CHEMOTHERAPY FOR BLADDER CANCER
NEOADJUVANT
The landmark 2003 study showed the median survival among patients assigned to surgery alone was 46 months, as compared with 77 mo with neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin. Significantly more patients in the combination-therapy group had no residual disease than patients in the cystectomy group (38 percent vs. 15 percent, P<0.001). (8)
Between 1998-2003, neoadjuvant chemotherapy (NAC) was administered to 1.2% of patients with stage 3 bladder cancer while adjuvant chemotherapy (AC) was given to 10.4% of cases. (1) Then from 2003 to 2007, the rate increased to more than 30%. (2) A Meta-analysis including 11 randomized trails covering 3005 patients concluded that NAC provides a 14% reduction in risk of death and gives a 5 year 5% OS benefit improving 45% to 50% 5 year OS. (9)
Cisplatin based regimens are first line, however patients may be ineligible due to poor kidney function, hearing deficit or heart failure, resulting in 40% of patients w/ MIBC being ineligible. Some patients may be obstructed by the actual tumor, with ureteral stent or nephrostomy tube alleviating this allowing eligibility with improved kidney function.
NAC regimens of ddMVAC and GC have comparable efficacy to MVAC with ddMVAC increased efficacy and decreased toxicity. (3,4,5) MVAC toxicities include grade 4 neutropenia (33%) and grade 3 GI toxicities (17%). (6, 8)) ddMVAC abnd GC have a lower toxicity profile. (4,7) Clinical trials of NAC for MICB have indicated no delays in cystectomy performance caused by toxicity from chemotherapy. (8) No prospective studies comparing regimens have occurred in the U.S. yet. 95% of patients complete 4 cycles of ddMVAC resulting in 26%-38% pT0 post RC # A metaanalysis of NAC shows there is a 5% overall survival benefit, increasing OS from 45% to 50% at 5 years. (9)
GC has a lower toxicity profile and is non-inferior.
Bevacizumab has pathological response w/ ddMVAC
Sunitinib + cisplatin based therapies has been looked at
Cisplatin ineligible patients include renal dysfunction (Cr cl <50), hearing dysfunction or heart failure resulting in 40% of patients being ineligible. Some patients may have an obstruction causing elevated Cr and if stented or nephrostomy tube placed may become eligible. 13% of those in their 60's and 47% of those in their 70's have Cr Cl <50ml/min. (10) Carboplain requires less kidney function and in retrospective studies has similar pT0 rates, however has not shown the level of activity that ddMVAC or GC has shown.
ADJUVANT CHEMOTHERAPY
Adjuvant chemotherapy have not had many randomized prospective trials and the ones that have taken place have been underpowered and inconclusive. There is a trend towards improved survival in some studies. Retrospective studies also suggest a survival benefit.
METASTATIC
Neoadjuvant cisplatin based chemostherapy is first line treatment. If patients are ineligible for cisplatin then carboplatin is an option OR either atezolumab (IMvigor-210) or pembrolizumab (KEYNOTE-052) if they have PD-L1 expression in tumor. If ineligible for cisplatin and carboplatin then atezolumab or pembrolizumab is first line regardless of PD-L1 expression level.
OTHER STUDIES
One study found no difference between 3 and 5 rounds of platinum based 1st line chemo for UCC. (11)
The landmark 2003 study showed the median survival among patients assigned to surgery alone was 46 months, as compared with 77 mo with neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin. Significantly more patients in the combination-therapy group had no residual disease than patients in the cystectomy group (38 percent vs. 15 percent, P<0.001). (8)
Between 1998-2003, neoadjuvant chemotherapy (NAC) was administered to 1.2% of patients with stage 3 bladder cancer while adjuvant chemotherapy (AC) was given to 10.4% of cases. (1) Then from 2003 to 2007, the rate increased to more than 30%. (2) A Meta-analysis including 11 randomized trails covering 3005 patients concluded that NAC provides a 14% reduction in risk of death and gives a 5 year 5% OS benefit improving 45% to 50% 5 year OS. (9)
Cisplatin based regimens are first line, however patients may be ineligible due to poor kidney function, hearing deficit or heart failure, resulting in 40% of patients w/ MIBC being ineligible. Some patients may be obstructed by the actual tumor, with ureteral stent or nephrostomy tube alleviating this allowing eligibility with improved kidney function.
NAC regimens of ddMVAC and GC have comparable efficacy to MVAC with ddMVAC increased efficacy and decreased toxicity. (3,4,5) MVAC toxicities include grade 4 neutropenia (33%) and grade 3 GI toxicities (17%). (6, 8)) ddMVAC abnd GC have a lower toxicity profile. (4,7) Clinical trials of NAC for MICB have indicated no delays in cystectomy performance caused by toxicity from chemotherapy. (8) No prospective studies comparing regimens have occurred in the U.S. yet. 95% of patients complete 4 cycles of ddMVAC resulting in 26%-38% pT0 post RC # A metaanalysis of NAC shows there is a 5% overall survival benefit, increasing OS from 45% to 50% at 5 years. (9)
GC has a lower toxicity profile and is non-inferior.
Bevacizumab has pathological response w/ ddMVAC
Sunitinib + cisplatin based therapies has been looked at
Cisplatin ineligible patients include renal dysfunction (Cr cl <50), hearing dysfunction or heart failure resulting in 40% of patients being ineligible. Some patients may have an obstruction causing elevated Cr and if stented or nephrostomy tube placed may become eligible. 13% of those in their 60's and 47% of those in their 70's have Cr Cl <50ml/min. (10) Carboplain requires less kidney function and in retrospective studies has similar pT0 rates, however has not shown the level of activity that ddMVAC or GC has shown.
ADJUVANT CHEMOTHERAPY
Adjuvant chemotherapy have not had many randomized prospective trials and the ones that have taken place have been underpowered and inconclusive. There is a trend towards improved survival in some studies. Retrospective studies also suggest a survival benefit.
METASTATIC
Neoadjuvant cisplatin based chemostherapy is first line treatment. If patients are ineligible for cisplatin then carboplatin is an option OR either atezolumab (IMvigor-210) or pembrolizumab (KEYNOTE-052) if they have PD-L1 expression in tumor. If ineligible for cisplatin and carboplatin then atezolumab or pembrolizumab is first line regardless of PD-L1 expression level.
OTHER STUDIES
One study found no difference between 3 and 5 rounds of platinum based 1st line chemo for UCC. (11)
- David, Kevin A., et al. "Low incidence of perioperative chemotherapy for stage III bladder cancer 1998 to 2003: a report from the National Cancer Data Base." The Journal of urology 178.2 (2007): 451-454.
- Fedeli, Ugo, Stacey A. Fedewa, and Elizabeth M. Ward. "Treatment of muscle invasive bladder cancer: evidence from the National Cancer Database, 2003 to 2007." The Journal of urology 185.1 (2011): 72-78.
- von der Maase, Hans, et al. "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." Journal of clinical oncology 18.17 (2000): 3068-3077.
- Schultz, Paul K., et al. "Neoadjuvant chemotherapy for invasive bladder cancer: prognostic factors for survival of patients treated with M-VAC with 5-year follow-up." Journal of clinical oncology 12.7 (1994): 1394-1401.
- Sternberg, C. N., et al. "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." Journal of Clinical Oncology 19.10 (2001): 2638-2646.
- Sonpavde, Guru, and Cora N. Sternberg. "Neoadjuvant systemic therapy for urological malignancies." BJU international 106.1 (2010): 6-22.
- Sternberg, C. N., et al. "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." European journal of cancer 42.1 (2006): 50-54.
- Grossman, H. Barton, et al. "Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer." New England Journal of Medicine 349.9 (2003): 859-866.
- Vale, C., and Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. "Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis." The Lancet 361.9373 (2003): 1927-1934.
- Sternberg, Cora N., et al. "ICUD-EAU International Consultation on Bladder Cancer 2012: chemotherapy for urothelial carcinoma—neoadjuvant and adjuvant settings." European urology 63.1 (2013): 58-66.
- Sonpavde, Guru P., et al. “Impact of the Number of Cycles of Platinum Based First Line Chemotherapy for Advanced Urothelial Carcinoma.” The Journal of Urology, vol. 200, no. 6, 2018, pp. 1207–1214.