Difference between revisions of "Urothelial carcinoma"
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*'''2017:''' Chang et al. [http://www.auanet.org/guidelines/muscle-invasive-bladder-cancer-new-(2017) Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/28456635 PubMed] | *'''2017:''' Chang et al. [http://www.auanet.org/guidelines/muscle-invasive-bladder-cancer-new-(2017) Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/28456635 PubMed] | ||
+ | |||
+ | ==EAU-ESMO== | ||
+ | *'''2019:''' Horwich et al. [https://academic.oup.com/annonc/article/30/11/1697/5629133 EAU–ESMO consensus statements on the management of advanced and variant bladder cancer—an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees] | ||
==[http://www.esmo.org/ ESMO]== | ==[http://www.esmo.org/ ESMO]== |
Revision as of 02:26, 28 December 2019
Page editor | Section editor | ||
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Ali Raza Khaki, MD University of Washington Seattle, WA arkhaki |
Eddy J. Chen, MD Massachusetts General Hospital Boston, MA |
31 regimens on this page
47 variants on this page
|
Guidelines
AUA, ASCO, ASTRO, SUO
- 2017: Chang et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline PubMed
EAU-ESMO
ESMO
- 2014: Bellmunt et al. Bladder cancer: ESMO Clinical Practice Guidelines PubMed
NCCN
Intravesical chemotherapy
Bacillus Calmette-Guérin (BCG) monotherapy
Bacillus Calmette-Guérin (BCG) intravesicular chemotherapy in bladder cancer
Doxorubicin monotherapy
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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 (SWOG 8216) | Phase III (C) | BCG | Seems to have inferior DFS |
Inferior to BCG, included for reference purposes only.
Chemotherapy
15 or more treatments
References
- Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. link to SD article contains partial protocol PubMed
- SWOG 8216: Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA Jr, Sullivan J, Sarosdy MF, Crissman JD, Coltman CA. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med. 1991 Oct 24;325(17):1205-9. link to original article PubMed
Gemcitabine monotherapy
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Variant #1, 1 treatment
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Messing et al. 2018 (SWOG S0337) | Phase III (E-esc) | Placebo (saline) | Superior TTR |
Preceding treatment
- TURBT, up to 3 hours prior
Chemotherapy
- Gemcitabine (Gemzar) 2000 mg in 100 mL of saline instilled intravesicularly for up to 60 minutes
One treatment
Variant #2, 6 treatments
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Addeo et al. 2009 | Phase III (E-switch-ic) | Mitomycin | Superior DFS |
Chemotherapy
- Gemcitabine (Gemzar) 2000 mg in 50 mL of saline instilled intravesicularly for up to 60 minutes once per day on days 1, 8, 15, 22, 29, 36
6-week course
References
- Addeo R, Caraglia M, Bellini S, Abbruzzese A, Vincenzi B, Montella L, Miragliuolo A, Guarrasi R, Lanna M, Cennamo G, Faiola V, Del Prete S. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. J Clin Oncol. 2010 Feb 1;28(4):543-8. Epub 2009 Oct 19. link to original article contains verified protocol PubMed
- SWOG S0337: Messing EM, Tangen CM, Lerner SP, Sahasrabudhe DM, Koppie TM, Wood DP Jr, Mack PC, Svatek RS, Evans CP, Hafez KS, Culkin DJ, Brand TC, Karsh LI, Holzbeierlein JM, Wilson SS, Wu G, Plets M, Vogelzang NJ, Thompson IM Jr. Effect of intravesical instillation of gemcitabine vs saline immediately following resection of suspected low-grade non-muscle-invasive bladder cancer on tumor recurrence: SWOG S0337 randomized clinical trial. JAMA. 2018 May 8;319(18):1880-1888. link to original article contains verified protocol PubMed
Mitomycin monotherapy
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Variant #1, 30 mg x 12
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Ojea et al. 2007 (CUETO study 95011) | Phase III (C) | 1. BCG; low-dose | Inferior DFS |
2. BCG; very-low-dose | Did not meet efficacy endpoints |
Preceding treatment
- TURBT, 14 to 21 days prior
Chemotherapy
- Mitomycin (Mutamycin) as follows:
- Cycles 1 to 3: 30 mg intravesicularly once per day on days 1 & 8
- Cycles 4 to 9: 30 mg intravesicularly once on day 1
14-day cycle for 9 cycles
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
- Mitomycin (Mutamycin) 40 mg intravesicularly once on day 1
7-day cycle for 4 cycles, then monthly cycle for 4 cycles, then 3-month cycle for 3 cycles
References
- CUETO study 95011: Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, Chantada V, Camacho JE, Piñeiro LM, Rodríguez RH, Isorna S, Blas M, Martínez-Piñeiro JA, Madero R; CUETO 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
- 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
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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
- 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
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Ito et al. 2013 (THP Monotherapy Study Group Trial) | Phase III (E-esc) | 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
- 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
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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
- Thiotepa (Thioplex) 50 mg intravesicularly x 15 treatments
References
- Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, Fiter L, Mosteiro JA, Navarro J, García Matres MJ, Cárcamo P. Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol. 1990 Mar;143(3):502-6. link to SD article contains partial protocol PubMed
Valrubicin monotherapy
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Regimen
FDA-recommended dose |
Study | Evidence |
---|---|
Steinberg et al. 2000 | Non-randomized (RT) |
Chemotherapy
- Valrubicin (Valstar) 800 mg intravesicularly once per day on days 1, 8, 15, 22, 29, 36
6-week course
References
- Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M; The Valrubicin Study Group. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guérin refractory carcinoma in situ of the bladder. J Urol. 2000 Mar;163(3):761-7. Erratum in: J Urol. 2008 Jan;179(1):386. link to original article contains protocol PubMed
Neoadjuvant chemotherapy
Atezolizumab monotherapy
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Regimen
Study | Evidence |
---|---|
Powles et al. 2019 (ABACUS) | Phase II |
Chemotherapy
- Atezolizumab 1200 mg IV over 60 minutes once on day 1
21-day cycle for 2 cycles
Subsequent treatment
- Radical cystectomy to be performed 4 to 8 weeks after completion of chemotherapy
References
- ABACUS: Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, Szabados B, Pous AF, Gravis G, Herranz UA, Protheroe A, Ravaud A, Maillet D, Mendez MJ, Suarez C, Linch M, Prendergast A, van Dam PJ, Stanoeva D, Daelemans S, Mariathasan S, Tea JS, Mousa K, Banchereau R, Castellano D. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019 Nov 4. Link to original article PubMed
Cisplatin & Gemcitabine
Cisplatin & Gemcitabine for bladder cancer, neoadjuvant
MCV
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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-esc) | No neoadjuvant chemotherapy | Did not meet primary endpoint of OS |
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
- Cisplatin (Platinol) 70 mg/m2 IV once on day 2
- Vinblastine (Velban) 3 mg/m2 IV once per day on days 2, 15, 22
28-day cycle for 2 cycles
Subsequent treatment
- Kaufman et al. 1993, CR: Cisplatin & RT consolidation
- RTOG 88-02 & 89-03: Cisplatin & RT induction
Variant #2, 3 cycles
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Griffiths et al. 1999 (BA06 30894) | Phase III (E-esc) | 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
- Methotrexate (MTX) 30 mg/m2 IV bolus once per day on days 1 & 8
- Cisplatin (Platinol) 100 mg/m2 IV once on day 2, before hydration
- Vinblastine (Velban) 4 mg/m2 IV bolus once per day on days 1 & 8
Supportive medications
- BA06 30894: Folinic acid (Leucovorin) 15 mg/m2 IV or PO every 6 hours on days 2 & 9, given after hydration, with the first dose 24 hours after the previous day's dose of Methotrexate (MTX) (total dose per cycle: 120 mg/m2)
21-day cycle for 3 cycles
Subsequent treatment
- Zapatero et al. 2000: after 3 cycles of chemotherapy, patients underwent cystoscopy, biopsy, and abdominal CT
- Patients with CR or who were not surgical candidates: RT consolidation which begins 4 to 6 weeks after completion of chemotherapy
- Otherwise, patients proceeded to cystectomy
References
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Update: Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. link to original article PubMed
MVAC
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MVAC: Methotrexate, Vinblastine, Adriamycin (Doxorubicin), Cisplatin
Variant #1, 2 cycles
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Kitamura et al. 2014 (JCOG0209) | Phase III (E-esc) | No neoadjuvant therapy | Might have superior OS |
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
- Vinblastine (Velban) 3 mg/m2 IV once per day on days 2, 15, 22
- Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 2
- Cisplatin (Platinol) 70 mg/m2 IV once on day 2
28-day cycle for 2 cycles
Subsequent treatment
Variant #2, 3 cycles
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Grossman et al. 2003 (SWOG S8710) | Phase III (E-esc) | No neoadjuvant therapy | Might have superior OS |
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
- Vinblastine (Velban) 3 mg/m2 IV once per day on days 2, 15, 22
- Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 2
- Cisplatin (Platinol) 70 mg/m2 IV once on day 2
28-day cycle for 3 cycles
Subsequent treatment
References
- SWOG S8710: Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003 Aug 28;349(9):859-66. link to original article contains verified protocol PubMed
- JCOG0209: Kitamura H, Tsukamoto T, Shibata T, Masumori N, Fujimoto H, Hirao Y, Fujimoto K, Kitamura Y, Tomita Y, Tobisu K, Niwakawa M, Naito S, Eto M, Kakehi Y; Urologic Oncology Study Group of the Japan Clinical Oncology Group. Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209. Ann Oncol. 2014 Jun;25(6):1192-8. link to original article PubMed
MVAC, dose-dense
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ddMVAC: dose-dense Methotrexate, Vinblastine, Adriamycin (Doxorubicin), Cisplatin
AMVAC: Accelerated Methotrexate, Vinblastine, Adriamycin (Doxorubicin), Cisplatin
Variant #1, 3 cycles
Study | Evidence |
---|---|
Plimack et al. 2014 | Phase II |
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV over 30 minutes once on day 1
- Vinblastine (Velban) 3 mg/m2 IV push once on day 2
- Doxorubicin (Adriamycin) 30 mg/m2 IV push once on day 2
- Cisplatin (Platinol) 70 mg/m2 IV in 1 liter normal saline once on day 2
- Split dose could be used at physician discretion for patients with CrCl less than 60 mL/min/1.73m2: 35 mg/m2 IV once per day on days 1 & 2
Supportive medications
- Pegfilgrastim (Neulasta) 6 mg SC once, 24 to 48 hours after completion of chemotherapy
- Antiemetics used often included Aprepitant (Emend), Ondansetron (Zofran), and Dexamethasone (Decadron) but were not specified by the trial.
14-day cycle for 3 cycles
Subsequent treatment
- Radical cystectomy with bilateral lymphadenectomy, within 4 to 8 weeks after the last cycle of chemotherapy
Variant #2, 4 cycles
Study | Evidence |
---|---|
Choueiri et al. 2014 | Phase II |
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV over 30 minutes once on day 1
- Vinblastine (Velban) 3 mg/m2 IV push once on day 2
- Doxorubicin (Adriamycin) 30 mg/m2 IV push once on day 2
- Cisplatin (Platinol) 70 mg/m2 IV in 1 liter normal saline once on day 2
Supportive medications
- Pegfilgrastim (Neulasta) 6 mg SC once on day 3 (approximately 24 hours after day 2 chemotherapy)
14-day cycle for 4 cycles
Subsequent treatment
- Cystectomy to be performed 4 to 10 weeks after completion of chemotherapy
References
- 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
- 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 | Comparative Efficacy |
---|---|---|---|
Martinez-Piñeiro et al. 1995 | Phase III (C) | Cisplatin | Did not meet primary endpoint of OS |
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
- Martinez-Piñeiro JA, Gonzalez Martin M, Arocena F, Flores N, Roncero CR, Portillo JA, Escudero A, Jimenez Cruz F, Isorna S. Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. J Urol. 1995 Mar;153(3 Pt 2):964-73. link to original article PubMed
- 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
- 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
- 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
- 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
Pembrolizumab monotherapy
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Regimen
Study | Evidence |
---|---|
Necchi et al. 2018 (PURE-01) | Phase II |
Chemotherapy
- Pembrolizumab 200 mg IV over 30 minutes once on day 1
21-day cycle for 3 cycles
Subsequent treatment
- Radical cystectomy, within 1 to 3 weeks after the last cycle of chemotherapy
References
- PURE-01: Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucianò R, Colecchia M, Giannatempo P, Mortarini R, Bianchi M, Farè E, Monopoli F, Colombo R, Gallina A, Salonia A, Messina A, Ali SM, Madison R, Ross JS, Chung JH, Salvioni R, Mariani L, Montorsi F. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 2018 Oct 20. Link to original article contains verified protocol PubMed
- Update: Necchi A, Raggi D, Gallina A, Madison R, Colecchia M, Lucianò R, Montironi R, Giannatempo P, Farè E, Pederzoli F, Bandini M, Bianchi M, Colombo R, Gandaglia G, Fossati N, Marandino L, Capitanio U, Dehò F, Ali SM, Chung JH, Ross JS, Salonia A, Briganti A, Montorsi F. Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies. Eur Urol. 2019 Nov 7. link to SD article PubMed
Induction chemoradiotherapy
Cisplatin & RT
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Cisplatin & RT: Cisplatin & 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
- 3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
- Patients with complete regression (R0): Cisplatin & RT consolidation
- Nonresponders: Cystectomy
Variant #2, cisplatin 70 mg/m2 q3wk x 2
Study | Evidence |
---|---|
Tester et al. 1996 (RTOG 88-02) | Phase II |
Preceding treatment
- MCV x 2
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
21-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)
4.5-week course
Subsequent treatment
- Patient is restaged 2 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, urinary cytology, and computed tomographic scan of pelvis."
- Patients with CR: Cisplatin & RT consolidation
- Patients without CR proceeded immediately to: cystectomy
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
- RTOG 89-03: MCV versus no neoadjuvant therapy
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV once on day 1
21-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 1.8 Gy fractions x 22 fractions (total dose: 39.6 Gy)
4.5-week course
Subsequent treatment
- RTOG 89-03: Patient is restaged 4 weeks after completion of radiation with "examination under anesthesia, cystoscopy with tumor-site biopsy, and urinary cytology."
- Patients not in CR usually proceeded to: cystectomy
- Patients in complete remission usually proceeded to: cisplatin & RT consolidation
References
- Shipley WU, Prout GR Jr, Einstein AB, Coombs LJ, Wajsman Z, Soloway MS, Englander L, Barton BA, Hafermann MD. Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery. JAMA. 1987 Aug 21;258(7):931-5. link to original article PubMed
- RTOG 88-02: Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, True L, Shipley W. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol. 1996 Jan;14(1):119-26. link to original article contains verified protocol PubMed
- RTOG 89-03: Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998 Nov;16(11):3576-83. link to original article contains verified protocol PubMed
- Pooled Update: Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. link to original article link to PMC article PubMed
- Pooled Update: Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. link to original article contains verified protocol link to PMC article PubMed
- RTOG 97-06: Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. link to original article contains verified protocol PubMed
- Pooled Update: Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. link to original article link to PMC article PubMed
- Pooled Update: Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. link to original article contains verified protocol link to PMC article PubMed
- Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. link to original article contains verified protocol PubMed
- Update: Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. link to original article contains verified protocol PubMed
Cisplatin, Fluorouracil, RT
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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
- Cisplatin (Platinol) 15 mg/m2 IV over 60 minutes once per day on days 1 to 3, given second, before radiation
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 3, given first
Supportive medications
- IV hydration at 500 mL/H (no total volume specified) prior to Fluorouracil (5-FU)
14-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 3 Gy fractions twice per day, with the first fraction of each day given 1 to 2 hours after completion of chemotherapy and at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total induction dose: 24 Gy), administered to the whole bladder, bladder tumor volume, and pelvic lymph nodes
17-day course
Dose modifications
- Patients with grade III hematologic toxicity, defined as platelets less than 50 x 109/L or ANC less than 1800/uL, had chemotherapy and radiation therapy held for at least one week, with therapy resuming when platelets were at least 100 x 109/L and ANC at least 1800/uL.
Subsequent treatment
- Treatment followed by repeat cystoscopy, biopsy, and urine cytology in week 7 or 8
- Patients with complete response: CF & RT consolidation in week 9
- Incomplete responders were recommended to undergo radical cystectomy
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
- Cisplatin (Platinol) 15 mg/m2 IV once per day on days 1 to 3, 8 to 10, 15 to 17
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 3, 15 to 17
Radiotherapy
- Concurrent radiation therapy, with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:
- 1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
- 1.5 Gy fractions to the bladder every evening on days 1 to 5
- 1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
- Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
17-day course
Subsequent treatment
- Treatment followed by repeat cystoscopy & biopsy
- Patients with complete response: CF & RT consolidation
- Incomplete responders: Radical cystectomy
Variant #3, 135/3600/40.3
Study | Evidence | Comparator |
---|---|---|
Mitin et al. 2013 (RTOG 02-33) | Randomized Phase II (E-switch-ic) | Cisplatin, Paclitaxel, RT |
Chemotherapy
- Cisplatin (Platinol) 15 mg/m2 IV once per day on days 1 to 3
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 3
7-day cycle for 3 cycles
Radiotherapy
- Concurrent radiation therapy, with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:
- 1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
- 1.5 Gy fractions to the bladder every evening on days 1 to 5
- 1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
- Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
3-week course
Subsequent treatment
- On week 7, patients under reevaluation for response.
- Patients with less than stage T1 disease: CF & RT consolidation
- Patients with at least stage T1 disease: Radical cystectomy on week 9, then adjuvant PGC
References
- 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
- 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
- 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
- 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
- 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
- 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
- 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
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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
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 & 2
- Paclitaxel (Taxol) 50 mg/m2 IV once on day 1
7-day cycle for 3 cycles
Radiotherapy
- Concurrent radiation therapy, with twice per day RT on days 1 to 5, 8 to 12, 15 to 17; 4 to 6 hours between radiation sessions. Kaufman et al. 2009 (RTOG 99-06) was unclear about exact radiation treatment plan, but it appears to have been the same as described in Mitin et al. 2013 (RTOG 02-33), which used radiation as follows:
- 1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
- 1.5 Gy fractions to the bladder every evening on days 1 to 5
- 1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
- Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
3-week course
Subsequent treatment
- On week 7, over 3 weeks after induction therapy, patients under reevaluation with exam under anesthesia, cystoscopy with tumor site biopsy, and urine cytology
- Patients with less than stage ypT1 disease: Cisplatin, paclitaxel, RT consolidation
- Patients with at least stage ypT1 disease: Radical cystectomy, then adjuvant cisplatin & gemcitabine
Variant #2, 45/50 x 3 + 40.3 Gy
Study | Evidence | Comparator |
---|---|---|
Mitin et al. 2013 (RTOG 02-33) | Randomized Phase II (E-switch-ic) | Cisplatin, Fluorouracil, RT |
Chemotherapy
- Cisplatin (Platinol) 15 mg/m2 IV once per day on days 1 to 3
- Paclitaxel (Taxol) 50 mg/m2 IV once on day 1
7-day cycle for 3 cycles
Radiotherapy
- Concurrent radiation therapy, with twice per day RT, with at least 4 hours between radiation therapy sessions as follows:
- 1.6 Gy fractions to the pelvis every morning on days 1 to 5, 8 to 12, 15 to 17
- 1.5 Gy fractions to the bladder every evening on days 1 to 5
- 1.5 Gy fractions to the tumor every evening on days 8 to 12, 15 to 17
- Total doses: pelvis: 20.8 Gy; whole bladder: 28.3 Gy; bladder tumor volume 40.3 Gy.
3-week course
Subsequent treatment
- On week 7, patients under reevaluation for response
- Patients with less than stage ypT1 disease: Cisplatin, paclitaxel, RT consolidation
- Patients with at least stage ypT1 disease: Radical cystectomy on week 9, then adjuvant PGC
References
- 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
- 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
- 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
- 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
- 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
- Pooled Update: Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. link to original article contains verified protocol link to PMC article PubMed
Fluorouracil, Mitomycin, RT
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Fluorouracil, Mitomycin, RT: Fluorouracil, Mitomycin, Radiation Therapy
Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
James et al. 2012 (BC2001) | Phase III (E-esc) | Radiation therapy | Seems to have superior locoregional DFS |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2/day IV continuous infusion for 10 total days (total dose: 5000 mg/m2) during radiation fractions 1 to 5, 16 to 20
- Mitomycin (Mutamycin) 12 mg/m2 IV bolus once on day 1
Radiotherapy
- External beam radiotherapy given according to one of the following plans:
- Concurrent radiation therapy, 2.75 Gy fractions x 20 fractions (total dose: 55 Gy)
- Concurrent radiation therapy, 2 Gy fractions x 32 fractions (total dose: 64 Gy)
4- to 6.5-week course
References
- 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
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Regimen
Study | Evidence | Comparator |
---|---|---|
Coen et al. 2018 (RTOG 0712) | Randomized Phase II (E-de-esc) | CF & RT |
Note: this trial was not statistically powered to compare regimens.
Chemotherapy
- Gemcitabine (Gemzar) 27 mg/m2 IV once per day on days 1, 4, 8, 11
14-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy 2 Gy per day to the pelvis on days 1 to 10, then 2 Gy per day to the bladder on days 11 to 14, then 2 Gy per day to the bladder tumor on days 15 to 20
- Total doses: pelvis: 20 Gy; whole bladder: 28 Gy; bladder tumor volume 40 Gy
3-week course
Subsequent treatment
- Treatment followed by repeat cystoscopy & biopsy
- Patients with complete response: Gemcitabine & RT consolidation
- Incomplete responders: Radical cystectomy
References
- 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
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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.
Chemotherapy
- Paclitaxel (Taxol) 50 mg/m2 IV once per week, given 6 hours before radiation therapy
Radiotherapy
- Concurrent radiation therapy according to one of the following:
- Accelerated hyperfractionated RT (AHFRT) with twice per day radiation, consisting of 1.8 Gy fractions x 12 fractions to the bladder and regional lymph nodes; 6 hours later, a 1.6 Gy fraction x 12 fractions is given to the "bladder tumor plus wide margin." Total induction dose to bladder tumor: 40.8 Gy; total induction dose to regional lymph nodes: 21.6 Gy. Zapatero et al. 2012 did not specify the precise schedule of radiation therapy.
- Normo-fractionated concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.
One course
Subsequent treatment
- 3 weeks after finishing radiation and chemotherapy, patients underwent restaging TURBT
- Patients with complete regression (R0): Paclitaxel & RT consolidation
- Nonresponders: Cystectomy
References
- Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. link to original article contains verified protocol PubMed
Radiation therapy
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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
- 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
- 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
- Update: Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. link to original article PubMed
- BC2001: James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. link to original article contains verified protocol PubMed
Consolidation chemoradiotherapy
Cisplatin & RT
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Cisplatin & RT: Cisplatin & 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
- Depending on response: Cisplatin & RT induction or cystectomy
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1 & 2 (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
- RTOG 97-06: Adjuvant MCV
Variant #2, cisplatin 70 mg/m2 x 1
Study | Evidence |
---|---|
Tester et al. 1996 (RTOG 88-02) | Phase II |
Preceding treatment
- Depending on response, treatment preceded by cisplatin & RT induction or cystectomy
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
Radiotherapy
- Concurrent radiation therapy, 1.8 Gy fractions x 14 fractions (total dose in consolidation phase: 25.2 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)
3-week course
Variant #3, cisplatin 100 mg/m2 x 1
Study | Evidence |
---|---|
Shipley et al. 1998 (RTOG 89-03) | Non-randomized portion of RCT |
Preceding treatment
- Depending on response, treatment preceded by cisplatin & RT induction or cystectomy
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV once on day 1
Radiotherapy
- Concurrent radiation therapy, 1.8 Gy fractions x 14 fractions (total dose in consolidation phase: 39.6 Gy; total overall dose in induction and consolidation phases: 64.8 Gy)
3-week course
References
- 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
- 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
- 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
- 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
- Zapatero A, Martín de Vidales C, Marín A, Cerezo L, Arellano R, Rabadán M, Pérez-Torrubia A. Invasive bladder cancer: a single-institution experience with bladder-sparing approach. Int J Cancer. 2000 Oct 20;90(5):287-94. link to original article PubMed
- Update: Zapatero A, Martín de Vidales C, Arellano R, Bocardo G, Pérez M, Ríos P. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2010 Jul-Aug;28(4):368-74. Epub 2009 Apr 11. link to original article contains verified protocol PubMed
- Update: Zapatero A, Martín de Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology. 2012 Nov;80(5):1056-62. Epub 2012 Sep 19. link to original article contains verified protocol PubMed
- RTOG 97-06: Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):665-72. link to original article contains verified protocol PubMed
- Pooled Update: Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. link to original article link to PMC article PubMed
- Pooled Update: Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. link to original article contains verified protocol link to PMC article PubMed
Cisplatin, Fluorouracil, RT
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Variant #1, 30/1200 x 2 + 64.3 Gy
Study | Evidence | Comparator |
---|---|---|
Mitin et al. 2013 (RTOG 02-33) | Randomized Phase II (E-switch-ic) | Cisplatin, Paclitaxel, RT |
Consolidation starts starts on week 8.
Preceding treatment
Chemotherapy
Starts on week 8.
- Cisplatin (Platinol) 15 mg/m2 IV once per day on days 1 & 2
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 3
7-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 1.5 Gy fractions x 16 fractions, given twice per day x 8 days. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.
2-week course
Subsequent treatment
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
- Depending on response, treatment preceded by cisplatin, fluorouracil, RT induction or cystectomy
Chemotherapy
- Cisplatin (Platinol) 15 mg/m2 IV over 60 minutes once per day on days 1 to 3, given second
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 to 3, given first
14-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 2.5 Gy fractions twice per day, with at least 4 hours between fractions, x 8 fractions, given on days 1, 3, 15, 17 (total consolidation dose: 20 Gy), administered to the whole bladder and bladder tumor volume. The total dose to the whole bladder and bladder tumor volume was 44 Gy in 16 fractions; the total dose to the pelvic lymph nodes was 24 Gy in 8 fractions.
Dose modifications
- Patients with grade III hematologic toxicity, defined as platelets less than 50 x 109/L or ANC less than 1800/uL, had chemotherapy and radiation therapy held for at least one week, with therapy resuming when platelets were at least 100 x 109/L and ANC at least 1800/uL.
Supportive medications
- IV hydration at 500 mL/H (no total volume specified) prior to Fluorouracil (5-FU)
17-day course
References
- 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
- 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
- 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
- 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
- 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
- Pooled Update: Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. link to original article contains verified protocol link to PMC article PubMed
Cisplatin, Paclitaxel, RT
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Variant #1, 30/50 x 2 + 64.3 Gy
Study | Evidence | Comparator |
---|---|---|
Mitin et al. 2013 (RTOG 02-33) | Randomized Phase II (E-switch-ic) | Cisplatin, 5-FU, RT |
Consolidation starts starts on week 8.
Preceding treatment
Chemotherapy
- Cisplatin (Platinol) 15 mg/m2 IV once per day on days 1 & 2
- Paclitaxel (Taxol) 50 mg/m2 IV once on day 1
7-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 1.5 Gy fractions x 16 fractions, given twice per day x 8 days. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.
2-week course
Subsequent treatment
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
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 & 2
- Paclitaxel (Taxol) 50 mg/m2 IV once on day 1
7-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 1.5 Gy fractions x 16 fractions, given twice per day (4 to 6 hour interval between treatments) on days 1 to 5, 8 to 10. Total dose during consolidation is 24 Gy. Total dose after induction therapy and consolidation therapy: pelvis: 44.8 Gy; whole bladder: 52.3 Gy; bladder tumor volume 64.3 Gy.
2-week course
Subsequent treatment
References
- RTOG 99-06: Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. link to original article contains verified protocol PubMed
- Pooled Update: Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. link to original article link to PMC article PubMed
- Pooled Update: Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. link to original article contains verified protocol link to PMC article PubMed
- RTOG 02-33: Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. contains verified protocol link to PMC article PubMed
- Pooled Update: Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. link to original article link to PMC article PubMed
- Pooled Update: Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. link to original article contains verified protocol link to PMC article PubMed
Paclitaxel & RT
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Regimen
Study | Evidence |
---|---|
Zapatero et al. 2012 | Non-randomized, <20 pts |
Preceding treatment
- Depending on response, treatment preceded by paclitaxel & RT induction or cystectomy
Chemotherapy
- Paclitaxel (Taxol) 50 mg/m2 IV once per week, given 6 hours before radiation therapy
Radiotherapy
- Concurrent radiation therapy according to one of the following:
- Accelerated hyperfractionated RT (AHFRT), 1.5 Gy fractions twice per day x 16 fractions (total consolidation dose: 24 Gy). After induction radiation therapy and consolidation radiation therapy, total dose to the bladder is 64.8 Gy; total dose to lymph nodes is 45.6 Gy.
- Normo-fractionated concurrent radiation therapy, total induction and consolidation dose of 64 to 66 Gy; Zapatero et al. 2012 did not specify how much of this dose was given during induction therapy vs. consolidation therapy.
One course
References
- 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
- Depending on response to induction, treatment starts 12 weeks after cisplatin, paclitaxel, RT consolidation, or 8 weeks after cystectomy
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
28-day cycle for 4 cycles
References
- Kaufman DS, Winter KA, Shipley WU, Heney NM, Wallace HJ 3rd, Toonkel LM, Zietman AL, Tanguay S, Sandler HM. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology. 2009 Apr;73(4):833-7. link to original article contains verified protocol PubMed
- Pooled Update: Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM, Sandler HM. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol. 2009 Sep 1;27(25):4055-61. link to original article link to PMC article PubMed
- Pooled Update: Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, Kaufman DS, Heney NM, Zietman AL. Long-Term Outcomes in Patients With Muscle-Invasive Bladder Cancer After Selective Bladder-Preserving Combined-Modality Therapy: A Pooled Analysis of Radiation Therapy Oncology Group Protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014 Dec 1;32(34):3801-9. Epub 2014 Nov 3. link to original article contains verified protocol link to PMC article PubMed
Cisplatin & Methotrexate
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Regimen
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Lehmann et al. 2005 (AUO-AB 05/95) | Phase III (E-de-esc) | M-VEC x 3 | Inconclusive whether non-inferior PFS | Less toxic |
Preceding treatment
Chemotherapy
References
- AUO-AB 05/95: Lehmann J, Retz M, Wiemers C, Beck J, Thüroff J, Weining C, Albers P, Frohneberg D, Becker T, Funke PJ, Walz P, Langbein S, Reiher F, Schiller M, Miller K, Roth S, Kälble T, Sternberg D, Wellek S, Stöckle M; AUO-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
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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
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
- Cisplatin (Platinol) 25 mg/m2 IV once per day on days 2 to 4
- Vinblastine (Velban) 3 mg/m2 IV once per day on days 2, 15, 22
28-day cycle for 3 cycles
References
- 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
- 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
- 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
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Paz-Ares et al 2010 (SOGUG 99/01) | Phase III (C) | PGC | Inferior OS |
Stadler et al. 2011 (SWOG-4B951) | Phase III (C) | MVAC | Did not meet primary endpoint of RFS |
Cognetti et al. 2011 | Phase III (C) | Cisplatin & Gemcitabine | Did not meet primary endpoint of OS |
Sternberg et al. 2014 (EORTC 30994) | Phase III (C) | MVAC | Did not meet primary endpoint of 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. In SWOG-4B951, only patients with positive p53 staining were randomized.
Preceding treatment
Subsequent treatment
- EORTC 30994, upon relapse: MVAC x 6
References
- Abstract: L. G. Paz-Ares, E. Solsona, E. Esteban, A. Saez, J. Gonzalez-Larriba, A. Anton, M. Hevia, F. de la Rosa, V. Guillem, and J. Bellmunt. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. ASCO MEETING ABSTRACTS Jun 22, 2010:LBA4518. link to abstract contains verified protocol
- SWOG-4B951: 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
- 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
- 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
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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-esc) | Observation | Superior OS |
Patients in SOGUG 99/01 had pT3-4 and/or pN positive disease with adequate renal function (CrCl greater than 50 mL/min/1.73m2). The study prematurely closed due to poor recruitment and lacks adequate power to make firm conclusions.
Preceding treatment
- Cystectomy; the median time treatment started post-cystectomy was 48 days
Chemotherapy
- Paclitaxel (Taxol) 80 mg mg/2 IV once per day on days 1 & 8
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Variant #2
Study | Evidence |
---|---|
Mitin et al. 2013 (RTOG 02-33) | Non-randomized portion of RCT |
Preceding treatment
- Depending on response, adjuvant chemotherapy began 12 weeks after cisplatin, paclitaxel, RT versus cisplatin, 5-FU, RT or 8 weeks after cystectomy
Chemotherapy
- Cisplatin (Platinol) 35 mg/m2 IV once per day on days 1 & 8
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
- Paclitaxel (Taxol) 50 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles
References
- 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
- 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
- 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
- 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
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Regimen
Study | Evidence | Efficacy |
---|---|---|
Balar et al. 2016 (IMvigor210 Cohort 2) | Phase II (RT) | 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
- Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
References
- IMvigor210 Cohort 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
Carboplatin & Gemcitabine
Carboplatin & gemcitabine for unresectable or metastatic bladder cancer
Carboplatin & Paclitaxel
back to top |
Regimen
Study | Evidence | Efficacy |
---|---|---|
Vaughn et al. 2002 (ECOG E2896) | Phase II | ORR: 24% (95% CI 12-42) |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 225 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 6 cycles
References
- 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 | Comparator | Efficacy | ORR | Comparator ORR |
---|---|---|---|---|---|
Sternberg et al. 1977 | Non-randomized, <20 pts | ||||
Logothetis et al. 1990 | Phase III (E-switch-ic) | MVAC | Inferior OS | 46% (95% CI 32-62) | 65% (95% CI 52-77) |
Chemotherapy
- Cyclophosphamide (Cytoxan) 650 mg/m2 IV once on day 1
- Cisplatin (Platinol) 100 mg/m2 IV once on day 2
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 2
Supportive medications
- Forced mannitol diuresis with Cisplatin (Platinol)
21-day cycle for up to 6 cycles
References
- Sternberg JJ, Bracken RB, Handel PB, Johnson DE. Combination chemotherapy (CISCA) for advanced urinary tract carcinoma: a preliminary report. JAMA. 1977 Nov 21;238(21):2282-7. link to original article PubMed
- Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. link to original article contains verified protocol PubMed
Cisplatin monotherapy
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Soloway et al. 1983 | Randomized (C) | Cisplatin & Cyclophosphamide | Did not meet primary endpoint of ORR |
Khandekar et al. 1985 | Randomized (C) | CAD | Might have inferior ORR |
Troner et al. 1987 | Phase III (C) | CAD | Did not meet endpoint of ORR |
Hillcoat et al. 1989 | Phase III (C) | Cisplatin & Methotrexate | Did not meet efficacy endpoints |
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
- 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
- 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
- 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
- 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
- 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
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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-esc) | Cisplatin & Gemcitabine; q4wk | Not reported |
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV over 30 to 60 minutes once on day 2
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
Supportive medications
- 2 liters of fluid and "appropriate antiemetic therapy" given with Cisplatin (Platinol)
- "blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
21-day 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-de-esc) | MVAC | Did not meet primary endpoint of OS |
Soto Parra et al. 2002 | Randomized Phase II, <20 pts in this subgroup (E-de-esc) | 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 | Did not meet primary endpoint of 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
- Cisplatin (Platinol) 70 mg/m2 IV over 30 to 60 minutes once on day 2
- Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 to 60 minutes once per day on days 1, 8, 15
Supportive medications
- Per Soto Parra et al. 2002:
- 2 liters of fluid and "appropriate antiemetic therapy" given with Cisplatin (Platinol)
- "blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
28-day cycle for up to 6 cycles
Variant #3, 70/1250, q3wk
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Dogliotti et al. 2006 | Randomized Phase II (C) | Carboplatin & Gemcitabine | Did not meet primary endpoint of reduced toxicity |
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 2
- Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 to 60 minutes once per day on days 1 & 8
21-day cycle for up to 6 cycles
References
- 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
- Update: von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. link to original article PubMed
- Soto Parra H, Cavina R, Latteri F, Sala A, Dambrosio M, Antonelli G, Morenghi E, Alloisio M, Ravasi G, Santoro A. Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol. 2002 Jul;13(7):1080-6. link to original article contains verified protocol PubMed
- Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. link to original article contains verified protocol PubMed
- EORTC 30987: Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. link to original article contains verified protocol link to PMC article PubMed
- 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
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Variant #1
Study | Evidence | Efficacy |
---|---|---|
Calabrò et al. 2009 | Phase II | ORR: 37% |
Chemotherapy
- Gemcitabine (Gemzar) 2500 mg/m2 IV over 30 minutes once on day 1, given second
- Paclitaxel (Taxol) 150 mg/m2 IV over 3 hours once on day 1, given first
14-day cycle for 6 to 12 cycles
Variant #2
Study | Evidence | Efficacy |
---|---|---|
Meluch et al. 2001 | Phase II | ORR: 54% (95% CI 40-67) |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 6 cycles
References
- Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. link to original article PubMed
- Calabrò F, Lorusso V, Rosati G, Manzione L, Frassineti L, Sava T, Di Paula ED, Alonso S, Sternberg CN. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer. 2009 Jun 15;115(12):2652-9. link to original article contains verified protocol PubMed
MVAC
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MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin
Variant #1, standard
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Logothetis et al. 1990 | Phase III (E-switch-ic) | CISCA | Superior OS |
Loehrer et al. 1992 | Phase III (E-esc) | Cisplatin | Superior OS |
von der Maase et al. 2000 | Phase III (C) | Cisplatin & Gemcitabine | Did not meet primary endpoint of OS |
Sternberg et al. 2001 (EORTC 30924) | Phase III (C) | Dose-dense MVAC | Seems to have inferior OS (*) |
Siefker-Radtke et al. 2002 | Phase III (C) | FAP | Did not meet primary endpoint of OS50% |
Note: reported efficacy for EORTC 30924 is based on the 2005 update.
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
- Vinblastine (Velban) 3 mg/m2 IV once per day on days 2, 15, 22
- Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 2
- Cisplatin (Platinol) 70 mg/m2 IV once on either day 1 or 2
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
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
- Vinblastine (Velban) 3 mg/m2 IV once per day on days 1, 15, 22
- Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 1
- Cisplatin (Platinol) 70 mg/m2 IV over 60 minutes once on day 1
Supportive medications
- Filgrastim (Neupogen) (dose not specified) SC once per day on days 7, 8, 9, 25, 26
28-day cycles
References
- 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
- 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
- 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
- Update: von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. link to original article PubMed
- EORTC 30924: Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; 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
- 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
- Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002 Mar 1;20(5):1361-7. link to original article PubMed
- Bamias A, Aravantinos G, Deliveliotis C, Bafaloukos D, Kalofonos C, Xiros N, Zervas A, Mitropoulos D, Samantas E, Pectasides D, Papakostas P, Gika D, Kourousis C, Koutras A, Papadimitriou C, Bamias C, Kosmidis P, Dimopoulos MA; Hellenic Cooperative Oncology Group. Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol. 2004 Jan 15;22(2):220-8. Epub 2003 Dec 9. Erratum in: J Clin Oncol. 2004 May 1;22(9):1771. link to original article contains verified protocol PubMed
MVAC, dose-dense
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ddMVAC: dose-dense Methotrexate, Vinblastine, Adriamycin, Cisplatin
Regimen
Study | Evidence | Comparator | Efficacy | ORR | Comparator ORR |
---|---|---|---|---|---|
Sternberg et al. 2001 (EORTC 30924) | Phase III (E-esc) | MVAC | Seems to have superior OS (*) | 62% (95% CI 54-70) | 50% (95% CI 42-59) |
Bamias et al. 2012 (HE 16/03) | Phase III (C) | DD-GC | Did not meet primary endpoint of OS |
Note: In contrast to Sternberg et al. 2001, Sternberg et al. 2006 specified 15-day cycles. Reported efficacy for EORTC 30924 is based on the 2005 update.
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV once on day 1
- Vinblastine (Velban) 3 mg/m2 IV once on day 2
- Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 2
- Cisplatin (Platinol) 70 mg/m2 IV once on day 2
Supportive medications
- G-CSF 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
- 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
- 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
- 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
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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-esc) | Cisplatin & Gemcitabine | Might have superior OS | 56% (95% CI NR) | 44% (95% CI NR) |
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 to 60 minutes once per day on days 1 & 8
- Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1 & 8, given first
21-day cycle for up to 6 cycles
References
- 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
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Regimen
Study | Evidence | Efficacy |
---|---|---|
Balar et al. 2017 (KEYNOTE-052) | Phase II (RT) | ORR: 24% (95% CI 20-29) |
On 5/18/2018 the FDA released a warning that patients in the monotherapy arms of the ongoing KEYNOTE-361 trial with PD-L1 low status had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy.
Immunotherapy
- Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycles
References
- KEYNOTE-052: Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. Epub 2017 Sep 26. link to original article PubMed
Maintenance after first-line therapy
Placebo
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Powles et al. 2016 (LaMB) | Phase III (C) | Lapatinib | Did not meet primary endpoint of PFS |
No active antineoplastic treatment.
References
- 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
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Powles et al. 2014 | Phase 1 | ||
Rosenberg et al. 2016 (IMvigor210) | Phase II (RT) | ORR: 15% (95% CI 11-20) | |
Powles et al. 2017 (IMvigor211) | Phase III (E-switch-ood) | 1. Docetaxel 2. Paclitaxel 3. Vinflunine |
Did not meet primary endpoint of OS |
Note: this regimen did not meet its primary endpoint in phase III; here for historical reference only.
Immunotherapy
- Atezolizumab (Tecentriq) 1200 mg IV once on day 1
21-day cycles
References
- 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
- 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
- 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
Avelumab (Bavencio) for metastatic bladder cancer
Best supportive care
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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
- 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
- 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
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Regimen
Study | Evidence | Comparator | Efficacy | ORR | Comparator ORR |
---|---|---|---|---|---|
McCaffrey et al. 1997 | Phase II | 13% (95% CI 4-31) | |||
Choueiri et al. 2012 (DFCI 06-116) | Phase III (C) | Docetaxel & Vandetanib | Did not meet primary endpoint of PFS | 11% (95% CI NR) | 7% (95% CI NR) |
Petrylak et al. 2016 (JCDC) | Randomized Phase II (C) | 1. Docetaxel & Icrucumab | Did not meet primary endpoint of PFS | ||
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 | Did not meet primary endpoint of OS |
Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycles
References
- McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. link to original article PubMed
- DFCI 06-116: Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012 Feb 10;30(5):507-12. link to original article link to PMC article PubMed
- JCDC: Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. link to original article PubMed
- 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
- 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
- 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
- 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
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Petrylak et al. 2016 (JCDC) | Randomized Phase II (E-esc) | Docetaxel | Superior PFS |
Petrylak et al. 2017 (RANGE) | Phase III (E-esc) | Docetaxel | Seems to have superior PFS |
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Ramucirumab (Cyramza) 10 mg/kg IV once on day 1
21-day cycles
References
- JCDC: Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016 May 1;34(13):1500-9. Epub 2016 Feb 29. link to original article contains verified protocol PubMed
- RANGE: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. link to original article contains verified protocol PubMed
Durvalumab monotherapy
Durvalumab (Imfinzi) for metastatic bladder cancer
Enfortumab vedotin monotherapy
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Regimen
FDA-recommended dose |
Study | Evidence |
---|---|
Rosenberg et al. 2018 (EV-201) | Phase II (RT) |
Chemotherapy
- Enfortumab vedotin (Padcev) 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1, 8, 15
28-day cycles
References
- Abstract: EV-201 Study: A single-arm, open-label, multicenter study of enfortumab vedotin for treatment of patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor therapy. Jonathan E. Rosenberg, Elisabeth I. Heath, Peter H. O'Donnell, Noah M. Hahn, Arjun Vasant Balar, Elaina M. Gartner, Amal Melhem-Bertrandt, and Daniel Peter Petrylak. Journal of Clinical Oncology 2018 36:15_suppl, TPS4590-TPS4590 link to abstract
Erdafitinib monotherapy
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Regimen
FDA-recommended dose |
Study | Evidence |
---|---|
Loriot et al. 2019 (BLC2001) | Phase II (RT) |
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
- BLC2001: Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Zhong B, Stuyckens K, Santiago-Walker A, De Porre P, O'Hagan A, Avadhani A, Siefker-Radtke AO; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348. link to original article PubMed
Gemcitabine & Paclitaxel
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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) | GP; prolonged | Did not meet primary endpoint of OS |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 minutes once per day on days 1 & 8
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 6 cycles
Variant #2, weekly gemcitabine
Study | Evidence | Efficacy |
---|---|---|
Meluch et al. 2001 | Phase II, <20 pts in this subgroup | ORR: 47% |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 6 cycles
References
- Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. link to original article PubMed
- AUO AB 20/99: Albers P, Park SI, Niegisch G, Fechner G, Steiner U, Lehmann J, Heimbach D, Heidenreich A, Fimmers R, Siener R; AUO Bladder Cancer Group. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Ann Oncol. 2011 Feb;22(2):288-94. Epub 2010 Aug 2. link to original article contains verified protocol PubMed
MVAC
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MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin
Regimen
Study | Evidence | Efficacy |
---|---|---|
Han et al. 2008 | Phase II | ORR: 30% |
Chemotherapy
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
- Vinblastine (Velban) 3 mg/m2 IV once per day on days 2, 15, 22
- Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 2
- Cisplatin (Platinol) 70 mg/m2 IV once on day 2
28-day cycles (number of cycles and criteria to continue therapy varies depending on reference)
References
- Han KS, Joung JY, Kim TS, Jeong IG, Seo HK, Chung J, Lee KH. Methotrexate, vinblastine, doxorubicin and cisplatin combination regimen as salvage chemotherapy for patients with advanced or metastatic transitional cell carcinoma after failure of gemcitabine and cisplatin chemotherapy. Br J Cancer. 2008 Jan 15;98(1):86-90. Epub 2007 Dec 18. link to original article contains verified protocol link to PMC article PubMed
Nivolumab monotherapy
Nivolumab (Opdivo) for unresectable or metastatic bladder cancer
Paclitaxel monotherapy
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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 | Did not meet primary endpoint of OS |
Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.
Chemotherapy
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
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
- Paclitaxel (Taxol) 80 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
28-day cycles
References
- Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. link to original article contains protocol PubMed
- Retrospective: Sideris S, Aoun F, Zanaty M, Martinez NC, Latifyan S, Awada A, Gil T. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016 Jun;4(6):1063-1067. Epub 2016 Mar 17. link to PMC article PubMed
- KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains verified protocol PubMed
- 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
- 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
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Regimen
Study | Evidence | Efficacy |
---|---|---|
Ko et al. 2013 | Phase II | ORR: 28% (95% CI 17-44) |
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV once on day 1
21-day cycles
Dose modifications
- "Two dose reductions were permitted, to 240 mg/m2 and then to 180 mg/m2. When further dose reductions were required, study treatment was discontinued. Patients with febrile neutropenia, or delay of cycle because of persistent neutropenia, ANC of less than 500/uL for 1 week, or grade 3 or 4 thrombocytopenia required dose reductions. When sensory neuropathy of grade 2 or higher occurred, study drug was withheld until resolution to grade 2 or better, then reinstituted at the next lower dose. When mucositis or diarrhea of grade 3 or higher occurred, study drug was withheld until resolution to grade 1 or better, then reinstituted at the next lower dose. Patients with mucositis or diarrhea of grade 4 were removed from the trial."
References
- 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
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Bellmunt et al. 2017 (KEYNOTE-045) | Phase III (E-RT-switch-ooc) | Investigator's choice of: Docetaxel Paclitaxel Vinflunine |
Superior OS |
Immunotherapy
- Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycles
References
- KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains verified protocol PubMed
- 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
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Regimen
Study | Evidence | Efficacy |
---|---|---|
Sweeney et al. 2006 | Phase II | ORR: 28% (95% CI 16-43) |
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
21-day cycles
References
- Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006 Jul 20;24(21):3451-7. link to original article contains protocol PubMed
Vinflunine monotherapy
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Bellmunt et al. 2009 | Phase III (E-esc) | 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 | Did not meet primary endpoint of OS |
Note: reported efficacy for Bellmunt et al. 2009 is based on the 2013 update.
Chemotherapy
- Vinflunine (Javlor) 320 mg/m2 IV once on day 1
21-day cycles
References
- 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
- Update: Bellmunt J, Fougeray R, Rosenberg JE, von der Maase H, Schutz FA, Salhi Y, Culine S, Choueiri TK. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann Oncol. 2013 Jun;24(6):1466-72. Epub 2013 Feb 17. link to original article PubMed
- KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article contains verified protocol PubMed
- 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
- 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
- EORTC Risk Tables for Predicting Recurrence and Progression in Individual Patients with Stage Ta T1 Bladder Cancer - predicts probability of recurrence and progression in 1 to 5 years
Urine assays
These are assays intended/being investigated as adjuncts to urine cytology and cystoscopy.
- Cxbladder (uRNA-2), a "urine based bladder cancer test (uRNA-2) which detects RNA markers in urine."
- ImmunoCyt™/uCyt+™, a cell-based detection assay which "uses fluorescent-labeled antibodies to 3 markers that are commonly found on malignant exfoliated urothelial cells."[1]
- UroVysion (Abbott Molecular) "designed to detect aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus via fluorescence in situ hybridization (FISH) in urine specimens from persons with hematuria suspected of having bladder cancer."
References
- ↑ Greene KL, Berry A, Konety BR. Diagnostic Utility of the ImmunoCyt/uCyt+ Test in Bladder Cancer. Rev Urol. 2006 Fall;8(4):190-7. link to PMC article PubMed