Difference between revisions of "Urothelial carcinoma"

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{{TOC limit|limit=3}}
 
{{TOC limit|limit=3}}
 
=Guidelines=
 
=Guidelines=
−
==AUA, ASCO, ASTRO, SUO==
 
−
*'''2017:''' Chang et al. [https://doi.org/10.1016/j.juro.2017.04.086 Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline] [https://pubmed.ncbi.nlm.nih.gov/28456635/ PubMed]
 
−
==EAU-ESMO==
 
−
*'''2019:''' Horwich et al. [https://doi.org/10.1093/annonc/mdz296 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] [https://pubmed.ncbi.nlm.nih.gov/31740927/ PubMed]
 
 
==[http://www.esmo.org/ ESMO]==
 
==[http://www.esmo.org/ 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]
 
*'''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]
Line 31: Line 27:
 
==SITC==
 
==SITC==
 
*'''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]
 
*'''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]
−
=Nonmuscle invasive bladder cancer=
+
=Adjuvant therapy=
−
==Bacillus Calmette-Guérin (BCG) monotherapy {{#subobject:eojb2c|Regimen=1}}==
+
 
−
{| class="wikitable" style="color:white; background-color:#9e4244"
+
==Nivolumab monotherapy {{#subobject:23ugd2|Regimen=1}}==
−
|<small>'''AIM pathway regimen 2022-08-01'''</small>
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, q2wks {{#subobject:gu17g8|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, low-dose (27 mg) {{#subobject:52ca75|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
Line 46: Line 43:
 
! 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/j.eururo.2007.04.062 Ojea et al. 2007 (CUETO study 95011)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215888/ Bajorin et al. 2021 (CheckMate 274)]
−
| rowspan="2" |1995-1998
+
{| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
−
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-esc)
+
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-324-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
−
|1. [[Urothelial_carcinoma#Intravesicular_Mitomycin_monotherapy|Mitomycin]]
 
−
| style="background-color:#1a9850" |Superior DFS (primary endpoint)
 
 
|-
 
|-
−
|2. [[#Bacillus_Calmette-Guérin_.28BCG.29_monotherapy|BCG]]; very-low-dose
+
|}
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+
|2016-2020
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[Urothelial_carcinoma_-_null_regimens#Placebo|Placebo]]
 +
| 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">
 
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[Surgery#TURBT|TURBT]], within 14 to 21 days
+
*CheckMate 274: [[Surgery#Radical_surgery|Radical surgery]]
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunotherapy====
 
====Immunotherapy====
−
*[[Bacillus Calmette-Guérin (BCG)|Bacillus Calmette-Guérin (Connaught strain)]] as follows:
+
*[[Nivolumab (Opdivo)]] 240 mg IV once on day 1
−
**Cycle 1: 27 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36
+
'''14-day cycle for up to 26 cycles (1 year)'''
−
**Cycles 2 to 7: 27 mg intravesicularly once on day 1
 
−
'''42-day course, then 14 day cycles for 6 cycles'''
 
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, intravesical (81 mg) & percutaneous, with maintenance therapy {{#subobject:221dfe|Variant=1}}===
+
===Regimen variant #2, q4wks {{#subobject:hy27g8|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
+
{| class="wikitable" style="color:white; background-color:#404040"
−
! style="width: 20%" |Study
+
|<small>'''FDA-recommended dose'''</small>
−
! 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]]
 
−
|-
 
−
|[http://www.auajournals.org/article/S0022-5347(05)67707-5 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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%" |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]]
 
−
|-
 
−
|[http://www.auajournals.org/article/S0022-5347(05)67707-5 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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%" |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/NEJM199110243251703 Lamm et al. 1991 (SWOG 8216)]
 
−
|1983-1985
 
−
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 
−
|[[Urothelial_carcinoma_-_historical#Intravesicular_Doxorubicin_monotherapy|Doxorubicin]]
 
−
| style="background-color:#91cf60" |Seems to have superior DFS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%" |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/10.1016/s0022-5347(17)40002-4 Martínez-Piñeiro et al. 1990]
 
−
| rowspan="2" |1980-1988
 
−
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 
−
|1. [[Urothelial_carcinoma_-_historical#Intravesicular_Doxorubicin_monotherapy|Doxorubicin]]<br>2. [[Urothelial_carcinoma_-_historical#Intravesicular_Thiotepa_monotherapy|Thiotepa]]
 
−
| style="background-color:#1a9850" |Superior RFS
 
−
|-
 
−
|}
 
−
''Note: details are very sparse in the abstract and this variant is probably only of historic interest.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Immunotherapy====
 
−
*[[Bacillus Calmette-Guérin (BCG)]] 150 mg intravesicularly x 15 treatments
 
−
</div></div>
 
−
===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://doi.org/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 link to original article] '''contains dosing details in manuscript''' [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 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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17485161/ PubMed]
 
−
==Intravesicular Gemcitabine monotherapy {{#subobject:343fc9|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, 1 treatment {{#subobject:170d3b|Variant=1}}===
 
−
{| class="wikitable" style="color:white; background-color:#9e4244"
 
−
|<small>'''AIM pathway regimen 2022-08-01'''</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://www.ncbi.nlm.nih.gov/pmc/articles/pmc6583489/ Messing et al. 2018 (SWOG S0337)]
 
−
|2008-2012
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[#Placebo_888|Placebo (saline)]]
 
−
| style="background-color:#1a9850" |Superior TTR (primary endpoint)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[Surgery#TURBT|TURBT]], up to 3 hours prior
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Gemcitabine (Gemzar)]] 2000 mg in 100 mL of saline instilled intravesicularly for up to 60 minutes
 
−
'''One treatment'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%" |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/10.1200/JCO.2008.20.8199 Addeo et al. 2009]
 
−
|2003-2005
 
−
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 
−
|[[#Intravesicular_Mitomycin_monotherapy|Mitomycin]]
 
−
| style="background-color:#1a9850" |Superior DFS (co-primary endpoint)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div></div>
 
−
===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 dosing details in manuscript''' [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 dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6583489/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29801011/ PubMed] [https://clinicaltrials.gov/study/NCT00445601 NCT00445601]
 
−
==Intravesicular Mitomycin monotherapy {{#subobject:2e5944|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%" |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/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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[Surgery#TURBT|TURBT]], 14 to 21 days prior
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%" |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/10.1200/JCO.2011.39.2936 Lammers et al. 2012]
 
−
|2003-2007
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Keyhole_limpet_hemocyanin_monotherapy_777|KLH]]
 
−
| style="background-color:#1a9850" |Superior RFS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[Surgery#TURBT|TURBT]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div></div>
 
−
===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 dosing details in manuscript''' [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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22585689/ PubMed]
 
−
==Nadofaragene firadenovec monotherapy {{#subobject:3cbigc|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:chwee3|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]]
 
−
|-
 
−
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7988888/ Boorjian et al. 2020 (rAd-IFN-CS-003)]
 
−
|2016-2019
 
−
| style="background-color:#91cf61" |Non-randomized (RT)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Immunotherapy====
 
−
*[[Nadofaragene firadenovec (Adstiladrin)]] 75 mL intravesicularly once on day 1
 
−
'''3-month cycle for 4 cycles'''
 
−
</div></div>
 
−
===References===
 
−
#'''rAd-IFN-CS-003:''' Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, Bivalacqua TJ, Montgomery JS, Lerner SP, Busby JE, Poch M, Crispen PL, Steinberg GD, Schuckman AK, Downs TM, Svatek RS, Mashni J Jr, Lane BR, Guzzo TJ, Bratslavsky G, Karsh LI, Woods ME, Brown G, Canter D, Luchey A, Lotan Y, Krupski T, Inman BA, Williams MB, Cookson MS, Keegan KA, Andriole GL Jr, Sankin AI, Boyd A, O'Donnell MA, Sawutz D, Philipson R, Coll R, Narayan VM, Treasure FP, Yla-Herttuala S, Parker NR, Dinney CPN. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021 Jan;22(1):107-117. Epub 2020 Nov 27. [https://doi.org/10.1016/s1470-2045(20)30540-4 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7988888/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33253641/ PubMed] [https://clinicaltrials.gov/study/NCT02773849 NCT02773849]
 
−
==Pembrolizumab monotherapy {{#subobject:3cb963|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:7ae9e3|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/s1470-2045(21)00147-9 Balar et al. 2021 (KEYNOTE-057)]
 
−
{| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 
−
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-288-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 
−
|-
 
−
|}
 
−
|2015-2018
 
−
| style="background-color:#91cf61" |Phase 2 (RT)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Immunotherapy====
 
−
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 
−
'''21-day cycle for 35 cycles (2 years)'''
 
−
</div></div>
 
−
===References===
 
−
 
 
−
#'''KEYNOTE-057:''' Balar AV, Kamat AM, Kulkarni GS, Uchio EM, Boormans JL, Roumiguié M, Krieger LEM, Singer EA, Bajorin DF, Grivas P, Seo HK, Nishiyama H, Konety BR, Li H, Nam K, Kapadia E, Frenkl T, de Wit R. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021 Jul;22(7):919-930. Epub 2021 May 26. Erratum in: Lancet Oncol. 2021 Aug;22(8):e347. [https://doi.org/10.1016/s1470-2045(21)00147-9 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34051177/ PubMed] [https://clinicaltrials.gov/study/NCT02625961 NCT02625961]
 
−
==Intravesicular Valrubicin monotherapy {{#subobject:58jgac|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%" |Dates of enrollment
 
−
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2805)67799-3 Steinberg et al. 2000]
 
−
|1993-1996
 
−
| style="background-color:#91cf61" |Non-randomized (RT)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Valrubicin (Valstar)]] 800 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36
 
−
'''6-week course'''
 
−
</div></div>
 
−
===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)67799-3 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10687972/ PubMed]
 
−
=Neoadjuvant chemotherapy=
 
−
==Cisplatin & Gemcitabine (GC) {{#subobject:d08e11|Regimen=1}}==
 
−
GC: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, 70/2000; single-dose cisplatin {{#subobject:dc99d5|Variant=1}}===
 
−
{| class="wikitable" style="color:white; background-color:#9e4244"
 
−
|<small>'''AIM pathway regimen 2022-08-01'''</small>
 
−
|-
 
−
|}
 
−
{| 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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Bladder_cancer_surgery|Surgery]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, 70/2000; split-dose cisplatin {{#subobject:be43aa|Variant=1}}===
 
−
{| class="wikitable" style="color:white; background-color:#9e4244"
 
−
|<small>'''AIM pathway regimen 2022-08-01'''</small>
 
−
|-
 
−
|}
 
−
{| 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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Bladder_cancer_surgery|Surgery]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #3, 70/2500 {{#subobject:22jg1e|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://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)
 
−
|[[Urothelial carcinoma#MVAC.2C dose-dense|ddMVAC]] x 6
 
−
| style="background-color:#fee08b" |Might have inferior PFS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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 therapy====
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day from day 3 to day 7 if febrile neutropenia or if cycle shift 7 or more days due to neutropenia in a prior cycle.
 
−
*Antiemetics used included:
 
−
**[[Aprepitant (Emend)]]
 
−
**[[Ondansetron (Zofran)]]
 
−
**[[Methylprednisolone (Solumedrol)]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Cystectomy|Cystectomy]] to be performed up to 8 weeks after completion of chemotherapy
 
−
</div></div>
 
−
===References===
 
−
#'''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 dosing details in manuscript''' [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 Jun 20;40(18):2013-2022. Epub 2022 Mar 7. [https://doi.org/10.1200/JCO.21.02051 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35254888/ PubMed] [https://clinicaltrials.gov/study/NCT01812369 NCT01812369]
 
−
#'''KEYNOTE-B15:''' [https://clinicaltrials.gov/study/NCT04700124 NCT04700124]
 
−
#'''KEYNOTE-866:''' [https://clinicaltrials.gov/study/NCT03924856 NCT03924856]
 
−
==Cisplatin & Gemcitabine (GC) & Pembrolizumab {{#subobject:hy2e11|Regimen=1}}==
 
−
GC & Pembrolizumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, Pembrolizumab
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:beyaba|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]]
 
−
|-
 
−
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8478388/ Rose et al. 2021 (LCCC 1520)]
 
−
|2016-2020
 
−
| style="background-color:#91cf61" |Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Bladder_cancer_surgery|Radical cystectomy]]
 
−
</div></div>
 
−
===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 Oct 1;39(28):3140-3148. Epub 2021 Aug 24. [https://doi.org/10.1200/jco.21.01003 link to original article] '''contains dosing details in abstract''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8478388/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34428076/ PubMed] [https://clinicaltrials.gov/study/NCT02690558 NCT02690558]
 
−
#'''KEYNOTE-866:''' [https://clinicaltrials.gov/study/NCT03924856 NCT03924856]
 
−
==MCV {{#subobject:553fe2|Regimen=1}}==
 
−
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
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%" |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/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)
 
−
|[[Urothelial_carcinoma_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant chemotherapy]]
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Kaufman et al. 1993, CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT]] consolidation
 
−
*RTOG 88-02 & RTOG 89-03: [[#Cisplatin_.26_RT|Cisplatin & RT]] induction
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, 3 cycles {{#subobject:3d008f|Variant=1}}===
 
−
{| class="wikitable" style="color:white; background-color:#9e4244"
 
−
|<small>'''AIM pathway regimen 2022-08-01'''</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/10.1016/S0140-6736(99)02292-8 Griffiths et al. 1999 (BA06 30894)]
 
−
|1989-1995
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[Urothelial_carcinoma_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]
 
−
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup> (primary endpoint)<br>Median OS: 44 vs 37 mo<br>(HR 0.84, 95% CI 0.72-0.99)
 
−
|-
 
−
|[https://doi.org/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>
 
−
<div class="toccolours" style="background-color:#fdcdac">
 
−
====Eligibility criteria====
 
−
*Zapatero et al. 2000: T2 to T4 Nx M0 disease
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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 therapy====
 
−
*'''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 (total dose per cycle: 120 mg/m<sup>2</sup>)
 
−
'''21-day cycle for 3 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Zapatero et al. 2000: after 3 cycles of chemotherapy, patients underwent cystoscopy, biopsy, and abdominal CT
 
−
**Zapatero et al. 2000, patients with CR or who were not surgical candidates: [[#Radiation_therapy|RT]] consolidation which begins 4 to 6 weeks after completion of chemotherapy
 
−
**Zapatero et al. 2000, patients without CR who were surgical candidates: [[Surgery#Cystectomy|cystectomy]]
 
−
</div></div>
 
−
===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://doi.org/10.1056/NEJM199311043291903 link to original article] '''contains dosing details in manuscript''' [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 dosing details in manuscript''' [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 dosing details in manuscript''' [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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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://doi.org/10.1016/S0140-6736(99)02292-8 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 dosing details in manuscript''' [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://doi.org/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] '''contains dosing details in manuscript''' [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. [https://doi.org/10.1016/j.urolonc.2009.01.031 link to original article] '''contains dosing details in manuscript''' [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. [https://doi.org/10.1016/j.urology.2012.07.045 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22999456/ PubMed]
 
−
==MVAC {{#subobject:701fbe|Regimen=1}}==
 
−
MVAC: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''isplatin
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%" |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/10.1093/annonc/mdu126 Kitamura et al. 2014 (JCOG0209)]
 
−
|2003-2009
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[Urothelial_carcinoma_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]
 
−
| style="background-color:#d9ef8b" |Might have superior OS (primary endpoint)<br>Median OS: 102 vs 82 mo<br>(HR 0.65, 99.99% CI 0.19-2.18)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Radical_cystectomy|Radical cystectomy]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%" |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/NEJMoa022148 Grossman et al. 2003 (SWOG S8710)]
 
−
|1987-1998
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[Urothelial_carcinoma_-_null_regimens#No_neoadjuvant_therapy|No neoadjuvant therapy]]
 
−
| style="background-color:#d9ef8b" |Might have superior OS (primary endpoint)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Radical_cystectomy|Radical cystectomy]]
 
−
</div></div>
 
−
===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://doi.org/10.1056/NEJMoa022148 link to original article] '''contains dosing details in manuscript''' [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. Epub 2014 Mar 24. [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}}==
 
−
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
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|Dates 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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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)]] by the following laboratory-based criteria:
 
−
**Patients with CrCl of at least 60 mL/min/1.73m<sup>2</sup>: 70 mg/m<sup>2</sup> IV 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 therapy====
 
−
*[[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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Radical_cystectomy|Radical cystectomy]] with bilateral [[Surgery#Lymphadenectomy|lymphadenectomy]], within 4 to 8 weeks after the last cycle of chemotherapy
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|Dates 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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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 once on day 2
 
−
====Supportive therapy====
 
−
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 3 (approximately 24 hours after day 2 chemotherapy)
 
−
'''14-day cycle for 4 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Cystectomy|Cystectomy]] to be performed 4 to 10 weeks after completion of chemotherapy
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #3 (ddMVAC), 6 cycles {{#subobject:7aegh3|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%" |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 (E-esc)
 
−
|[[Urothelial carcinoma#Cisplatin .26 Gemcitabine .28GC.29|Cisplatin and Gemcitabine (GC)]]
 
−
| style="background-color:#d9ef8b" |Might have superior PFS (primary endpoint)<br>PFS36: 64% vs 56%<br>(HR 0.77, 95% CI 0.57-1.02)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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 once on day 2
 
−
====Supportive therapy====
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Cystectomy|Cystectomy]] to be performed 4 to 10 weeks after completion of chemotherapy
 
−
</div></div>
 
−
===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 dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7057274/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24821883/ PubMed] [https://clinicaltrials.gov/study/NCT00808639 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 dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050203/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24821881/ PubMed] [https://clinicaltrials.gov/study/NCT01031420 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 Jun 20;40(18):2013-2022. Epub 2022 Mar 7. [https://doi.org/10.1200/JCO.21.02051 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35254888/ PubMed] [https://clinicaltrials.gov/study/NCT01812369 NCT01812369]
 
−
==Pembrolizumab monotherapy {{#subobject:3cfac3|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:c4bf38|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/10.1200/jco.18.01148 Necchi et al. 2018 (PURE-01)]
 
−
|2017-2018
 
−
| style="background-color:#91cf61" |Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Immunotherapy====
 
−
*[[Pembrolizumab (Keytruda)|Pembrolizumab]] 200 mg IV over 30 minutes once on day 1
 
−
'''21-day cycle for 3 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Radical_cystectomy|Radical cystectomy]], within 1 to 3 weeks after the last cycle of chemotherapy
 
−
</div></div>
 
−
===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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/30343614/ PubMed] [https://clinicaltrials.gov/study/NCT02736266 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}}==
 
−
Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|Dates of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1016/j.urolonc.2009.01.031 Zapatero et al. 2009]
 
−
|1990-2007
 
−
| style="background-color:#91cf61" |Non-randomized
 
−
|-
 
−
|[https://doi.org/10.1016/s0360-3016(03)00718-1 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. 2009.''
 
−
<div class="toccolours" style="background-color:#fdcdac">
 
−
====Eligibility criteria====
 
−
*Zapatero et al. 2009: T2 to T4 N0 M0 disease
 
−
*RTOG 97-06: T2 to T4a N0 M0 disease without hydronephrosis
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16, '''given first'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] twice per day on days 1 to 5, 8 to 12, 15, 16, 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.
 
−
'''16-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
 
−
**RTOG 97-06, patients with complete regression (R0): [[#Cisplatin_.26_RT_2|Cisplatin & RT]] consolidation
 
−
**RTOG 97-06, nonresponders: [[Surgery#Cystectomy|Cystectomy]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|Dates 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
 
−
|-
 
−
|}
 
−
''Note: Patients were restaged 2 weeks after completion of radiation with examination under anesthesia, cystoscopy with tumor-site biopsy, urinary cytology, and computed tomographic scan of pelvis.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#MCV|MCV]] x 2
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 22
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 1.8 Gy once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29, 30 (22 fractions; total dose: 39.6 Gy)
 
−
'''4.5-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*RTOG 88-02, patients with CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT]] consolidation
 
−
*RTOG 88-02, patients without CR: Immediate [[Surgery#Cystectomy|cystectomy]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|Dates 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 part of phase 3 RCT
 
−
|-
 
−
|}
 
−
''Note: In RTOG 89-03, the patient is restaged 4 weeks after completion of radiation with examination under anesthesia, cystoscopy with tumor-site biopsy, and urinary cytology.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*RTOG 89-03: [[#MCV|MCV]] versus [[Urothelial_carcinoma_-_null_regimens#No_neoadjuvant_therapy|no neoadjuvant therapy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 22
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 1.8 Gy once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29, 30 (22 fractions; total dose: 39.6 Gy)
 
−
'''4.5-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*RTOG 89-03, patients not in CR: [[Surgery#Cystectomy|Cystectomy]]
 
−
*RTOG 89-03, patients in CR: [[#Cisplatin_.26_RT_2|Cisplatin & RT]] consolidation
 
−
</div></div>
 
−
===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 dosing details in manuscript''' [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 dosing details in manuscript''' [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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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. [https://doi.org/10.1016/s0360-3016(03)00718-1 link to original article] '''contains dosing details in manuscript''' [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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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. [https://doi.org/10.1016/j.urolonc.2009.01.031 link to original article] '''contains dosing details in manuscript''' [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. [https://doi.org/10.1016/j.urology.2012.07.045 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22999456/ PubMed]
 
−
#'''SunRISe-2:''' [https://clinicaltrials.gov/study/NCT04658862 NCT04658862]
 
−
#'''SWOG S1806:''' [https://clinicaltrials.gov/study/NCT03775265 NCT03775265]
 
−
==Cisplatin & Fluorouracil (CF) & RT {{#subobject:b5e26|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|Dates 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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#fdcdac">
 
−
====Eligibility criteria====
 
−
*RTOG 95-06: Clinical T2 to T4a Nx M0 disease without hydronephrosis and CrCl of at least 60 mL/min/1.73m<sup>2</sup>
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3, 15 to 17 '''given second, before radiation'''
 
−
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, 15 to 17 '''given first'''
 
−
====Supportive therapy====
 
−
*IV [[:Category:Hydration|hydration]] at 500 mL/h (no total volume specified) prior to 5-FU
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 3 Gy fractions twice per day on days 1, 3, 15, 17, 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 (total induction dose: 24 Gy), administered to the whole bladder, bladder tumor volume, and pelvic lymph nodes
 
−
'''17-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#fff2ae">
 
−
====Dose and schedule modifications====
 
−
*Patients with grade III hematologic toxicity, defined as platelets less than 50 x 10<sup>9</sup>/L or ANC less than 1800/μL, 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/μL.
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Treatment followed by repeat cystoscopy, biopsy, and urine cytology in week 7 or 8
 
−
**RTOG 95-06, patients with complete response: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT]] consolidation in week 9
 
−
**RTOG 95-06, incomplete responders: recommended to undergo [[Surgery#Radical_cystectomy|radical cystectomy]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|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://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
 
−
|-
 
−
|[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>RTOG 0712 was not statistically powered to compare regimens.''<br>
 
−
''Note: Treatment was followed by repeat cystoscopy and biopsy. In RTOG 02-33, patients underwent reevaluation for response on week 7.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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:
 
−
**Days 1 to 5, 8 to 12, 15 to 17: 1.6 Gy fractions to the pelvis every morning
 
−
**Days 1 to 5: 1.5 Gy fractions to the bladder every evening
 
−
**Days 8 to 12, 15 to 17: 1.5 Gy fractions to the tumor every evening
 
−
**Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
 
−
'''17-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*RTOG 02-33, patients with less than stage T1 disease: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT]] consolidation
 
−
*RTOG 02-33, patients with at least stage T1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]] on week 9, then adjuvant [[#PGC|PGC]]
 
−
*RTOG 0712, patients with complete response: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT_2|CF & RT]] consolidation
 
−
*RTOG 0712, incomplete responders: [[Surgery#Radical_cystectomy|Radical cystectomy]]
 
−
</div></div>
 
−
===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 dosing details in manuscript''' [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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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. Epub 2013 Jul 1. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157/ PubMed] [https://clinicaltrials.gov/study/NCT00055601 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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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 dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30433852/ PubMed] [https://clinicaltrials.gov/study/NCT00777491 NCT00777491]
 
−
==Cisplatin, Paclitaxel, RT {{#subobject:803f28|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|Dates of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1016/j.urology.2008.09.036 Kaufman et al. 2008 (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. On week 7, over 3 weeks after induction therapy, patients under reevaluation with exam under anesthesia, cystoscopy with tumor site biopsy, and urine cytology.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[Surgery#TURBT|TURBT]], within 4 to 6 weeks
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16
 
−
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] twice per day 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:
 
−
**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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*RTOG 02-33, patients with less than stage ypT1 disease: [[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, paclitaxel, RT]] consolidation
 
−
*RTOG 02-33, patients with at least stage ypT1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]], then adjuvant [[#Cisplatin_.26_Gemcitabine_.28GC.29_2|GC]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|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://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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1 to 3, 8 to 10, 15 to 17
 
−
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] twice per day on days 1 to 5, 8 to 12, 15 to 17, with at least 4 hours between radiation therapy sessions:
 
−
**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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*On week 7, patients under reevaluation for response
 
−
**RTOG 02-33, patients with less than stage ypT1 disease: [[#Cisplatin.2C_Paclitaxel.2C_RT_2|Cisplatin, paclitaxel, RT]] consolidation
 
−
**RTOG 02-33, patients with at least stage ypT1 disease: [[Surgery#Radical_cystectomy|Radical cystectomy]] on week 9, then adjuvant [[#PGC|PGC]]
 
−
</div></div>
 
−
===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. [https://doi.org/10.1016/j.urology.2008.09.036 link to original article] '''contains dosing details in manuscript''' [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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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. Epub 2013 Jul 1. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157/ PubMed] [https://clinicaltrials.gov/study/NCT00055601 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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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}}==
 
−
Fluorouracil, Mitomycin, RT: Fluorouracil, Mitomycin, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, 55 Gy {{#subobject:6a18dc|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/NEJMoa1106106 James et al. 2012 (BC2001)]
 
−
|2001-2008
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[#Radiation_therapy_2|Radiation therapy]]
 
−
| style="background-color:#d9ef8b" |Might have superior DFS<sup>1</sup> (secondary endpoint)<br>(HR 0.78, 95% CI 0.60-1.02)
 
−
|-
 
−
|}
 
−
''<sup>1</sup>Reported efficacy is based on the 2022 update.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on days 1 & 16 (total dose: 5000 mg/m<sup>2</sup>)
 
−
*[[Mitomycin (Mutamycin)]] 12 mg/m<sup>2</sup> IV bolus once on day 1
 
−
====Radiotherapy====
 
−
*Concurrent [[External beam radiotherapy]] 2.75 Gy once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26 (20 fractions; total dose: 55 Gy)
 
−
'''4-week course'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, 64 Gy {{#subobject:6a18dc|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/NEJMoa1106106 James et al. 2012 (BC2001)]
 
−
|2001-2008
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[#Radiation_therapy_2|Radiation therapy]]
 
−
| style="background-color:#d9ef8b" |Might have superior DFS<sup>1</sup> (secondary endpoint)<br>(HR 0.78, 95% CI 0.60-1.02)
 
−
|-
 
−
|}
 
−
''<sup>1</sup>Reported efficacy is based on the 2022 update.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on days 1 & 16 (total dose: 5000 mg/m<sup>2</sup>)
 
−
*[[Mitomycin (Mutamycin)]] 12 mg/m<sup>2</sup> IV bolus once on day 1
 
−
====Radiotherapy====
 
−
*Concurrent [[External beam radiotherapy]] 2 Gy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 40, 42, 43 (32 fractions; total dose: 64 Gy)
 
−
'''6.5-week course'''
 
−
</div></div>
 
−
===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://doi.org/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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22512481/ PubMed] [https://clinicaltrials.gov/study/NCT00024349 NCT00024349]
 
−
##'''Update:''' Hall E, Hussain SA, Porta N, Lewis R, Crundwell M, Jenkins P, Rawlings C, Tremlett J, Sreenivasan T, Wallace J, Syndikus I, Sheehan D, Lydon A, Huddart R, James N; BC2001 Investigators. Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial. Eur Urol. 2022 Sep;82(3):273-279. Epub 2022 May 14. [https://doi.org/10.1016/j.eururo.2022.04.017 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35577644/ PubMed]
 
−
==Gemcitabine & RT {{#subobject:91c0ea|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:6333a7|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://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.''<br>
 
−
''Note: Treatment was followed by repeat cystoscopy and biopsy.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Gemcitabine (Gemzar)]] 27 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11, 15, 18, 22, 25
 
−
====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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*RTOG 0712, patients with complete response: [[#Gemcitabine_.26_RT_888|Gemcitabine & RT]] consolidation
 
−
*RTOG 0712, incomplete responders: [[Surgery#Radical_cystectomy|Radical cystectomy]]
 
−
</div></div>
 
−
===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 dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354769/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30433852/ PubMed] [https://clinicaltrials.gov/study/NCT00777491 NCT00777491]
 
−
#'''SunRISe-2:''' [https://clinicaltrials.gov/study/NCT04658862 NCT04658862]
 
−
==Paclitaxel & RT {{#subobject:89c0ea|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, normo-fractionated RT {{#subobject:6222a7|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/j.urology.2012.07.045 Zapatero et al. 2012]
 
−
|1990-2010
 
−
| style="background-color:#ffffbe" |Non-randomized, fewer than 20 pts
 
−
|-
 
−
|}
 
−
''Note: Patients who had "mild renal insufficiency" received paclitaxel instead of cisplatin and had T2 to T4 N0 M0 disease.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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]], 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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*3 weeks after finishing radiation and chemotherapy, patients underwent restaging [[Surgery#TURBT|TURBT]]
 
−
**Zapatero et al. 2012, patients with complete regression (R0): [[#Paclitaxel_.26_RT_2|Paclitaxel & RT]] consolidation
 
−
**Zapatero et al. 2012, nonresponders: [[Surgery#Cystectomy|Cystectomy]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, AHFRT {{#subobject:6222a7|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/j.urology.2012.07.045 Zapatero et al. 2012]
 
−
|1990-2010
 
−
| style="background-color:#ffffbe" |Non-randomized, fewer than 20 pts
 
−
|-
 
−
|}
 
−
''Note: Patients who had "mild renal insufficiency" received paclitaxel instead of cisplatin and had T2 to T4 N0 M0 disease.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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]] 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.
 
−
'''One course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*3 weeks after finishing radiation and chemotherapy, patients underwent restaging [[Surgery#TURBT|TURBT]]
 
−
**Zapatero et al. 2012, patients with complete regression (R0): [[#Paclitaxel_.26_RT_2|Paclitaxel & RT]] consolidation
 
−
**Zapatero et al. 2012, nonresponders: [[Surgery#Cystectomy|Cystectomy]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #3, 64.8 Gy {{#subobject:6222a7|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/pmc5536836/ Michaelson et al. 2016 (RTOG 0524)]
 
−
|2005-2013
 
−
| style="background-color:#91cf61" |Phase 1/2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36, 42
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 1.80 Gy per day; 64.8 Gy total in 36 fractions
 
−
'''One course'''
 
−
</div></div>
 
−
===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. [https://doi.org/10.1016/j.urology.2012.07.045 link to original article] '''contains dosing details in manuscript''' [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}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:e0ed54|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/10.1002/1097-0215%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://doi.org/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:#fee08b" |Might have inferior DFS<sup>1</sup>
 
−
|-
 
−
|}
 
−
''<sup>1</sup>Reported efficacy is based on the 2022 update.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Zapatero et al. 2000, depending on response: [[#MCV|MCV]] x 3 or [[Surgery#Cystectomy|cystectomy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Radiotherapy====
 
−
*[[External beam radiotherapy]] by the following response-based 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.
 
−
</div></div>
 
−
===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://doi.org/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 link to original article] '''contains dosing details in manuscript''' [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. [https://doi.org/10.1016/j.urolonc.2009.01.031 link to original article] '''contains dosing details in manuscript''' [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. [https://doi.org/10.1016/j.urology.2012.07.045 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://doi.org/10.1056/NEJMoa1106106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22512481/ PubMed] [https://clinicaltrials.gov/study/NCT00024349 NCT00024349]
 
−
##'''Update:''' Hall E, Hussain SA, Porta N, Lewis R, Crundwell M, Jenkins P, Rawlings C, Tremlett J, Sreenivasan T, Wallace J, Syndikus I, Sheehan D, Lydon A, Huddart R, James N; BC2001 Investigators. Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial. Eur Urol. 2022 Sep;82(3):273-279. Epub 2022 May 14. [https://doi.org/10.1016/j.eururo.2022.04.017 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35577644/ PubMed]
 
−
=Consolidation chemoradiotherapy=
 
−
==Cisplatin & RT {{#subobject:308d11|Regimen=1}}==
 
−
Cisplatin & RT: Cisplatin & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, cisplatin 40 mg/m<sup>2</sup>/wk x 2, AHFRT {{#subobject:dc2b84|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/10.1002/1097-0215%2820001020%2990%3A5%3C287%3A%3AAID-IJC6%3E3.0.CO%3B2-9 Zapatero et al. 2000]
 
−
|1989-1997
 
−
| style="background-color:#91cf61" |Non-randomized
 
−
|-
 
−
|[https://doi.org/10.1016/s0360-3016(03)00718-1 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.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Zapatero et al. 2000, depending on response: [[#Cisplatin_.26_RT|Cisplatin & RT]] induction or [[Surgery#Cystectomy|cystectomy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 2, 8, 9 '''given first'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 1.5 Gy fractions twice per day on days 1 to 5, 8 to 12, 15, 16 (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.
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*RTOG 97-06: Adjuvant [[#MCV_2|MCV]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|Dates 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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*RTOG 88-02, depending on response, treatment preceded by: [[#Cisplatin_.26_RT|cisplatin & RT]] induction or [[Surgery#Cystectomy|cystectomy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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 once per day on days 1 to 5, 8 to 12, 15 to 18 (14 fractions; total dose in consolidation phase: 25.2 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)
 
−
'''3-week course'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|Dates 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 part of phase 3 RCT
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*RTOG 89-03, depending on response, treatment preceded by: [[#Cisplatin_.26_RT|cisplatin & RT]] induction or [[Surgery#Cystectomy|cystectomy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 1
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 1.8 Gy per day on days 1 to 5, 8 to 12, 15 to 18 (14 fractions; total dose in consolidation phase: 39.6 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)
 
−
'''3-week course'''
 
−
</div></div>
 
−
===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 dosing details in manuscript''' [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 dosing details in manuscript''' [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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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://doi.org/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. [https://doi.org/10.1016/j.urolonc.2009.01.031 link to original article] '''contains dosing details in manuscript''' [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. [https://doi.org/10.1016/j.urology.2012.07.045 link to original article] '''contains dosing details in manuscript''' [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. [https://doi.org/10.1016/s0360-3016(03)00718-1 link to original article] '''contains dosing details in manuscript''' [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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|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://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.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|Cisplatin, 5-FU, RT]] induction
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
''Starts on week 8.''
 
−
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9
 
−
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, 8 to 10
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 1.5 Gy twice per day on days 1 to 5, 8 to 10 (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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Adjuvant [[#PGC|PGC]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|Dates 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.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*RTOG 95-06, depending on response, treatment preceded by: [[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|cisplatin, fluorouracil, RT]] induction or [[Surgery#Cystectomy|cystectomy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3, 15 to 17, '''given second'''
 
−
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 to 3, 15 to 17, '''given first'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 2.5 Gy fractions twice per day on days 1, 3, 15, 17, with at least 4 hours between fractions, x 8 fractions (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.
 
−
====Supportive therapy====
 
−
*IV [[:Category:Hydration|hydration]] at 500 mL/h (no total volume specified) prior to 5-FU
 
−
'''17-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#fff2ae">
 
−
====Dose and schedule modifications====
 
−
*Patients with grade III hematologic toxicity, defined as platelets less than 50 x 10<sup>9</sup>/L or ANC less than 1800/μL, 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/μL.
 
−
</div></div>
 
−
===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 dosing details in manuscript''' [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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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. Epub 2013 Jul 1. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157/ PubMed] [https://clinicaltrials.gov/study/NCT00055601 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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|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://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.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT]] induction
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9
 
−
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 1.5 Gy twice per day on days 1 to 5, 8 to 10 (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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Adjuvant [[#PGC|PGC]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|Dates of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1016/j.urology.2008.09.036 Kaufman et al. 2008 (RTOG 99-06)]
 
−
|NR in abstract
 
−
| style="background-color:#91cf61" |Phase 1/2
 
−
|-
 
−
|}
 
−
''Consolidation starts starts on week 8.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Cisplatin.2C_Paclitaxel.2C_RT|Cisplatin, Paclitaxel, RT]] induction
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9
 
−
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
'''7-day cycle for 2 cycles'''
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 1.5 Gy twice per day on days 1 to 5, 8 to 10 (16 fractions, given twice per day at a 4 to 6 hour interval between treatments). 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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Adjuvant [[#Cisplatin_.26_Gemcitabine_.28GC.29_2|GC]]
 
−
</div></div>
 
−
===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. Epub 2008 Dec 18. [https://doi.org/10.1016/j.urology.2008.09.036 link to original article] '''contains dosing details in manuscript''' [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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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. Epub 2013 Jul 1. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157/ PubMed] [https://clinicaltrials.gov/study/NCT00055601 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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, normo-fractionated RT {{#subobject:de252a|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/j.urology.2012.07.045 Zapatero et al. 2012]
 
−
|1990-2010
 
−
| style="background-color:#ffffbe" |Non-randomized, fewer than 20 pts
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Zapatero et al. 2012, depending on response, treatment preceded by: [[#Paclitaxel_.26_RT|paclitaxel & RT]] induction or [[Surgery#Cystectomy|cystectomy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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]], 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'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, AHFRT {{#subobject:de252a|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/j.urology.2012.07.045 Zapatero et al. 2012]
 
−
|1990-2010
 
−
| style="background-color:#ffffbe" |Non-randomized, fewer than 20 pts
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Zapatero et al. 2012, depending on response, treatment preceded by: [[#Paclitaxel_.26_RT|paclitaxel & RT]] induction or [[Surgery#Cystectomy|cystectomy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Paclitaxel (Taxol)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8, given 6 hours before radiation therapy
 
−
====Radiotherapy====
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]] 1.5 Gy twice per day on days 1 to 5, 8 to 10 (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.
 
−
'''One course'''
 
−
</div></div>
 
−
===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. [https://doi.org/10.1016/j.urology.2012.07.045 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22999456/ PubMed]
 
−
=Adjuvant therapy=
 
−
==Cisplatin & Gemcitabine (GC) {{#subobject:684e48|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:72a413|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/j.urology.2008.09.036 Kaufman et al. 2008 (RTOG 99-06)]
 
−
|NR in abstract
 
−
| style="background-color:#91cf61" |Phase 1/2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*RTOG 99-06, 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]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div></div>
 
−
===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. [https://doi.org/10.1016/j.urology.2008.09.036 link to original article] '''contains dosing details in manuscript''' [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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:72a413|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 17%"|Study
 
−
!style="width: 15%"|Dates 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_888|M-VEC]] x 3
 
−
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)
 
−
| style="background-color:#1a9850" |Less toxic
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[Surgery#Cystectomy|Radical cystectomy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cisplatin (Platinol)]]
 
−
*[[Methotrexate (MTX)]]
 
−
</div></div>
 
−
===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}}==
 
−
MCV: '''<u>M</u>'''ethotrexate, '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:ca6708|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/s0360-3016(03)00718-1 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.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Cisplatin_.26_RT_2|Cisplatin & RT]] consolidation
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div></div>
 
−
===References===
 
−
#'''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. [https://doi.org/10.1016/s0360-3016(03)00718-1 link to original article] '''contains dosing details in manuscript''' [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. Epub 2009 Jul 27. [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 dosing details in manuscript''' [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}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, q2wks {{#subobject:gu17g8|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://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
 
−
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 
−
|[[Urothelial_carcinoma_-_null_regimens#Placebo|Placebo]]
 
−
| 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====
 
−
*CheckMate 274: [[Surgery#Radical_surgery|Radical surgery]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Immunotherapy====
 
−
*[[Nivolumab (Opdivo)]] 240 mg IV once on day 1
 
−
'''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}}===
 
−
{| class="wikitable" style="color:white; background-color:#404040"
 
−
|<small>'''FDA-recommended dose'''</small>
 
 
|-
 
|-
 
|}
 
|}
Line 1,650: Line 72:
 
<div class="toccolours" style="background-color:#cbd5e8">
 
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*CheckMate 274: [[Surgery#Radical_surgery|Radical surgery]]
+
*CheckMate 274: [[Surgery#Radical_surgery|Radical surgery]]
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Immunotherapy====
 
−
*[[Nivolumab (Opdivo)]] 480 mg IV once on day 1
 
−
'''28-day cycle for up to 13 cycles (1 year)'''
 
−
</div></div>
 
−
===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] [https://clinicaltrials.gov/study/NCT02632409 NCT02632409]
 
−
##'''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]
 
−
#'''VOLGA:''' [https://clinicaltrials.gov/study/NCT04960709 NCT04960709]
 
−
==PGC {{#subobject:22e1d2|Regimen=1}}==
 
−
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
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, 100/2000/70 {{#subobject:29bee9|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/PMC3955198/ Mitin et al. 2013 (RTOG 02-33)]
 
−
|2002-2008
 
−
| style="background-color:#91cf61" |Non-randomized part of phase 2 RCT
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*RTOG 02-33, 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]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Paclitaxel (Taxol)]] 50 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
 
−
*[[Cisplatin (Platinol)]] 35 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
'''21-day cycle for 4 cycles'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, 160/2000/70 {{#subobject:ad1bc8|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/10.1200/jco.2010.28.18_suppl.lba4518 Paz-Ares et al 2010 (SOGUG 99/01)]
 
−
|2000-2007
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[Urothelial_carcinoma_-_null_regimens#Observation_2|Observation]]
 
−
| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>OS60: 60% vs 31%
 
−
|-
 
−
|}
 
−
''Note: This study prematurely closed due to poor recruitment and lacked adequate power to make firm conclusions, and has never been published in manuscript format to our knowledge.''
 
−
<div class="toccolours" style="background-color:#fdcdac">
 
−
====Eligibility criteria====
 
−
*SOGUG 99/01: pT3-4 and/or pN positive disease with adequate renal function (CrCl greater than 50 mL/min/1.73m<sup>2</sup>)
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[Surgery#Cystectomy|Cystectomy]]; the median time treatment started post-cystectomy was 48 days
 
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunotherapy====
−
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 8
+
*[[Nivolumab (Opdivo)]] 480 mg IV once on day 1
−
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
+
'''28-day cycle for up to 13 cycles (1 year)'''
−
*[[Cisplatin (Platinol)]] 70 mg/m<sup>2</sup> IV once on day 1
 
−
'''21-day cycle for 4 cycles'''
 
 
</div></div>
 
</div></div>
 
===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 dosing details in manuscript'''
+
#'''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] [https://clinicaltrials.gov/study/NCT02632409 NCT02632409]
−
#'''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. Epub 2013 Jul 1. [https://doi.org/10.1016/s1470-2045(13)70255-9 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955198/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23823157/ PubMed] [https://clinicaltrials.gov/study/NCT00055601 NCT00055601]
+
##'''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]
−
##'''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. Epub 2009 Jul 27. [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]
+
#'''VOLGA:''' [https://clinicaltrials.gov/study/NCT04960709 NCT04960709]
−
##'''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 dosing details in manuscript''' [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=
 
=Locally advanced or metastatic disease, first-line, platinum-ineligible=
 
==Pembrolizumab monotherapy {{#subobject:7fc2f6|Regimen=1}}==
 
==Pembrolizumab monotherapy {{#subobject:7fc2f6|Regimen=1}}==
Line 3,170: Line 1,529:
 
===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 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]
 
#'''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=
 
−
*[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
 
−
=Urine assays=
 
−
''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:Urothelial carcinoma regimens]]
 
[[Category:Urothelial carcinoma regimens]]
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
 
[[Category:Genitourinary cancers]]
 
[[Category:Genitourinary cancers]]

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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

ESMO

Older

NCCN

Older

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)
ESMO-MCBS (A)
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 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

Pembrolizumab monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Balar et al. 2017 (KEYNOTE-052)
ESMO-MCBS (3)
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 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

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

Carboplatin & Gemcitabine (GCb)

GCb: Gemcitabine & Carboplatin

Regimen variant #1, AUC 4.5/1000

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
Powles et al. 2020 (DANUBE) 2015-2017 Phase 3 (C) 1. Durvalumab Did not meet primary endpoint of OS More toxic
2. Durvalumab & Tremelimumab Might have inferior OS Not more toxic
Galsky et al. 2020 (IMvigor130) 2016-2018 Phase 3 (C) 1. Atezolizumab Did not meet primary endpoint of OS
2a. GCb & Atezolizumab
2b. GC & Atezolizumab 		Seems to have inferior OS

1Reported efficacy for EORTC 30986 is based on the 2011 update.
Note: this was the lower bound of AUC specified by DANUBE. Patients on the DANUBE trial received up to 6 cycles.

Chemotherapy

21-day cycles (see note) Patients who achieved complete response were given two additional cycles of treatment.


Regimen variant #2, AUC 5/1000

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 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

Note: this was the upper bound of AUC specified by DANUBE.

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #3, 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
  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: NCT04223856

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)
2. Pembrolizumab Not reported

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

CISCA

CISCA: CISplatin, Cyclophosphamide, Adriamycin (Doxorubicin)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sternberg et al. 1977 1976-1977 Non-randomized, fewer than 20 pts
Logothetis et al. 1990 1985-1989 Phase 3 (E-switch-ic) MVAC Inferior OS

Note: ORR for this arm of Logothetis et al. 1990 was 46% (95% CI 32-62) versus 65% (95% CI 52-77) in the control arm.

Chemotherapy

Supportive therapy

  • Forced mannitol diuresis with cisplatin

21-day cycle for up to 6 cycles

References

  1. 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. link to original article PubMed
  2. 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

Cisplatin & Gemcitabine (GC)

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

AIM pathway regimen 2022-08-01

Regimen variant #1, 70/2000; q3wk

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
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 primary endpoint of OS
2. Durvalumab & Tremelimumab Might have inferior OS
Galsky et al. 2020 (IMvigor130) 2016-2018 Phase 3 (C) 1. Atezolizumab Did not meet primary endpoint of OS
2a. GCb & Atezolizumab
2b. GC & Atezolizumab 		Seems to 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

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 (up to 6 cycles in CALGB 90601, DANUBE, KEYNOTE-361)


Regimen variant #2, 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 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 #3, 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 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
  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. EV-302: NCT04223856

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) & 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)
2. Pembrolizumab Not reported

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

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 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)
ESMO-MCBS (4)
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

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

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

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.

Prior treatment criteria

  • KEYNOTE-045: Exposure to platinum-based chemotherapy

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. 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
    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
  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 PubMed NCT03474107
  8. SWOG S1937: NCT04579224
  9. 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) Docetaxel Superior PFS (primary endpoint)
Median PFS: 5.4 vs 2.8 mo
(sHR 0.39, 95% CI 0.235-0.64)
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

FDA-recommended dose
Study Dates of enrollment Evidence Efficacy
Loriot et al. 2019 (BLC2001)
ESMO-MCBS (1)
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 days 1 to 21: 8 mg PO once per day
    • Cycle 1 day 22 onwards: If serum phosphorus level and tolerability are acceptable, increase to 9 mg PO once per day
    • Additional dose adjustments per package insert

28-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

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

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

Study Dates of enrollment Evidence Efficacy
Sharma et al. 2017 (CheckMate 275)
ESMO-MCBS (1)
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%

Prior treatment criteria

Immunotherapy

  • 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

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

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

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. 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
    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
  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 PubMed NCT03474107
  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)
ESMO-MCBS (4)
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)

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) 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

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. 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
    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

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)

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

Prior treatment criteria

  • KEYNOTE-045: Exposure to platinum-based chemotherapy

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. 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
    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
  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 PubMed NCT03474107
  5. 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)
ESMO-MCBS (3)
2017-10-08 to 2018-07-02 Phase 2 (RT) ORR: 44% (95% CI 35.2-53.2)
Powles et al. 2021 (EV-301)
ESMO-MCBS (4)
2018-2020 Phase 3 (E-RT-switch-ooc) Investigator's choice of:
1a. Docetaxel
1b. Paclitaxel
1c. Vinflunine 		Superior OS (primary endpoint)
Median OS: 12.9 vs 9 mo
(HR 0.70, 95% CI 0.56-0.89)

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 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

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
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