Outcomes and Evolving Treatment Paradigms for Small Cell Carcinoma of the Bladder

Abstract

Small cell carcinoma of the bladder (SmCCB) is a rare histology with a poor prognosis and an unclear treatment paradigm. To better define treatment paradigms and patient/tumor characteristics correlating with outcomes in patients with SmCCB and mixed urothelial/neuroendocrine carcinoma (NE). We retrospectively evaluated our single institution experience in patients with SmCCB/NE. Time to event analysis was performed with Kaplan-Meier estimates. Univariable (UVA), multivariable (MVA) analyses were performed to assess the impact of patient and tumor characteristics on outcomes. Between 2001-2018, 51 patients with SmCCB/NE were treated. Median age at diagnosis was 71 (range 47-85). 84% (n=43) were smokers with a median pack-year history of 30 (range 1.5-200). The proportions of clinical Stage I/II/III /IV patients at diagnosis were 4% (n=2)/57% (n=29)/24% (n=12) /16% (n=8); 16 patients were node positive (31%). A majority (82%) received neoadjuvant chemotherapy (NACT, median 4 cycles, range 1-12) and surgery (n=28, 55%; 26 radical cystectomy, 2 partial cystectomy, all with a pelvic lymph node dissection), whereas 29% (n=15) underwent definitive radiation (XRT) (13 chemoradiation, 2 XRT alone) and 18% (n=9) underwent adjuvant chemotherapy (ACT). 81% (n=34) of NACT regimens consisted of a platinum/etoposide (P/E) doublet. Of the surgical patients, 18% (n=5) had positive margins, 21% (n=6) had perineural invasion (PNI), 43% (n=12) had lymphovascular invasion (LVSI), and 25% had extracapsular extension (ECE). Proportions of pathologic Stage 0/I/II/III/IV patients were 43% (n=12)/4% (n=1)/7% (n=2)/36% (n=10)/11% (n=3). Of the NACT+surgery patients (n=24), 50% had no invasive disease (ypT0/T0is). Immunotherapy was first given to relapsed patients in 2016. Of the 14 failures since then, 50% have received immunotherapy, of whom all are still alive. With a median follow-up of 19 months (range 3-91), the median, 12- and 18-month locoregional control (LRC) was not reached/72%/68%; distant control (DC) was not reached/60%/54%; and overall survival (OS) was 39 months/67%/57%. On UVA, smokers (p=0.006) and NACT (p=0.03) had improved LRC; smokers (p=0.031) and no LVSI (p=0.037) had improved DC; smokers (p=0.031), ypT0/T0is (p=0.015), no LVSI (p=0.003), and no ECE (p=0.002) had improved OS. Gender, clinical stage, percent SmCCB/NE, P/E vs other CT, margin status, PNI, and all therapies (NACT, surgery, XRT, ACT) had no influence on OS. On MVA no variable remained predictive. Even in a modern series of SmCCB/NE, prognoses remain poor. However, NACT can successfully induce pCR, improving survival. Survival otherwise doesn’t seem influenced by any specific treatment regimen. Although prospective validation is needed, adverse surgical features, including LVSI or ECE should prompt consideration of adjuvant therapy. As with other small cell carcinomas, novel therapies, such as immunotherapy, may improve outcomes.