Gemcitabine and cisplatin neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma: Predicting response and assessing outcomes

Abstract

Purpose To evaluate gemcitabine-cisplatin (GC) neoadjuvant cisplatin-based chemotherapy (NAC) for pathologic response (pR) and cancer-specific outcomes following radical cystectomy (RC) for muscle-invasive bladder cancer and identify clinical parameters associated with pR. Materials and methods We studied 150 consecutive cases of muscle-invasive bladder cancer that received GC NAC followed by open RC (2000–2013). A cohort of 121 patients treated by RC alone was used for comparison. Pathologic response and cancer-specific survival (CSS) were compared. We created the Johns Hopkins Hospital Dose Index to characterize chemotherapeutic dosing regimens and accurately assess sufficient neoadjuvant dosing regarding patient tolerance. Results No significant difference was noted in 5-year CSS between GC NAC (58%) and non-NAC cohorts (61%). The median follow-up was 19.6 months (GC NAC) and 106.5 months (non-NAC). Patients with residual non–muscle-invasive disease after GC NAC exhibit similar 5-year CSS relative to patients with no residual carcinoma (P = 0.99). NAC pR (≤pT1) demonstrated improved 5-year CSS rates (90.6% vs. 27.1%, P < 0.01) and decreased nodal positivity rates (0% vs. 41.3%, P < 0.01) when compared with nonresponders (≥pT2). Clinicopathologic outcomes were inferior in NAC pathologic nonresponders when compared with the entire RC-only–treated cohort. A lower pathologic nonresponder rate was seen in patients tolerating sufficient dosing of NAC as stratified by the Johns Hopkins Hospital Dose Index (P = 0.049), congruent with the National Comprehensive Cancer Network guidelines. A multivariate classification tree model demonstrated 60 years of age or younger and clinical stage cT2 as significant of NAC response (P < 0.05). Conclusions Pathologic nonresponders fare worse than patients proceeding directly to RC alone do. Multiple predictive models incorporating clinical, histopathologic, and molecular features are currently being developed to identify patients who are most likely to benefit from GC NAC.

The ratio of CD8 to Treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive urothelial carcinoma of the bladder

“…The cohort has been previously reported on by our group in two related publications in which further detail on the composition of the cohort can be found. 8,23 …”

“…The overall response rate to cNAC is 40–50%; therefore, a little over half of patients with MIBC would be amenable to an alternative therapeutic intervention prior to RC if one were available and efficacious. 8 …”

Mutually exclusive mutation profiles define functionally related genes in muscle invasive bladder cancer

“…Current 1st line systemic therapy for MIBC is cisplatin-based chemotherapy, which appears to substantially improve survival in a significant minority of patients [ 9 , 10 ]. Mechanistically, cisplatin may exploit SSL through hindered DDR by causing inter-strand and intra-strand crosslinks in DNA [ 11 ].…”

Effect of neoadjuvant chemotherapy on overall survival of patients with T2-4aN0M0 bladder cancer: A systematic review and meta-analysis according to EAU COVID-19 recommendation

“…Moreover, detailed analysis according to the regimen or cycle of NAC was not performed. Incomplete chemotherapy has been recently associated with pathological progression during NAC and an inferior pathological response after RC [ 29 , 30 ]. Therefore, when evaluating patient outcomes, it is necessary to carefully consider the regimen and cycle of NAC.…”