Bladder cancer

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Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!.
Note: much of the content that was previously on this page has recently been moved to the Urothelial carcinoma page to reflect the fact that many regimens, especially for metastatic disease, are generic to urothelial cancer. This page has regimens specific to bladder cancer.

27 regimens on this page
47 variants on this page


Guidelines

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

AUA, ASCO, ASTRO, SUO

EAU-ESMO

ESMO

NCCN

Nonmuscle invasive bladder cancer

BCG vaccine monotherapy

AIM pathway regimen 2022-08-01

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

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ojea et al. 2007 (CUETO study 95011) 1995-1998 Phase 3 (E-esc) 1. Mitomycin Superior DFS (primary endpoint)
2. BCG; very-low-dose Did not meet primary endpoint of DFS

Preceding treatment

  • TURBT, within 14 to 21 days

Immunotherapy

42-day course, then 14 day cycles for 6 cycles


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

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lamm et al. 2000 (SWOG 8507) 1985-1988 Phase 3 (E-RT-esc) BCG; Intravesical & percutaneous BCG, without maintenance therapy Superior RFS

Immunotherapy, induction

  • Bacillus Calmette-Guérin (Connaught strain) 81 mg in 50.5 mL saline suspension is created and administered as follows:
    • Days 1, 8, 15, 22, 29, 36: 50 mL (~80.2 mg) intravesicularly, delivered through a catheter into the bladder. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.
    • Days 1, 8, 15, 22, 29, 36: 0.5 mL (~0.8 mg) SC applied once per day on 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:
    • Days 1, 8, 15: 50 mL (~80.2 mg) intravesicularly. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.
    • Days 1, 8, 15: 0.5 mL (~0.8 mg) SC applied once per day to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).

3-week courses; each course is given at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, and 36 months after the start of induction therapy


Regimen variant #3, intravesical (81 mg) & percutaneous, without maintenance therapy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lamm et al. 2000 (SWOG 8507) 1985-1988 Phase 3 (C) BCG; Intravesical & percutaneous BCG, with maintenance therapy Inferior RFS

Immunotherapy

  • Bacillus Calmette-Guérin (Connaught strain) 81 mg in 50.5 mL saline suspension is created and administered as follows:
    • Days 1, 8, 15, 22, 29, 36: 50 mL (~80.2 mg) intravesicularly. Patients lie on their abdomen for 15 minutes and retain the BCG suspension for up to 2 hours if possible.
    • Days 1, 8, 15, 22, 29, 36: 0.5 mL (~0.8 mg) SC applied once per day to the inner thigh, which is first cleaned with alcohol. For percutaneous administration, the skin is punctured 3 times with a sterile 28 gauge needle. Each subsequent administration alternates between thighs (i.e. left thigh on one week, right thigh the next week, left thigh the week after, etc.).

6-week course


Regimen variant #4, intravesical (120 mg) & percutaneous, with maintenance therapy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lamm et al. 1991 (SWOG 8216) 1983-1985 Phase 3 (E-RT-switch-ooc) Doxorubicin Seems to have superior DFS

Immunotherapy, induction

  • Bacillus Calmette-Guérin (Connaught strain) 120 mg (3 vials) in 50.5 mL saline suspension is created and administered as follows:
    • 50 mL (~120 mg) intravesicularly, and delivered through a catheter into the bladder once per day on days 1, 8, 15, 22, 29, 36. Patients retain the BCG suspension for up to 2 hours if possible.
    • 0.5 mL (~1.2 mg) applied once per day on days 1, 8, 15, 22, 29, 36 to the upper part of the inner thigh

6-week course, then proceed to maintenance therapy

Immunotherapy, maintenance

  • Bacillus Calmette-Guérin (Connaught strain) 120 mg (3 vials) in 50.5 mL saline suspension is created and administered as follows:
    • 50 mL (~120 mg) intravesicularly once on day 1. Patients retain the BCG suspension for up to 2 hours if possible.
    • 0.5 mL (~1.2 mg) applied once on day 1 to the upper part of the inner thigh

Given at 3 months, 6 months, 12 months, 18 months, and 24 months


Regimen variant #5, 150 mg

Historic variant
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martínez-Piñeiro et al. 1990 1980-1988 Phase 3 (E-switch-ooc) 1. Doxorubicin
2. Thiotepa 		Superior RFS

Note: details are very sparse in the abstract and this variant is probably only of historic interest.

Immunotherapy

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 S8795: Lamm DL, Blumenstein BA, David Crawford E, Crissman JD, Lowe BA, Smith JA Jr, Sarosdy MF, Schellhammer PF, Sagalowsky AI, Messing EM, Loehrer P, Barton Grossman H. Randomized intergroup comparison of bacillus calmette-guerin immunotherapy and mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder a southwest oncology group study. Urol Oncol. 1995 May-Jun;1(3):119-26. link to original article PubMed
  4. SWOG 8507: Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, Sarosdy MF, Bohl RD, Grossman HB, Beck TM, Leimert JT, Crawford ED. Maintenance bacillus Calmette-Guérin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000 Apr;163(4):1124-9. link to original article contains dosing details in manuscript PubMed
  5. 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
  6. CUETO study 95011: Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, Chantada V, Camacho JE, Piñeiro LM, Rodríguez RH, Isorna S, Blas M, Martínez-Piñeiro JA, Madero R; CUETO. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guérin (27 mg) versus very low-dose bacillus Calmette-Guérin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27. link to original article contains dosing details in manuscript PubMed

Intravesicular Gemcitabine monotherapy

Regimen variant #1, 1 treatment

AIM pathway regimen 2022-08-01
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Messing et al. 2018 (SWOG S0337) 2008-2012 Phase 3 (E-esc) Placebo (saline) Superior TTR (primary endpoint)

Preceding treatment

  • TURBT, up to 3 hours prior

Chemotherapy

One treatment


Regimen variant #2, 6 treatments

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Addeo et al. 2009 2003-2005 Phase 3 (E-switch-ic) Mitomycin Superior DFS (co-primary endpoint)

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 dosing details in manuscript 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 dosing details in manuscript link to PMC article PubMed NCT00445601

Intravesicular Mitomycin monotherapy

Regimen variant #1, 30 mg x 12

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ojea et al. 2007 (CUETO study 95011) 1995-1998 Phase 3 (C) 1. BCG; low-dose Inferior DFS
2. BCG; very-low-dose Did not meet efficacy endpoints

Preceding treatment

  • TURBT, 14 to 21 days prior

Chemotherapy

  • Mitomycin (Mutamycin) as follows:
    • Cycles 1 to 3: 30 mg intravesicularly once per day on days 1 & 8
    • Cycles 4 to 9: 30 mg intravesicularly once on day 1

14-day cycle for 9 cycles


Regimen variant #2, 40 mg x 11

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

Preceding treatment

Chemotherapy

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

References

  1. SWOG S8795: Lamm DL, Blumenstein BA, David Crawford E, Crissman JD, Lowe BA, Smith JA Jr, Sarosdy MF, Schellhammer PF, Sagalowsky AI, Messing EM, Loehrer P, Barton Grossman H. Randomized intergroup comparison of bacillus calmette-guerin immunotherapy and mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder a southwest oncology group study. Urol Oncol. 1995 May-Jun;1(3):119-26. link to original article PubMed
  2. CUETO study 95011: Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, Chantada V, Camacho JE, Piñeiro LM, Rodríguez RH, Isorna S, Blas M, Martínez-Piñeiro JA, Madero R; CUETO. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guérin (27 mg) versus very low-dose bacillus Calmette-Guérin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27. link to original article contains dosing details in manuscript PubMed
  3. Lammers RJ, Witjes WP, Janzing-Pastors MH, Caris CT, Witjes JA. Intracutaneous and intravesical immunotherapy with keyhole limpet hemocyanin compared with intravesical mitomycin in patients with non-muscle-invasive bladder cancer: results from a prospective randomized phase III trial. J Clin Oncol. 2012 Jun 20;30(18):2273-9. Epub 2012 May 14. link to original article contains dosing details in manuscript PubMed

Nadofaragene firadenovec monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence
Boorjian et al. 2020 (rAd-IFN-CS-003) 2016-2019 Non-randomized (RT)

Immunotherapy

3-month cycle for 4 cycles

References

  1. rAd-IFN-CS-003: Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, Bivalacqua TJ, Montgomery JS, Lerner SP, Busby JE, Poch M, Crispen PL, Steinberg GD, Schuckman AK, Downs TM, Svatek RS, Mashni J Jr, Lane BR, Guzzo TJ, Bratslavsky G, Karsh LI, Woods ME, Brown G, Canter D, Luchey A, Lotan Y, Krupski T, Inman BA, Williams MB, Cookson MS, Keegan KA, Andriole GL Jr, Sankin AI, Boyd A, O'Donnell MA, Sawutz D, Philipson R, Coll R, Narayan VM, Treasure FP, Yla-Herttuala S, Parker NR, Dinney CPN. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021 Jan;22(1):107-117. Epub 2020 Nov 27. link to original article link to PMC article PubMed NCT02773849

Pembrolizumab monotherapy

Regimen

Study Dates of enrollment Evidence
Balar et al. 2021 (KEYNOTE-057) 2015-2018 Phase 2 (RT)

Immunotherapy

21-day cycle for 35 cycles (2 years)

References

  1. KEYNOTE-057: Balar AV, Kamat AM, Kulkarni GS, Uchio EM, Boormans JL, Roumiguié M, Krieger LEM, Singer EA, Bajorin DF, Grivas P, Seo HK, Nishiyama H, Konety BR, Li H, Nam K, Kapadia E, Frenkl T, de Wit R. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021 Jul;22(7):919-930. Epub 2021 May 26. Erratum in: Lancet Oncol. 2021 Aug;22(8):e347. link to original article contains dosing details in abstract PubMed NCT02625961

Intravesicular Valrubicin monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence
Steinberg et al. 2000 1993-1996 Non-randomized (RT)

Chemotherapy

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 dosing details in abstract PubMed

Neoadjuvant chemotherapy

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine, Cisplatin

Regimen variant #1, 70/2000; single-dose cisplatin

AIM pathway regimen 2022-08-01
Study Evidence
Dash et al. 2008 Retrospective

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #2, 70/2000; split-dose cisplatin

AIM pathway regimen 2022-08-01
Study Evidence
Dash et al. 2008 Retrospective

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #3, 70/2500

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pfister et al. 2022 (VESPER) 2013-2018 Phase 3 (C) ddMVAC x 6 Might have inferior PFS

Chemotherapy

21-day cycle for 4 cycles

Supportive therapy

Subsequent treatment

  • Cystectomy to be performed up to 8 weeks after completion of chemotherapy

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 dosing details in manuscript PubMed
  2. VESPER: Pfister C, Gravis G, Fléchon A, Chevreau C, Mahammedi H, Laguerre B, Guillot A, Joly F, Soulié M, Allory Y, Harter V, Culine S; VESPER Trial Investigators. Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol. 2022 Jun 20;40(18):2013-2022. Epub 2022 Mar 7. link to original article contains dosing details in manuscript PubMed NCT01812369
    1. Update: Pfister C, Gravis G, Flechon A, Chevreau C, Mahammedi H, Laguerre B, Guillot A, Joly F, Soulie M, Allory Y, Harter V, Culine S; VESPER Trial Investigators. Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study. Lancet Oncol. 2024 Feb;25(2):255-264. Epub 2023 Dec 21. link to original article PubMed
  3. KEYNOTE-B15: NCT04700124
  4. KEYNOTE-866: NCT03924856

Cisplatin & Gemcitabine (GC) & Pembrolizumab

GC & Pembrolizumab: Gemcitabine, Cisplatin, Pembrolizumab

Regimen

Study Dates of enrollment Evidence
Rose et al. 2021 (LCCC 1520) 2016-2020 Phase 2

Chemotherapy

Immunotherapy

21-day cycle for 4 cycles

Subsequent treatment

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 Oct 1;39(28):3140-3148. Epub 2021 Aug 24. link to original article contains dosing details in abstract link to PMC article PubMed NCT02690558
  2. KEYNOTE-866: NCT03924856

MCV

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

Regimen variant #1, 2 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kaufman et al. 1993 NR Phase 2
Tester et al. 1996 (RTOG 88-02) 1988-1990 Phase 2
Shipley et al. 1998 (RTOG 89-03) 1990-1993 Phase 3 (E-esc) No neoadjuvant chemotherapy Did not meet primary endpoint of OS

Chemotherapy

28-day cycle for 2 cycles

Subsequent treatment


Regimen variant #2, 3 cycles

AIM pathway regimen 2022-08-01
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Griffiths et al. 1999 (BA06 30894) 1989-1995 Phase 3 (E-esc) No neoadjuvant therapy Seems to have superior OS1 (primary endpoint)
Median OS: 44 vs 37 mo
(HR 0.84, 95% CI 0.72-0.99)
Zapatero et al. 2000 1989-1997 Non-randomized

1Reported efficacy for BA06 30894 is based on the 2011 update.

Eligibility criteria

  • Zapatero et al. 2000: T2 to T4 Nx M0 disease

Chemotherapy

Supportive therapy

  • BA06 30894: Leucovorin (Folinic acid) 15 mg/m2 IV or PO every 6 hours on days 2 & 9, given after hydration, with the first dose 24 hours after the previous day's dose of methotrexate (total dose per cycle: 120 mg/m2)

21-day cycle for 3 cycles

Subsequent treatment

  • Zapatero et al. 2000: after 3 cycles of chemotherapy, patients underwent cystoscopy, biopsy, and abdominal CT
    • Zapatero et al. 2000, patients with CR or who were not surgical candidates: RT consolidation which begins 4 to 6 weeks after completion of chemotherapy
    • Zapatero et al. 2000, patients without CR who were surgical candidates: cystectomy

References

  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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript 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

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

Regimen variant #1, 2 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kitamura et al. 2014 (JCOG0209) 2003-2009 Phase 3 (E-esc) No neoadjuvant therapy Might have superior OS (primary endpoint)
Median OS: 102 vs 82 mo
(HR 0.65, 99.99% CI 0.19-2.18)

Chemotherapy

28-day cycle for 2 cycles

Subsequent treatment


Regimen variant #2, 3 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Grossman et al. 2003 (SWOG S8710) 1987-1998 Phase 3 (E-esc) No neoadjuvant therapy Might have superior OS (primary endpoint)

Chemotherapy

28-day cycle for 3 cycles

Subsequent treatment

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 dosing details in manuscript 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. Epub 2014 Mar 24. link to original article contains dosing details in manuscript 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

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

Regimen variant #1 (AMVAC), 3 cycles

Study Dates of enrollment Evidence
Plimack et al. 2014 (FER-GU-026) 2009-2012 Phase 2

Chemotherapy

Supportive therapy

14-day cycle for 3 cycles

Subsequent treatment


Regimen variant #2 (ddMVAC), 4 cycles

Study Dates of enrollment Evidence
Choueiri et al. 2014 (DFCI 08-208) 2008-2012 Phase 2

Chemotherapy

Supportive therapy

14-day cycle for 4 cycles

Subsequent treatment

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


Regimen variant #3 (ddMVAC), 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pfister et al. 2022 (VESPER) 2013-2018 Phase 3 (E-esc) Cisplatin and Gemcitabine (GC) Might have superior PFS (primary endpoint)
PFS36: 64% vs 56%
(HR 0.77, 95% CI 0.57-1.02)

Chemotherapy

Supportive therapy

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 dosing details in manuscript 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 dosing details in manuscript link to PMC article PubMed NCT01031420
  3. VESPER: Pfister C, Gravis G, Fléchon A, Chevreau C, Mahammedi H, Laguerre B, Guillot A, Joly F, Soulié M, Allory Y, Harter V, Culine S; VESPER Trial Investigators. Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol. 2022 Jun 20;40(18):2013-2022. Epub 2022 Mar 7. link to original article contains dosing details in manuscript PubMed NCT01812369
    1. Update: Pfister C, Gravis G, Flechon A, Chevreau C, Mahammedi H, Laguerre B, Guillot A, Joly F, Soulie M, Allory Y, Harter V, Culine S; VESPER Trial Investigators. Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study. Lancet Oncol. 2024 Feb;25(2):255-264. Epub 2023 Dec 21. link to original article PubMed

Pembrolizumab monotherapy

Regimen

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

Immunotherapy

21-day cycle for 3 cycles

Subsequent treatment

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 Dec 1;36(34):3353-3360. Epub 2018 Oct 20. Link to original article contains dosing details in manuscript 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. 2020 Apr;77(4):439-446. Epub 2019 Nov 8. link to original article PubMed

Induction chemoradiotherapy

Cisplatin & RT

Cisplatin & RT: Cisplatin & Radiation Therapy

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

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

Note: Dosing is per Figure 1 of Zapatero et al. 2009.

Eligibility criteria

  • Zapatero et al. 2009: T2 to T4 N0 M0 disease
  • RTOG 97-06: T2 to T4a N0 M0 disease without hydronephrosis

Chemotherapy

  • Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16, given first

Radiotherapy

  • Concurrent radiation therapy twice per day on days 1 to 5, 8 to 12, 15, 16, consisting of 180 cGy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 160 cGy 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: 4080 cGy; total induction dose to regional lymph nodes: 2160 cGy.

16-day course

Subsequent treatment

  • 3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT


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

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

Note: Patients were restaged 2 weeks after completion of radiation with examination under anesthesia, cystoscopy with tumor-site biopsy, urinary cytology, and computed tomographic scan of pelvis.

Preceding treatment

  • Neoadjuvant MCV x 2

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy 180 cGy once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29, 30 (22 fractions; total dose: 3960 cGy)

4.5-week course

Subsequent treatment


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

Study Dates of enrollment Evidence
Shipley et al. 1988 1980-1985 Non-randomized
Shipley et al. 1998 (RTOG 89-03) 1990-1993 Non-randomized part of phase 3 RCT

Note: In RTOG 89-03, the patient is restaged 4 weeks after completion of radiation with examination under anesthesia, cystoscopy with tumor-site biopsy, and urinary cytology.

Preceding treatment

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy 180 cGy once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29, 30 (22 fractions; total dose: 3960 cGy)

4.5-week course

Subsequent treatment

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 dosing details in manuscript 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 dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript 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 dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript PubMed
  6. SunRISe-2: NCT04658862
  7. SWOG S1806: NCT03775265

Cisplatin & Fluorouracil (CF) & RT

Regimen variant #1, 90/2400/24

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

Eligibility criteria

  • RTOG 95-06: Clinical T2 to T4a Nx M0 disease without hydronephrosis and CrCl 60 mL/min/1.73m2 or more

Chemotherapy

  • Cisplatin (Platinol) 15 mg/m2 IV over 60 minutes once per day on days 1 to 3, 15 to 17 given second, before radiation
  • Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 3, 15 to 17 given first

Supportive therapy

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

Radiotherapy

  • Concurrent radiation therapy 300 cGy fractions twice per day on days 1, 3, 15, 17, with the first fraction of each day given 1 to 2 hours after completion of chemotherapy and at least 4 hours between fractions, x 8 fractions (total induction dose: 2400 cGy), administered to the whole bladder, bladder tumor volume, and pelvic lymph nodes

17-day course

Dose and schedule modifications

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

Subsequent treatment

  • Treatment followed by repeat cystoscopy, biopsy, and urine cytology in week 7 or 8
    • RTOG 95-06, patients with complete response: CF & RT consolidation in week 9
    • RTOG 95-06, incomplete responders: recommended to undergo radical cystectomy


Regimen variant #2, 135/2400/40.3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mitin et al. 2013 (RTOG 02-33) 2002-2008 Randomized Phase 2 (E-switch-ic) Cisplatin, Paclitaxel, RT Not reported
Coen et al. 2018 (RTOG 0712) 2008-2014 Randomized Phase 2 (C) Gemcitabine & RT Not reported1

1RTOG 0712 was not statistically powered to compare regimens.
Note: Treatment was followed by repeat cystoscopy and biopsy. In RTOG 02-33, patients underwent reevaluation for response on week 7.

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:
    • Days 1 to 5, 8 to 12, 15 to 17: 160 cGy fractions to the pelvis every morning
    • Days 1 to 5: 150 cGy fractions to the bladder every evening
    • Days 8 to 12, 15 to 17: 150 cGy fractions to the tumor every evening
    • Total doses: pelvis: 2080 cGy; whole bladder: 2830 cGy; bladder tumor volume 4030 cGy.

17-day course

Subsequent treatment

  • RTOG 02-33, patients with less than stage T1 disease: CF & RT consolidation
  • RTOG 02-33, patients with at least stage T1 disease: Radical cystectomy on week 9, then adjuvant PGC
  • RTOG 0712, patients with complete response: CF & RT consolidation
  • RTOG 0712, incomplete responders: Radical cystectomy

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 dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript 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. Epub 2013 Jul 1. link to original article contains dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript 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 dosing details in manuscript link to PMC article PubMed NCT00777491

Cisplatin, Paclitaxel, RT

Regimen variant #1, 40/50 x 3 + 4030 cGy

Study Dates of enrollment Evidence
Kaufman et al. 2008 (RTOG 99-06) NR in abstract Phase 1/2

Note: the abstract of Kaufman et al. 2009 said that patients with "greater than Stage T1 disease" were recommended for cystectomy, but Figure 1 clarified that it was greater than or equal to ypT1 disease. On week 7, over 3 weeks after induction therapy, patients under reevaluation with exam under anesthesia, cystoscopy with tumor site biopsy, and urine cytology.

Preceding treatment

  • TURBT, within 4 to 6 weeks

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy twice per day on days 1 to 5, 8 to 12, 15 to 17; 4 to 6 hours between radiation sessions. Kaufman et al. 2008 (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:
    • 160 cGy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
    • 150 cGy fractions to the bladder every evening on days 1 to 5
    • 150 cGy fractions to the tumor every evening on days 8 to 12, 15 to 17
    • Total doses: pelvis: 2080 cGy; whole bladder: 2830 cGy; bladder tumor volume 4030 cGy.

3-week course

Subsequent treatment


Regimen variant #2, 45/50 x 3 + 4030 cGy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mitin et al. 2013 (RTOG 02-33) 2002-2008 Randomized Phase 2 (E-switch-ic) Cisplatin, Fluorouracil, RT Not reported

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy twice per day on days 1 to 5, 8 to 12, 15 to 17, with at least 4 hours between radiation therapy sessions:
    • 160 cGy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
    • 150 cGy fractions to the bladder every evening on days 1 to 5
    • 150 cGy fractions to the tumor every evening on days 8 to 12, 15 to 17
    • Total doses: pelvis: 2080 cGy; whole bladder: 2830 cGy; bladder tumor volume 4030 cGy.

3-week course

Subsequent treatment

  • On week 7, patients under reevaluation for response

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. Epub 2008 Dec 18. link to original article contains dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript 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. Epub 2013 Jul 1. link to original article contains dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript link to PMC article PubMed

Fluorouracil, Mitomycin, RT

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

Regimen variant #1, 5500 cGy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
James et al. 2012 (BC2001) 2001-2008 Phase 3 (E-esc) Radiation therapy Might have superior DFS1 (secondary endpoint)
(HR 0.78, 95% CI 0.60-1.02)

1Reported efficacy is based on the 2022 update.

Chemotherapy

Radiotherapy

  • Concurrent External beam radiotherapy 2.7500 cGy once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26 (20 fractions; total dose: 5500 cGy)

4-week course


Regimen variant #2, 6400 cGy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
James et al. 2012 (BC2001) 2001-2008 Phase 3 (E-esc) Radiation therapy Might have superior DFS1 (secondary endpoint)
(HR 0.78, 95% CI 0.60-1.02)

1Reported efficacy is based on the 2022 update.

Chemotherapy

Radiotherapy

  • Concurrent External beam radiotherapy 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 40, 42, 43 (32 fractions; total dose: 6400 cGy)

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 dosing details in manuscript PubMed NCT00024349
    1. Update: Hall E, Hussain SA, Porta N, Lewis R, Crundwell M, Jenkins P, Rawlings C, Tremlett J, Sreenivasan T, Wallace J, Syndikus I, Sheehan D, Lydon A, Huddart R, James N; BC2001 Investigators. Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial. Eur Urol. 2022 Sep;82(3):273-279. Epub 2022 May 14. link to original article PubMed

Gemcitabine & RT

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Coen et al. 2018 (RTOG 0712) 2008-2014 Randomized Phase 2 (E-de-esc) CF & RT Not reported1

1This trial was not statistically powered to compare regimens.
Note: Treatment was followed by repeat cystoscopy and biopsy.

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy 200 cGy per day to the pelvis on days 1 to 10, then 200 cGy per day to the bladder on days 11 to 14, then 200 cGy per day to the bladder tumor on days 15 to 20
    • Total doses: pelvis: 2000 cGy; whole bladder: 2800 cGy; bladder tumor volume 4000 cGy

4-week course

Subsequent treatment

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 dosing details in manuscript link to PMC article PubMed NCT00777491
  2. SunRISe-2: NCT04658862

Paclitaxel & RT

Regimen variant #1, normo-fractionated RT

Study Dates of enrollment Evidence
Zapatero et al. 2012 1990-2010 Non-randomized, fewer than 20 pts

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

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, total induction and consolidation dose of 64 to 6600 cGy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.

One course

Subsequent treatment

  • 3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
    • Zapatero et al. 2012, patients with complete regression (R0): Paclitaxel & RT consolidation
    • Zapatero et al. 2012, nonresponders: Cystectomy


Regimen variant #2, AHFRT

Study Dates of enrollment Evidence
Zapatero et al. 2012 1990-2010 Non-randomized, fewer than 20 pts

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

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy with twice per day radiation, consisting of 180 cGy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 160 cGy fraction x 12 fractions is given to the "bladder tumor plus wide margin." Total induction dose to bladder tumor: 4080 cGy; total induction dose to regional lymph nodes: 2160 cGy. Zapatero et al. 2012 did not specify the precise schedule of radiation therapy.

One course

Subsequent treatment

  • 3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
    • Zapatero et al. 2012, patients with complete regression (R0): Paclitaxel & RT consolidation
    • Zapatero et al. 2012, nonresponders: Cystectomy


Regimen variant #3, 6480 cGy

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

Chemotherapy

Radiotherapy

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 dosing details in manuscript 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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zapatero et al. 2000 1989-1997 Non-randomized
James et al. 2012 (BC2001) 2001-2008 Phase 3 (C) Fluorouracil, Mitomycin, RT Might have inferior DFS1

1Reported efficacy is based on the 2022 update.

Preceding treatment

  • Zapatero et al. 2000, depending on response: MCV x 3 or cystectomy

Radiotherapy

  • External beam radiotherapy by the following response-based criteria:
    • CR: 200 cGy fractions given 5 days per week, with total bladder dose of 6000 cGy. Total dose to regional lymph nodes: 5000 cGy.
    • Less than CR: total dose to the bladder of 64 to 6600 cGy. 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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00024349
    1. Update: Hall E, Hussain SA, Porta N, Lewis R, Crundwell M, Jenkins P, Rawlings C, Tremlett J, Sreenivasan T, Wallace J, Syndikus I, Sheehan D, Lydon A, Huddart R, James N; BC2001 Investigators. Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial. Eur Urol. 2022 Sep;82(3):273-279. Epub 2022 May 14. link to original article PubMed

Consolidation chemoradiotherapy

Cisplatin & RT

Cisplatin & RT: Cisplatin & Radiation Therapy

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

Study Dates of enrollment Evidence
Zapatero et al. 2000 1989-1997 Non-randomized
Hagan et al. 2003 (RTOG 97-06) 1998-2000 Phase 1/2

Note: Dosing is per Figure 1 of Zapatero et al. 2010.

Preceding treatment

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy 150 cGy fractions twice per day on days 1 to 5, 8 to 12, 15, 16 (16 fractions; total consolidation dose: 2400 cGy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 6480 cGy; total dose to lymph nodes is 4560 cGy.

Subsequent treatment

  • RTOG 97-06: Adjuvant MCV


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

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

Preceding treatment

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy 180 cGy fractions once per day on days 1 to 5, 8 to 12, 15 to 18 (14 fractions; total dose in consolidation phase: 2520 cGy; total overall dose in induction and consolidation phases: 6480 cGy)

3-week course


Regimen variant #3, cisplatin 100 mg/m2 x 1

Study Dates of enrollment Evidence
Shipley et al. 1998 (RTOG 89-03) 1990-1993 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 18 (14 fractions; total dose in consolidation phase: 3960 cGy; total overall dose in induction and consolidation phases: 6480 cGy)

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 dosing details in manuscript 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 dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript link to PMC article PubMed

Cisplatin & Fluorouracil (CF) & RT

Regimen variant #1, 30/1200 x 2 + 6430 cGy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mitin et al. 2013 (RTOG 02-33) 2002-2008 Randomized Phase 2 (E-switch-ic) Cisplatin, Paclitaxel, RT Not reported

Note: Consolidation starts starts on week 8.

Preceding treatment

Chemotherapy

Starts on week 8.

Radiotherapy

  • Concurrent radiation therapy 150 cGy twice per day on days 1 to 5, 8 to 10 (16 fractions, given twice per day x 8 days). Total dose during consolidation is 2400 cGy. Total dose after induction therapy and consolidation therapy: pelvis: 4480 cGy; whole bladder: 5230 cGy; bladder tumor volume 6430 cGy.

2-week course

Subsequent treatment


Regimen variant #2, 45/1200 x 2 + 4400 cGy

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

Treatment starts on week 9.

Preceding treatment

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy 250 cGy fractions twice per day on days 1, 3, 15, 17, with at least 4 hours between fractions, x 8 fractions (total consolidation dose: 2000 cGy), administered to the whole bladder and bladder tumor volume. The total dose to the whole bladder and bladder tumor volume was 4400 cGy in 16 fractions; the total dose to the pelvic lymph nodes was 2400 cGy in 8 fractions.

Supportive therapy

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

17-day course

Dose and schedule modifications

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

References

  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 dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript 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. Epub 2013 Jul 1. link to original article contains dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript link to PMC article PubMed

Cisplatin, Paclitaxel, RT

Regimen variant #1, 30/50 x 2 + 6430 cGy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mitin et al. 2013 (RTOG 02-33) 2002-2008 Randomized Phase 2 (E-switch-ic) Cisplatin, 5-FU, RT Not reported

Note: Consolidation starts starts on week 8.

Preceding treatment

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy 150 cGy twice per day on days 1 to 5, 8 to 10 (16 fractions, given twice per day x 8 days). Total dose during consolidation is 2400 cGy. Total dose after induction therapy and consolidation therapy: pelvis: 4480 cGy; whole bladder: 5230 cGy; bladder tumor volume 6430 cGy.

2-week course

Subsequent treatment


Regimen variant #2, 40/50 x 2 + 6430 cGy

Study Dates of enrollment Evidence
Kaufman et al. 2008 (RTOG 99-06) NR in abstract Phase 1/2

Consolidation starts starts on week 8.

Preceding treatment

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy 150 cGy twice per day on days 1 to 5, 8 to 10 (16 fractions, given twice per day at a 4 to 6 hour interval between treatments). Total dose during consolidation is 2400 cGy. Total dose after induction therapy and consolidation therapy: pelvis: 4480 cGy; whole bladder: 5230 cGy; bladder tumor volume 6430 cGy.

14-day course

Subsequent treatment

  • Adjuvant GC

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. Epub 2008 Dec 18. link to original article contains dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript 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. Epub 2013 Jul 1. link to original article contains dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript link to PMC article PubMed

Gemcitabine & RT

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Coen et al. 2018 (RTOG 0712) 2008-2014 Randomized Phase 2 (E-de-esc) CF & RT Not reported1

1This trial was not statistically powered to compare regimens.

Preceding treatment

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy 200 cGy per day in 12 fractions to the pelvis on days 1 to 5, 8 to 12, 15, 16
    • Total doses including induction: pelvis: 4400 cGy; whole bladder: 5200 cGy; bladder tumor volume 6400 cGy

16-day course

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 dosing details in manuscript link to PMC article PubMed NCT00777491

Paclitaxel & RT

Regimen variant #1, normo-fractionated RT

Study Dates of enrollment Evidence
Zapatero et al. 2012 1990-2010 Non-randomized, fewer than 20 pts

Preceding treatment

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, total induction and consolidation dose of 64 to 6600 cGy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.

One course


Regimen variant #2, AHFRT

Study Dates of enrollment Evidence
Zapatero et al. 2012 1990-2010 Non-randomized, fewer than 20 pts

Preceding treatment

Chemotherapy

  • Paclitaxel (Taxol) 50 mg/m2 IV once per day on days 1 & 8, given 6 hours before radiation therapy

Radiotherapy

  • Concurrent radiation therapy 150 cGy twice per day on days 1 to 5, 8 to 10 (16 fractions; total consolidation dose: 2400 cGy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 6480 cGy; total dose to lymph nodes is 4560 cGy.

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 dosing details in manuscript PubMed

Adjuvant therapy

Cisplatin & Gemcitabine (GC)

Regimen

Study Dates of enrollment Evidence
Kaufman et al. 2008 (RTOG 99-06) NR in abstract Phase 1/2

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles

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. Epub 2008 Dec 18. link to original article contains dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript link to PMC article PubMed

Cisplatin & Methotrexate

CM: Cisplatin & Methotrexate

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Lehmann et al. 2005 (AUO-AB 05/95) 1994-2000 Phase 3 (E-de-esc) M-VEC x 3 Inconclusive whether non-inferior PFS (primary endpoint) Less toxic

Preceding treatment

Chemotherapy

21-day cycle for up to 3 cycles

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 contains dosing details in manuscript PubMed

MCV

MCV: Methotrexate, Cisplatin, Vinblastine

Regimen

Study Dates of enrollment Evidence
Hagan et al. 2003 (RTOG 97-06) 1998-2000 Phase 1/2

Begins 8 weeks after consolidation. Note that only 45% of patients in RTOG 97-06 were able to complete all 3 cycles of MCV.

Preceding treatment

Chemotherapy

28-day cycle for 3 cycles

References

  1. RTOG 97-06: Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. link to original article contains dosing details in manuscript PubMed
    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. Epub 2009 Jul 27. 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 dosing details in manuscript link to PMC article PubMed

MVEC

MVEC: Methotrexate, Vinblastine, Epirubicin, Cisplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Lehmann et al. 2005 (AUO-AB 05/95) 1994-2000 Phase 3 (C) CM x 3 Inconclusive whether non-inferior PFS (primary endpoint) More toxic

Preceding treatment

Chemotherapy

28-day cycle for up to 3 cycles

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 contains dosing details in manuscript PubMed

PGC

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

Regimen variant #1, 100/2000/70

Study Dates of enrollment Evidence
Mitin et al. 2013 (RTOG 02-33) 2002-2008 Non-randomized part of phase 2 RCT

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles


Regimen variant #2, 160/2000/70

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paz-Ares et al 2010 (SOGUG 99/01) 2000-2007 Phase 3 (E-esc) Observation Superior OS (primary endpoint)
OS60: 60% vs 31%

Note: This study prematurely closed due to poor recruitment and lacked adequate power to make firm conclusions, and has never been published in manuscript format to our knowledge.

Eligibility criteria

  • SOGUG 99/01: pT3-4 and/or pN positive disease with adequate renal function (CrCl more than 50 mL/min/1.73m2)

Preceding treatment

  • Cystectomy; the median time treatment started post-cystectomy was 48 days

Chemotherapy

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 dosing details in manuscript
  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. Epub 2013 Jul 1. link to original article contains dosing details in manuscript 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. Epub 2009 Jul 27. 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 dosing details in manuscript link to PMC article PubMed

Links

Urine assays

These are assays intended/being investigated as adjuncts to urine cytology and cystoscopy.

  • Cxbladder (uRNA-2), a "urine based bladder cancer test (uRNA-2) which detects RNA markers in urine."
  • ImmunoCyt™/uCyt+™, a cell-based detection assay which "uses fluorescent-labeled antibodies to 3 markers that are commonly found on malignant exfoliated urothelial cells."[1]
  • UroVysion (Abbott Molecular) "designed to detect aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus via fluorescence in situ hybridization (FISH) in urine specimens from persons with hematuria suspected of having bladder cancer."

References

  1. ↑ Greene KL, Berry A, Konety BR. Diagnostic Utility of the ImmunoCyt/uCyt+ Test in Bladder Cancer. Rev Urol. 2006 Fall;8(4):190-7. link to PMC article PubMed
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