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.

Keywords: Bladder cancer; Gemcitabine-cisplatin; Neoadjuvant chemotherapy; Pathologic response; Urothelial carcinoma.

Fig. 1

(A) The 5-year CSS for GC NAC and non-NAC RC-alone cohorts, no significant difference by log-rank test was observed, P = 0.18. (B) The 5-year CSS for the GC NAC cohort stratified by pathologic stage relative to the 5-year CSS for non-NAC. The 5-year CSS for ypT0 is equivalent to that for pTis, pTa, pT1; therefore, responders to GC NAC were defined as pT0 and residual pTa, pTis, and pT1, as has been previously reported. The 5-year CSS for GC NAC responders, GC NAC nonresponders, and the non-NAC cohort are all statistically different from each other by log-rank test, P < 0.01.

Fig. 2

(A) Using clinical T stage and age at cystectomy in classification tree analysis resulted in stratification of the NAC cohort to 3 grouping as shown. GC NAC pNR was highly correlated with these groupings by the Fisher exact test but adequacy of therapy was not. (B) The 5-year CSS for the GC NAC cohort is significantly stratified by the classification tree model from (A). (C) By contrast, no significant stratification of the 5-year CSS for the non-NAC cohort is observed when the classification tree model is applied to this cohort.