Introduction:

Viable disease in the bladder or regional lymph nodes following neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer (MIBC) is associated with a poor prognosis. However, previous investigations have been limited by the inclusion of non-cisplatin regimens, variability in surgical treatment, and the use of adjuvant therapies. There is a renewed interest in adjuvant trials given the recent FDA approval of several novel immunotherapies and targeted therapies in patients with metastatic urothelial carcinoma. To inform the interpretation and development of adjuvant trials for patients with residual disease after cisplatin-based NAC, we sought to investigate the clinical, pathological, and surgical factors that influence recurrence risk within a large cohort of patients with residual chemotherapy resistant disease from a single high-volume center.

Methods:

We performed a retrospective analysis of patients undergoing standardized radical cystectomy (RC) and pelvic lymph node dissection (PLND) at Memorial Sloan Kettering Cancer Center (MSKCC) from 5/15/2001 to 8/15/2019. Only patients with predominant urothelial carcinoma histology and clinical stage cT2-4aN0M0 who successfully completed four cycles of planned cisplatin-containing NAC followed by RC with curative intent at our center were included. We excluded any patient who received adjuvant therapy to allow an accurate investigation of the underlying recurrence pattern of cisplatin-chemotherapy resistant bladder cancer. Survival was estimated using the Kaplan Meier method and compared between cohorts using the log-rank test. A multivariable Cox proportional hazards model was used to compare recurrence-free survival (RFS) between cohorts.

Results:

We identified 195 patients with residual MIBC (>pT2) after NAC who met inclusion criteria. Demographics were representative of a typical cystectomy cohort. As shown in Figure 1, higher pathologic stage, positive soft tissue margins, lymphovascular invasion (LVI), and lymph node involvement significantly increased the risk of disease recurrence. When looking only at patients with organ confined chemotherapy resistant MIBC (n=51), we found lymphovascular invasion (LVI) to be the strongest predictor of recurrence risk on multivariate analysis (HR 5.84, 95% CI 1.58-21.5, Figure 1d). Compared to pathologic stage matched patients treated by RC alone, without prior NAC or adjuvant chemotherapy, patients with chemotherapy resistant disease demonstrated a consistently worse RFS (International Bladder Cancer Nomogram Consortium, J Clin Oncol, 2006). 

Conclusion:

This data demonstrates the natural history of cisplatin chemotherapy resistant disease and confirms the poor prognosis for these patients. This data further informs the development and benchmarking of adjuvant clinical trials. Specifically, our findings suggest that LVI may provide further risk stratification compared to TNM staging alone and should be considered in patient counselling and interpretation of adjuvant trials. Ongoing genomic analyses should provide further information on treatment selection criteria for neoadjuvant and adjuvant trials. 

Funding: Sidney Kimmel Center for Prostate and Urologic Cancers, Cycle for Survival, Marie-Josee and Henry R. Kravis Center for Molecular Oncology, NIH/NCATS Grant Number UL1-TR002384, National Cancer Institute Cancer Center Core Grant Number P30-CA008748, MSKCC SPORE in Bladder Cancer P50- CA221745, MSK Bladder Cancer SPORE Career Enhancement Award, Bochner Fleisher Scholars in Bladder Cancer Award, NIH/NCI K12 Paul Calabresi Career Development Award for Clinical Oncology (K12 CA184746), Wofchuck Family Young Investigator Award