Bladder cancer

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34 regimens on this page
47 variants on this page

Contents


Guidelines

AUA, ASCO, ASTRO, SUO

ESMO

NCCN

Intravesical chemotherapy

Bacillus Calmette-Guerin (BCG) monotherapy

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

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Regimen #1, intravesical & percutaneous, with maintenance therapy

Study Evidence Comparator Efficacy
Lamm et al. 2000 Phase III Intravesical & percutaneous BCG, without maintenance therapy Superior RFS

Induction therapy

  • Bacillus Calmette-Guerin (BCG) (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

Maintenance therapy

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

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

Regimen #2, intravesical & percutaneous, without maintenance therapy

Study Evidence Comparator Efficacy
Lamm et al. 2000 Phase III Intravesical & percutaneous BCG, with maintenance therapy Inferior RFS

Immunotherapy

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

6-week course

Regimen #3, low-dose BCG

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

Treatment begins 14 to 21 days after transurethral resection of bladder cancer.

Induction therapy

6-week course, then proceed to additional therapy

Additional therapy

12-week course; 6 doses given during this course (i.e. once on weeks 1, 3, 5, 7, 9, 11)

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-Guerin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. PubMed
  2. 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-Guerin 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
  3. Sylvester RJ, van der MEIJDEN AP, Lamm DL. Intravesical bacillus Calmette-Guerin 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
  4. 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-Guerin (27 mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27. link to SD article contains verified protocol PubMed


Doxorubicin monotherapy

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Regimen

Study Evidence Comparator Efficacy
Martínez-Piñeiro et al. 1990 Phase III BCG Inferior RFS
Thiotepa 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-Guerin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. PubMed

Mitomycin monotherapy

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Regimen

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

Treatment begins 14 to 21 days after transurethral resection of bladder cancer.

Chemotherapy, part 1

6-week course, then proceed to additional therapy

Chemotherapy, part 2

12-week course; 6 doses given during this course (i.e. once on weeks 1, 3, 5, 7, 9, 11)

References

  1. 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-Guerin (27 mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27. link to SD article contains verified protocol PubMed

Pirarubicin monotherapy

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Regimen

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

Pirarubicin was given within 48 hours after nephroureterectomy.

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. 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

Placebo or observation

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Regimen

Study Evidence Comparator Efficacy
Ito et al. 2013 Phase III Pirarubicin Seems to have inferior RFS

No active antineoplastic treatment; used as a comparator arm and included for reference purposes only.

References

  1. 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

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Regimen

Study Evidence Comparator Efficacy
Martínez-Piñeiro et al. 1990 Phase III BCG Inferior RFS
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-Guerin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. PubMed

Neoadjuvant chemotherapy

Cisplatin & Gemcitabine

Source: Cisplatin & Gemcitabine for bladder cancer, neoadjuvant

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GC: Gemcitabine, Cisplatin

Regimen #1, single-dose cisplatin

Study Evidence
Dash et al. 2008 Retrospective

Chemotherapy

21-day cycle for 4 cycles

Regimen #2, split-dose cisplatin

Study Evidence
Dash et al. 2008 Retrospective

Chemotherapy

21-day cycle for 4 cycles

References

  1. 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

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

Regimen

Study Evidence Comparator Efficacy
International Collaboration of Trialists et al. 1999 (BA06 30894) Phase III No neoadjuvant therapy Seems to have superior OS

Chemotherapy

Supportive medications

  • Folinic acid (Leucovorin) 15 mg PO/IV every 6 hours for 4 doses (total daily dose: 60 mg/m2) on days 2 & 9; given after hydration, with the first dose 24 hours after the previous day's dose of methotrexate

21-day cycle for 3 cycles

References

  1. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. International collaboration of trialists. Lancet. 1999 Aug 14;354(9178):533-40. Erratum in: Lancet 1999 Nov 6;354(9190):1650. link to original article PubMed
    1. Update: 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, Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK. 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

MVAC

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

Regimen

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

Chemotherapy

28-day cycle for 3 cycles

References

  1. 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. 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/accelerated)

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

Regimen #1, dose-dense MVAC

Study Evidence
Choueiri et al. 2014 Phase II

Chemotherapy

Supportive medications

14-day cycle for 4 cycles

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

Regimen #2, accelerated MVAC

Study Evidence
Plimack et al. 2014 Phase II

Chemotherapy

Supportive medications

14-day cycle for 3 cycles

Radical cystectomy with bilateral lymphadenectomy to be done within 4 to 8 weeks after the last cycle 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

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Regimen

Study Evidence Comparator Efficacy
International Collaboration of Trialists et al. 1999 (BA06 30894) Phase III CMV Seems to have inferior OS
Grossman et al. 2003 (SWOG S8710) Phase III MVAC Might have inferior OS

No preoperative treatment; used as a comparator arm and here for reference purposes only.

References

  1. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. International collaboration of trialists. Lancet. 1999 Aug 14;354(9178):533-40. Erratum in: Lancet 1999 Nov 6;354(9190):1650. link to original article PubMed
    1. Update: 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, Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK. 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. 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. 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

Neoadjuvant chemoradiotherapy

Cisplatin & RT

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RT: Radiation Therapy

Regimen #1

Study Evidence Comparator Efficacy
Shipley et al. 1998 (RTOG 89-03) Phase III MCV, then Cisplatin & RT Seems not superior

Chemoradiotherapy, induction

  • Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1 & 22
  • Concurrent radiation therapy, 1.8 Gy fractions x 22 fractions, given 5 times per week (total dose: 39.6 Gy)

1 treatment course patient is restaged 4 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, and urinary cytology." Patients not in complete remission usually proceeded to cystectomy. Patients in compete remission usually proceeded to consolidation therapy.

Chemoradiotherapy, consolidation

  • Cisplatin (Platinol) 100 mg/m2 IV once on day 1
  • Concurrent radiation therapy, 1.8 Gy fractions x 14 fractions, given 5 times per week (total dose in consolidation phase: 39.6 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)

3-week course

Regimen #2, weekly cisplatin

Study Evidence
Zapatero et al. 2000 Non-randomized

Patients had T2 to T4 N0 M0 disease.

Chemoradiotherapy, induction

  • Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16 (per Figure 1 of Zapatero, et al. 2010), given before radiation therapy.
  • 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." Radiation therapy given 5 days per week; treatment on days 1 to 5, 8 to 12, 15 to 16. Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy.
    • 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.

16-day course of therapy (for AHFRT). 3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT. Patient with complete regression (R0) continued to consolidation therapy. Nonresponders proceeded to cystectomy.

Chemoradiotherapy, consolidation

  • Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1, 2, 8, 9 (per Figure 1 of Zapatero, et al. 2010), given before radiation therapy.
  • Concurrent radiation therapy according to one of the following:
    • Accelerated hyperfractionated RT (AHFRT), 1.5 Gy fractions twice per day x 16 fractions, treatment given on days 1 to 5, 8 to 10 (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, 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.

16-day course of therapy (for AHFRT)

References

  1. 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: 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 Nov 3. link to original article contains verified protocol link to PMC article PubMed
  2. Zapatero A, Martin 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, Martin 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

Fluorouracil, Cisplatin, RT

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Regimen

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.

Chemoradiotherapy, induction

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

Dose modifications

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

Supportive medications

  • IV hydration at 500 mL/H (no total volume specified) prior to fluorouracil

17-day course, then followed by repeat cystoscopy, biopsy, and urine cytology in week 7 or 8. Patients with complete response proceeded to consolidation chemotherapy/radiation in week 9. Incomplete responders were recommended to undergo radical cystectomy.

Chemoradiotherapy, consolidation

Starts on week 9.

  • Fluorouracil (5-FU) 400 mg/m2 IV push once per day on days 1 to 3, 15 to 17, given first, before radiation and cisplatin
  • Cisplatin (Platinol) 15 mg/m2 IV over 1 hour once per day on days 1 to 3, 15 to 17, given second, before radiation
  • Concurrent radiation therapy, 2.5 Gy fractions twice per day, with at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total consolidation dose: 20 Gy), administered to the whole bladder and bladder tumor volume. The total dose to the whole bladder and bladder tumor volume was 44 Gy in 16 fractions; the total dose to the pelvic lymph nodes was 24 Gy in 8 fractions.

Dose modifications

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

Supportive medications

  • IV hydration at 500 mL/H (no total volume specified) prior to fluorouracil

17-day course

References

  1. 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 Nov 3. link to original article contains verified protocol link to PMC article PubMed

Fluorouracil, Mitomycin, RT

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RT: Radiation Therapy

Regimen

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

Chemoradiotherapy

  • Fluorouracil (5-FU) 500 mg/m2/day IV continuous infusion for 10 total days (total dose: 5000 mg/m2) during radiation fractions 1 to 5, 16 to 20
  • Mitomycin (Mutamycin) 12 mg/m2 IV bolus once on day 1
  • Radiation therapy given according to one of the following plans:
    • Concurrent radiation therapy, 2.75 Gy fractions x 20 fractions (total dose: 55 Gy) over 4 weeks
    • Concurrent radiation therapy, 2 Gy fractions x 32 fractions (total dose: 64 Gy) over 6.5 weeks

References

  1. 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

MCV, then RT

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Regimen

Study Evidence
Zapatero et al. 2000 Non-randomized

Patients had T2 to T4 Nx M0 disease.

Chemotherapy

21-day cycle for 3 cycles; after 3 cycles of chemotherapy, patients underwent cystoscopy, biopsy, and abdominal CT. Patients with complete response or who were not surgical candidates proceeded to radiation therapy which begins 4 to 6 weeks after completion of chemotherapy. Otherwise, patients proceeded to cystectomy.

Radiotherapy

Radiation therapy starts 4 to 6 weeks after completion of chemotherapy.

  • Patients who had complete response received radiation therapy, 2 Gy fractions given 5 days per week, with total bladder dose of 60 Gy. Total dose to regional lymph nodes: 50 Gy.
    • Patients who did not have complete response received radiation therapy for a 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, Martin 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, Martin 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

MCV, then Cisplatin & RT

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MCV: Methotrexate, Cisplatin, Vinblastine
RT: Radiation Therapy

Regimen #1

Study Evidence Comparator Efficacy
Shipley et al. 1998 (RTOG 89-03) Phase III Cisplatin & RT Seems not superior

Chemotherapy

28-day cycle for 2 cycles, followed by:

Chemoradiotherapy, induction

  • Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1 & 22
  • Concurrent radiation therapy, 1.8 Gy fractions x 22 fractions, given 5 times per week (total dose: 39.6 Gy)

1 treatment course; patient is restaged 4 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, and urinary cytology." Patients not in complete remission usually proceeded to cystectomy. Patients in compete remission usually proceeded to consolidation therapy.

Chemoradiotherapy, consolidation

  • Cisplatin (Platinol) 100 mg/m2 IV once on day 1
  • Concurrent radiation therapy, 1.8 Gy fractions x 14 fractions, given 5 times per week (total dose in consolidation phase: 25.2 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)

3-week course

Regimen #2

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

Chemotherapy

28-day cycle for 2 cycles, then patients proceeded to concurrent chemotherapy & radiation therapy

Chemoradiotherapy, induction

  • Cisplatin (Platinol) 70 mg/m2 IV once per day on days 1 & 22
  • Concurrent radiation therapy, 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)

1 treatment course; patient is restaged 2 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, urinary cytology, and computed tomographic scan of pelvis." Patients with complete response--no evidence of disease on this evaluation--proceeded to consolidation radiotherapy. Patients without complete response proceeded immediately to cystectomy.

Chemoradiotherapy, consolidation

  • Cisplatin (Platinol) 70 mg/m2 IV once on day 1
  • 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

References

  1. 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. 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 Nov 3. link to original article contains verified protocol link to PMC article PubMed

Paclitaxel & RT

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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.

Chemoradiotherapy, induction

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

3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT. Patient with complete regression (R0) continued to consolidation therapy. Nonresponders proceeded to cystectomy.

Chemoradiotherapy, consolidation

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

References

  1. Zapatero A, Martin 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

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Regimen

Study Evidence Comparator Efficacy
James et al. 2012 (BC2001) Phase III Fluorouracil, Mitomycin, RT Seems to have inferior locoregional DFS

Included here for reference purposes only.

References

  1. 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

Adjuvant chemotherapy

Observation

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Regimen

Study Evidence Comparator Efficacy
Paz-Ares et al 2010 (SOGUG 99/01) Phase III PGC Inferior 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). This arm underwent cystectomy and no further treatment. The study prematurely closed due to poor recruitment and lacks adequate power to make firm conclusions.

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

PGC

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PGC: Paclitaxel, Gemcitabine, Cisplatin

Regimen

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

Patients initially underwent cystectomy; the median time treatment started post-cystectomy was 48 days.

Chemotherapy

21-day cycle for 4 cycles

References

  1. Abstract: L. G. Paz-Ares, E. Solsona, E. Esteban, A. Saez, J. Gonzalez-Larriba, A. Anton, M. Hevia, F. de la Rosa, V. Guillem, and J. Bellmunt. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. ASCO MEETING ABSTRACTS Jun 22, 2010:LBA4518. link to abstract contains verified protocol

Concurrent chemotherapy & radiation, then adjuvant chemotherapy

Cisplatin & RT, then MCV

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MCV: Methotrexate, Cisplatin, Vinblastine

Regimen

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

Patients in RTOG 97-06 had T2 to T4a N0 M0 disease without hydronephrosis.

Chemoradiotherapy, induction

Patients initially underwent "aggressive transurethral resection of bladder tumor (TURBT)".

  • Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16, given before radiation therapy.
  • Accelerated concurrent radiation therapy, 1.8 Gy fractions x 12 fractions to the bladder tumor, bladder, and regional lymph nodes; 4 to 6 hours later, a 1.6 Gy fraction x 12 fractions is given to the tumor plus a 2 cm margin. Radiation therapy given 5 days per week; treatment on days 1 to 5, 8 to 12, 15 to 16. Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy.

16-day course. 3 weeks after chemotherapy & radiation, patients were restaged with cystoscopy, tumor site biopsy, and urine cytology. Patients with complete response proceeded to consolidation therapy. Patients who did not achieve complete response proceeded to cystectomy.

Chemoradiotherapy, consolidation

  • Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1, 2, 8, 9, given before radiation therapy.

Concurrent radiation therapy according to one of the following:

  • Accelerated concurrent radiation therapy, 1.5 Gy fractions twice per day x 16 fractions, treatment given on days 1 to 5, 8 to 10 (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.

10-day course

Chemotherapy

Begins 8 weeks after initial therapy. Only 45% of patients in Hagan, et al. 2003 (RTOG 97-06) were able to complete 3 cycles of MCV

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 content property of HemOnc.org
    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 Nov 3. link to original article contains verified protocol link to PMC article PubMed

Cisplatin, Paclitaxel, RT --> Cisplatin & Gemcitabine

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Regimen

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

Chemoradiotherapy, induction

Starts 4 to 6 weeks after TURBT.

  • Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
  • Paclitaxel (Taxol) 50 mg/m2 IV once per day on days 1, 8, 15
  • Concurrent radiation therapy, with BID 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. On week 7, over 3 weeks after induction therapy, patients under reevaluation with exam under anesthesia, cystoscopy with tumor site biopsy, and urine cytology. Patients with less than stage T1 disease proceeded to consolidation therapy. Patients with at least Stage T1 disease proceeded to radical cystectomy, followed by adjuvant chemotherapy. Note: The abstract of Kaufman, et al. 2009 (RTOG 99-06) 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 T1 disease.

Chemotherapy, consolidation

Starts on week 8.

  • Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1, 2, 8, 9
  • Paclitaxel (Taxol) 50 mg/m2 IV once per day on days 1 & 8
  • 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

Chemotherapy

Starts "12 weeks after consolidation chemoradiotherapy, or 8 weeks after cystectomy."

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: 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 Nov 3. link to original article contains verified protocol link to PMC article PubMed

Cisplatin, Paclitaxel, RT --> Cisplatin, Gemcitabine, Paclitaxel

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Regimen

Study Evidence Comparator Efficacy
Mitin et al. 2013 (RTOG 02-33) Randomized Phase II Fluorouracil, Cisplatin, RT --> Cisplatin, Gemcitabine, Paclitaxel Not reported

Chemoradiotherapy, induction

  • Cisplatin (Platinol) 15 mg/m2 IV once per day on days 1 to 3, 8 to 10, 15 to 17
  • Paclitaxel (Taxol) 50 mg/m2 IV once per day on days 1, 8, 15
  • Concurrent radiation therapy, with BID RT, with at least 4 hours between radiation therapy sessions:
    • 1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
    • 1.5 Gy fractions to the bladder every evening on days 1 to 5
    • 1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
    • Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.

3-week course. On week 7, patients under reevaluation for response. Patients with less than stage T1 disease proceeded to consolidation therapy. Patients with at least stage T1 disease proceeded to radical cystectomy on week 9, followed by adjuvant chemotherapy.

Chemoradiotherapy, consolidation

Starts on week 8.

  • Cisplatin (Platinol) 15 mg/m2 IV once per day on days 1, 2, 8, 9
  • Paclitaxel (Taxol) 50 mg/m2 IV once per day on days 1 & 8
  • 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

Chemotherapy

"Adjuvant chemotherapy began 12 weeks after consolidation chemoradiotherapy or 8 weeks after cystectomy."

21-day cycle for 4 cycles

References

  1. 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: 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 Nov 3. link to original article contains verified protocol link to PMC article PubMed

Fluorouracil, Cisplatin, RT --> Cisplatin, Gemcitabine, Paclitaxel

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Regimen

Study Evidence Comparator Efficacy
Mitin et al. 2013 (RTOG 02-33) Randomized Phase II Cisplatin, Paclitaxel, RT --> Cisplatin, Gemcitabine, Paclitaxel Not reported

Chemoradiotherapy, induction

  • Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 3, 8 to 10, 15 to 17
  • Cisplatin (Platinol) 15 mg/m2 IV once per day on days 1 to 3, 8 to 10, 15 to 17
  • Concurrent radiation therapy, with BID RT, with at least 4 hours between radiation therapy sessions:
    • 1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
    • 1.5 Gy fractions to the bladder every evening on days 1 to 5
    • 1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
    • Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.

3-week course. On week 7, patients under reevaluation for response. Patients with less than stage T1 disease proceeded to consolidation therapy. Patients with at least stage T1 disease proceeded to radical cystectomy on week 9, followed by adjuvant chemotherapy.

Chemotherapy, consolidation

Starts on week 8.

  • Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 3, 8 to 10
  • Cisplatin (Platinol) 15 mg/m2 IV once per day on days 1, 2, 8, 9
  • 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

Chemotherapy

"Adjuvant chemotherapy began 12 weeks after consolidation chemoradiotherapy or 8 weeks after cystectomy."

21-day cycle for 4 cycles

References

  1. 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: 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 Nov 3. link to original article contains verified protocol link to PMC article PubMed

Locally advanced or metastatic disease

Atezolizumab monotherapy

Source: Atezolizumab (Tecentriq) for metastatic bladder cancer

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Regimen

Study Evidence ORR
Rosenberg et al. 2016 (IMvigor211) Phase II 15% (95% CI 11-20%)
Balar et al. 2016 (IMvigor210) Phase II 23% (95% CI 16-31%)

Immunotherapy

21-day cycles, given until progression of disease

References

  1. 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
  2. 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

Avelumab monotherapy

Source: Avelumab (Bavencio) for metastatic bladder cancer

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Regimen

Study Evidence ORR
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, given until progression of disease or unacceptable toxicity

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

Carboplatin & Gemcitabine

Source: Carboplatin & gemcitabine for unresectable or metastatic bladder cancer

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GC: Gemcitabine, Carboplatin

Regimen #1

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

Chemotherapy

21-day cycle for up to 6 cycles

Regimen #2

Study Evidence ORR Comparator Comparator ORR Efficacy Toxicity Pt Population
De Santis et al. 2009 (EORTC 30986)
De Santis et al. 2012 (EORTC 30986)
Randomized Phase II/III Intention to treat:
38% (2009)
41.2% (2012)
M-CAVI Intention to treat:
20% (2009)
30.3% (2012)
No significant difference in efficacy Lower toxicity than M-CAVI Chemo-naive

Chemotherapy

21-day cycles, given until disease progression or unacceptable toxicity. Patients who achieved complete response were given two additional cycles of treatment.

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 SD article contains verified protocol PubMed
  2. 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 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 contains verified protocol PubMed

Carboplatin & Paclitaxel

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Regimen

Study Evidence ORR Pt Population
Vaughn et al. 2002 (ECOG E2896) Phase II 24% (95% CI 12-42%) Chemo-naive

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

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CISCA: CISplatin, Cyclophosphamide, Adriamycin (Doxorubicin)

Regimen

Study Evidence ORR Comparator Comparator ORR Efficacy Pt Population
Logothetis et al. 1990 Phase III 46% (95% CI 32-62%) MVAC 65% (95% CI 52-77%) Inferior OS Chemo-naive

Chemotherapy

Supportive medications

21-day cycle for up to 6 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

Cisplatin & Gemcitabine

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

Regimen #1, 4-week schedule

Study Evidence Comparator Efficacy
von der Maase et al. 2000 Phase III MVAC Seems not superior
Soto Parra et al. 2002 Randomized Phase II, <20 pts in this subgroup Cisplatin & Gemcitabine, 3-week schedule, gemcitabine at 1000 mg/m2 Not reported
Bellmunt et al. 2012 (EORTC 30987) Phase III PCG Might have inferior OS

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
  • "blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"

28-day cycle for up to 6 cycles, progression of disease, unacceptable toxicity, or physician discretion based on patient's best interests

Regimen #2, 3-week schedule, gemcitabine at 1250 mg/m2

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

Chemotherapy

21-day cycle for up to 6 cycles, until progression of disease, unacceptable toxicity, or physician discretion based on patient's best interests

Regimen #3, 3-week schedule, gemcitabine at 1000 mg/m2

Study Evidence Comparator Efficacy Pt Population
Soto Parra et al. 2002 Randomized Phase II, <20 pts in this subgroup Cisplatin & Gemcitabine, 4-week schedule Not reported Chemo-naive

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, progression of disease, unacceptable toxicity, or physician discretion based on patient's best interests

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 SD article contains verified protocol PubMed
  4. 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

Docetaxel monotherapy

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Regimen

Study Evidence ORR Comparator Comparator ORR Efficacy Pt Population
Choueiri et al. 2012 Phase III 11% (95% CI NR) Docetaxel & Vandetanib 7% (95% CI NR) Seems not superior Mix of chemo-naive and treated
Bellmunt et al. 2017 (KEYNOTE-045) Phase III Pembrolizumab Inferior OS Second-line

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. 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

Durvalumab monotherapy

Source: Durvalumab (Imfinzi) for metastatic bladder cancer

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Regimen

Study Evidence ORR Pt Population
Massard et al. 2016 Phase I/II 31.0% (95% CI 17.6 to 47.1) pts "who had progressed on, been ineligible for, or refused any number of prior therapies"

Immunotherapy

14-day cycles for up to 12 months, given until progression of disease or unacceptable toxicity. 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 ASCO Annual meeting abstract; A Phase 1/2 Study to Evaluate MEDI4736 (NCT01693562) at ClinicalTrials.gov

Gemcitabine & Paclitaxel

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Regimen #1

Study Evidence ORR Pt Population
Calabrò et al. 2009 Phase II 37% untreated

Chemotherapy

14-day cycle for 6 to 12 cycles

Regimen #2

Study Evidence ORR Pt Population
Meluch et al. 2001 Phase II 54% (95% CI 40-67%) mix of chemo-naive and exposed (but not with gemcitabine or paclitaxel)

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

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MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin

Regimen #1, dose-dense

Study Evidence ORR Comparator Comparator ORR Efficacy Pt Population
Sternberg et al. 2001 (EORTC 30924) Phase III 62% (95% CI 54-70%) Standard MVAC 50% (95% CI 42-59%) Seems to have superior PFS Chemo-naive

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, given until progression of disease or unacceptable toxicity

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

Regimen #2, standard

Study Evidence Comparator Efficacy
Logothetis et al. 1990 Phase III CISCA Superior OS
von der Maase et al. 2000 Phase III Cisplatin & Gemcitabine Seems not superior
Sternberg et al. 2001 (EORTC 30924) Phase III Dose-dense MVAC Seems to have inferior PFS
Han et al. 2008 Phase II

Chemotherapy

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

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. 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
  3. 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 SD article contains verified protocol PubMed
  4. 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

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Regimen

Study Evidence ORR 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, given until progression of disease or unacceptable toxicity

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

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Regimen, q3wks

Study Evidence Comparator Efficacy Pt Population
Bellmunt et al. 2017 (KEYNOTE-045) Phase III Pembrolizumab Inferior OS Second-line

Chemotherapy

21-day cycles

Regimen #2, 3 out of 4 weeks

Study Evidence ORR Pt Population
Vaughn et al. 2002 Phase II 10% (95% CI 0-20%) One prior regimen

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. 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

Paclitaxel, nanoparticle albumin-bound monotherapy

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Regimen

Study Evidence ORR Pt Population
Ko et al. 2013 Phase II 28% (95% CI 17-44%) One prior platinum regimen

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

PCG

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PCG: Paclitaxel, Cisplatin, Gemcitabine

Regimen

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

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. 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

Source: Pembrolizumab (Keytruda) for unresectable or metastatic bladder cancer

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Regimen

Study Evidence ORR Pt Population Comparator Efficacy
Bellmunt et al. 2017 (KEYNOTE-045) Phase III 21% second-line therapy Paclitaxel
Docetaxel
Vinflunine
Superior OS
Balar et al. 2016 (KEYNOTE-052) Phase II 28.6% (95% CI 24 to 34%) first-line therapy none

Immunotherapy

21-day cycles

References

  1. Abstract: A. Balar, J. Bellmunt, P.H. O'Donnell, D. Castellano, P. Grivas, J. Vuky, T. Powles, E.R. Plimack, N.M. Hahn, R. de Wit, L. Pang, M.J. Savage, R. Perini, S. Keefe, D. Bajorin. Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: Preliminary results from the phase 2 KEYNOTE-052 study. Ann Oncol (2016) 27 (suppl_6): LBA32_PR. link to abstract
  2. 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

Pemetrexed monotherapy

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Regimen

Study Evidence ORR Pt Population
Sweeney, et al. 2006 Phase II 28% (95% CI 16-43%) One prior regimen

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

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