q4wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von der Maase et al. 2000 1996-1998 Phase 3 (E-de-esc) MVAC Did not meet primary endpoint of OS
Soto Parra et al. 2002 1998-2000 Randomized Phase 2, fewer than 20 pts in this subgroup (E-de-esc) Cisplatin & Gemcitabine; q3wk Not reported
Bellmunt et al. 2012 (EORTC 30987) 2001-2004 Phase 3 (C) PCG Might have inferior OS
Sternberg et al. 2013 (CILAB) 2008-2010 Phase 3 (C) Cisplatin & Larotaxel Did not meet primary endpoint of OS
Powles et al. 2020 (DANUBE) 2015-2017 Phase 3 (C) 1. Durvalumab Did not meet co-primary endpoint of OS
2. Durvalumab & Tremelimumab Might have inferior OS

Note: Only a minority of patients in Soto Parra et al. 2002 had bladder cancer. The majority of patients had non-small cell lung cancer.

Chemotherapy

Supportive therapy

  • Per Soto Parra et al. 2002:
  • 2 liters of fluid and "appropriate antiemetic therapy" given with cisplatin
  • "blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"

28-day cycle for up to 6 cycles

References

  1. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. link to original article contains dosing details in manuscript PubMed
    1. Update: von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. link to original article PubMed
  2. Soto Parra H, Cavina R, Latteri F, Sala A, Dambrosio M, Antonelli G, Morenghi E, Alloisio M, Ravasi G, Santoro A. Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol. 2002 Jul;13(7):1080-6. link to original article contains dosing details in manuscript PubMed
  3. Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. link to original article contains dosing details in manuscript PubMed
  4. EORTC 30987: Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00022191
  5. CILAB: Sternberg CN, Skoneczna IA, Castellano D, Theodore C, Blais N, Voog E, Bellmunt J, Peters F, Le-Guennec S, Cerbone L, Risse ML, Machiels JP. Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB). Oncology. 2013;85(4):208-15. Epub 2013 Sep 24. link to original article contains dosing details in abstract PubMed NCT00625664
  6. IMvigor130: Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. link to original article contains dosing details in manuscript PubMed NCT02807636
    1. Update: Grande E, Arranz JÁ, De Santis M, Bamias A, Kikuchi E, Del Muro XG, Park SH, De Giorgi U, Alekseev B, Mencinger M, Izumi K, Schutz FA, Puente J, Li JR, O'Donnell PH, Kalebasty AR, Ye D, Mariathasan S, Bene-Tchaleu F, Bernhard S, Lee C, Davis ID, Galsky MD. Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study. Lancet Oncol. 2024 Jan;25(1):29-45. Epub 2023 Dec 12. link to original article PubMed
  7. DANUBE: Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1574-1588. Epub 2020 Sep 21. link to original article PubMed NCT02516241
  8. KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article contains dosing details in abstract PubMed NCT02853305
  9. CALGB 90601: Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, Stadler WM, Teply BA, Picus J, Tagawa ST, Katragadda S, Vaena D, Misleh J, Hoimes C, Plimack ER, Flaig TW, Dreicer R, Bajorin D, Hahn O, Small EJ, Morris MJ. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J Clin Oncol. 2021 Aug 1;39(22):2486-2496. Epub 2021 May 14. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00942331
  10. CheckMate 901 part 1: van der Heijden MS, Sonpavde G, Powles T, Necchi A, Burotto M, Schenker M, Sade JP, Bamias A, Beuzeboc P, Bedke J, Oldenburg J, Chatta G, Ürün Y, Ye D, He Z, Valderrama BP, Ku JH, Tomita Y, Filian J, Wang L, Purcea D, Patel MY, Nasroulah F, Galsky MD; CheckMate 901 Trial Investigators. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023 Nov 9;389(19):1778-1789. Epub 2023 Oct 22. link to original article contains dosing details in supplement PubMed NCT03036098
  11. EV-302: Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. link to original article contains dosing details in manuscript PubMed NCT04223856
  12. NILE: NCT03682068
  13. RC48-C016: NCT05302284

Cisplatin & Gemcitabine (GC) & Bevacizumab

GCB: Gemcitabine, Cisplatin, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rosenberg et al. 2021 (CALGB 90601) 2009-2014 Phase 3 (E-esc) GC Might have superior OS (primary endpoint)
Median OS: 14.5 vs 14.3 mo
(HR 0.87, 95% CI 0.72-1.05)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. CALGB 90601: Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, Stadler WM, Teply BA, Picus J, Tagawa ST, Katragadda S, Vaena D, Misleh J, Hoimes C, Plimack ER, Flaig TW, Dreicer R, Bajorin D, Hahn O, Small EJ, Morris MJ. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J Clin Oncol. 2021 Aug 1;39(22):2486-2496. Epub 2021 May 14. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00942331

Cisplatin & Gemcitabine (GC) & Nivolumab

GC & Nivolumab: Gemcitabine, Cisplatin, Nivolumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
van der Heijden et al. 2023 (CheckMate 901 part 1) 2018-01-30 to 2022-09-28 Phase 3 (E-RT-esc) GC x 6 Seems to have superior OS (co-primary endpoint)
Median OS: 21.7 vs 18.9 mo
(HR 0.78, 95% CI 0.63-0.96)

Superior PFS (co-primary endpoint)
Median PFS: 7.9 vs 7.6 mo
(HR 0.72, 95% CI 0.59-0.88)

Chemotherapy

Immunotherapy

  • Nivolumab (Opdivo) as follows:
    • Cycles 1 to 6: 360 mg IV once on day 1
    • Cycle 7 up to 28: 480 mg IV once on day 1

21-day cycle for 6 cycles, then 28-day cycle for up to 22 cycles (2 years)

References

  1. CheckMate 901 part 1: van der Heijden MS, Sonpavde G, Powles T, Necchi A, Burotto M, Schenker M, Sade JP, Bamias A, Beuzeboc P, Bedke J, Oldenburg J, Chatta G, Ürün Y, Ye D, He Z, Valderrama BP, Ku JH, Tomita Y, Filian J, Wang L, Purcea D, Patel MY, Nasroulah F, Galsky MD; CheckMate 901 Trial Investigators. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023 Nov 9;389(19):1778-1789. Epub 2023 Oct 22. link to original article contains dosing details in supplement PubMed NCT03036098

Cisplatin & Gemcitabine (GC) & Pembrolizumab

GC & Pembrolizumab: Gemcitabine, Cisplatin, Pembrolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Powles et al. 2021 (KEYNOTE-361) 2016-2018 Phase 3 (E-RT-esc) 1a. GC
1b. GCb 		Might have superior OS (co-primary endpoint)
Median OS: 17 vs 14.3 mo
(HR 0.86, 95% CI 0.72-1.02)

Might have superior PFS1 (co-primary endpoint)
Median PFS: 8.3 vs 7.1 mo
(HR 0.78, 95% CI 0.65-0.3)
2. Pembrolizumab Not reported

1Reported efficacy did not meet the prespecified boundary for statistical significance.

Chemotherapy

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article contains dosing details in abstract PubMed NCT02853305

Enfortumab vedotin & Pembrolizumab

Regimen variant #1, q3wk pembrolizumab

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Powles et al. 2024 (EV-302) 2020-2023 Phase 3 (E-RT-switch-ooc) 1a. GC
1b. GCb 		Superior OS (co-primary endpoint)
Median OS: 31.5 vs 16.1 mo
(HR 0.47, 95% CI 0.38-0.58)

Superior PFS (co-primary endpoint)
Median PFS: 12.5 vs 6.3 mo
(HR 0.45, 95% CI 0.38-0.54)

Antibody-drug conjugate therapy

Immunotherapy

21-day cycles


Regimen variant #2, q6wk pembrolizumab

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Powles et al. 2024 (EV-302) 2020-2023 Phase 3 (E-RT-switch-ooc) 1a. GC
1b. GCb 		Superior OS (co-primary endpoint)
Median OS: 31.5 vs 16.1 mo
(HR 0.47, 95% CI 0.38-0.58)

Superior PFS (co-primary endpoint)
Median PFS: 12.5 vs 6.3 mo
(HR 0.45, 95% CI 0.38-0.54)

Note: Dosing is as described in the FDA approval announcement; this dosing was not reported in Powles et al. 2024.

Antibody-drug conjugate therapy

Immunotherapy

42-day cycles

References

  1. EV-302: Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. link to original article contains dosing details in manuscript PubMed NCT04223856

Gemcitabine & Paclitaxel

Regimen variant #1

Study Dates of enrollment Evidence Efficacy
Calabrò et al. 2009 2003-2005 Phase 2 ORR: 37%

Chemotherapy

14-day cycle for 6 to 12 cycles


Regimen variant #2

Study Dates of enrollment Evidence Efficacy
Meluch et al. 2001 1997-1999 Phase 2 ORR: 54% (95% CI 40-67)

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. link to original article PubMed
  2. Calabrò F, Lorusso V, Rosati G, Manzione L, Frassineti L, Sava T, Di Paula ED, Alonso S, Sternberg CN. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer. 2009 Jun 15;115(12):2652-9. link to original article contains dosing details in manuscript PubMed

MVAC

MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin

Regimen variant #1, standard

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Loehrer et al. 1992 (ECOG E5886) 1984-1989 Phase 3 (E-esc) Cisplatin Superior OS
Logothetis et al. 1990 1985-1989 Phase 3 (E-switch-ic) CISCA Superior OS
Siefker-Radtke et al. 2002 1992-1999 Phase 3 (C) FAP Did not meet primary endpoint of OS50%
Sternberg et al. 2001 (EORTC 30924) 1993-1998 Phase 3 (C) Dose-dense MVAC Seems to have inferior OS1
von der Maase et al. 2000 1996-1998 Phase 3 (C) GC Did not meet primary endpoint of OS
Dreicer et al. 2004 (ECOG E4897) 1998-2001 Phase 3 (C) CP Did not meet primary endpoint of OS

1Reported efficacy for EORTC 30924 is based on the 2005 update.

Chemotherapy

28-day cycles (number of cycles and criteria to continue therapy varies depending on reference)


Regimen variant #2, with G-CSF support

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bamias et al. 2003 1997-2002 Phase 3 (C) Cisplatin & Docetaxel Seems to have superior OS

Chemotherapy

Supportive therapy

28-day cycles

References

  1. Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. link to original article contains dosing details in manuscript PubMed
  2. ECOG E5886: Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. link to original article contains dosing details in manuscript PubMed
    1. Update: Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. link to original article PubMed
  3. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. link to original article contains dosing details in manuscript PubMed
    1. Update: von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. link to original article PubMed
  4. EORTC 30924: Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; EORTC Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. link to original article contains dosing details in manuscript PubMed
    1. Update: Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; EORTC Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. link to original article contains dosing details in manuscript PubMed
  5. Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002 Mar 1;20(5):1361-7. link to original article contains dosing details in manuscript PubMed
  6. Bamias A, Aravantinos G, Deliveliotis C, Bafaloukos D, Kalofonos C, Xiros N, Zervas A, Mitropoulos D, Samantas E, Pectasides D, Papakostas P, Gika D, Kourousis C, Koutras A, Papadimitriou C, Bamias C, Kosmidis P, Dimopoulos MA; Hellenic Cooperative Oncology Group. Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol. 2004 Jan 15;22(2):220-8. Epub 2003 Dec 9. Erratum in: J Clin Oncol. 2004 May 1;22(9):1771. link to original article contains dosing details in manuscript PubMed
  7. ECOG E4897: Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. link to original article contains dosing details in manuscript PubMed NCT00003376

MVAC, dose-dense

ddMVAC: dose-dense Methotrexate, Vinblastine, Adriamycin, Cisplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sternberg et al. 2001 (EORTC 30924) 1993-1998 Phase 3 (E-esc) MVAC Seems to have superior OS1
Bamias et al. 2012 (HE 16/03) 2003-2008 Phase 3 (C) DD-GC Did not meet primary endpoint of OS

1Reported efficacy for EORTC 30924 is based on the 2005 update.
Note: In contrast to Sternberg et al. 2001, Sternberg et al. 2006 specified 15-day cycles. ORR for this arm of EORTC 30924 was 62% (95% CI 54-70) versus 50% (95% CI 42-59) in the control arm.

Chemotherapy

Supportive therapy

  • G-CSF (type not specified) 240 mcg/m2 SC once per day on days 4 to 10 (additional use up to a total of 14 consecutive days if needed), injected at alternating sites, discontinued if ANC greater than 30,000/μL.
    • In contrast to Sternberg et al. 2001, Sternberg et al. 2006 said G-CSF was given on days 3 to 7.

14-day cycles

References

  1. EORTC 30924: Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; EORTC Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. link to original article contains dosing details in manuscript PubMed
    1. Update: Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; EORTC Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. link to original article contains dosing details in manuscript PubMed
  2. HE 16/03: Bamias A, Dafni U, Karadimou A, Timotheadou E, Aravantinos G, Psyrri A, Xanthakis I, Tsiatas M, Koutoulidis V, Constantinidis C, Hatzimouratidis C, Samantas E, Visvikis A, Chrisophos M, Stravodimos K, Deliveliotis C, Eleftheraki A, Pectasides D, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol. 2013 Apr;24(4):1011-7. Epub 2012 Nov 7. link to original article contains dosing details in abstract PubMed ACTRN12610000845033

PGC

PGC: Paclitaxel, Gemcitabine, Cisplatin
PCG: Paclitaxel, Cisplatin, Gemcitabine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bellmunt et al. 2012 (EORTC 30987) 2001-2004 Phase 3 (E-esc) Cisplatin & Gemcitabine Might have superior OS (primary endpoint)
Median OS: 15.8 vs 12.7 mo
(HR 0.85, 95% CI 0.72-1.02)

Note: ORR for this arm of EORTC 30987 was 56% vs 44% in the control arm.

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. EORTC 30987: Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00022191

Locally advanced or metastatic disease, maintenance after platinum chemotherapy

Avelumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Powles et al. 2020 (JAVELIN Bladder 100) 2016-2019 Phase 3 (E-RT-esc) Best supportive care Superior OS1 (primary endpoint)
Median OS: 23.8 vs 15 mo
(HR 0.76, 95% CI 0.63-0.91) 		More toxic

1Reported efficacy is based on the 2023 update.

Preceding treatment

  • First-line GC x 4 to 6 or GCb x 4 to 6

Immunotherapy

Supportive therapy

Premedication with a histamine H1 receptor (H1) blocker and acetaminophen approximately 30 to 60 minutes prior to each dose of avelumab for the first 4 doses; for example:

28-day cycles

References

  1. JAVELIN Bladder 100: Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. Epub 2020 Sep 18. link to original article contains dosing details in manuscript PubMed NCT02603432
    1. PRO analysis: Grivas P, Kopyltsov E, Su PJ, Parnis FX, Park SH, Yamamoto Y, Fong PC, Tournigand C, Climent Duran MA, Bamias A, Caserta C, Chang J, Cislo P, di Pietro A, Wang J, Powles T. Patient-reported Outcomes from JAVELIN Bladder 100: Avelumab First-line Maintenance Plus Best Supportive Care Versus Best Supportive Care Alone for Advanced Urothelial Carcinoma. Eur Urol. 2023 Apr;83(4):320-328. Epub 2022 May 30. link to original article PubMed
    2. Update: Powles T, Park SH, Caserta C, Valderrama BP, Gurney H, Ullén A, Loriot Y, Sridhar SS, Sternberg CN, Bellmunt J, Aragon-Ching JB, Wang J, Huang B, Laliberte RJ, di Pietro A, Grivas P. Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up. J Clin Oncol. 2023 Jul 1;41(19):3486-3492. Epub 2023 Apr 18. link to original article link to PMC article PubMed
  2. MAIN-CAV: NCT05092958

Pembrolizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Galsky et al. 2020 (HCRN GU14-182) 2015-2018 Randomized Phase 2 (E-esc) Placebo Seems to have superior PFS (primary endpoint)
Median PFS: 5.4 vs 3 mo
(HR 0.65, 95% CI 0.43-0.97) 		More toxic

Preceding treatment

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. HCRN GU14-182: Galsky MD, Mortazavi A, Milowsky MI, George S, Gupta S, Fleming MT, Dang LH, Geynisman DM, Walling R, Alter RS, Kassar M, Wang J, Gupta S, Davis N, Picus J, Philips G, Quinn DI, Haines GK 3rd, Hahn NM, Zhao Q, Yu M, Pal SK. Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer. J Clin Oncol. 2020 Jun 1;38(16):1797-1806. Epub 2020 Apr 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02500121

Locally advanced or metastatic disease, refractory/intolerant to platinum chemotherapy

Avelumab monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Apolo et al. 2017 (JAVELIN Solid Tumor) 2014-2016 Phase 1b (RT) ORR: 17% (95% CI 11-24)1

1Reported efficacy is based on the 2017 update.

Immunotherapy

Supportive therapy

Per Apolo et al. 2017:

  • "All patients were premedicated with an antihistamine and acetaminophen (doses and routes not given)
  • The avelumab package insert suggests "Premedicate with acetaminophen and an antihistamine for the first 4 infusions and subsequently as needed."

14-day cycles

References

  1. JAVELIN Solid Tumor: Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, Safran H, Stinchcombe TE, Srdanov M, Gelb AB, Schlichting M, Chin K, Gulley JL. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase Ib study. J Clin Oncol. 2017 Jul 1;35(19):2117-2124. Epub 2017 Apr 4. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01772004
    1. Update: Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Aljumaily R, Britten CD, Dirix L, Lee KW, Taylor M, Schöffski P, Wang D, Ravaud A, Gelb AB, Xiong J, Rosen G, Gulley JL, Apolo AB. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018 Jan;19(1):51-64. Epub 2017 Dec 5. Erratum in: Lancet Oncol. 2018 Jul;19(7):e335. link to original article link to PMC article PubMed

Docetaxel monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
McCaffrey et al. 1997 1993-1995 Phase 2
Choueiri et al. 2011 (DFCI 06-116) 2007-2010 Phase 3 (C) Docetaxel & Vandetanib Did not meet primary endpoint of PFS
Petrylak et al. 2016 (JCDC) 2011-2014 Randomized Phase 2 (C) 1. Docetaxel & Icrucumab Did not meet primary endpoint of PFS
2. Docetaxel & Ramucirumab Inferior PFS
Bellmunt et al. 2017 (KEYNOTE-045) 2014-11-05 to 2015-11-13 Phase 3 (C) Pembrolizumab Inferior OS
Powles et al. 2017 (IMvigor211) 2015-01-13 to 2016-02-15 Phase 3 (C) Atezolizumab Did not meet primary endpoint of OS
Petrylak et al. 2017 (RANGE) 2015-2017 Phase 3 (C) Docetaxel & Ramucirumab Inferior PFS1
Powles et al. 2021 (EV-301) 2018-2020 Phase 3 (C) Enfortumab vedotin Inferior OS
Loriot et al. 2023 (THOR cohort 1) 2018-08-06 to NR Phase 3 (C) Erdafitinib Inferior OS

1Reported efficacy for RANGE is based on the 2019 update.
Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.

Biomarker eligibility criteria

  • THOR cohort 1: Susceptible FGFR2 or FGFR3 alterations

Prior treatment criteria

  • KEYNOTE-045: Exposure to platinum-based chemotherapy
  • EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
  • THOR cohort 1: Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.

Chemotherapy

21-day cycles

References

  1. McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. link to original article PubMed
  2. DFCI 06-116: Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012 Feb 10;30(5):507-12. Epub 2011 Dec 19. link to original article link to PMC article PubMed NCT00880334
  3. JCDC: Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. link to original article PubMed NCT01282463
  4. KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02256436
    1. HRQoL analysis: Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. link to original article PubMed
    2. Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article PubMed
    3. Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article PubMed
  5. RANGE: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. link to original article contains dosing details in manuscript PubMed NCT02426125
    1. Update: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. link to original article link to PMC article PubMed
  6. IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article contains dosing details in abstract PubMed NCT02302807
  7. EV-301: Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03474107
    1. Update: Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. link to original article PubMed
    2. HRQoL analysis: Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. link to original article PubMed
  8. THOR cohort 1: Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. link to original article contains dosing details in manuscript PubMed NCT03390504
  9. SWOG S1937: NCT04579224
  10. TROPiCS-04: NCT04527991

Docetaxel & Ramucirumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Petrylak et al. 2016 (JCDC) 2011-2014 Randomized Phase 2 (E-esc) 1. Docetaxel Superior PFS (primary endpoint)
Median PFS: 5.4 vs 2.8 mo
(sHR 0.39, 95% CI 0.235-0.64)
2. Docetaxel & Icrucumab Not reported
Petrylak et al. 2017 (RANGE) 2015-2017 Phase 3 (E-esc) Docetaxel Superior PFS1 (primary endpoint)
(HR 0.70, 95% CI 0.57-0.85)

1Reported efficacy for RANGE is based on the 2019 update.

Chemotherapy

Targeted therapy

21-day cycles

References

  1. JCDC: Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. link to original article contains dosing details in manuscript PubMed NCT01282463
  2. RANGE: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. link to original article contains dosing details in manuscript PubMed NCT02426125
    1. Update: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. link to original article link to PMC article PubMed

Enfortumab vedotin & Pembrolizumab

Regimen

Study Dates of enrollment Evidence Efficacy
Hoimes et al. 2022 (EV-103) 2017-2020 Phase 1b/2 (RT) ORR: 73.3%
CR: 15.6%

Antibody-drug conjugate therapy

Immunotherapy

21-day cycles

References

  1. EV-103: Hoimes CJ, Flaig TW, Milowsky MI, Friedlander TW, Bilen MA, Gupta S, Srinivas S, Merchan JR, McKay RR, Petrylak DP, Sasse C, Moreno BH, Yu Y, Carret AS, Rosenberg JE. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023 Jan 1;41(1):22-31. Epub 2022 Aug 30. link to original article PubMed NCT03288545

Erdafitinib monotherapy

Regimen variant #1

FDA-recommended dose
Study Dates of enrollment Evidence Efficacy
Loriot et al. 2019 (BLC2001) 2015-2018 Phase 2 (RT) ORR 40% (95% CI 31-50)

Biomarker eligibility criteria

  • Alterations: FGFR3 mutation, FGFR2 fusion, or FGFR3 fusion

Targeted therapy

  • Erdafitinib (Balversa) as follows:
    • Cycle 1: 8 mg PO once per day on days 1 to 21, then 9 mg PO once per day on days 22 to 28 if serum phosphorus level and tolerability are acceptable
    • Cycle 2 onwards: 9 mg PO once per day on days 1 to 28

28-day cycles


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Loriot et al. 2023 (THOR cohort 1) 2018-08-06 to NR Phase 3 (E-RT-switch-ooc) 1a. Docetaxel
1b. Vinflunine 		Superior OS (primary endpoint)
Median OS: 12.1 vs 7.8 mo
(HR 0.64, 95% CI 0.47-0.88)

Note: The details of pharmacodynamic guidance were not described in the manuscript.

Biomarker eligibility criteria

  • Susceptible FGFR2 or FGFR3 alterations

Prior treatment criteria

  • Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.

Targeted therapy

  • Erdafitinib (Balversa) as follows:
    • Cycle 1: 8 mg PO once per day on days 1 to 13, then 9 mg PO once per day on days 14 to 21, guided by pharmacodynamics
    • Cycle 2 onwards: 9 mg PO once per day on days 1 to 21

21-day cycles

References

  1. BLC2001: Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Zhong B, Stuyckens K, Santiago-Walker A, De Porre P, O'Hagan A, Avadhani A, Siefker-Radtke AO; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348. link to original article PubMed NCT02365597
    1. Update: Siefker-Radtke AO, Necchi A, Park SH, García-Donas J, Huddart RA, Burgess EF, Fleming MT, Rezazadeh Kalebasty A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Akapame S, Santiago-Walker AE, Monga M, O'Hagan A, Loriot Y; BLC2001 Study Group. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol. 2022 Feb;23(2):248-258. Epub 2022 Jan 11. link to original article PubMed
  2. THOR cohort 1: Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. link to original article contains dosing details in manuscript PubMed NCT03390504
  3. THOR cohort 2: Siefker-Radtke AO, Matsubara N, Park SH, Huddart RA, Burgess EF, Özgüroğlu M, Valderrama BP, Laguerre B, Basso U, Triantos S, Akapame S, Kean Y, Deprince K, Mukhopadhyay S, Loriot Y; THOR cohort 2 investigators. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Ann Oncol. 2024 Jan;35(1):107-117. Epub 2023 Oct 21. link to original article PubMed NCT03390504

Gemcitabine monotherapy

AIM pathway regimen 2022-08-01

Regimen

Study Dates of enrollment Evidence
Lorusso et al. 1998 NR in abstract Phase 2

Chemotherapy

28-day cycles

References

  1. Lorusso V, Pollera CF, Antimi M, Luporini G, Gridelli C, Frassineti GL, Oliva C, Pacini M, De Lena M; Italian Co-operative Group on Bladder Cancer. A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Eur J Cancer. 1998 Jul;34(8):1208-12. link to original article PubMed

Gemcitabine & Paclitaxel

GP: Gemcitabine & Paclitaxel

Regimen variant #1, gemcitabine 2 out of 3 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Albers et al. 2010 (AUO AB 20/99) 2001-2005 Phase 3 (C) GP; prolonged Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #2, weekly gemcitabine

Study Dates of enrollment Evidence Efficacy
Meluch et al. 2001 1997-1999 Phase 2, fewer than 20 pts in this subgroup ORR: 47%

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. link to original article PubMed
  2. AUO AB 20/99: Albers P, Park SI, Niegisch G, Fechner G, Steiner U, Lehmann J, Heimbach D, Heidenreich A, Fimmers R, Siener R; AUO Bladder Cancer Group. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Ann Oncol. 2011 Feb;22(2):288-94. Epub 2010 Aug 2. link to original article contains dosing details in manuscript PubMed

MVAC

MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin

Regimen

Study Dates of enrollment Evidence Efficacy
Han et al. 2008 2002-2006 Phase 2 ORR: 30%

Chemotherapy

28-day cycles

References

  1. Han KS, Joung JY, Kim TS, Jeong IG, Seo HK, Chung J, Lee KH. Methotrexate, vinblastine, doxorubicin and cisplatin combination regimen as salvage chemotherapy for patients with advanced or metastatic transitional cell carcinoma after failure of gemcitabine and cisplatin chemotherapy. Br J Cancer. 2008 Jan 15;98(1):86-90. Epub 2007 Dec 18. link to original article contains dosing details in manuscript link to PMC article PubMed

Nivolumab monotherapy

Regimen variant #1, weight-based

Study Dates of enrollment Evidence Efficacy
Sharma et al. 2017 (CheckMate 275) 2015 Phase 2 (RT) 19.6% overall
PD-L1 expression at least 5%: 28.4%
PD-L1 expression at least 1%: 23.8%
PD-L1 expression less than 1%: 16.1%

Note: this is the dosing used in the study but is not the FDA-recommended dose.

Prior treatment criteria

Immunotherapy

14-day cycles


Regimen variant #2, flat dosing

FDA-recommended dose

Immunotherapy

14-day cycles

References

  1. CheckMate 275: Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, Arranz JÁ, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017 Mar;18(3):312-322. Epub 2017 Jan 25. link to original article contains dosing details in abstract PubMed NCT02387996
    1. Update: Galsky MD, Saci A, Szabo PM, Han GC, Grossfeld G, Collette S, Siefker-Radtke A, Necchi A, Sharma P. Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275. Clin Cancer Res. 2020 Oct 1;26(19):5120-5128. Epub 2020 Jun 12. link to original article link to PMC article PubMed

nab-Paclitaxel monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Ko et al. 2013 (ABX207-GU07CA) 2008-2010 Phase 2 ORR: 28% (95% CI 17-44)

Chemotherapy

21-day cycles

Dose and schedule modifications

  • "Two dose reductions were permitted, to 240 mg/m2 and then to 180 mg/m2. When further dose reductions were required, study treatment was discontinued. Patients with febrile neutropenia, or delay of cycle because of persistent neutropenia, ANC of less than 500/μL for 1 week, or grade 3 or 4 thrombocytopenia required dose reductions. When sensory neuropathy of grade 2 or higher occurred, study drug was withheld until resolution to grade 2 or better, then reinstituted at the next lower dose. When mucositis or diarrhea of grade 3 or higher occurred, study drug was withheld until resolution to grade 1 or better, then reinstituted at the next lower dose. Patients with mucositis or diarrhea of grade 4 were removed from the trial."

References

  1. ABX207-GU07CA: Ko YJ, Canil CM, Mukherjee SD, Winquist E, Elser C, Eisen A, Reaume MN, Zhang L, Sridhar SS. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 2013 Jul;14(8):769-76. Epub 2013 May 22. link to original article contains dosing details in abstract PubMed NCT00683059

Paclitaxel monotherapy

AIM pathway regimen 2022-08-01

Regimen variant #1, q3wks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bellmunt et al. 2017 (KEYNOTE-045) 2014-11-05 to 2015-11-13 Phase 3 (C) Pembrolizumab Inferior OS
Powles et al. 2017 (IMvigor211) 2015-01-13 to 2016-02-15 Phase 3 (C) Atezolizumab Did not meet primary endpoint of OS
Powles et al. 2021 (EV-301) 2018-2020 Phase 3 (C) Enfortumab vedotin Inferior OS

Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm. IMvigor211 allowed up to 2 prior lines of platinum-containing chemotherapy.

Prior treatment criteria

  • KEYNOTE-045: Exposure to platinum-based chemotherapy
  • EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression

Chemotherapy

21-day cycles


Regimen variant #2, 3 out of 4 weeks

Study Dates of enrollment Evidence Efficacy
Vaughn et al. 2002 NR Phase 2 ORR: 10% (95% CI 0-20)

Chemotherapy

28-day cycles


Regimen variant #3, weekly

Study Dates of enrollment Evidence
Sideris et al. 2016 2004-2014 Retrospective

Chemotherapy

21-day cycles

References

  1. Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. link to original article contains dosing details in abstract PubMed
  2. Retrospective: Sideris S, Aoun F, Zanaty M, Martinez NC, Latifyan S, Awada A, Gil T. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016 Jun;4(6):1063-1067. Epub 2016 Mar 17. link to original article link to PMC article PubMed
  3. KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02256436
    1. HRQoL analysis: Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. link to original article PubMed
    2. Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article PubMed
    3. Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article PubMed
  4. IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article contains dosing details in abstract PubMed NCT02302807
  5. EV-301: Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03474107
    1. Update: Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. link to original article PubMed
    2. HRQoL analysis: Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. link to original article PubMed
  6. TROPiCS-04: NCT04527991

Pembrolizumab monotherapy

AIM pathway regimen 2022-08-01

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bellmunt et al. 2017 (KEYNOTE-045) 2014-11-05 to 2015-11-13 Phase 3 (E-RT-switch-ooc) Investigator's choice of:
1a. Docetaxel
1b. Paclitaxel
1c. Vinflunine 		Superior OS (co-primary endpoint)
Median OS: 10 vs 7 mo
(HR 0.73, 95% CI 0.59-0.91)
Siefker-Radtke et al. 2023 (THOR cohort 2) 2018-04-26 to NR Phase 3 (C) Erdafitinib Did not meet primary endpoint of OS

Biomarker eligibility criteria

  • THOR cohort 2: Susceptible FGFR2 or FGFR3 alterations

Eligibility criteria

  • KEYNOTE-045: For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) at least 10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.

Prior treatment criteria

  • KEYNOTE-045: Exposure to platinum-based chemotherapy
  • THOR cohort 2: Exposure to one prior treatment that did NOT include an anti-PD-1 antibody or anti-PD-L1 antibody (anti-PD-(L)1-naive).

Immunotherapy

21-day cycles

References

  1. KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02256436
    1. HRQoL analysis: Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. link to original article PubMed
    2. Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article PubMed
    3. Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article PubMed
  2. THOR cohort 2: Siefker-Radtke AO, Matsubara N, Park SH, Huddart RA, Burgess EF, Özgüroğlu M, Valderrama BP, Laguerre B, Basso U, Triantos S, Akapame S, Kean Y, Deprince K, Mukhopadhyay S, Loriot Y; THOR cohort 2 investigators. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Ann Oncol. 2024 Jan;35(1):107-117. Epub 2023 Oct 21. link to original article cotains dosing details in manuscript PubMed NCT03390504

Pemetrexed monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Sweeney et al. 2006 2001-2004 Phase 2 ORR: 28% (95% CI 16-43)

Chemotherapy

21-day cycles

References

  1. Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006 Jul 20;24(21):3451-7. link to original article contains dosing details in abstract PubMed

Tislelizumab monotherapy

Regimen

Study Dates of enrollment Evidence
Awaiting publication (RATIONALE-204) 2017-NR Phase 2

Immunotherapy

21-day cycles

References

  1. RATIONALE-204: NCT04004221

Toripalimab monotherapy

Regimen

Study Dates of enrollment Evidence
Awaiting publication (Junshi-JS001-009) 2017-NR Phase 2

Immunotherapy

14-day cycles

References

  1. Junshi-JS001-009: contains dosing details on CT.gov NCT03113266

Vinflunine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bellmunt et al. 2009 (CA183004) 2003-2006 Phase 3 (E-esc) Best supportive care Superior OS1 (primary endpoint)
Median OS: 6.9 vs 4.6 mo
(aHR 0.72, 95% CI 0.57-0.91)
Bellmunt et al. 2017 (KEYNOTE-045) 2014-11-05 to 2015-11-13 Phase 3 (C) Pembrolizumab Inferior OS
Powles et al. 2017 (IMvigor211) 2015-01-13 to 2016-02-15 Phase 3 (C) Atezolizumab Did not meet primary endpoint of OS
Median OS: 10.6 vs 11.1 mo
(HR 1.15, 95% CI 0.83-1.59)
Powles et al. 2021 (EV-301) 2018-2020 Phase 3 (C) Enfortumab vedotin Inferior OS
Loriot et al. 2023 (THOR cohort 1) 2018-08-06 to NR Phase 3 (C) Erdafitinib Inferior OS

1Reported efficacy for CA183004 is based on the 2013 update.

Biomarker eligibility criteria

  • THOR cohort 1: Susceptible FGFR2 or FGFR3 alterations

Prior treatment criteria

  • KEYNOTE-045: Exposure to platinum-based chemotherapy
  • EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
  • THOR cohort 1: Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.

Chemotherapy

21-day cycles

References

  1. CA183004: Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, Jagiello-Gruszfeld A, Karyakin O, Delgado FM, Hurteloup P, Winquist E, Morsli N, Salhi Y, Culine S, von der Maase H. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 20;27(27):4454-61. Epub 2009 Aug 17. Erratum in: J Clin Oncol. 2010 Jan 1;28(1):182. Winquist, Eric [added]. link to original article contains dosing details in abstract PubMed NCT00315237
    1. Update: Bellmunt J, Fougeray R, Rosenberg JE, von der Maase H, Schutz FA, Salhi Y, Culine S, Choueiri TK. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann Oncol. 2013 Jun;24(6):1466-72. Epub 2013 Feb 17. link to original article PubMed
  2. KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02256436
    1. HRQoL analysis: Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. link to original article PubMed
    2. Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article PubMed
    3. Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article PubMed
  3. IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article contains dosing details in abstract PubMed NCT02302807
  4. EV-301: Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03474107
    1. Update: Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. link to original article PubMed
    2. HRQoL analysis: Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. link to original article PubMed
  5. THOR cohort 1: Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. link to original article contains dosing details in manuscript PubMed NCT03390504
  6. TROPiCS-04: NCT04527991

Locally advanced or metastatic disease, refractory/intolerant to platinum chemotherapy and/or immune checkpoint inhibitor

Enfortumab vedotin monotherapy

AIM pathway regimen 2022-08-01

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rosenberg et al. 2018 (EV-201) 2017-10-08 to 2018-07-02 Phase 2 (RT) ORR: 44% (95% CI 35.2-53.2)
Powles et al. 2021 (EV-301) 2018-2020 Phase 3 (E-RT-switch-ooc) Investigator's choice of:
1a. Docetaxel
1b. Paclitaxel
1c. Vinflunine 		Superior OS1 (primary endpoint)
Median OS: 12.91 vs 8.94 mo
(HR 0.70, 95% CI 0.58-0.85)

1Reported efficacy for EV-301 is based on the 2023 update.
Note: ORR in this arm of EV-301 (ITT) was 40.6% vs 17.9 % in the control arm (ITT).

Prior treatment criteria

  • Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression

Antibody-drug conjugate therapy

28-day cycles

References

  1. EV-201: Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, Galsky MD, Hahn NM, Gartner EM, Pinelli JM, Liang SY, Melhem-Bertrandt A, Petrylak DP. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10;37(29): 2592-2600. Epub 2019 Jul 29. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03219333
    1. Update: Yu EY, Petrylak DP, O'Donnell PH, Lee JL, van der Heijden MS, Loriot Y, Stein MN, Necchi A, Kojima T, Harrison MR, Hoon Park S, Quinn DI, Heath EI, Rosenberg JE, Steinberg J, Liang SY, Trowbridge J, Campbell M, McGregor B, Balar AV. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):872-882. Epub 2021 May 12. Erratum in: Lancet Oncol. 2021 Jun;22(6):e239. link to original article PubMed
  2. EV-301: Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03474107
    1. Update: Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. link to original article PubMed
    2. HRQoL analysis: Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. link to original article PubMed

Sacituzumab govitecan monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Efficacy
Tagawa et al. 2021 (TROPHY-U-01) 2018-2019 Phase 2 (RT) ORR: 27% (95% CI 19.5-37)

Prior treatment criteria

  • Exposure to platinum-based therapy and checkpoint inhibitor, with progression

Antibody-drug conjugate therapy

21-day cycles

References

  1. TROPHY-U-01: Tagawa ST, Balar AV, Petrylak DP, Kalebasty AR, Loriot Y, Fléchon A, Jain RK, Agarwal N, Bupathi M, Barthelemy P, Beuzeboc P, Palmbos P, Kyriakopoulos CE, Pouessel D, Sternberg CN, Hong Q, Goswami T, Itri LM, Grivas P. TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. J Clin Oncol. 2021 Aug 1;39(22):2474-2485. Epub 2021 Apr 30. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03547973
    1. Update: Loriot Y, Petrylak DP, Rezazadeh Kalebasty A, Fléchon A, Jain RK, Gupta S, Bupathi M, Beuzeboc P, Palmbos P, Balar AV, Kyriakopoulos CE, Pouessel D, Sternberg CN, Tonelli J, Sierecki M, Zhou H, Grivas P, Barthélémy P, Tagawa ST. TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes. Ann Oncol. 2024 Apr;35(4):392-401. Epub 2024 Jan 18. link to original article PubMed
  2. TROPiCs-04: NCT04527991
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