Bladder cancer

From HemOnc.org - A Hematology Oncology Wiki
Jump to: navigation, search
Section editor
ChenEddy Sept2016.jpg
Eddy J. Chen, MD
Massachusetts General Hospital
Boston, MA
45 regimens on this page
73 variants on this page

Contents


Guidelines

AUA, ASCO, ASTRO, SUO

ESMO

NCCN

Intravesical chemotherapy

Bacillus Calmette-Guérin (BCG) monotherapy

Source: Bacillus Calmette-Guérin (BCG) intravesicular chemotherapy in bladder cancer

back to top

Variant #1, low-dose (27 mg)

Study Evidence Comparator Comparative Efficacy
Ojea et al. 2007 (CUETO study 95011) Phase III (E) 1. Mitomycin Superior DFS
2. Very-low-dose BCG Seems not superior

Preceding treatment

  • TURBT, within 14 to 21 days

Immunotherapy, induction

6-week course, then proceed to additional therapy

Immunotherapy, continuation

14-day cycle for 6 cycles

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

Study Evidence Comparator Comparative Efficacy
Lamm et al. 2000 Phase III (E) 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

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

Study Evidence Comparator Comparative Efficacy
Lamm et al. 2000 Phase III (C) 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

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

Study Evidence Comparator Comparative Efficacy
Lamm et al. 1991 Phase III (E) 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

Variant #5, 150 mg

Study Evidence Comparator Comparative Efficacy
Martínez-Piñeiro et al. 1990 Phase III (E) 1. Doxorubicin
2. Thiotepa
Superior RFS

Note: details are very sparse in the abstract and this 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 SD article contains partial protocol PubMed
  2. 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. 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 Group (Club Urológico Español De Tratamiento Oncológico). 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

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Martínez-Piñeiro et al. 1990 Phase III (C) 1. BCG Inferior RFS
2. Thiotepa Not reported
Lamm et al. 1991 Phase III (C) BCG Seems to have inferior DFS

Inferior to BCG, included for reference purposes only.

Chemotherapy

15 or more 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 SD article contains partial protocol PubMed
  2. 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

Gemcitabine monotherapy

back to top

Variant #1, 1 treatment

Study Evidence Comparator Comparative Efficacy
Messing et al. 2018 (SWOG S0337) Phase III (E) Placebo (saline) Superior TTR

Preceding treatment

  • TURBT, up to 3 hours prior

Chemotherapy

One treatment

Variant #2, 6 treatments

Study Evidence Comparator Comparative Efficacy
Addeo et al. 2009 Phase III (E) 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

Mitomycin monotherapy

back to top

Variant #1, 30 mg x 12

Study Evidence Comparator Comparative Efficacy
Ojea et al. 2007 (CUETO study 95011) Phase III (C) 1. Low-dose BCG Inferior DFS
2. Very-low-dose BCG Seems not superior

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

Variant #2, 40 mg x 11

Study Evidence Comparator Comparative Efficacy
Lammers et al. 2012 Phase III (C) Keyhole limpet hemocyanin 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. 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 Group (Club Urológico Español De Tratamiento Oncológico). 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

Observation

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Ito et al. 2013 (THP Monotherapy Study Group Trial) Phase III (C) Pirarubicin Seems to have inferior RFS

No active antineoplastic treatment after surgery.

Preceding treatment

References

  1. THP Monotherapy Study Group Trial: Ito A, Shintaku I, Satoh M, Ioritani N, Aizawa M, Tochigi T, Kawamura S, Aoki H, Numata I, Takeda A, Namiki S, Namima T, Ikeda Y, Kambe K, Kyan A, Ueno S, Orikasa K, Katoh S, Adachi H, Tokuyama S, Ishidoya S, Yamaguchi T, Arai Y. Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol. 2013 Apr 10;31(11):1422-7. Epub 2013 Mar 4. link to original article contains verified protocol PubMed

Pirarubicin monotherapy

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Ito et al. 2013 (THP Monotherapy Study Group Trial) Phase III (E) Observation Seems to have superior RFS

Pirarubicin was given within 48 hours after nephroureterectomy.

Preceding treatment

Chemotherapy

  • Pirarubicin (THP) 30 mg in 30 mL normal saline intravesicularly, delivered through a catheter into the bladder, and retained for 30 minutes

1 dose

References

  1. THP Monotherapy Study Group Trial: Ito A, Shintaku I, Satoh M, Ioritani N, Aizawa M, Tochigi T, Kawamura S, Aoki H, Numata I, Takeda A, Namiki S, Namima T, Ikeda Y, Kambe K, Kyan A, Ueno S, Orikasa K, Katoh S, Adachi H, Tokuyama S, Ishidoya S, Yamaguchi T, Arai Y. Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol. 2013 Apr 10;31(11):1422-7. Epub 2013 Mar 4. link to original article contains verified protocol PubMed

Thiotepa monotherapy

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Martínez-Piñeiro et al. 1990 Phase III (C) 1. BCG Inferior RFS
2. Doxorubicin Not reported

Inferior to BCG, included for reference purposes only.

Chemotherapy

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 SD article contains partial protocol PubMed

Neoadjuvant chemotherapy

Cisplatin & Gemcitabine

Source: Cisplatin & Gemcitabine for bladder cancer, neoadjuvant

back to top


GC: Gemcitabine, Cisplatin

Variant #1, single-dose cisplatin

Study Evidence
Dash et al. 2008 Retrospective

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

Variant #2, split-dose cisplatin

Study Evidence
Dash et al. 2008 Retrospective

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

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

MCV

back to top

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

Variant #1, 2 cycles

Study Evidence Comparator Comparative Efficacy
Kaufman et al. 1993 Phase II
Tester et al. 1996 (RTOG 88-02) Phase II
Shipley et al. 1998 (RTOG 89-03) Phase III (E) No neoadjuvant chemotherapy Seems not superior

Chemotherapy

28-day cycle for 2 cycles

Subsequent treatment

Variant #2, 3 cycles

Study Evidence Comparator Comparative Efficacy
Griffiths et al. 1999 (BA06 30894) Phase III (E) No neoadjuvant therapy Seems to have superior OS (*)
Zapatero et al. 2000 Non-randomized

Patients in Zapatero et al. 2000 had T2 to T4 Nx M0 disease. Reported efficacy for BA06 30894 is based on the 2011 update.

Chemotherapy

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; 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
    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); European Organisation for Research and Treatment of Cancer 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

back to top

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

Variant #1, 2 cycles

Study Evidence Comparator Comparative Efficacy
Kitamura et al. 2014 (JCOG0209) Phase III (E) No neoadjuvant therapy Might have superior OS

Chemotherapy

28-day cycle for 2 cycles

Subsequent treatment

Variant #2, 3 cycles

Study Evidence Comparator Comparative Efficacy
Grossman et al. 2003 (SWOG S8710) Phase III (E) No neoadjuvant therapy Might have superior OS

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 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

MVAC, dose-dense

back to top

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

Variant #1, 3 cycles

Study Evidence
Plimack et al. 2014 Phase II

Chemotherapy

Supportive medications

14-day cycle for 3 cycles

Subsequent treatment

Variant #2, 4 cycles

Study Evidence
Choueiri et al. 2014 Phase II

Chemotherapy

Supportive medications

14-day cycle for 4 cycles

Subsequent treatment

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

References

  1. 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 PubMed
  2. 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

No neoadjuvant therapy

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Griffiths et al. 1999 (BA06 30894) Phase III (C) CMV Seems to have inferior OS (*)
Grossman et al. 2003 (SWOG S8710) Phase III (C) MVAC Might have inferior OS
Kitamura et al. 2014 (JCOG0209) Phase III (C) MVAC Might have inferior OS

No preoperative treatment; used as a comparator arm and here for reference purposes only. Reported efficacy for BA06 30894 is based on the 2011 update.

Subsequent treatment

References

  1. BA06 30894: Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; 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
    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); European Organisation for Research and Treatment of Cancer 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
  2. 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
  3. 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

Induction chemoradiotherapy

Cisplatin & RT

back to top

RT: Radiation Therapy

Variant #1, cisplatin 40 mg/m2 qwk x 3

Study Evidence
Hagan et al. 2003 (RTOG 97-06) Phase I/II
Zapatero et al. 2009 Non-randomized

Patients in Zapatero et al. 2000 had T2 to T4 N0 M0 disease. Patients in RTOG 97-06 had 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 (per Figure 1 of Zapatero, et al. 2010), 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

Variant #2, cisplatin 70 mg/m2 q3wk x 2

Study Evidence
Tester et al. 1996 (RTOG 88-02) Phase II

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

Radiotherapy

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."

Variant #3, cisplatin 100 mg/m2 q3wk x 2

Study Evidence
Shipley et al. 1988 Non-randomized
Shipley et al. 1998 (RTOG 89-03) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

Radiotherapy

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."

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

Cisplatin, Fluorouracil, RT

back to top

Variant #1, 90/2400/24

Study Evidence
Kaufman et al. 2000 (RTOG 95-06) Phase I/II

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

Supportive medications

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

Variant #2, 135/2400/40.3

Study Evidence Comparator
Coen et al. 2018 (RTOG 0712) Randomized Phase II (C) Gemcitabine & RT

Note: this trial was not statistically powered to compare regimens.

Chemotherapy

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

Variant #3, 135/3600/40.3

Study Evidence Comparator
Mitin et al. 2013 (RTOG 02-33) Randomized Phase II (E) Cisplatin, Paclitaxel, RT

Chemotherapy

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

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. contains verified protocol link to PMC article 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. 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

Cisplatin, Paclitaxel, RT

back to top

Variant #1, 40/50 x 3 + 40.3 Gy

Study Evidence
Kaufman et al. 2009 (RTOG 99-06) Phase I/II

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

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

Variant #2, 45/50 x 3 + 40.3 Gy

Study Evidence Comparator
Mitin et al. 2013 (RTOG 02-33) Randomized Phase II (E) Cisplatin, Fluorouracil, RT

Chemotherapy

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

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. contains verified protocol link to PMC article 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

Fluorouracil, Mitomycin, RT

back to top

RT: Radiation Therapy

Regimen

Study Evidence Comparator Comparative Efficacy
James et al. 2012 (BC2001) Phase III (E) Radiation therapy Seems to have superior locoregional DFS

Chemotherapy

Radiotherapy

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

Gemcitabine & RT

back to top

Regimen

Study Evidence Comparator
Coen et al. 2018 (RTOG 0712) Randomized Phase II (E) CF & RT

Note: this trial was not statistically powered to compare regimens.

Chemotherapy

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

Paclitaxel & RT

back to top

Regimen

Study Evidence
Zapatero et al. 2012 Non-randomized, <20 pts

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

Chemotherapy

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

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

Radiation therapy

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Zapatero et al. 2000 Non-randomized
James et al. 2012 (BC2001) Phase III (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 as follows:
    • 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

Consolidation chemoradiotherapy

Cisplatin & RT

back to top

RT: Radiation Therapy

Variant #1, cisplatin 40 mg/m2/wk x 2

Study Evidence
Zapatero et al. 2000 Non-randomized
Hagan et al. 2003 (RTOG 97-06) Phase I/II

Preceding treatment

Chemotherapy

  • Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1 & 2 (per Figure 1 of Zapatero et al. 2010), 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

Variant #2, cisplatin 70 mg/m2 x 1

Study Evidence
Tester et al. 1996 (RTOG 88-02) Phase II

Preceding treatment

Chemotherapy

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

Variant #3, cisplatin 100 mg/m2 x 1

Study Evidence
Shipley et al. 1998 (RTOG 89-03) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

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, RT

back to top

Variant #1, 30/1200 x 2 + 64.3 Gy

Study Evidence Comparator
Mitin et al. 2013 (RTOG 02-33) Randomized Phase II (E) Cisplatin, Paclitaxel, RT

Consolidation starts starts on week 8.

Preceding treatment

Chemotherapy

Starts on week 8.

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

Variant #2, 45/1200 x 2 + 44 Gy

Study Evidence
Kaufman et al. 2000 (RTOG 95-06) Phase I/II

Treatment starts on week 9.

Preceding treatment

Chemotherapy

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

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. contains verified protocol link to PMC article 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, Paclitaxel, RT

back to top

Variant #1, 30/50 x 2 + 64.3 Gy

Study Evidence Comparator
Mitin et al. 2013 (RTOG 02-33) Randomized Phase II (E) Cisplatin, 5-FU, RT

Consolidation starts starts on week 8.

Preceding treatment

Chemotherapy

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

Variant #2, 40/50 x 2 + 64.3 Gy

Study Evidence
Kaufman et al. 2009 (RTOG 99-06) Phase I/II

Consolidation starts starts on week 8.

Preceding treatment

Chemotherapy

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

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. contains verified protocol link to PMC article 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

Paclitaxel & RT

back to top

Regimen

Study Evidence
Zapatero et al. 2012 Non-randomized, <20 pts

Preceding treatment

Chemotherapy

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 chemotherapy

Cisplatin & Gemcitabine

back to top

Regimen

Study Evidence
Kaufman et al. 2009 (RTOG 99-06) Phase I/II

Preceding treatment

Chemotherapy

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

back to top

Regimen

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Lehmann et al. 2005 (AUO-AB 05/95) Phase III (E) M-VEC x 3 Seems not superior Less toxic

Preceding treatment

Chemotherapy

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-AB 05/95 Study Group. 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

back to top

MCV: Methotrexate, Cisplatin, Vinblastine

Regimen

Study Evidence
Hagan et al. 2003 (RTOG 97-06) Phase I/II

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. 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

Observation

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Paz-Ares et al 2010 (SOGUG 99/01) Phase III (C) PGC Inferior OS
Stadler et al. 2011 Phase III (C) MVAC Seems not superior
Cognetti et al. 2011 Phase III (C) Cisplatin & Gemcitabine Seems not superior
Sternberg et al. 2014 (EORTC 30994) Phase III (C) MVAC Seems not superior

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). This arm underwent cystectomy and no further treatment. The study prematurely closed due to poor recruitment and lacks adequate power to make firm conclusions. In Stadler et al. 2011, only patients with positive p53 staining were randomized.

Preceding treatment

Subsequent treatment

  • EORTC 30994, upon relapse: MVAC x 6

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. Stadler WM, Lerner SP, Groshen S, Stein JP, Shi SR, Raghavan D, Esrig D, Steinberg G, Wood D, Klotz L, Hall C, Skinner DG, Cote RJ. Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. J Clin Oncol. 2011 Sep 1;29(25):3443-9. Epub 2011 Aug 1. link to original article link to PMC article PubMed
  3. Cognetti F, Ruggeri EM, Felici A, Gallucci M, Muto G, Pollera CF, Massidda B, Rubagotti A, Giannarelli D, Boccardo F; Study Group. Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. Ann Oncol. 2012 Mar;23(3):695-700. Epub 2011 Aug 22. link to original article PubMed
  4. EORTC 30994: Sternberg CN, Skoneczna I, Kerst JM, Albers P, Fossa SD, Agerbaek M, Dumez H, de Santis M, Théodore C, Leahy MG, Chester JD, Verbaeys A, Daugaard G, Wood L, Witjes JA, de Wit R, Geoffrois L, Sengelov L, Thalmann G, Charpentier D, Rolland F, Mignot L, Sundar S, Symonds P, Graham J, Joly F, Marreaud S, Collette L, Sylvester R; European Organisation for Research and Treatment of Cancer Genito-Urinary Cancers Group; Groupe d'Etude des Tumeurs Urogénitales; National Cancer Research Institute Bladder Cancer Study Group; National Cancer Institute of Canada Clinical Trials Group; German Association of Urologic Oncology. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015 Jan;16(1):76-86. Epub 2014 Dec 11. link to original article PubMed

PGC

back to top

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

Variant #1

Study Evidence Comparator Comparative Efficacy
Paz-Ares et al 2010 (SOGUG 99/01) Phase III (E) 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.

Preceding treatment

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

Chemotherapy

21-day cycle for 4 cycles

Variant #2

Study Evidence
Mitin et al. 2013 (RTOG 02-33) Non-randomized portion of RCT

Preceding treatment

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 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. contains verified protocol link to PMC article 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

Locally advanced or metastatic disease, first-line

Atezolizumab monotherapy

back to top

Regimen

Study Evidence Efficacy
Balar et al. 2016 (IMvigor210) Phase II ORR: 23% (95% CI 16-31)

On 5/18/2018 the FDA released a warning that patients in the monotherapy arms of the ongoing IMVIGOR-130 trial with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.

Immunotherapy

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 PubMed IMvigor210 at ClinicalTrials.gov

Carboplatin & Gemcitabine

Source: Carboplatin & gemcitabine for unresectable or metastatic bladder cancer

back to top

GC: Gemcitabine, Carboplatin

Variant #1, AUC 4.5/1000

Study Evidence Comparator Efficacy Toxicity ORR Comparator ORR
De Santis et al. 2009 (EORTC 30986) Randomized Phase II/III (E) M-CAVI Seems not superior Lower toxicity than M-CAVI Intention to treat:
38% (2009)
41.2% (2012)
Intention to treat:
20% (2009)
30.3% (2012)

Chemotherapy

21-day cycles

Patients who achieved complete response were given two additional cycles of treatment.

Variant #2, AUC 5/1250

Study Evidence Comparator Efficacy ORR Comparator ORR
Dogliotti et al. 2006 Randomized Phase II (E) Cisplatin & Gemcitabine Seems not superior 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

21-day cycle for up to 6 cycles

References

  1. 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
  2. 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
    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

Carboplatin & Paclitaxel

back to top

Regimen

Study Evidence Efficacy
Vaughn et al. 2002 (ECOG E2896) Phase II ORR: 24% (95% CI 12-42)

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. 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

CISCA

back to top

CISCA: CISplatin, Cyclophosphamide, Adriamycin (Doxorubicin)

Regimen

Study Evidence Comparator Efficacy ORR Comparator ORR
Sternberg et al. 1977 Non-randomized, <20 pts
Logothetis et al. 1990 Phase III (E) MVAC Inferior OS 46% (95% CI 32-62) 65% (95% CI 52-77)

Chemotherapy

Supportive medications

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 monotherapy

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Soloway et al. 1983 Randomized (C) Cisplatin & Cyclophosphamide Seems not superior
Khandekar et al. 1985 Randomized (C) CAD Seems not superior
Troner et al. 1987 Phase III (C) CAD Seems not superior
Hillcoat et al. 1989 Phase III (C) Cisplatin & Methotrexate Seems not superior
Loehrer et al. 1992 Phase III (C) MVAC Inferior OS

For historic reference. To our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.

Chemotherapy

References

  1. Soloway MS, Einstein A, Corder MP, Bonney W, Prout GR Jr, Coombs J. A comparison of cisplatin and the combination of cisplatin and cyclophosphamide in advanced urothelial cancer: a National Bladder Cancer Collaborative Group A study. Cancer. 1983 Sep 1;52(5):767-72. link to original article PubMed
  2. Khandekar JD, Elson PJ, DeWys WD, Slayton RE, Harris DT. Comparative activity and toxicity of cis-diamminedichloroplatinum (DDP) and a combination of doxorubicin, cyclophosphamide, and DDP in disseminated transitional cell carcinomas of the urinary tract. J Clin Oncol. 1985 Apr;3(4):539-45. link to original article PubMed
  3. Troner M, Birch R, Omura GA, Williams S. Phase III comparison of cisplatin alone versus cisplatin, doxorubicin and cyclophosphamide in the treatment of bladder (urothelial) cancer: a Southeastern Cancer Study Group trial. J Urol. 1987 Apr;137(4):660-2. link to SD article PubMed
  4. Hillcoat BL, Raghavan D, Matthews J, Kefford R, Yuen K, Woods R, Olver I, Bishop J, Pearson B, Coorey G, Levi J, Abbott RL, Aroney R, Gill PG, McLennan R. A randomized trial of cisplatin versus cisplatin plus methotrexate in advanced cancer of the urothelial tract. J Clin Oncol. 1989 Jun;7(6):706-9. link to original article PubMed
  5. 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

Cisplatin & Gemcitabine

back to top

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

Variant #1, 70/1000, q3wk

Study Evidence Comparator Comparative Efficacy
Soto Parra et al. 2002 Randomized Phase II, <20 pts in this subgroup (E) Cisplatin & Gemcitabine q4wk Not reported

Chemotherapy

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 cycle for up to 6 cycles

Variant #2, 70/1000, q4wk

Study Evidence Comparator Comparative Efficacy
von der Maase et al. 2000 Phase III (E) MVAC Seems not superior
Soto Parra et al. 2002 Randomized Phase II, <20 pts in this subgroup (E) Cisplatin & Gemcitabine q3wk Not reported
Bellmunt et al. 2012 (EORTC 30987) Phase III (C) PCG Might have inferior OS
Sternberg et al. 2013 (CILAB) Phase III (C) Cisplatin & Larotaxel Seems not superior

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

Chemotherapy

Supportive 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

Variant #3, 70/1250, q3wk

Study Evidence Comparator Efficacy ORR Comparator ORR
Dogliotti et al. 2006 Randomized Phase II (C) Carboplatin & Gemcitabine Seems not superior Intention to treat: 49% (95% CI NR)
Evaluable patients only: 66%
(95% CI: 49–80)
Intention to treat: 40% (95% CI NR)
Evaluable patients only: 56%
(95% CI: 40–72)

Chemotherapy

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
  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

Gemcitabine & Paclitaxel

back to top

Variant #1

Study Evidence Efficacy
Calabrò et al. 2009 Phase II ORR: 37%

Chemotherapy

14-day cycle for 6 to 12 cycles

Variant #2

Study Evidence Efficacy
Meluch et al. 2001 Phase II ORR: 54% (95% CI 40-67)

Chemotherapy

21-day cycle for up to 6 cycles

References

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

MVAC

back to top

MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin

Variant #1, standard

Study Evidence Comparator Comparative Efficacy
Logothetis et al. 1990 Phase III (E) CISCA Superior OS
Loehrer et al. 1992 Phase III (E) Cisplatin Superior OS
von der Maase et al. 2000 Phase III (C) Cisplatin & Gemcitabine Seems not superior
Sternberg et al. 2001 (EORTC 30924) Phase III (C) Dose-dense MVAC Seems to have inferior PFS
Siefker-Radtke et al. 2002 Phase III (C) FAP Seems not superior

Chemotherapy

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

Variant #2, with G-CSF support

Study Evidence Comparator Comparative Efficacy
Bamias et al. 2003 Phase III (C) Cisplatin & Docetaxel Seems to have superior OS

Chemotherapy

Supportive medications

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
  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; European Organization for Research and Treatment of Cancer 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 Organization 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

MVAC, dose-dense

back to top

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

Regimen

Study Evidence Comparator Efficacy ORR Comparator ORR
Sternberg et al. 2001 (EORTC 30924) Phase III (E) MVAC Seems to have superior PFS 62% (95% CI 54-70) 50% (95% CI 42-59)
Bamias et al. 2012 (HE 16/03) Phase III (C) DD-GC Seems not superior

Note: In contrast to Sternberg et al. 2001, Sternberg et al. 2006 specified 15-day cycles

Chemotherapy

Supportive medications

  • G-CSF 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; European Organization for Research and Treatment of Cancer 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 Organization 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. 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

PGC

back to top

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

Regimen

Study Evidence Comparator Efficacy ORR Comparator ORR
Bellmunt et al. 2012 (EORTC 30987) Phase III (E) Cisplatin & Gemcitabine Might have superior OS 56% (95% CI NR) 44% (95% CI NR)

Chemotherapy

21-day cycle for up to 6 cycles

References

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

Pembrolizumab monotherapy

back to top

Regimen

Study Evidence Efficacy
Balar et al. 2017 (KEYNOTE-052) Phase II 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.

Immunotherapy

21-day cycles

References

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

Maintenance after first-line therapy

Placebo

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Powles et al. 2016 (LaMB) Phase III (C) Lapatinib Seems not superior

No active antineoplastic treatment.

References

  1. LaMB: Powles T, Huddart RA, Elliott T, Sarker SJ, Ackerman C, Jones R, Hussain S, Crabb S, Jagdev S, Chester J, Hilman S, Beresford M, Macdonald G, Santhanam S, Frew JA, Stockdale A, Hughes S, Berney D, Chowdhury S. Phase III, double-blind, randomized trial that compared maintenance lapatinib versus placebo after first-line chemotherapy in patients with human epidermal growth factor receptor 1/2-positive metastatic bladder cancer. J Clin Oncol. 2017 Jan;35(1):48-55. Epub 2016 Oct 28. link to original article PubMed

Locally advanced or metastatic disease, subsequent lines

Atezolizumab monotherapy

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Powles et al. 2014 Phase 1
Rosenberg et al. 2016 (IMvigor210) Phase II ORR: 15% (95% CI 11-20)
Powles et al. 2017 (IMvigor211) Phase III (E) 1. Docetaxel
2. Paclitaxel
3. Vinflunine
Seems not superior

Note: this regimen did not meet its primary endpoint in phase III; here for historical reference only.

Immunotherapy

21-day cycles

References

  1. Phase 1: Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL, Shen X, Boyd Z, Hegde PS, Chen DS, Vogelzang NJ. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014 Nov 27;515(7528):558-62. link to original article PubMed
  2. IMvigor210: Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016 May 7;387(10031):1909-20. Epub 2016 Mar 4. link to original article link to PMC article contains protocol 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

Avelumab monotherapy

Source: Avelumab (Bavencio) for metastatic bladder cancer

back to top

Regimen

Study Evidence Efficacy
Apolo et al. 2017 (JAVELIN) Phase Ib 18% (95% CI 8-33)

Immunotherapy

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 PubMed

Best supportive care

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Bellmunt et al. 2009 Phase III (C) Vinflunine Inferior OS (*)

No active antineoplastic treatment. Reported efficacy is based on the 2013 update.

References

  1. 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
    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

Docetaxel monotherapy

back to top

Regimen

Study Evidence Comparator Efficacy ORR Comparator ORR
McCaffrey et al. 1997 Phase II 13% (95% CI 4-31)
Choueiri et al. 2012 Phase III (C) Docetaxel & Vandetanib Seems not superior 11% (95% CI NR) 7% (95% CI NR)
Petrylak et al. 2016 Randomized Phase II (C) 1. Docetaxel & Icrucumab Seems not superior
2. Docetaxel & Ramucirumab Inferior PFS
Bellmunt et al. 2017 (KEYNOTE-045) Phase III (C) Pembrolizumab Inferior OS
Petrylak et al. 2017 (RANGE) Phase III (C) Docetaxel & Ramucirumab Seems to have inferior PFS
Powles et al. 2017 (IMvigor211) Phase III (C) Atezolizumab Seems not superior

Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.

Chemotherapy

21-day cycles

References

  1. McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. link to original article PubMed
  2. 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
  3. 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
  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
    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 May 3. [Epub ahead of print] link to original article PubMed
  5. RANGE: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. link to original article contains verified protocol 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

Docetaxel & Ramucirumab

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Petrylak et al. 2016 Randomized Phase II (E) Docetaxel Superior PFS
Petrylak et al. 2017 (RANGE) Phase III (E) Docetaxel Seems to have superior PFS

Chemotherapy

21-day cycles

References

  1. 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
  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

Durvalumab monotherapy

Source: Durvalumab (Imfinzi) for metastatic bladder cancer

back to top

Regimen

Study Evidence Efficacy Pt Population
Massard et al. 2016 Phase I/II ORR: 31% (95% CI 18 to 47) pts "who had progressed on, been ineligible for, or refused any number of prior therapies"

Immunotherapy

14-day cycle for up to 26 cycles (1 year). Patients could receive another 12 months of treatment if they experienced disease progression, had not received other anticancer treatment, and did not meet criteria for discontinuation.

References

  1. Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, Curiel TJ, Colon-Otero G, Hamid O, Sanborn RE, O'Donnell PH, Drakaki A, Tan W, Kurland JF, Rebelatto MC, Jin X, Blake-Haskins JA, Gupta A, Segal NH. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016 Sep 10;34(26):3119-25. link to original article link to PMC article PubMed

Erdafitinib monotherapy

back to top

Regimen

FDA-recommended dose
Study Evidence
Siefker-Radtke et al. (BLC2001) Phase II

To our knowledge there were no peer-reviewed publications from this trial at the time of this addition.

Chemotherapy

  • 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. Abstract: Arlene O. Siefker-Radtke, Andrea Necchi, Se Hoon Park, Jesus Garcia-Donas, Robert A Huddart, Earle Frederick Burgess, Mark T. Fleming, Arash Rezazadeh, Begona Mellado, Sergei Varlamov, Monika Joshi, Ignacio Duran, Scott T. Tagawa, Anne OHagan, Anjali Narayan Avadhani, Bob Zhong, Peter De Porre, Yohann Loriot, on behalf of the BLC2001 Study Group. First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt). 2018 ASCO Annual Meeting abstract 4503 link to abstract contains verified protocol
  2. BLC2001: CT.gov

Gemcitabine & Paclitaxel

back to top

GP: Gemcitabine & Paclitaxel

Variant #1, gemcitabine 2 out of 3 weeks

Study Evidence Comparator Comparative Efficacy
Albers et al. 2010 (AUO AB 20/99) Phase III (C) Prolonged GP Seems not superior

Chemotherapy

21-day cycle for up to 6 cycles

Variant #2, weekly gemcitabine

Study Evidence Efficacy
Meluch et al. 2001 Phase II, <20 pts in this subgroup ORR: 47%

Chemotherapy

21-day cycle for up to 6 cycles

References

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

MVAC

back to top

MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin

Regimen

Study Evidence Efficacy
Han et al. 2008 Phase II ORR: 30%

Chemotherapy

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

References

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

Nivolumab monotherapy

Source: Nivolumab (Opdivo) for unresectable or metastatic bladder cancer

back to top

Regimen

Study Evidence Efficacy Pt Population
Sharma et al. 2017 (CheckMate 275) Phase II 19.6% overall
PD-L1 expression ≥5%: 28.4%
PD-L1 expression ≥1%: 23.8%
PD-L1 expression <1%: 16.1%
Prior treatment with least one platinum-based therapy

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. 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

Paclitaxel monotherapy

back to top

Regimen, q3wks

Study Evidence Comparator Comparative Efficacy
Bellmunt et al. 2017 (KEYNOTE-045) Phase III (C) Pembrolizumab Inferior OS
Powles et al. 2017 (IMvigor211) Phase III (C) Atezolizumab Seems not superior

Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.

Chemotherapy

21-day cycles

Variant #2, 3 out of 4 weeks

Study Evidence Efficacy
Vaughn et al. 2002 Phase II ORR: 10% (95% CI 0-20)

Chemotherapy

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 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
    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 May 3. [Epub ahead of print] link to original article PubMed
  4. IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article contains protocol PubMed

nab-Paclitaxel monotherapy

back to top

Regimen

Study Evidence Efficacy
Ko et al. 2013 Phase II ORR: 28% (95% CI 17-44)

Chemotherapy

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

Pembrolizumab monotherapy

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Bellmunt et al. 2017 (KEYNOTE-045) Phase III (E) Investigator's choice of:
Docetaxel
Paclitaxel
Vinflunine
Superior OS

Immunotherapy

21-day cycles

References

  1. KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains verified protocol PubMed
    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 May 3. [Epub ahead of print] link to original article PubMed

Pemetrexed monotherapy

back to top

Regimen

Study Evidence Efficacy
Sweeney et al. 2006 Phase II ORR: 28% (95% CI 16-43)

Chemotherapy

21-day cycles

References

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

Vinflunine monotherapy

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Bellmunt et al. 2009 Phase III (E) Best supportive care Superior OS (*)
Bellmunt et al. 2017 (KEYNOTE-045) Phase III (C) Pembrolizumab Inferior OS
Powles et al. 2017 (IMvigor211) Phase III (C) Atezolizumab Seems not superior

Note: reported efficacy for Bellmunt et al. 2009 is based on the 2013 update.

Chemotherapy

21-day cycles

References

  1. 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
    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
    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 May 3. [Epub ahead of print] link to original article PubMed
  3. IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article contains protocol 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