Alicia K. Morgans, MD Assistant Professor of Medicine Division of Hematology/Oncology Vanderbilt University Medical Center January 24, 2015
Overview Background Perioperative chemotherapy in MIBC Neoadjuvant chemotherapy Adjuvant chemotherapy Cisplatin-ineligble patients Bladder-sparing protocols Summary
Background 74,690 new diagnoses of bladder cancer in 2014 in the US 15,580 deaths in the US in 2014 5-yr overall survival 77.4% Howlader N, et al. SEER Cancer Statistics Review, 1975-2011.
Stage predicts survival Howlader N, et al. SEER Cancer Statistics Review, 1975-2011.
Standard of Care Radical cystectomy (RC) 50% of pts die of recurrent disease Median survival for advanced disease = 14-15 months Unchanged in 30+ years Limited systemic treatment options (40-60% response) Low response rate to 2nd line therapies (10-20%) Berdoorn. Oncol 2013;27(3):219. Abdollah. Cancer Epidemiol 2013;37:219.
Neoadjuvant chemotherapy (NAC) Several chemotherapy options available Gemcitabine and cisplatin (GC) 4 cycles, 21 days each (12 weeks) Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (DDMVAC) 3 or 4 cycles, 14 days each (6-8 weeks) DDMVAC is better tolerated and more effective than MVAC Cisplatin, methotrexate, and vinblastine (CMV) 3 cycles, 21 days each (9 weeks)
Benefit of NAC Permits down-staging of primary tumor Predict long-term prognosis Pathologic complete response (pcr) Improves overall survival 5% absolute improvement in OS at 5 years Petrelli. Eur Urol 2014;65: 350-357. ABC Meta-analysis Collaboration. Lancet 2003;361-1927.
5 year OS NAC + RC 57% RC only 43% p=0.06 NAC + RC RC only Grossman. N Engl J Med 2003;349:859.
HR 84% (95% CI 0.72-0.99) 16% reduction in mortality International Collaboration of Trialists (MRC) 2011;29:2171-2177.
Meta-analysis NAC and survival 3000 pts, 11 trials All received platinumbased NAC 90% cisplatin-based 5% benefit at 5 years HR= 0.86; 95% CI, 0.77-0.95 Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Eur Urol 2005;48:202.
Meta-analysis - NAC and pcr 13 trials, 887 patients pcr = no residual disease bladder or nodes NAC increased pcr rate from 10-15% to 28.6% 55% lower risk of death with pcr than residual disease 81% lower risk of recurrence with pcr than residual disease NNT to prevent 1 death = 3.7 5 year OS for pcr is >85% Petrelli. Eur Urol 2014;65(2):350-7.
pcr Tis+ Grossman. N Engl J Med 2003;349:859.
But wait Survival in T2 pts may be better than reported in RCTs In contemporary series of RC alone 10 yr disease specific survival of pt2n0 ~ 66% (vs <50% in Grossman study for RC+NAC) Are we really adding anything? pcr = good prognosis, with NAC or TURBT Are patients with no remaining disease after TURBT overtreated with NAC? Hautmann RE, et al. Euro Urol 2012;61:1039-47.
Another Approach: Adjuvant Chemotherapy
Adjuvant Chemotherapy (AC) Recent evidence suggests benefit similar to NAC 2014 meta-analysis (9 studies) finds survival benefit HR 0.77, 95% CI 0.59-0.99 Recent retrospective study found ~30% reduction in mortality HR 0.71, 95% CI 0.62-0.81 Controversial evidence All included trials closed early, were underpowered Two largest studies reported conflicting data Population-based study non-randomized Leow JJ, et al. Eur Urol 2014; 66:42-54. ABC Meta-analysis Collaboration. Eur Urol 2005;48:189. Freiha. J Urol 1996;155:495. Stockle. J Urol 1995;153:47. Stockle. J Urol 1992;148:302. Booth CM, et al. Cancer 2014;120:1630-8.
Leow JJ, et al. Eur Urol 2014; 66:42-54.
AC and Prognostic Factors Overall survival in N+ pts Overall survival in N- pts Involved lymph nodes and positive surgical margins had most benefit from AC. Booth CM, et al. BJU Int. 2014; [Epub ahead of print]
Practical Concerns Delay to definitive treatment (RC) SWOG/Intergroup NAC study RC performed in ~80% of patients in both arms No toxic deaths in study No increase in post-op complications International Trialists study 4/561 (0.7%) did not receive RC due to chemo toxicity No significant difference in post-op complications or deaths Grossman. N Engl J Med 2003;349:859. International collaboration of trialists. Lancet 1999;354(9178):533-40.
Practical Concerns Clinical staging is challenging Bimanual exam accurate in only 57% of pts Understages 31% of patients Up to 42% of pts staged as ct2 are upstaged at RC 40% of pts with non-muscle-invasive disease are staged as pt2 at RC Ploeg M, et al. Urol Oncol 2012;30:247-51. Svatek RS, et al. BJU Int 2011;107:898-904.
Practical Concerns Fewer pts eligible for AC than NAC Mayo Registry 768 MIBC patients undergoing RC 47% had GFR >60 pre-rc vs 35.4% GFR > 60 post-rc 25% reduction 30% of patients ineligible for AC within 90 days of RC post-op complications slow recovery renal dysfunction Houston Thompson. BJU Int 2014; 113:E17-E21. Donat. Eur Urol 2009;55:177.
Cisplatin-ineligible patients No data to support use of carboplatin regimens Some pts treated with split-dose cisplatin to spare renal function Consider if GFR >40-45
Bottom Line Consider early referral of clinical T3 and T4 patients to discuss NAC with a medical oncologist. Think critically about ct2n0 patients, and consider discussing with medical oncologist. NAC before RC vs RC then AC for appropriate patients.
Bladder sparing protocols 5 yr overall survival 36-74% 70-80% of patients retain bladder at 5 yrs Select patient population Early stage tumor Complete TURBT No ureteral obstruction Willing to engage in intense follow-up Mak RH, et al. J Clin Oncol 2014;32:3801-3809. Ploussard G, et al. Eur Urol 2014;66:120-137. Rodel C, et al. J Cllin Oncol 2002;20:3061-3071.
Mak RH, et al. J Clin Oncol 2014;32:3801-3809.
Summary T2 MIBC can be tricky no clearly right answer. Best evidence is for NAC. Strength of evidence modest due to Poor and prolonged study accrual Limited power AC after RC may be better option for ct2 patients. Bladder-sparing protocols may work for very specific patient population.