Bladder cancer
Page editor | Section editor | ||
---|---|---|---|
Michael J. Glover, MD Stanford University Palo Alto, CA |
Ali Raza Khaki, MD Stanford University Palo Alto, CA |
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: the page has adjuvant and perioperative regimens specific to bladder cancer as well as systemic regimens for the more general category of urothelial cancer.
- See the upper tract urothelial carcinoma page for regimens specific to UTUC.
53 regimens on this page
85 variants on this page
|
Guidelines
AUA, ASCO, ASTRO, SUO
- 2017: Chang et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline PubMed
EAU-ESMO
- 2019: Horwich et al. 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 PubMed
ESMO
- 2022: Powles et al. Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up PubMed
- 2019: eUpdate – Bladder Cancer Treatment Recommendations
- 2019: eUpdate – Bladder Cancer Treatment Recommendations - Subsequent treatments post-chemotherapy or immunotherapy
Older
- 2014: Bellmunt et al. Bladder cancer: ESMO Clinical Practice Guidelines PubMed
NCCN
Older
- 2017: Spiess et al. Bladder Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology PubMed
- 2009: Montie et al. Bladder cancer PubMed
SITC
- 2021: Galsky et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of urothelial cancer PubMed
Nonmuscle invasive bladder cancer
Bacillus Calmette-Guérin (BCG) monotherapy
AIM pathway regimen 2022-08-01 |
Regimen variant #1, low-dose (27 mg)
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ojea et al. 2007 (CUETO study 95011) | 1995-1998 | Phase 3 (E-esc) | 1. Mitomycin | Superior DFS |
2. BCG; very-low-dose | Did not meet primary endpoint of DFS |
Preceding treatment
- TURBT, within 14 to 21 days
Immunotherapy
- Bacillus Calmette-Guérin (Connaught strain) as follows:
- Cycle 1: 27 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36
- Cycles 2 to 7: 27 mg intravesicularly once on day 1
42-day cycle for 1 cycle, then 14 day cycles for 6 cycles
Regimen variant #2, intravesical (81 mg) & percutaneous, with maintenance therapy
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lamm et al. 2000 (SWOG 8507) | 1985-1988 | Phase 3 (E-RT-esc) | BCG; Intravesical & percutaneous BCG, without maintenance therapy | Superior RFS |
Immunotherapy, induction
- 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 (Connaught strain) 81 mg in 50.5 mL saline suspension is created and administered as follows:
- 50 mL (~80.2 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.
- 0.5 mL (~0.8 mg) applied once per day on days 1, 8, 15 to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).
3-week courses; each course is given at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, and 36 months after the start of induction therapy
Regimen variant #3, intravesical (81 mg) & percutaneous, without maintenance therapy
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lamm et al. 2000 (SWOG 8507) | 1985-1988 | Phase 3 (C) | BCG; Intravesical & percutaneous BCG, with maintenance therapy | Inferior RFS |
Immunotherapy
- Bacillus Calmette-Guérin (Connaught strain) 81 mg in 50.5 mL saline suspension is created and administered as follows:
- 50 mL (~80.2 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15, 22, 29, 36. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.
- 0.5 mL (~0.8 mg) applied once per day on days 1, 8, 15, 22, 29, 36 to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).
6-week course
Regimen variant #4, intravesical (120 mg) & percutaneous, with maintenance therapy
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lamm et al. 1991 (SWOG 8216) | 1983-1985 | Phase 3 (E-RT-switch-ooc) | Doxorubicin | Seems to have superior DFS |
Immunotherapy, induction
- 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 (Connaught strain) 120 mg (3 vials) in 50.5 mL saline suspension is created and administered as follows:
- 50 mL (~120 mg) intravesicularly once on day 1. Patients retain the BCG suspension for up to 2 hours if possible.
- 0.5 mL (~1.2 mg) applied once on day 1 to the upper part of the inner thigh
Given at 3 months, 6 months, 12 months, 18 months, and 24 months
Regimen variant #5, 150 mg
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Martínez-Piñeiro et al. 1990 | 1980-1988 | Phase 3 (E-switch-ooc) | 1. Doxorubicin 2. Thiotepa |
Superior RFS |
Note: details are very sparse in the abstract and this variant is probably only of historic interest.
Immunotherapy
- Bacillus Calmette-Guérin (BCG) 150 mg intravesicularly x 15 treatments
References
- Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. link to original article contains partial protocol 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. link to original article 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. link to original article contains dosing details in manuscript 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. link to original article 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. link to original article contains dosing details in manuscript PubMed
Intravesicular Gemcitabine monotherapy
Regimen variant #1, 1 treatment
AIM pathway regimen 2022-08-01 |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Messing et al. 2018 (SWOG S0337) | 2008-2012 | Phase 3 (E-esc) | Placebo (saline) | Superior TTR |
Preceding treatment
- TURBT, up to 3 hours prior
Chemotherapy
- Gemcitabine (Gemzar) 2000 mg in 100 mL of saline instilled intravesicularly for up to 60 minutes
One treatment
Regimen variant #2, 6 treatments
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Addeo et al. 2009 | 2003-2005 | Phase 3 (E-switch-ic) | Mitomycin | Superior DFS |
Chemotherapy
- Gemcitabine (Gemzar) 2000 mg in 50 mL of saline instilled intravesicularly for up to 60 minutes once per day on days 1, 8, 15, 22, 29, 36
6-week course
References
- Addeo R, Caraglia M, Bellini S, Abbruzzese A, Vincenzi B, Montella L, Miragliuolo A, Guarrasi R, Lanna M, Cennamo G, Faiola V, Del Prete S. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. J Clin Oncol. 2010 Feb 1;28(4):543-8. Epub 2009 Oct 19. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
Intravesicular Mitomycin monotherapy
Regimen variant #1, 30 mg x 12
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ojea et al. 2007 (CUETO study 95011) | 1995-1998 | Phase 3 (C) | 1. BCG; low-dose | Inferior DFS |
2. BCG; very-low-dose | Did not meet efficacy endpoints |
Preceding treatment
- TURBT, 14 to 21 days prior
Chemotherapy
- Mitomycin (Mutamycin) as follows:
- Cycles 1 to 3: 30 mg intravesicularly once per day on days 1 & 8
- Cycles 4 to 9: 30 mg intravesicularly once on day 1
14-day cycle for 9 cycles
Regimen variant #2, 40 mg x 11
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lammers et al. 2012 | 2003-2007 | Phase 3 (C) | KLH | Superior RFS |
Preceding treatment
Chemotherapy
- Mitomycin (Mutamycin) 40 mg intravesicularly once on day 1
7-day cycle for 4 cycles, then monthly cycle for 4 cycles, then 3-month cycle for 3 cycles
References
- CUETO study 95011: Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, Chantada V, Camacho JE, Piñeiro LM, Rodríguez RH, Isorna S, Blas M, Martínez-Piñeiro JA, Madero R; CUETO. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guérin (27 mg) versus very low-dose bacillus Calmette-Guérin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript PubMed
Nadofaragene firadenovec monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Boorjian et al. 2020 (rAd-IFN-CS-003) | 2016-2019 | Non-randomized (RT) |
Immunotherapy
- Nadofaragene firadenovec (Adstiladrin) 75 mL intravesicularly once on day 1
3-month cycle for 4 cycles
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. link to original article link to PMC article PubMed Clinical Trial Registry
Pembrolizumab monotherapy
Regimen
Study | Dates of enrollment | Evidence | |
---|---|---|---|
Balar et al. 2021 (KEYNOTE-057)
|
2015-2018 | Phase 2 (RT) |
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. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
Intravesicular Valrubicin monotherapy
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence |
---|---|---|
Steinberg et al. 2000 | 1993-1996 | Non-randomized (RT) |
Chemotherapy
- Valrubicin (Valstar) 800 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36
6-week course
References
- Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M; Valrubicin Study Group. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guérin refractory carcinoma in situ of the bladder. J Urol. 2000 Mar;163(3):761-7. Erratum in: J Urol. 2008 Jan;179(1):386. link to original article contains dosing details in abstract PubMed
Neoadjuvant chemotherapy
Cisplatin & Gemcitabine (GC)
GC: Gemcitabine, Cisplatin
Regimen variant #1, 70/2000; single-dose cisplatin
AIM pathway regimen 2022-08-01 |
Study | Evidence |
---|---|
Dash et al. 2008 | Retrospective |
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles
Subsequent treatment
Regimen variant #2, 70/2000; split-dose cisplatin
AIM pathway regimen 2022-08-01 |
Study | Evidence |
---|---|
Dash et al. 2008 | Retrospective |
Chemotherapy
- Cisplatin (Platinol) 35 mg/m2 IV once per day on days 1 & 8
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles
Subsequent treatment
Regimen variant #3, 70/2500
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Pfister et al. 2022 (GETUG-AFU V05 VESPER) | 2013-2018 | Phase 3 (C) | ddMVAC x 6 | Might have inferior PFS |
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once per day on day 1
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles
Supportive therapy
- Filgrastim (Neupogen) 5 mcg/kg/ day as a subcutaneous injection from day 3 to day 7 if febrile neutropenia or if cycle shift ≥ 7 days due to neutropenia.
- Antiemetics used included Aprepitant (Emend), Ondansetron (Zofran), and Methylprednisolone (Solumedrol).
Subsequent treatment
- Cystectomy to be performed up to 8 weeks after completion of chemotherapy
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. link to PMC article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- KEYNOTE-B15: Clinical Trial Registry
- KEYNOTE-866: Clinical Trial Registry
Cisplatin & Gemcitabine (GC) & Pembrolizumab
GC & Pembrolizumab: Gemcitabine, Cisplatin, Pembrolizumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Rose et al. 2021 (LCCC 1520) | 2016-2020 | Phase 2 |
Chemotherapy
- Cisplatin (Platinol) 35 mg/m2 IV once per day on days 1 & 8
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
Immunotherapy
- Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
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. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
- KEYNOTE-866: Clinical Trial Registry
MCV
MCV: Methotrexate, Cisplatin, Vinblastine
CMV: Cisplatin, Methotrexate, Vinblastine
Regimen variant #1, 2 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kaufman et al. 1993 | NR | Phase 2 | ||
Tester et al. 1996 (RTOG 88-02) | 1988-1990 | Phase 2 | ||
Shipley et al. 1998 (RTOG 89-03) | 1990-1993 | Phase 3 (E-esc) | No neoadjuvant chemotherapy | Did not meet primary endpoint of OS |
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
- Cisplatin (Platinol) 70 mg/m2 IV once on day 2
- Vinblastine (Velban) 3 mg/m2 IV once per day on days 2, 15, 22
28-day cycle for 2 cycles
Subsequent treatment
- Kaufman et al. 1993, CR: Cisplatin & RT consolidation
- RTOG 88-02 & RTOG 89-03: Cisplatin & RT induction
Regimen variant #2, 3 cycles
AIM pathway regimen 2022-08-01 |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Griffiths et al. 1999 (BA06 30894) | 1989-1995 | Phase 3 (E-esc) | No neoadjuvant therapy | Seems to have superior OS1 Median OS: 44 vs 37 mo (HR 0.84, 95% CI 0.72-0.99) |
Zapatero et al. 2000 | 1989-1997 | Non-randomized |
1Reported efficacy for BA06 30894 is based on the 2011 update.
Eligibility criteria
- Zapatero et al. 2000: T2 to T4 Nx M0 disease
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV bolus once per day on days 1 & 8
- Cisplatin (Platinol) 100 mg/m2 IV once on day 2, before hydration
- Vinblastine (Velban) 4 mg/m2 IV bolus once per day on days 1 & 8
Supportive therapy
- BA06 30894: Folinic acid (Leucovorin) 15 mg/m2 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/m2)
21-day cycle for 3 cycles
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: RT consolidation which begins 4 to 6 weeks after completion of chemotherapy
- Zapatero et al. 2000, patients without CR who were surgical candidates: cystectomy
References
- Kaufman DS, Shipley WU, Griffin PP, Heney NM, Althausen AF, Efird JT. Selective bladder preservation by combination treatment of invasive bladder cancer. N Engl J Med. 1993 Nov 4;329(19):1377-82. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article 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); 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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript 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. link to original article PubMed
MVAC
MVAC: Methotrexate, Vinblastine, Adriamycin (Doxorubicin), Cisplatin
Regimen variant #1, 2 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kitamura et al. 2014 (JCOG0209) | 2003-2009 | Phase 3 (E-esc) | No neoadjuvant therapy | Might have superior OS Median OS: 102 vs 82 mo (HR 0.65, 99.99% CI 0.19-2.18) |
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
- Vinblastine (Velban) 3 mg/m2 IV once per day on days 2, 15, 22
- Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 2
- Cisplatin (Platinol) 70 mg/m2 IV once on day 2
28-day cycle for 2 cycles
Subsequent treatment
Regimen variant #2, 3 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Grossman et al. 2003 (SWOG S8710) | 1987-1998 | Phase 3 (E-esc) | No neoadjuvant therapy | Might have superior OS |
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
- Vinblastine (Velban) 3 mg/m2 IV once per day on days 2, 15, 22
- Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 2
- Cisplatin (Platinol) 70 mg/m2 IV once on day 2
28-day cycle for 3 cycles
Subsequent treatment
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. link to original article contains dosing details in manuscript 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. link to original article 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. link to original article PubMed
MVAC, dose-dense
ddMVAC: dose-dense Methotrexate, Vinblastine, Adriamycin (Doxorubicin), Cisplatin
AMVAC: Accelerated Methotrexate, Vinblastine, Adriamycin (Doxorubicin), Cisplatin
Regimen variant #1 (AMVAC), 3 cycles
Study | Dates of enrollment | Evidence |
---|---|---|
Plimack et al. 2014 (FER-GU-026) | 2009-2012 | Phase 2 |
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV over 30 minutes once on day 1
- Vinblastine (Velban) 3 mg/m2 IV push once on day 1
- Doxorubicin (Adriamycin) 30 mg/m2 IV push once on day 1
- Cisplatin (Platinol) by the following laboratory-based criteria:
- Patients with CrCl of at least 60 mL/min/1.73m2: 70 mg/m2 IV once on day 1
- Split dose could be used at physician discretion for patients with CrCl less than 60 mL/min/1.73m2: 35 mg/m2 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
Subsequent treatment
- Radical cystectomy with bilateral lymphadenectomy, within 4 to 8 weeks after the last cycle of chemotherapy
Regimen variant #2 (ddMVAC), 4 cycles
Study | Dates of enrollment | Evidence |
---|---|---|
Choueiri et al. 2014 (DFCI 08-208) | 2008-2012 | Phase 2 |
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV over 30 minutes once on day 1
- Vinblastine (Velban) 3 mg/m2 IV push once on day 2
- Doxorubicin (Adriamycin) 30 mg/m2 IV push once on day 2
- Cisplatin (Platinol) 70 mg/m2 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
Subsequent treatment
- Cystectomy to be performed 4 to 10 weeks after completion of chemotherapy
Regimen variant #3 (ddMVAC), 6 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Pfister et al. 2022 (GETUG-AFU V05 VESPER) | 2013-2018 | Phase 3 (E-esc) | Cisplatin and Gemcitabine (GC) | Might have superior PFS (primary endpoint) PFS36: 64% vs 56% (HR 0.77, 95% CI 0.57-1.02) |
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV over 30 minutes once on day 1
- Vinblastine (Velban) 3 mg/m2 IV push once on day 2
- Doxorubicin (Adriamycin) 30 mg/m2 IV push once on day 2
- Cisplatin (Platinol) 70 mg/m2 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
Subsequent treatment
- Cystectomy to be performed 4 to 10 weeks after completion of chemotherapy
References
- DFCI 08-208: Choueiri TK, Jacobus S, Bellmunt J, Qu A, Appleman LJ, Tretter C, Bubley GJ, Stack EC, Signoretti S, Walsh M, Steele G, Hirsch M, Sweeney CJ, Taplin ME, Kibel AS, Krajewski KM, Kantoff PW, Ross RW, Rosenberg JE. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol. 2014 Jun 20;32(18):1889-94. Epub 2014 May 12. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- 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. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- 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. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
Pembrolizumab monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Necchi et al. 2018 (PURE-01) | 2017-2018 | Phase 2 |
Subsequent treatment
- Radical cystectomy, within 1 to 3 weeks after the last cycle of chemotherapy
References
- PURE-01: Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucianò R, Colecchia M, Giannatempo P, Mortarini R, Bianchi M, Farè E, Monopoli F, Colombo R, Gallina A, Salonia A, Messina A, Ali SM, Madison R, Ross JS, Chung JH, Salvioni R, Mariani L, Montorsi F. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 2018 Oct 20. Link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- 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. link to original article PubMed
Induction chemoradiotherapy
Cisplatin & RT
Cisplatin & RT: Cisplatin & Radiation Therapy
Regimen variant #1, cisplatin 40 mg/m2 qwk x 3
Study | Dates of enrollment | Evidence |
---|---|---|
Zapatero et al. 2009 | 1990-2007 | Non-randomized |
Hagan et al. 2003 (RTOG 97-06) | 1998-2000 | Phase 1/2 |
Note: Dosing is per Figure 1 of Zapatero et al. 2009.
Eligibility criteria
- Zapatero et al. 2009: T2 to T4 N0 M0 disease
- RTOG 97-06: T2 to T4a N0 M0 disease without hydronephrosis
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1 & 2, given first
7-day cycle for 3 cycles
Radiotherapy
- Concurrent 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." 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.
Subsequent treatment
- 3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
- RTOG 97-06, patients with complete regression (R0): Cisplatin & RT consolidation
- RTOG 97-06, nonresponders: Cystectomy
Regimen variant #2, cisplatin 70 mg/m2 q3wk x 2
Study | Dates of enrollment | Evidence |
---|---|---|
Tester et al. 1996 (RTOG 88-02) | 1988-1990 | 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.
Preceding treatment
- MCV x 2
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
21-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)
4.5-week course
Subsequent treatment
- RTOG 88-02, patients with CR: Cisplatin & RT consolidation
- RTOG 88-02, patients without CR: Immediate cystectomy
Regimen variant #3, cisplatin 100 mg/m2 q3wk x 2
Study | Dates of enrollment | Evidence |
---|---|---|
Shipley et al. 1988 | 1980-1985 | Non-randomized |
Shipley et al. 1998 (RTOG 89-03) | 1990-1993 | 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.
Preceding treatment
- RTOG 89-03: MCV versus no neoadjuvant therapy
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV once on day 1
21-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)
4.5-week course
Subsequent treatment
- RTOG 89-03, patients not in CR: Cystectomy
- RTOG 89-03, patients in CR: Cisplatin & RT consolidation
References
- Shipley WU, Prout GR Jr, Einstein AB, Coombs LJ, Wajsman Z, Soloway MS, Englander L, Barton BA, Hafermann MD. Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery. JAMA. 1987 Aug 21;258(7):931-5. link to original article 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. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article contains dosing details in manuscript 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript PubMed
- SunRISe-2: Clinical Trial Registry
- SWOG S1806: Clinical Trial Registry
Cisplatin & Fluorouracil (CF) & RT
Regimen variant #1, 90/2400/24
Study | Dates of enrollment | Evidence |
---|---|---|
Kaufman et al. 2000 (RTOG 95-06) | 1995-1997 | Phase 1/2 |
Eligibility criteria
- RTOG 95-06: Clinical T2 to T4a Nx M0 disease without hydronephrosis and CrCl of at least 60 mL/min/1.73m2
Chemotherapy
- Cisplatin (Platinol) 15 mg/m2 IV over 60 minutes once per day on days 1 to 3, given second, before radiation
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 3, given first
Supportive therapy
- IV hydration at 500 mL/H (no total volume specified) prior to 5-FU
14-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 3 Gy fractions twice per day, with the first fraction of each day given 1 to 2 hours after completion of chemotherapy and at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total induction dose: 24 Gy), administered to the whole bladder, bladder tumor volume, and pelvic lymph nodes
17-day course
Dose modifications
- Patients with grade III hematologic toxicity, defined as platelets less than 50 x 109/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 109/L and ANC at least 1800/μL.
Subsequent treatment
- Treatment followed by repeat cystoscopy, biopsy, and urine cytology in week 7 or 8
- RTOG 95-06, patients with complete response: CF & RT consolidation in week 9
- RTOG 95-06, incomplete responders: recommended to undergo radical cystectomy
Regimen variant #2, 135/2400/40.3
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Coen et al. 2018 (RTOG 0712) | 2008-2014 | Randomized Phase 2 (C) | Gemcitabine & RT | Not reported1 |
1This trial was not statistically powered to compare regimens.
Note: Treatment was followed by repeat cystoscopy and biopsy.
Chemotherapy
- Cisplatin (Platinol) 15 mg/m2 IV once per day on days 1 to 3, 8 to 10, 15 to 17
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 3, 15 to 17
Radiotherapy
- Concurrent radiation therapy, with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:
- 1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
- 1.5 Gy fractions to the bladder every evening on days 1 to 5
- 1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
- Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
17-day course
Subsequent treatment
- RTOG 0712, patients with complete response: CF & RT consolidation
- RTOG 0712, incomplete responders: Radical cystectomy
Regimen variant #3, 135/3600/40.3
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mitin et al. 2013 (RTOG 02-33) | 2002-2008 | Randomized Phase 2 (E-switch-ic) | Cisplatin, Paclitaxel, RT | Not reported |
Note: Patients underwent reevaluation for response on week 7.
Chemotherapy
- Cisplatin (Platinol) 15 mg/m2 IV once per day on days 1 to 3
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 3
7-day cycle for 3 cycles
Radiotherapy
- Concurrent radiation therapy, with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:
- 1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
- 1.5 Gy fractions to the bladder every evening on days 1 to 5
- 1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
- Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
3-week course
Subsequent treatment
- RTOG 02-33, patients with less than stage T1 disease: CF & RT consolidation
- RTOG 02-33, patients with at least stage T1 disease: Radical cystectomy on week 9, then adjuvant PGC
References
- RTOG 95-06: Kaufman DS, Winter KA, Shipley WU, Heney NM, Chetner MP, Souhami L, Zlotecki RA, Sause WT, True LD. The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response. Oncologist. 2000;5(6):471-6. link to original article contains dosing details in manuscript 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
Cisplatin, Paclitaxel, RT
Regimen variant #1, 40/50 x 3 + 40.3 Gy
Study | Dates of enrollment | Evidence |
---|---|---|
Kaufman et al. 2008 (RTOG 99-06) | NR in abstract | 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.
Preceding treatment
- TURBT, within 4 to 6 weeks
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 & 2
- Paclitaxel (Taxol) 50 mg/m2 IV once on day 1
7-day cycle for 3 cycles
Radiotherapy
- Concurrent radiation therapy, with twice per day RT on days 1 to 5, 8 to 12, 15 to 17; 4 to 6 hours between radiation sessions. Kaufman et al. 2009 (RTOG 99-06) was unclear about exact radiation treatment plan, but it appears to have been the same as described in Mitin et al. 2013 (RTOG 02-33), which used radiation as follows:
- 1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
- 1.5 Gy fractions to the bladder every evening on days 1 to 5
- 1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
- Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
3-week course
Subsequent treatment
- RTOG 02-33, patients with less than stage ypT1 disease: Cisplatin, paclitaxel, RT consolidation
- RTOG 02-33, patients with at least stage ypT1 disease: Radical cystectomy, then adjuvant GC
Regimen variant #2, 45/50 x 3 + 40.3 Gy
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mitin et al. 2013 (RTOG 02-33) | 2002-2008 | Randomized Phase 2 (E-switch-ic) | Cisplatin, Fluorouracil, RT | Not reported |
Chemotherapy
- Cisplatin (Platinol) 15 mg/m2 IV once per day on days 1 to 3
- Paclitaxel (Taxol) 50 mg/m2 IV once on day 1
7-day cycle for 3 cycles
Radiotherapy
- Concurrent radiation therapy, with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:
- 1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
- 1.5 Gy fractions to the bladder every evening on days 1 to 5
- 1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
- Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
3-week course
Subsequent treatment
- On week 7, patients under reevaluation for response
- RTOG 02-33, patients with less than stage ypT1 disease: Cisplatin, paclitaxel, RT consolidation
- RTOG 02-33, patients with at least stage ypT1 disease: Radical cystectomy on week 9, then adjuvant PGC
References
- Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. link to original article contains dosing details in manuscript 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article PubMed
Fluorouracil, Mitomycin, RT
Fluorouracil, Mitomycin, RT: Fluorouracil, Mitomycin, Radiation Therapy
Regimen variant #1, 55 Gy
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
James et al. 2012 (BC2001) | 2001-2008 | Phase 3 (E-esc) | Radiation therapy | Might have superior DFS1 (HR 0.78, 95% CI 0.60-1.02) |
1Reported efficacy is based on the 2022 update.
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2/day IV continuous infusion for 10 total days (total dose: 5000 mg/m2) during radiation fractions 1 to 5, 16 to 20
- Mitomycin (Mutamycin) 12 mg/m2 IV bolus once on day 1
Radiotherapy
- External beam radiotherapy, 2.75 Gy fractions x 20 fractions (total dose: 55 Gy)
4-week course
Regimen variant #2, 64 Gy
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
James et al. 2012 (BC2001) | 2001-2008 | Phase 3 (E-esc) | Radiation therapy | Might have superior DFS1 (HR 0.78, 95% CI 0.60-1.02) |
1Reported efficacy is based on the 2022 update.
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2/day IV continuous infusion for 10 total days (total dose: 5000 mg/m2) during radiation fractions 1 to 5, 16 to 20
- Mitomycin (Mutamycin) 12 mg/m2 IV bolus once on day 1
Radiotherapy
- External beam radiotherapy, 2 Gy fractions x 32 fractions (total dose: 64 Gy)
6.5-week course
References
- BC2001: James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. link to original article link to supplementary index contains dosing details in manuscript PubMed Clinical Trial Registry
- 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. link to original article PubMed
Gemcitabine & RT
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Coen et al. 2018 (RTOG 0712) | 2008-2014 | Randomized Phase 2 (E-de-esc) | CF & RT | Not reported1 |
1This trial was not statistically powered to compare regimens.
Note: Treatment was followed by repeat cystoscopy and biopsy.
Chemotherapy
- Gemcitabine (Gemzar) 27 mg/m2 IV once per day on days 1, 4, 8, 11
14-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy 2 Gy per day to the pelvis on days 1 to 10, then 2 Gy per day to the bladder on days 11 to 14, then 2 Gy per day to the bladder tumor on days 15 to 20
- Total doses: pelvis: 20 Gy; whole bladder: 28 Gy; bladder tumor volume 40 Gy
3-week course
Subsequent treatment
- RTOG 0712, patients with complete response: Gemcitabine & RT consolidation
- RTOG 0712, incomplete responders: Radical cystectomy
References
- RTOG 0712: Coen JJ, Zhang P, Saylor PJ, Lee CT, Wu CL, Parker W, Lautenschlaeger T, Zietman AL, Efstathiou JA, Jani AB, Kucuk O, Souhami L, Rodgers JP, Sandler HM, Shipley WU. Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712-a randomized phase II trial. J Clin Oncol. 2019 Jan 1;37(1):44-51. Epub 2018 Nov 15. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- SunRISe-2: Clinical Trial Registry
Paclitaxel & RT
Regimen variant #1, normo-fractionated RT
Study | Dates of enrollment | Evidence |
---|---|---|
Zapatero et al. 2012 | 1990-2010 | Non-randomized, <20 pts |
Note: Patients who had "mild renal insufficiency" received paclitaxel instead of cisplatin and had T2 to T4 N0 M0 disease.
Chemotherapy
- Paclitaxel (Taxol) 50 mg/m2 IV once per week, given 6 hours before radiation therapy
Radiotherapy
- Concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.
One course
Subsequent treatment
- 3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
- Zapatero et al. 2012, patients with complete regression (R0): Paclitaxel & RT consolidation
- Zapatero et al. 2012, nonresponders: Cystectomy
Regimen variant #2, AHFRT
Study | Dates of enrollment | Evidence |
---|---|---|
Zapatero et al. 2012 | 1990-2010 | Non-randomized, <20 pts |
Note: Patients who had "mild renal insufficiency" received paclitaxel instead of cisplatin and had T2 to T4 N0 M0 disease.
Chemotherapy
- Paclitaxel (Taxol) 50 mg/m2 IV once per week, given 6 hours before radiation therapy
Radiotherapy
- Concurrent 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
Subsequent treatment
- 3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
- Zapatero et al. 2012, patients with complete regression (R0): Paclitaxel & RT consolidation
- Zapatero et al. 2012, nonresponders: Cystectomy
Regimen variant #3, 64.8 Gy
Study | Dates of enrollment | Evidence |
---|---|---|
Michaelson et al. 2016 (RTOG 0524) | 2005-2013 | Phase 1/2 |
Chemotherapy
- Paclitaxel (Taxol) 50 mg/m2 IV once per week for 7 weeks
Radiotherapy
- Concurrent daily radiation therapy 64.8 Gy total in 36 fractions
One course
References
- Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. link to original article contains dosing details in manuscript 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. link to original article link to PMC article PubMed
Radiation therapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Zapatero et al. 2000 | 1989-1997 | Non-randomized | ||
James et al. 2012 (BC2001) | 2001-2008 | Phase 3 (C) | Fluorouracil, Mitomycin, RT | Might have inferior DFS1 |
1Reported efficacy is based on the 2022 update.
Preceding treatment
- Zapatero et al. 2000, depending on response: MCV x 3 or cystectomy
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.
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. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript 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. link to original article 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. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- 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. link to original article PubMed
Consolidation chemoradiotherapy
Cisplatin & RT
Cisplatin & RT: Cisplatin & Radiation Therapy
Regimen variant #1, cisplatin 40 mg/m2/wk x 2, AHFRT
Study | Dates of enrollment | Evidence |
---|---|---|
Zapatero et al. 2000 | 1989-1997 | Non-randomized |
Hagan et al. 2003 (RTOG 97-06) | 1998-2000 | Phase 1/2 |
Note: Dosing is per Figure 1 of Zapatero et al. 2010.
Preceding treatment
- Zapatero et al. 2000, depending on response: Cisplatin & RT induction or cystectomy
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1 & 2, given first
7-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.
Subsequent treatment
- RTOG 97-06: Adjuvant MCV
Regimen variant #2, cisplatin 70 mg/m2 x 1
Study | Dates of enrollment | Evidence |
---|---|---|
Tester et al. 1996 (RTOG 88-02) | 1988-1990 | Phase 2 |
Preceding treatment
- RTOG 88-02, depending on response, treatment preceded by: cisplatin & RT induction or cystectomy
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
Radiotherapy
- Concurrent radiation therapy, 1.8 Gy fractions x 14 fractions (total dose in consolidation phase: 25.2 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)
3-week course
Regimen variant #3, cisplatin 100 mg/m2 x 1
Study | Dates of enrollment | Evidence |
---|---|---|
Shipley et al. 1998 (RTOG 89-03) | 1990-1993 | Non-randomized part of phase 3 RCT |
Preceding treatment
- RTOG 89-03, depending on response, treatment preceded by: cisplatin & RT induction or cystectomy
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV once on day 1
Radiotherapy
- Concurrent radiation therapy, 1.8 Gy fractions x 14 fractions (total dose in consolidation phase: 39.6 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)
3-week course
References
- RTOG 88-02: Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article 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. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article PubMed
Cisplatin & Fluorouracil (CF) & RT
Regimen variant #1, 30/1200 x 2 + 64.3 Gy
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mitin et al. 2013 (RTOG 02-33) | 2002-2008 | Randomized Phase 2 (E-switch-ic) | Cisplatin, Paclitaxel, RT | Not reported |
Note: Consolidation starts starts on week 8.
Preceding treatment
- Cisplatin, 5-FU, RT induction
Chemotherapy
Starts on week 8.
- Cisplatin (Platinol) 15 mg/m2 IV once per day on days 1 & 2
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 3
7-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 1.5 Gy fractions x 16 fractions, given twice per day x 8 days. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.
2-week course
Subsequent treatment
- Adjuvant PGC
Regimen variant #2, 45/1200 x 2 + 44 Gy
Study | Dates of enrollment | Evidence |
---|---|---|
Kaufman et al. 2000 (RTOG 95-06) | 1995-1997 | Phase 1/2 |
Treatment starts on week 9.
Preceding treatment
- RTOG 95-06, depending on response, treatment preceded by: cisplatin, fluorouracil, RT induction or cystectomy
Chemotherapy
- Cisplatin (Platinol) 15 mg/m2 IV over 60 minutes once per day on days 1 to 3, given second
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 3, given first
14-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 2.5 Gy fractions twice per day, with at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total consolidation dose: 20 Gy), administered to the whole bladder and bladder tumor volume. The total dose to the whole bladder and bladder tumor volume was 44 Gy in 16 fractions; the total dose to the pelvic lymph nodes was 24 Gy in 8 fractions.
Supportive therapy
- IV hydration at 500 mL/H (no total volume specified) prior to 5-FU
17-day course
Dose modifications
- Patients with grade III hematologic toxicity, defined as platelets less than 50 x 109/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 109/L and ANC at least 1800/μL.
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. link to original article contains dosing details in manuscript 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article PubMed
Cisplatin, Paclitaxel, RT
Regimen variant #1, 30/50 x 2 + 64.3 Gy
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mitin et al. 2013 (RTOG 02-33) | 2002-2008 | Randomized Phase 2 (E-switch-ic) | Cisplatin, 5-FU, RT | Not reported |
Note: Consolidation starts starts on week 8.
Preceding treatment
- Cisplatin, Paclitaxel, RT induction
Chemotherapy
- Cisplatin (Platinol) 15 mg/m2 IV once per day on days 1 & 2
- Paclitaxel (Taxol) 50 mg/m2 IV once on day 1
7-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 1.5 Gy fractions x 16 fractions, given twice per day x 8 days. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.
2-week course
Subsequent treatment
- Adjuvant PGC
Regimen variant #2, 40/50 x 2 + 64.3 Gy
Study | Dates of enrollment | Evidence |
---|---|---|
Kaufman et al. 2008 (RTOG 99-06) | NR in abstract | Phase 1/2 |
Consolidation starts starts on week 8.
Preceding treatment
- Cisplatin, Paclitaxel, RT induction
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 & 2
- Paclitaxel (Taxol) 50 mg/m2 IV once on day 1
7-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 1.5 Gy fractions x 16 fractions, given twice per day (4 to 6 hour interval between treatments) on days 1 to 5, 8 to 10. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.
2-week course
Subsequent treatment
- Adjuvant GC
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. link to original article contains dosing details in manuscript 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article PubMed
Paclitaxel & RT
Regimen variant #1, normo-fractionated RT
Study | Dates of enrollment | Evidence |
---|---|---|
Zapatero et al. 2012 | 1990-2010 | Non-randomized, <20 pts |
Preceding treatment
- Zapatero et al. 2012, depending on response, treatment preceded by: paclitaxel & RT induction or cystectomy
Chemotherapy
- Paclitaxel (Taxol) 50 mg/m2 IV once per week, given 6 hours before radiation therapy
Radiotherapy
- Concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.
One course
Regimen variant #2, AHFRT
Study | Dates of enrollment | Evidence |
---|---|---|
Zapatero et al. 2012 | 1990-2010 | Non-randomized, <20 pts |
Preceding treatment
- Zapatero et al. 2012, depending on response, treatment preceded by: paclitaxel & RT induction or cystectomy
Chemotherapy
- Paclitaxel (Taxol) 50 mg/m2 IV once per week, given 6 hours before radiation therapy
Radiotherapy
- Concurrent radiation therapy, 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.
One course
References
- Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. link to original article contains dosing details in manuscript PubMed
Adjuvant therapy
Cisplatin & Gemcitabine (GC)
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Kaufman et al. 2008 (RTOG 99-06) | NR in abstract | Phase 1/2 |
Preceding treatment
- RTOG 99-06, depending on response to induction, treatment starts: 12 weeks after cisplatin, paclitaxel, RT consolidation or 8 weeks after cystectomy
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
28-day cycle for 4 cycles
References
- Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. link to original article contains dosing details in manuscript 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article PubMed
Cisplatin & Methotrexate
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Lehmann et al. 2005 (AUO-AB 05/95) | 1994-2000 | Phase 3 (E-de-esc) | M-VEC x 3 | Inconclusive whether non-inferior PFS | Less toxic |
Preceding treatment
Chemotherapy
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. link to original article PubMed
MCV
MCV: Methotrexate, Cisplatin, Vinblastine
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Hagan et al. 2003 (RTOG 97-06) | 1998-2000 | Phase 1/2 |
Begins 8 weeks after consolidation. Note that only 45% of patients in RTOG 97-06 were able to complete all 3 cycles of MCV.
Preceding treatment
- Cisplatin & RT consolidation
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
- Cisplatin (Platinol) 25 mg/m2 IV once per day on days 2 to 4
- Vinblastine (Velban) 3 mg/m2 IV once per day on days 2, 15, 22
28-day cycle for 3 cycles
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. link to original article contains dosing details in manuscript 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article PubMed
Nivolumab monotherapy
Regimen variant #1, q2wks
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | |
---|---|---|---|---|---|
Bajorin et al. 2021 (CheckMate 274)
|
2016-2020 | Phase 3 (E-RT-esc) | Placebo | Superior DFS Median DFS: 20.8 vs 10.8 mo (HR 0.70, 98.22% CI 0.55-0.90) |
Preceding treatment
- CheckMate 274: Radical surgery
Regimen variant #2, q4wks
FDA-recommended dose |
Note: this is not the dose that was used in the registration study, CheckMate 274.
Preceding treatment
- CheckMate 274: Radical surgery
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. link to original article link to PMC article PubMed Clinical Trial Registry
- 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
- VOLGA: Clinical Trial Registry
PGC
PGC: Paclitaxel, Gemcitabine, Cisplatin
PCG: Paclitaxel, Cisplatin, Gemcitabine
Regimen variant #1, 100/2000/70
Study | Dates of enrollment | Evidence |
---|---|---|
Mitin et al. 2013 (RTOG 02-33) | 2002-2008 | Non-randomized part of phase 2 RCT |
Preceding treatment
- RTOG 02-33, depending on response, adjuvant chemotherapy began: 12 weeks after cisplatin, paclitaxel, RT versus cisplatin, 5-FU, RT or 8 weeks after cystectomy
Chemotherapy
- Paclitaxel (Taxol) 50 mg/m2 IV once per day on days 1 & 8
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
- Cisplatin (Platinol) 35 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles
Regimen variant #2, 160/2000/70
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paz-Ares et al 2010 (SOGUG 99/01) | 2000-2007 | Phase 3 (E-esc) | Observation | Superior OS |
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.
Eligibility criteria
- SOGUG 99/01: pT3-4 and/or pN positive disease with adequate renal function (CrCl greater than 50 mL/min/1.73m2)
Preceding treatment
- Cystectomy; the median time treatment started post-cystectomy was 48 days
Chemotherapy
- Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1 & 8
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
21-day cycle for 4 cycles
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. link to abstract contains dosing details in manuscript
- 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. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- 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. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article PubMed
Locally advanced or metastatic disease, first-line, platinum-ineligible
Pembrolizumab monotherapy
Regimen
Study | Dates of enrollment | Evidence | Efficacy | |
---|---|---|---|---|
Balar et al. 2017 (KEYNOTE-052)
|
2015-2016 | Phase 2 (RT) | ORR: 24% (95% CI 20-29) |
References
- KEYNOTE-052: Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. Epub 2017 Sep 26. link to original article PubMed Clinical Trial Registry
- 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
- 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 (Grouped with Cisplatin & Gemcitabine) | (Grouped with Cisplatin & Gemcitabine) More toxic |
2. Durvalumab & Tremelimumab, then Durvalumab maintenance | Might have inferior OS | (Grouped with Cisplatin & Gemcitabine) 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
- Carboplatin (Paraplatin) AUC 4.5 IV over 60 minutes once on day 1, given second
- Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 minutes once per day on days 1 & 8, given first
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, <20 pts | ||
Powles et al. 2020 (DANUBE) | 2015-2017 | Phase 3 (C) | 1. Durvalumab | Did not meet primary endpoint of OS (Grouped with Cisplatin & Gemcitabine) |
2. Durvalumab & Tremelimumab, then Durvalumab maintenance | 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
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
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
- Carboplatin (Paraplatin) AUC 5 IV over 30 to 60 minutes once on day 2
- Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 to 60 minutes once per day on days 1 & 8
21-day cycle for up to 6 cycles
References
- Carles J, Nogué M, Domènech M, Pérez C, Saigí E, Villadiego K, Guasch I, Ibeas R. Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function. Oncology. 2000 Jun;59(1):24-7. link to original article contains dosing details in abstract PubMed
- Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. link to original article contains dosing details in manuscript PubMed
- EORTC 30986: De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Skoneczna I, Marreaud S, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol. 2009 Nov 20;27(33):5634-9. Epub 2009 Sep 28. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
- 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
- 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 Clinical Trial Registry
- 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 Clinical Trial Registry
- 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 Clinical Trial Registry
- EV-302: Clinical Trial Registry
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 Median OS: 17 vs 14.3 mo (HR 0.86, 95% CI 0.72-1.02) |
2. Pembrolizumab | Not reported |
Chemotherapy
- Carboplatin (Paraplatin) as follows:
- Cycles 1 up to 6: AUC 5 IV once on day 1
- Gemcitabine (Gemzar) as follows:
- Cycles 1 up to 6: 1000 mg/m2 IV once per day on days 1 & 8
Immunotherapy
- Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles
References
- KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
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
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 225 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 6 cycles
References
- ECOG E2896: Vaughn DJ, Manola J, Dreicer R, See W, Levitt R, Wilding G. Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group. Cancer. 2002 Sep 1;95(5):1022-7. link to original article contains dosing details in abstract PubMed
- ECOG E4897: Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
CISCA
CISCA: CISplatin, Cyclophosphamide, Adriamycin (Doxorubicin)
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sternberg et al. 1977 | 1976-1977 | Non-randomized, <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
- Cyclophosphamide (Cytoxan) 650 mg/m2 IV once on day 1
- Cisplatin (Platinol) 100 mg/m2 IV once on day 2
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 2
Supportive therapy
- Forced mannitol diuresis with cisplatin
21-day cycle for up to 6 cycles
References
- Sternberg JJ, Bracken RB, Handel PB, Johnson DE. Combination chemotherapy (CISCA) for advanced urinary tract carcinoma: a preliminary report. JAMA. 1977 Nov 21;238(21):2282-7. link to original article PubMed
- Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. 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, <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 (Grouped with Carboplatin & Gemcitabine) |
2. Durvalumab & Tremelimumab, then Durvalumab maintenance | Might have inferior OS (Grouped with Carboplatin & Gemcitabine) | |||
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
- Cisplatin (Platinol) 70 mg/m2 IV over 30 to 60 minutes once on day 1 or 2
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
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 (Grouped with Carboplatin & Gemcitabine) | (Grouped with Carboplatin & Gemcitabine) More toxic |
2. Durvalumab & Tremelimumab, then Durvalumab maintenance | Might have inferior OS (Grouped with Carboplatin & Gemcitabine) | (Grouped with Carboplatin & Gemcitabine) Not more toxic |
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1 or 2
- Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 to 60 minutes once per day on days 1 & 8
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, <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 (Grouped with Carboplatin & Gemcitabine) |
2. Durvalumab & Tremelimumab, then Durvalumab maintenance | Might have inferior OS (Grouped with Carboplatin & Gemcitabine) |
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
- Cisplatin (Platinol) 70 mg/m2 IV over 30 to 60 minutes once on day 2
- Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 to 60 minutes once per day on days 1, 8, 15
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
- 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
- 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
- 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
- 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
- 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 Clinical Trial Registry
- 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 Clinical Trial Registry
- 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 Clinical Trial Registry
- 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 Clinical Trial Registry
- 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 Clinical Trial Registry
- 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 Clinical Trial Registry
- EV-302: Clinical Trial Registry
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 Median OS: 14.5 vs 14.3 mo (HR 0.87, 95% CI 0.72-1.05) |
Chemotherapy
- Cisplatin (Platinol) as follows:
- Cycles 1 to 6: 70 mg/m2 IV over 30 to 60 minutes once on day 1 or 2
- Gemcitabine (Gemzar) as follows:
- Cycles 1 to 6: 1000 mg/m2 IV once per day on days 1 & 8
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- CALGB 90601: Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, Stadler WM, Teply BA, Picus J, Tagawa ST, Katragadda S, Vaena D, Misleh J, Hoimes C, Plimack ER, Flaig TW, Dreicer R, Bajorin D, Hahn O, Small EJ, Morris MJ. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J Clin Oncol. 2021 Aug 1;39(22):2486-2496. Epub 2021 May 14. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
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 Median OS: 17 vs 14.3 mo (HR 0.86, 95% CI 0.72-1.02) |
2. Pembrolizumab | Not reported |
Chemotherapy
- Cisplatin (Platinol) as follows:
- Cycles 1 up to 6: 70 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) as follows:
- Cycles 1 up to 6: 1000 mg/m2 IV once per day on days 1 & 8
Immunotherapy
- Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles
References
- KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
Gemcitabine & Paclitaxel
Regimen variant #1
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Calabrò et al. 2009 | 2003-2005 | Phase 2 | ORR: 37% |
Chemotherapy
- Gemcitabine (Gemzar) 2500 mg/m2 IV over 30 minutes once on day 1, given second
- Paclitaxel (Taxol) 150 mg/m2 IV over 3 hours once on day 1, given first
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
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 6 cycles
References
- Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. link to original article PubMed
- Calabrò F, Lorusso V, Rosati G, Manzione L, Frassineti L, Sava T, Di Paula ED, Alonso S, Sternberg CN. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer. 2009 Jun 15;115(12):2652-9. 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
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
- Vinblastine (Velban) 3 mg/m2 IV once per day on days 2, 15, 22
- Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 2
- Cisplatin (Platinol) 70 mg/m2 IV once over 120 minutes on day 1 or 2
28-day cycles (number of cycles and criteria to continue therapy varies depending on reference)
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
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
- Vinblastine (Velban) 3 mg/m2 IV once per day on days 1, 15, 22
- Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 1
- Cisplatin (Platinol) 70 mg/m2 IV over 60 minutes once on day 1
Supportive therapy
- Filgrastim (Neupogen) (dose not specified) SC once per day on days 7, 8, 9, 25, 26
28-day cycles
References
- Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. link to original article contains dosing details in manuscript PubMed
- ECOG E5886: Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. link to original article contains dosing details in manuscript PubMed
- Update: Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. link to original article PubMed
- von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. link to original article contains dosing details in manuscript PubMed
- Update: von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. link to original article PubMed
- EORTC 30924: Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; 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
- 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
- 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
- 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
- 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 Clinical Trial Registry
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
- Methotrexate (MTX) 30 mg/m2 IV once on day 1
- Vinblastine (Velban) 3 mg/m2 IV once on day 2
- Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 2
- Cisplatin (Platinol) 70 mg/m2 IV once on day 2
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
- 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
- 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
- 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 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
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 to 60 minutes once per day on days 1 & 8
- Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1 & 8, given first
21-day cycle for up to 6 cycles
References
- EORTC 30987: Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
Locally advanced or metastatic disease, maintenance after platinum chemotherapy
Avelumab monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity | |
---|---|---|---|---|---|---|
Powles et al. 2020 (JAVELIN Bladder 100)
|
2016-2019 | Phase 3 (E-RT-esc) | Best supportive care | Superior OS Median OS: 21.4 vs 14.3 mo (HR 0.69, 95% CI 0.56-0.86) |
More toxic |
Preceding treatment
- Cisplatin & Gemcitabine x 4 to 6 or Carboplatin & Gemcitabine x 4 to 6 cycles
Immunotherapy
- Avelumab (Bavencio) 10 mg/kg IV over 60 minutes once per day on days 1 & 15
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:
- Diphenhydramine (Benadryl) 25 to 50 mg IV or PO equivalent
- Acetaminophen (Tylenol) 500 to 650 mg IV or PO equivalent
28-day cycles
References
- JAVELIN Bladder 100: Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. Epub 2020 Sep 18. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- 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
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 Median PFS: 5.4 vs 3 mo (HR 0.65, 95% CI 0.43-0.97) |
More toxic |
Preceding treatment
- First-line platinum-based combination chemotherapy for up to 8 cycles, without progression of disease
Immunotherapy
- Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
References
- HCRN GU14-182: Galsky MD, Mortazavi A, Milowsky MI, George S, Gupta S, Fleming MT, Dang LH, Geynisman DM, Walling R, Alter RS, Kassar M, Wang J, Gupta S, Davis N, Picus J, Philips G, Quinn DI, Haines GK 3rd, Hahn NM, Zhao Q, Yu M, Pal SK. Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer. J Clin Oncol. 2020 Jun 1;38(16):1797-1806. Epub 2020 Apr 9. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
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
- Avelumab (Bavencio) 10 mg/kg IV over 60 minutes once on day 1
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
- 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 Clinical Trial Registry
- 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
References
- McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. link to original article PubMed
- DFCI 06-116: Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012 Feb 10;30(5):507-12. Epub 2011 Dec 19. link to original article link to PMC article PubMed Clinical Trial Registry
- 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 Clinical Trial Registry
- 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 Clinical Trial Registry
- 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
- 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
- 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 Clinical Trial Registry
- 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
- 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 Clinical Trial Registry
- 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 Clinical Trial Registry
- SWOG S1937: Clinical Trial Registry
- TROPiCS-04: Clinical Trial Registry
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 |
Petrylak et al. 2017 (RANGE) | 2015-2017 | Phase 3 (E-esc) | Docetaxel | Superior PFS1 (HR 0.70, 95% CI 0.57-0.85) |
1Reported efficacy for RANGE is based on the 2019 update.
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
Targeted therapy
- Ramucirumab (Cyramza) 10 mg/kg IV once on day 1
21-day cycles
References
- JCDC: Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- 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 Clinical Trial Registry
- 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
Erdafitinib monotherapy
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Efficacy | |
---|---|---|---|---|
Loriot et al. 2019 (BLC2001)
|
2015-2018 | Phase 2 (RT) | ORR 40% (95% CI 31-50) |
Biomarker eligibility criteria
- Alterations: FGFR3 mutation, FGFR2 fusion, or FGFR3 fusion
Targeted therapy
- Erdafitinib (Balversa) as follows:
- Cycle 1 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
- 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 Clinical Trial Registry
- 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
- Gemcitabine (Gemzar) 1200 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
28-day cycles
References
- Lorusso V, Pollera CF, Antimi M, Luporini G, Gridelli C, Frassineti GL, Oliva C, Pacini M, De Lena M; Italian Co-operative Group on Bladder Cancer. A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Eur J Cancer. 1998 Jul;34(8):1208-12. 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
- Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 minutes once per day on days 1 & 8
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
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, <20 pts in this subgroup | ORR: 47% |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 6 cycles
References
- Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. link to original article PubMed
- AUO AB 20/99: Albers P, Park SI, Niegisch G, Fechner G, Steiner U, Lehmann J, Heimbach D, Heidenreich A, Fimmers R, Siener R; AUO Bladder Cancer Group. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Ann Oncol. 2011 Feb;22(2):288-94. Epub 2010 Aug 2. 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
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
- Vinblastine (Velban) 3 mg/m2 IV once per day on days 2, 15, 22
- Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 2
- Cisplatin (Platinol) 70 mg/m2 IV once on day 2
28-day cycles (number of cycles and criteria to continue therapy varies depending on reference)
References
- Han KS, Joung JY, Kim TS, Jeong IG, Seo HK, Chung J, Lee KH. Methotrexate, vinblastine, doxorubicin and cisplatin combination regimen as salvage chemotherapy for patients with advanced or metastatic transitional cell carcinoma after failure of gemcitabine and cisplatin chemotherapy. Br J Cancer. 2008 Jan 15;98(1):86-90. Epub 2007 Dec 18. 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)
|
2015 | Phase 2 (RT) | 19.6% overall PD-L1 expression ≥5%: 28.4% PD-L1 expression ≥1%: 23.8% PD-L1 expression less than 1%: 16.1% |
Prior treatment criteria
- At least one platinum-based therapy, with progression
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
- 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 Clinical Trial Registry
- 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
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV once on day 1
21-day cycles
Dose 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
- 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 Clinical Trial Registry
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
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
- Paclitaxel (Taxol) 80 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
28-day cycles
Regimen variant #3, weekly
Study | Dates of enrollment | Evidence |
---|---|---|
Sideris et al. 2016 | 2004-2014 | Retrospective |
References
- Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. link to original article contains dosing details in abstract PubMed
- Retrospective: Sideris S, Aoun F, Zanaty M, Martinez NC, Latifyan S, Awada A, Gil T. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016 Jun;4(6):1063-1067. Epub 2016 Mar 17. link to original article link to PMC article PubMed
- KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- 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
- 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
- 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 Clinical Trial Registry
- 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 Clinical Trial Registry
- TROPiCS-04: Clinical Trial Registry
Pembrolizumab monotherapy
AIM pathway regimen 2022-08-01 |
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | |
---|---|---|---|---|---|
Bellmunt et al. 2017 (KEYNOTE-045)
|
2014-11-05 to 2015-11-13 | Phase 3 (E-RT-switch-ooc) | Investigator's choice of: 1a. Docetaxel 1b. Paclitaxel 1c. Vinflunine |
Superior OS (co-primary endpoint) Median OS: 10 mo 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) ≥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
References
- KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- 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
- 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) |
References
- Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006 Jul 20;24(21):3451-7. 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 |
References
- RATIONALE-204: Clinical Trial Registry
Toripalimab monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Awaiting publication (Junshi-JS001-009) | 2017-NR | Phase 2 |
References
- Junshi-JS001-009: contains dosing details on CT.gov Clinical Trial Registry
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 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
References
- CA183004: Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, Jagiello-Gruszfeld A, Karyakin O, Delgado FM, Hurteloup P, Winquist E, Morsli N, Salhi Y, Culine S, von der Maase H. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 20;27(27):4454-61. Epub 2009 Aug 17. Erratum in: J Clin Oncol. 2010 Jan 1;28(1):182. Winquist, Eric [added]. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- 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
- 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 Clinical Trial Registry
- 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
- 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
- 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 Clinical Trial Registry
- 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 Clinical Trial Registry
- TROPiCS-04: Clinical Trial Registry
Locally advanced or metastatic disease, refractory/intolerant to platinum chemotherapy and/or immune checkpoint inhibitor
Enfortumab vedotin monotherapy
AIM pathway regimen 2022-08-01 |
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | |
---|---|---|---|---|---|
Rosenberg et al. 2018 (EV-201)
|
2017-10-08 to 2018-07-02 | Phase 2 (RT) | ORR: 44% (95% CI 35.2-53.2) | ||
Powles et al. 2021 (EV-301)
|
2018-2020 | Phase 3 (E-RT-switch-ooc) | Investigator's choice of: 1a. Docetaxel 1b. Paclitaxel 1c. Vinflunine |
Superior 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
- Enfortumab vedotin (Padcev) 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1, 8, 15
28-day cycles
References
- EV-201: Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, Galsky MD, Hahn NM, Gartner EM, Pinelli JM, Liang SY, Melhem-Bertrandt A, Petrylak DP. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10;37(29): 2592-2600. Epub 2019 Jul 29. link to original article link to PMC article PubMed Clinical Trial Registry
- 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
- 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 Clinical Trial Registry
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
- Sacituzumab govitecan (Trodelvy) 10 mg/kg IV once per day on days 1 & 8
21-day cycles
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. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
Links
- 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.
- Cxbladder (uRNA-2), a "urine based bladder cancer test (uRNA-2) which detects RNA markers in urine."
- ImmunoCyt™/uCyt+™, a cell-based detection assay which "uses fluorescent-labeled antibodies to 3 markers that are commonly found on malignant exfoliated urothelial cells."[1]
- 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
- ↑ Greene KL, Berry A, Konety BR. Diagnostic Utility of the ImmunoCyt/uCyt+ Test in Bladder Cancer. Rev Urol. 2006 Fall;8(4):190-7. link to PMC article PubMed