Urothelial carcinoma

Page editor		Section editor
	Risa L. Wong, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, WA RisaWongMD		Ali Raza Khaki, MD Stanford University Palo Alto, CA arkhaki

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.

31 regimens on this page 47 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

ESMO

• 2019: eUpdate – Bladder Cancer Treatment Recommendations
• 2019: eUpdate – Bladder Cancer Treatment Recommendations - Subsequent treatments post-chemotherapy or immunotherapy
• 2014: Bellmunt et al. Bladder cancer: ESMO Clinical Practice Guidelines PubMed

NCCN

• NCCN Guidelines - Bladder Cancer

Nonmuscle invasive bladder cancer/Intravesical chemotherapy

Bacillus Calmette-Guérin (BCG) monotherapy

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Regimen variant #1, low-dose (27 mg)

Study	Years 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, induction

• Bacillus Calmette-Guérin (Connaught strain) 27 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36

6-week course, then proceed to additional therapy

Immunotherapy, continuation

• Bacillus Calmette-Guérin (Connaught strain) 27 mg intravesicularly once on day 1

14-day cycle for 6 cycles

Regimen variant #2, intravesical (81 mg) & percutaneous, with maintenance therapy

Study	Years 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	Years 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	Years 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	Years 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 is probably only of historic interest.

Immunotherapy

• Bacillus Calmette-Guérin (BCG) 150 mg intravesicularly x 15 treatments

References

1. 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
2. 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
3. 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 verified protocol PubMed
4. 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
5. 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 verified protocol PubMed

Doxorubicin monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Martínez-Piñeiro et al. 1990	1980-1988	Phase 3 (C)	1. BCG	Inferior RFS
			2. Thiotepa	Not reported
Lamm et al. 1991 (SWOG 8216)	1983-1985	Phase 3 (C)	BCG	Seems to have inferior DFS

Inferior to BCG, included for reference purposes only.

Chemotherapy

• Doxorubicin (Adriamycin) 50 mg intravesicularly once on day 1

7-day cycle for 5 cycles, then 30-day cycle for 11 cycles (approximately 1 year)

References

1. 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
2. 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 contains verified protocol PubMed

Gemcitabine monotherapy

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Regimen variant #1, 1 treatment

Study	Years 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	Years 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

1. 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 verified protocol PubMed
2. 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 verified protocol PubMed NCT00445601

Mitomycin monotherapy

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Regimen variant #1, 30 mg x 12

Study	Years 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Lammers et al. 2012	2003-2007	Phase 3 (C)	KLH	Superior RFS

Preceding treatment

• TURBT

Chemotherapy

• Mitomycin (Mutamycin) 40 mg intravesicularly once on day 1

7-day cycle for 4 cycles, then monthly cycle for 4 cycles, then 3-month cycle for 3 cycles

References

1. 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 verified protocol PubMed
2. 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 verified protocol PubMed

Pembrolizumab monotherapy

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Regimen

Study	Years of enrollment	Evidence
Balar et al. (KEYNOTE-057)	NR in abstract	Phase 2 (RT)

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycle for 35 cycles (2 years)

References

1. Abstract: Keynote-057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guerin (BCG). Arjun Vasant Balar, Girish S. Kulkarni, Edward M. Uchio, Joost Boormans, Loic Mourey, Laurence Eliot Miles Krieger, Eric A. Singer, Dean F. Bajorin, Ashish M. Kamat, Petros Grivas, Ho Kyung Seo, Hiroyuki Nishiyama, Badrinath R. Konety, Kijoeng Nam, Ekta Kapadia, Tara L. Frenkl, Ronald De Wit. Journal of Clinical Oncology 2019 37:7_suppl, 350-350. link to abstract NCT02625961

Thiotepa monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Martínez-Piñeiro et al. 1990	1980-1988	Phase 3 (C)	1. BCG	Inferior RFS
			2. Doxorubicin	Not reported

Inferior to BCG, included for reference purposes only.

Chemotherapy

• Thiotepa (Thioplex) 50 mg intravesicularly x 15 treatments

References

1. 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

Valrubicin monotherapy

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Regimen

FDA-recommended dose

Study	Years 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

1. 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 protocol PubMed

Neoadjuvant chemotherapy

Atezolizumab monotherapy

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Regimen

Study	Years of enrollment	Evidence
Powles et al. 2019 (ABACUS)	2016-2018	Phase 2

Immunotherapy

• Atezolizumab 1200 mg IV over 60 minutes once on day 1

21-day cycle for 2 cycles

Subsequent treatment

• Radical cystectomy to be performed 4 to 8 weeks after completion of chemotherapy

References

1. ABACUS: Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, Szabados B, Pous AF, Gravis G, Herranz UA, Protheroe A, Ravaud A, Maillet D, Mendez MJ, Suarez C, Linch M, Prendergast A, van Dam PJ, Stanoeva D, Daelemans S, Mariathasan S, Tea JS, Mousa K, Banchereau R, Castellano D. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019 Nov 4. link to original article PubMed NCT02662309

Cisplatin & Gemcitabine (GC)

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GC: Gemcitabine, Cisplatin

Regimen variant #1, single-dose cisplatin

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

• Surgery

Regimen variant #2, split-dose cisplatin

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

• Surgery

References

1. 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 verified protocol PubMed
2. KEYNOTE-B15: NCT04700124
3. KEYNOTE-866: NCT03924856

Cisplatin & Gemcitabine (GC) & Pembrolizumab

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GC & Pembrolizumab: Gemcitabine, Cisplatin, Pembrolizumab

Regimen

Study	Years 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

• Radical cystectomy

References

1. LCCC 1520: Rose TL, Harrison MR, Deal AM, Ramalingam S, Whang YE, Brower B, Dunn M, Osterman CK, Heiling HM, Bjurlin MA, Smith AB, Nielsen ME, Tan HJ, Wallen E, Woods ME, George D, Zhang T, Drier A, Kim WY, Milowsky MI. Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer. J Clin Oncol. 2021 Aug 24:JCO2101003. Epub ahead of print. link to original article contains protocol PubMed NCT02690558
2. KEYNOTE-866: NCT03924856

MCV

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MCV: Methotrexate, Cisplatin, Vinblastine
CMV: Cisplatin, Methotrexate, Vinblastine

Regimen variant #1, 2 cycles

Study	Years 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 & 89-03: Cisplatin & RT induction

Regimen variant #2, 3 cycles

Study	Years 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
Zapatero et al. 2000	1989-1997	Non-randomized

¹Reported efficacy for BA06 30894 is based on the 2011 update.
Patients in Zapatero et al. 2000 had 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 medications

• 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 (MTX) (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
  • Patients with CR or who were not surgical candidates: RT consolidation which begins 4 to 6 weeks after completion of chemotherapy
  • Otherwise, patients proceeded to cystectomy

References

1. 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 verified protocol PubMed
2. 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 verified protocol PubMed
3. 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 verified protocol PubMed
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed
4. 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
   1. 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 verified protocol link to PMC article PubMed
5. 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 verified protocol PubMed
   1. 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 verified protocol PubMed
   2. 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

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MVAC: Methotrexate, Vinblastine, Adriamycin (Doxorubicin), Cisplatin

Regimen variant #1, 2 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kitamura et al. 2014 (JCOG0209)	2003-2009	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 2 cycles

Subsequent treatment

• Radical cystectomy

Regimen variant #2, 3 cycles

Study	Years 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

• Radical cystectomy

References

1. 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 verified protocol PubMed
2. 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. link to original article PubMed UMIN C000000093
   1. 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

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ddMVAC: dose-dense Methotrexate, Vinblastine, Adriamycin (Doxorubicin), Cisplatin
AMVAC: Accelerated Methotrexate, Vinblastine, Adriamycin (Doxorubicin), Cisplatin

Regimen variant #1 (AMVAC), 3 cycles

Study	Years 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) 70 mg/m² IV in 1 liter normal saline once on day 1
  • Split dose could be used at physician discretion for patients with CrCl less than 60 mL/min/1.73m²: 35 mg/m² IV once per day on days 1 & 2

Supportive medications

• Pegfilgrastim (Neulasta) 6 mg SC once, 24 to 48 hours after completion of chemotherapy
• Antiemetics used often included Aprepitant (Emend), Ondansetron (Zofran), and Dexamethasone (Decadron) but were not specified by the trial.

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	Years 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 in 1 liter normal saline once on day 2

Supportive medications

• Pegfilgrastim (Neulasta) 6 mg SC once on day 3 (approximately 24 hours after day 2 chemotherapy)

14-day cycle for 4 cycles

Subsequent treatment

• Cystectomy to be performed 4 to 10 weeks after completion of chemotherapy

Regimen variant #3 (ddMVAC), 6 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pfister et al. 2022 (GETUG-AFU V05 VESPER)	2013-2018	Phase 3	Gemcitabine and Cisplatin	pCR: 42% vs 36% DFS: HR 0.70 (95% CI 0.51-0.96)

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 in 1 liter normal saline once on day 2

Supportive medications

• Filgrastim (Neupogen) 5 μg/kg/ day as a subcutaneous injection from day 3 to day 9
• Antiemetics used often included Aprepitant (Emend), Ondansetron (Zofran), and Dexamethasone (Decadron) but were not specified by the trial.

14-day cycle for 6 cycles

Subsequent treatment

• Cystectomy to be performed 4 to 10 weeks after completion of chemotherapy

References

1. 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 verified protocol link to PMC article PubMed NCT00808639
2. 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 verified protocol link to PMC article PubMed NCT01031420
3. GETUG-AFU V05 VESPER: Pfister C, Gravis G, Fléchon A, Chevreau C, Mahammedi H, Laguerre B, Guillot A, Joly F, Soulié M, Allory Y, Harter V, Culine S; VESPER Trial Investigators. Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol. 2022 Mar 7:JCO2102051. Epub ahead of print. link to original article contains verified protocol PubMed NCT01812369

Pembrolizumab monotherapy

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Regimen

Study	Years of enrollment	Evidence
Necchi et al. 2018 (PURE-01)	2017-2018	Phase 2

Immunotherapy

• Pembrolizumab 200 mg IV over 30 minutes once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Radical cystectomy, within 1 to 3 weeks after the last cycle of chemotherapy

References

1. 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 verified protocol PubMed NCT02736266
   1. 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

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Cisplatin & RT: Cisplatin & Radiation Therapy

Regimen variant #1, cisplatin 40 mg/m² qwk x 3

Study	Years of enrollment	Evidence
Zapatero et al. 2009	1990-2007	Non-randomized
Hagan et al. 2003 (RTOG 97-06)	1998-2000	Phase 1/2

Patients in Zapatero et al. 2009 had T2 to T4 N0 M0 disease. Patients in RTOG 97-06 had T2 to T4a N0 M0 disease without hydronephrosis. Dosing is per Figure 1 of Zapatero et al. 2010.

Chemotherapy

• Cisplatin (Platinol) 20 mg/m² IV over 30 minutes once per day on days 1 & 2, given first

7-day cycle for 3 cycles

Radiotherapy

• Concurrent radiation therapy according to one of the following:
  • Both trials: Accelerated hyperfractionated RT (AHFRT) with twice per day radiation, consisting of 1.8 Gy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 1.6 Gy fraction x 12 fractions is given to the "bladder tumor plus wide margin." Radiation therapy given 5 days per week. Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy.
  • Zapatero et al. 2000 only: Normo-fractionated concurrent radiation therapy, 1.8 to 2 Gy fractions, given 5 times per week. Total induction and consolidation bladder dose of 64 to 66 Gy; total induction and consolidation pelvic lymph node dose of 44 to 46 Gy. Zapatero, et al. 2010 & Zapatero, et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy, nor what adjustments, if any, were made to chemotherapy for this radiation schedule.

Subsequent treatment

• 3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
  • Patients with complete regression (R0): Cisplatin & RT consolidation
  • Nonresponders: Cystectomy

Regimen variant #2, cisplatin 70 mg/m² q3wk x 2

Study	Years of enrollment	Evidence
Tester et al. 1996 (RTOG 88-02)	1988-1990	Phase 2

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

Patient is restaged 2 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, urinary cytology, and computed tomographic scan of pelvis."

• Patients with CR: Cisplatin & RT consolidation
• Patients without CR proceeded immediately to: cystectomy

Regimen variant #3, cisplatin 100 mg/m² q3wk x 2

Study	Years of enrollment	Evidence
Shipley et al. 1988	1980-1985	Non-randomized
Shipley et al. 1998 (RTOG 89-03)	1990-1993	Non-randomized portion of phase III RCT

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: Patient is restaged 4 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, and urinary cytology."

• RTOG 89-03; Patients not in CR usually proceeded to: cystectomy
• RTOG 89-03; Patients in complete remission usually proceeded to: cisplatin & RT consolidation

References

1. 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
2. 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 verified protocol PubMed
3. 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 verified protocol PubMed
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed
4. 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 verified protocol PubMed
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed
5. 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 verified protocol PubMed
   1. 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 verified protocol PubMed
6. SunRISe-2: NCT04658862
7. SWOG S1806: NCT03775265

Cisplatin & Fluorouracil (CF) & RT

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Regimen variant #1, 90/2400/24

Study	Years of enrollment	Evidence
Kaufman et al. 2000 (RTOG 95-06)	1995-1997	Phase 1/2

Patients in RTOG 95-06 had clinical T2 to T4a Nx M0 disease without hydronephrosis and CrCl of at least 60 mL/min/1.73m².

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 medications

• IV hydration at 500 mL/H (no total volume specified) prior to Fluorouracil (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/uL, 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/uL.

Subsequent treatment

• Treatment followed by repeat cystoscopy, biopsy, and urine cytology in week 7 or 8
  • Patients with complete response: CF & RT consolidation in week 9
  • Incomplete responders were recommended to undergo radical cystectomy

Regimen variant #2, 135/2400/40.3

Study	Years 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.

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

• Treatment followed by repeat cystoscopy & biopsy
  • Patients with complete response: CF & RT consolidation
  • Incomplete responders: Radical cystectomy

Regimen variant #3, 135/3600/40.3

Study	Years 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

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

• On week 7, patients under reevaluation for response.
  • Patients with less than stage T1 disease: CF & RT consolidation
  • Patients with at least stage T1 disease: Radical cystectomy on week 9, then adjuvant PGC

References

1. 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 verified protocol PubMed
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article PubMed NCT00055601
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed
3. 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 verified protocol link to PMC article PubMed NCT00777491

Cisplatin, Paclitaxel, RT

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Regimen variant #1, 40/50 x 3 + 40.3 Gy

Study	Years of enrollment	Evidence
Kaufman et al. 2009 (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.

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

• On week 7, over 3 weeks after induction therapy, patients under reevaluation with exam under anesthesia, cystoscopy with tumor site biopsy, and urine cytology
  • Patients with less than stage ypT1 disease: Cisplatin, paclitaxel, RT consolidation
  • Patients with at least stage ypT1 disease: Radical cystectomy, then adjuvant cisplatin & gemcitabine

Regimen variant #2, 45/50 x 3 + 40.3 Gy

Study	Years 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
  • Patients with less than stage ypT1 disease: Cisplatin, paclitaxel, RT consolidation
  • Patients with at least stage ypT1 disease: Radical cystectomy on week 9, then adjuvant PGC

References

1. 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 verified protocol PubMed
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article PubMed NCT00055601
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed

Fluorouracil, Mitomycin, RT

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Fluorouracil, Mitomycin, RT: Fluorouracil, Mitomycin, Radiation Therapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
James et al. 2012 (BC2001)	2001-2008	Phase 3 (E-esc)	Radiation therapy	Seems to have superior locoregional DFS DFS24: 67% vs 54% (HR 0.68, 95% CI 0.48-0.96)

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 given according to one of the following plans:
  • Concurrent radiation therapy, 2.75 Gy fractions x 20 fractions (total dose: 55 Gy)
  • Concurrent radiation therapy, 2 Gy fractions x 32 fractions (total dose: 64 Gy)

4- to 6.5-week course

References

1. 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 verified protocol PubMed NCT00024349

Gemcitabine & RT

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Regimen

Study	Years 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.

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

• Treatment followed by repeat cystoscopy & biopsy
  • Patients with complete response: Gemcitabine & RT consolidation
  • Incomplete responders: Radical cystectomy

References

1. 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 verified protocol link to PMC article PubMed NCT00777491
2. SunRISe-2: NCT04658862

Paclitaxel & RT

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Regimen variant #1

Study	Years of enrollment	Evidence
Zapatero et al. 2012	1990-2010	Non-randomized, <20 pts

Patients who had "mild renal insufficiency" received paclitaxel instead of cisplatin and had T2 to T4 N0 M0 disease.

Chemotherapy

• Paclitaxel (Taxol) 50 mg/m² IV once per week, given 6 hours before radiation therapy

Radiotherapy

• Concurrent radiation therapy according to one of the following:
  • Accelerated hyperfractionated RT (AHFRT) with twice per day radiation, consisting of 1.8 Gy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 1.6 Gy fraction x 12 fractions is given to the "bladder tumor plus wide margin." Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy. Zapatero et al. 2012 did not specify the precise schedule of radiation therapy.
  • Normo-fractionated concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.

One course

Subsequent treatment

• 3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
  • Patients with complete regression (R0): Paclitaxel & RT consolidation
  • Nonresponders: Cystectomy

Regimen variant #2

Study	Years of enrollment	Evidence
Michaelson et al. 2016 (RTOG 0524)	2005-2013	Phase 1/2, 47 pts

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

1. 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 verified protocol PubMed
2. 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

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Regimen

Study	Years 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	Seems to have inferior locoregional DFS

Preceding treatment

• Depending on response, treatment in Zapatero et al. 2000 preceded by MCV x 3 or cystectomy

Radiotherapy

• External beam radiotherapy by the following criteria:
  • CR: 2 Gy fractions given 5 days per week, with total bladder dose of 60 Gy. Total dose to regional lymph nodes: 50 Gy.
  • Less than CR: total dose to the bladder of 64 to 66 Gy. No further details given about fractionation, schedule, or dose to lymph nodes.

References

1. 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 verified protocol PubMed
   1. 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 verified protocol PubMed
   2. 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
2. 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 verified protocol PubMed NCT00024349

Consolidation chemoradiotherapy

Cisplatin & RT

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Cisplatin & RT: Cisplatin & Radiation Therapy

Regimen variant #1, cisplatin 40 mg/m²/wk x 2

Study	Years 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

• 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 according to one of the following:
  • Both trials: Accelerated hyperfractionated RT (AHFRT), 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.
  • Zapatero et al. 2000 only: Normo-fractionated concurrent radiation therapy, 1.8 to 2 Gy fractions, given 5 times per week. Total induction and consolidation bladder dose of 64 to 66 Gy; total induction and consolidation pelvic lymph node dose of 44 to 46 Gy. Zapatero, et al. 2010 & Zapatero, et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy, nor what adjustments, if any, were made to chemotherapy for this radiation schedule.

Subsequent treatment

• RTOG 97-06: Adjuvant MCV

Regimen variant #2, cisplatin 70 mg/m² x 1

Study	Years of enrollment	Evidence
Tester et al. 1996 (RTOG 88-02)	1988-1990	Phase 2

Preceding treatment

• 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	Years of enrollment	Evidence
Shipley et al. 1998 (RTOG 89-03)	1990-1993	Non-randomized portion of phase III RCT

Preceding treatment

• 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

1. 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 verified protocol PubMed
2. 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 verified protocol PubMed
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed
3. 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
   1. 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 verified protocol PubMed
   2. 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 verified protocol PubMed
4. 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 verified protocol PubMed
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed

Cisplatin & Fluorouracil (CF) & RT

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Regimen variant #1, 30/1200 x 2 + 64.3 Gy

Study	Years 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	Years of enrollment	Evidence
Kaufman et al. 2000 (RTOG 95-06)	1995-1997	Phase 1/2

Treatment starts on week 9.

Preceding treatment

• 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.

Dose modifications

• Patients with grade III hematologic toxicity, defined as platelets less than 50 x 10⁹/L or ANC less than 1800/uL, had chemotherapy and radiation therapy held for at least one week, with therapy resuming when platelets were at least 100 x 10⁹/L and ANC at least 1800/uL.

Supportive medications

• IV hydration at 500 mL/H (no total volume specified) prior to Fluorouracil (5-FU)

17-day course

References

1. 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 verified protocol PubMed
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article PubMed NCT00055601
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed

Cisplatin, Paclitaxel, RT

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Regimen variant #1, 30/50 x 2 + 64.3 Gy

Study	Years 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	Years of enrollment	Evidence
Kaufman et al. 2009 (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 cisplatin & gemcitabine

References

1. 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. link to original article contains verified protocol PubMed
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed
2. 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. link to original article contains verified protocol link to PMC article PubMed NCT00055601
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed

Paclitaxel & RT

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Regimen

Study	Years of enrollment	Evidence
Zapatero et al. 2012	1990-2010	Non-randomized, <20 pts

Preceding treatment

• 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 according to one of the following:
  • Accelerated hyperfractionated RT (AHFRT), 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.
  • Normo-fractionated concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.

One course

References

1. 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 verified protocol PubMed

Adjuvant therapy

Cisplatin & Gemcitabine (GC)

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Regimen

Study	Years of enrollment	Evidence
Kaufman et al. 2009 (RTOG 99-06)	NR in abstract	Phase 1/2

Preceding treatment

• 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

1. 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 verified protocol PubMed
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed

Cisplatin & Methotrexate

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Regimen

Study	Years 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

• Radical cystectomy

Chemotherapy

• Cisplatin (Platinol)
• Methotrexate (MTX)

References

1. 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

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MCV: Methotrexate, Cisplatin, Vinblastine

Regimen

Study	Years 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

1. 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 verified protocol PubMed
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed

Nivolumab monotherapy

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Regimen variant #1, q2wks

FDA-recommended dose

Study	Years 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

• Radical surgery

Immunotherapy

• Nivolumab (Opdivo) 240 mg IV once on day 1

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

Regimen variant #2, q4wks

FDA-recommended dose

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

Preceding treatment

• Radical surgery

Immunotherapy

• Nivolumab (Opdivo) 480 mg IV once on day 1

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

References

1. CheckMate 274: Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, Bamias A, Lebret T, Shariat SF, Park SH, Ye D, Agerbaek M, Enting D, McDermott R, Gajate P, Peer A, Milowsky MI, Nosov A, Neif Antonio J Jr, Tupikowski K, Toms L, Fischer BS, Qureshi A, Collette S, Unsal-Kacmaz K, Broughton E, Zardavas D, Koon HB, Galsky MD. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114. link to original article link to PMC article PubMed NCT02632409

PGC

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

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Paz-Ares et al 2010 (SOGUG 99/01)	2000-2007	Phase 3 (E-esc)	Observation	Superior OS

Patients in SOGUG 99/01 had pT3-4 and/or pN positive disease with adequate renal function (CrCl greater than 50 mL/min/1.73m²). The study prematurely closed due to poor recruitment and lacks adequate power to make firm conclusions, and has never been published in manuscript format.

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

Regimen variant #2

Study	Years of enrollment	Evidence
Mitin et al. 2013 (RTOG 02-33)	2002-2008	Non-randomized portion of phase II RCT

Preceding treatment

• Depending on response, adjuvant chemotherapy began 12 weeks after cisplatin, paclitaxel, RT versus cisplatin, 5-FU, RT or 8 weeks after cystectomy

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
• Paclitaxel (Taxol) 50 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

References

1. 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 verified protocol
2. 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. link to original article contains verified protocol link to PMC article PubMed NCT00055601
   1. 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. link to original article link to PMC article PubMed
   2. 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 verified protocol link to PMC article PubMed

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

Atezolizumab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Efficacy
Balar et al. 2016 (IMvigor210)	2014-2015	Phase 2 (RT)	ORR: 23% (95% CI 16-31)

On 8/16/2018 the FDA updated the prescribing information for atezolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible.

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV once on day 1

21-day cycles

References

1. IMvigor210: Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, Dawson NA, van der Heijden MS, Dreicer R, Srinivas S, Retz MM, Joseph RW, Drakaki A, Vaishampayan UN, Sridhar SS, Quinn DI, Durán I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE 3rd, Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thåström A, Abidoye OO, Fine GD, Bajorin DF; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017 Jan 7;389(10064):67-76. Epub 2016 Dec 8. link to original article contains protocol link to PMC article PubMed NCT02951767

Pembrolizumab monotherapy

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Regimen

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

On 5/18/2018 the FDA released a warning that patients in the monotherapy arms of the ongoing KEYNOTE-361 trial with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.

On 8/16/2018 the FDA updated the prescribing information for pembrolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible.

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycles

References

1. KEYNOTE-052: Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. Epub 2017 Sep 26. link to original article PubMed NCT02335424

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

Atezolizumab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Galsky et al. 2020 (IMvigor130)	2016-2018	Phase 3 (E-switch-ooc)	1. GCb 2. GC	Did not meet primary endpoint of OS
			3. GCb & Atezolizumab 4. GC & Atezolizumab	Not reported

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV once on day 1

21-day cycles

References

1. 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 verified protocol PubMed NCT02807636

Carboplatin & Gemcitabine (GCb)

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GCb: Gemcitabine & Carboplatin

Regimen variant #1, AUC 4.5/1000

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity	ORR	Comparator ORR
De Santis et al. 2009 (EORTC 30986)	2001-2005	Randomized Phase 2/3 (E-de-esc)	M-CAVI	Did not meet primary endpoint of ORR	Lower toxicity than M-CAVI	Intention to treat: 38% (2009) 41.2% (2012)	Intention to treat: 20% (2009) 30.3% (2012)
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	Intention to treat (Cisplatin-ineligible): 46%	Intention to treat (Cisplatin-ineligible): 24%
			2. Durvalumab & Tremelimumab, then Durvalumab maintenance	Might have inferior OS	(Grouped with Cisplatin & Gemcitabine) Not more toxic	Intention to treat (Cisplatin-ineligible): 46%	Intention to treat (Cisplatin-ineligible): 36%
Galsky et al. 2020 (IMvigor130)	2016-2018	Phase 3 (C)	1. Atezolizumab	Did not meet primary endpoint of OS
			2. GCb & Atezolizumab 3. GC & Atezolizumab	Seems to have inferior OS

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	Years 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)	1. GC & Pembrolizumab 2. GCb & Pembrolizumab	Did not meet primary endpoints of PFS/OS
			3. 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity	ORR	Comparator ORR
Dogliotti et al. 2006	2000-2002	Randomized Phase 2 (E-switch-ic)	Cisplatin & Gemcitabine		Did not meet primary endpoint of reduced toxicity	Intention to treat: 40% (95% CI NR) Evaluable patients only: 56% (95% CI: 40–72)	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

1. Carles J, Nogué M, Domènech M, Pérez C, Saigí E, Villadiego K, Guasch I, Ibeas R. Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function. Oncology. 2000 Jun;59(1):24-7. link to original article contains protocol PubMed
2. Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. link to original article contains verified protocol PubMed
3. EORTC 30986: De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Skoneczna I, Marreaud S, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol. 2009 Nov 20;27(33):5634-9. link to original article link to PMC article contains verified protocol PubMed NCT00111787
   1. Update: De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Gil T, Marreaud S, Daugaard G, Skoneczna I, Collette S, Lorent J, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012 Jan 10;30(2):191-9. link to original article link to PMC article contains verified protocol PubMed
4. IMvigor130: Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. link to original article contains verified protocol PubMed NCT02807636
5. DANUBE: Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Sep 21:S1470-2045(20)30541-6. Epub ahead of print. link to original article PubMed NCT02516241
6. KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article contains protocol PubMed NCT02853305

Carboplatin & Gemcitabine (GCb) & Atezolizumab

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GCb & Atezolizumab: Gemcitabine, Carboplatin, Atezolizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Galsky et al. 2020 (IMvigor130)	2016-2018	Phase 3 (E-RT-esc)	1. Atezolizumab	Not reported
			2. GCb 3. GC	Seems to have superior OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 4.5 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV once on day 1

21-day cycles

References

1. 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 verified protocol PubMed NCT02807636

Carboplatin & Paclitaxel (CP)

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Regimen

Study	Years 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

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

CISCA

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CISCA: CISplatin, Cyclophosphamide, Adriamycin (Doxorubicin)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
Sternberg et al. 1977	1976-1977	Non-randomized, <20 pts
Logothetis et al. 1990	1985-1989	Phase 3 (E-switch-ic)	MVAC	Inferior OS	46% (95% CI 32-62)	65% (95% CI 52-77)

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 medications

• Forced mannitol diuresis with Cisplatin (Platinol)

21-day cycle for up to 6 cycles

References

1. Sternberg JJ, Bracken RB, Handel PB, Johnson DE. Combination chemotherapy (CISCA) for advanced urinary tract carcinoma: a preliminary report. JAMA. 1977 Nov 21;238(21):2282-7. link to original article PubMed
2. Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. link to original article contains verified protocol PubMed

Cisplatin & Gemcitabine (GC)

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

Regimen variant #1, 70/1000, q3wk

Study	Years 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
			2. GCb & Atezolizumab 3. GC & Atezolizumab	Seems to have inferior OS
Powles et al. 2021 (KEYNOTE-361)	2016-2018	Phase 3 (C)	1. GC & Pembrolizumab 2. GCb & Pembrolizumab	Did not meet primary endpoints of PFS/OS
			3. 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 medications

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

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

Regimen variant #2, 70/1000, q4wk

Study	Years 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)

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 medications

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

28-day cycle for up to 6 cycles

Regimen variant #3, 70/1250, q3wk

Study	Years 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 2
  • In DANUBE, Cisplatin given on day 1.
• 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

1. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. link to original article contains verified protocol PubMed
   1. Update: von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. link to original article PubMed
2. Soto Parra H, Cavina R, Latteri F, Sala A, Dambrosio M, Antonelli G, Morenghi E, Alloisio M, Ravasi G, Santoro A. Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol. 2002 Jul;13(7):1080-6. link to original article contains verified protocol PubMed
3. Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. link to original article contains verified protocol PubMed
4. EORTC 30987: Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. link to original article contains verified protocol link to PMC article PubMed NCT00022191
5. CILAB: Sternberg CN, Skoneczna IA, Castellano D, Theodore C, Blais N, Voog E, Bellmunt J, Peters F, Le-Guennec S, Cerbone L, Risse ML, Machiels JP. Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB). Oncology. 2013;85(4):208-15. Epub 2013 Sep 24. link to original article contains protocol PubMed NCT00625664
6. IMvigor130: Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. link to original article contains verified protocol PubMed NCT02807636
7. DANUBE: Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Sep 21:S1470-2045(20)30541-6. Epub ahead of print. link to original article PubMed NCT02516241
8. KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article contains protocol PubMed NCT02853305
9. CALGB 90601: Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, Stadler WM, Teply BA, Picus J, Tagawa ST, Katragadda S, Vaena D, Misleh J, Hoimes C, Plimack ER, Flaig TW, Dreicer R, Bajorin D, Hahn O, Small EJ, Morris MJ. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J Clin Oncol. 2021 Aug 1;39(22):2486-2496. Epub 2021 May 14. link to original article contains verified protocol PubMed NCT00942331

Cisplatin & Gemcitabine (GC) & Atezolizumab

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GC & Atezolizumab: Gemcitabine, Cisplatin, Atezolizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Galsky et al. 2020 (IMvigor130)	2016-2018	Phase 3 (E-RT-esc)	1. Atezolizumab	Not reported
			2. GCb 3. GC	Seems to have superior OS

Chemotherapy

• Cisplatin (Platinol) 70 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV once on day 1

21-day cycles

References

1. 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 verified protocol PubMed NCT02807636

Cisplatin & Gemcitabine (GC) & Bevacizumab

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GCB: Gemcitabine, Cisplatin, Bevacizumab

Regimen

Study	Years 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

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

Gemcitabine & Paclitaxel

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Regimen variant #1

Study	Years 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	Years 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

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

MVAC

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MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin

Regimen variant #1, standard

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Loehrer et al. 1992	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	Years 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 medications

• Filgrastim (Neupogen) (dose not specified) SC once per day on days 7, 8, 9, 25, 26

28-day cycles

References

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

MVAC, dose-dense

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
Sternberg et al. 2001 (EORTC 30924)	1993-1998	Phase 3 (E-esc)	MVAC	Seems to have superior OS1	62% (95% CI 54-70)	50% (95% CI 42-59)
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.

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 medications

• 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/uL.
  • In contrast to Sternberg et al. 2001, Sternberg et al. 2006 said G-CSF was given on days 3 to 7.

14-day cycles

References

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

PGC

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
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)	56% (95% CI NR)	44% (95% CI NR)

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

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

Locally advanced or metastatic disease, maintenance after platinum chemotherapy

Avelumab monotherapy

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Regimen

Study	Years 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	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 Medications

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

1. JAVELIN Bladder 100: Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. Epub 2020 Sep 18. link to original article contains verified protocol PubMed NCT02603432

Pembrolizumab monotherapy

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Regimen

Study	Years 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

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

Locally advanced or metastatic disease, after platinum chemotherapy

Avelumab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Efficacy
Apolo et al. 2017 (JAVELIN)	2014	Phase 1b (RT)	18% (95% CI 8-33)

Immunotherapy

• Avelumab (Bavencio) 10 mg/kg IV over 60 minutes once on day 1

Supportive medications

Per Apolo et al. 2017 (JAVELIN):

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

14-day cycles

References

1. Phase 1: Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, Safran H, Stinchcombe TE, Srdanov M, Gelb AB, Schlichting M, Chin K, Gulley JL. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase Ib study. J Clin Oncol. 2017 Jul 1;35(19):2117-2124. Epub 2017 Apr 4. link to original article contains verified protocol link to PMC article PubMed NCT01772004

Docetaxel monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
McCaffrey et al. 1997	1993-1995	Phase 2
Choueiri et al. 2012 (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)	2014-2015	Phase 3 (C)	Pembrolizumab	Inferior OS
Powles et al. 2017 (IMvigor211)	2015-2016	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.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycles

References

1. McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. link to original article PubMed
2. DFCI 06-116: Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012 Feb 10;30(5):507-12. link to original article link to PMC article PubMed NCT00880334
3. JCDC: Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. link to original article PubMed NCT01282463
4. KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains verified protocol PubMed NCT02256436
   1. Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article PubMed
5. RANGE: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. link to original article contains verified protocol PubMed NCT02426125
   1. Update: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. Epub 2019 Nov 18. link to original article link to PMC article PubMed
6. IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article contains protocol PubMed NCT02302807
7. SWOG S1937: NCT04579224
8. TROPiCS-04: NCT04527991

Docetaxel & Ramucirumab

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Regimen

Study	Years 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

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

Erdafitinib monotherapy

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Regimen

FDA-recommended dose

Study	Years 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) 8 mg PO once per day
  • If serum phosphorus level and tolerability are acceptable at days 14 to 21, increase to 9 mg PO once per day
  • Additional dose adjustments per package insert

28-day cycles

References

1. BLC2001: Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Zhong B, Stuyckens K, Santiago-Walker A, De Porre P, O'Hagan A, Avadhani A, Siefker-Radtke AO; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348. link to original article PubMed NCT02365597

Gemcitabine & Paclitaxel

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GP: Gemcitabine & Paclitaxel

Regimen variant #1, gemcitabine 2 out of 3 weeks

Study	Years 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	Years 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

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

MVAC

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MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin

Regimen

Study	Years 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

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

Nivolumab monotherapy

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Regimen

Study	Years 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 <1%: 16.1%

Preceding treatment

• 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

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

nab-Paclitaxel monotherapy

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Regimen

Study	Years of enrollment	Evidence	Efficacy
Ko et al. 2013	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/uL for 1 week, or grade 3 or 4 thrombocytopenia required dose reductions. When sensory neuropathy of grade 2 or higher occurred, study drug was withheld until resolution to grade 2 or better, then reinstituted at the next lower dose. When mucositis or diarrhea of grade 3 or higher occurred, study drug was withheld until resolution to grade 1 or better, then reinstituted at the next lower dose. Patients with mucositis or diarrhea of grade 4 were removed from the trial."

References

1. 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. link to original article contains protocol PubMed NCT00683059

Paclitaxel monotherapy

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Regimen variant #1, q3wks

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bellmunt et al. 2017 (KEYNOTE-045)	2014-2015	Phase 3 (C)	Pembrolizumab	Inferior OS
Powles et al. 2017 (IMvigor211)	2015-2016	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.

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycles

Regimen variant #2, 3 out of 4 weeks

Study	Years 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

References

1. Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. link to original article contains protocol PubMed
2. Retrospective: Sideris S, Aoun F, Zanaty M, Martinez NC, Latifyan S, Awada A, Gil T. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016 Jun;4(6):1063-1067. Epub 2016 Mar 17. link to original article link to PMC article PubMed
3. KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains verified protocol PubMed NCT02256436
   1. Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article PubMed
4. IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article contains protocol PubMed NCT02302807
5. TROPiCS-04: NCT04527991

Pembrolizumab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bellmunt et al. 2017 (KEYNOTE-045)	2014-2015	Phase 3 (E-RT-switch-ooc)	Investigator's choice of: 1. Docetaxel 2. Paclitaxel 3. Vinflunine	Superior OS Median OS: 10 mo vs 7 mo (HR 0.73, 95% CI 0.59-0.91)

Biomarker eligibility criteria

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

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycles

References

1. KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains verified protocol PubMed NCT02256436
   1. Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article PubMed

Pemetrexed monotherapy

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Regimen

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

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1

21-day cycles

References

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

Vinflunine monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bellmunt et al. 2009 (CA183004)	2003-2006	Phase 3 (E-esc)	Best supportive care	Superior OS1 (HR 0.72, 95% CI 0.57-0.91)
Bellmunt et al. 2017 (KEYNOTE-045)	2014-2015	Phase 3 (C)	Pembrolizumab	Inferior OS
Powles et al. 2017 (IMvigor211)	2015-2016	Phase 3 (C)	Atezolizumab	Did not meet primary endpoint of OS

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

Chemotherapy

• Vinflunine (Javlor) 320 mg/m² IV once on day 1

21-day cycles

References

1. CA183004: Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, Jagiello-Gruszfeld A, Karyakin O, Delgado FM, Hurteloup P, Winquist E, Morsli N, Salhi Y, Culine S, von der Maase H. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 20;27(27):4454-61. Epub 2009 Aug 17. Erratum in: J Clin Oncol. 2010 Jan 1;28(1):182. Winquist, Eric [added]. link to original article contains protocol PubMed NCT00315237
   1. Update: Bellmunt J, Fougeray R, Rosenberg JE, von der Maase H, Schutz FA, Salhi Y, Culine S, Choueiri TK. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann Oncol. 2013 Jun;24(6):1466-72. Epub 2013 Feb 17. link to original article PubMed
2. KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains verified protocol PubMed NCT02256436
   1. Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article PubMed
3. IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article contains protocol PubMed NCT02302807
4. TROPiCS-04: NCT04527991

Locally advanced or metastatic disease, after platinum chemotherapy and/or immune checkpoint inhibitor

Enfortumab vedotin monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
Rosenberg et al. 2018 (EV-201)	2017-2018	Phase 2 (RT)			44% (95% CI 35.2-53.2)
Powles et al. 2021 (EV-301)	2018-2020	Phase 3 (E-RT-switch-ooc)	Investigator-chosen chemotherapy: 1. Docetaxel 2. Paclitaxel 3. Vinflunine	Superior OS	Intention to treat: 40.6%	Intention to treat: 17.9%

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

1. EV-201: Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, Galsky MD, Hahn NM, Gartner EM, Pinelli JM, Liang SY, Melhem-Bertrandt A, Petrylak DP. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10;37(29): 2592-2600. Epub 2019 Jul 29. link to original article link to PMC article Pubmed NCT03219333
2. EV-301: Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. link to original article contains verified protocol Pubmed NCT03474107

Sacituzumab govitecan monotherapy

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Regimen

FDA-recommended dose

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

Antibody-drug conjugate therapy

• Sacituzumab govitecan (Trodelvy) 10 mg/kg IV once per day on days 1 & 8

21-day cycles until unaccaptable toxicity or loss of clinical benefit

References

1. TROPHY-U-01: Tagawa ST, Balar AV, Petrylak DP, Kalebasty AR, Loriot Y, Fléchon A, Jain RK, Agarwal N, Bupathi M, Barthelemy P, Beuzeboc P, Palmbos P, Kyriakopoulos CE, Pouessel D, Sternberg CN, Hong Q, Goswami T, Itri LM, Grivas P. TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. J Clin Oncol. 2021 Apr 30. Epub ahead of print. link to original article Pubmed NCT03547973

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."
• 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."