Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates

Abstract

Purpose: In advanced urothelial cancer, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) results in a high response rate, less toxicity, and few dosing delays. We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive urothelial cancer (MIUC).

Patients and methods: Patients with cT2-cT4, N0-1, M0 MIUC were enrolled. Four cycles of ddMVAC were administered, followed by radical cystectomy. The primary end point was pathologic response (PaR) defined by pathologic downstaging to ≤ pT1N0M0. The study used Simon's optimal two-stage design to evaluate null and alternative hypotheses of PaR rate of 35% versus 55%. Secondary end points included toxicity, disease-free survival (DFS), radiologic response (RaR), and biomarker correlates, including ERCC1.

Results: Between December 2008 and April 2012, 39 patients (cT2N0, 33%; cT3N0, 18%; cT4N0, 3%; cT2-4N1, 43%; unspecified, 3%) were enrolled. Median follow-up was 2 years. Overall, 49% (80% CI, 38 to 61) achieved PaR of ≤ pT1N0M0, and we concluded this regimen was effective. High-grade (grade ≥ 3) toxicities were observed in 10% of patients, with no neutropenic fevers or treatment-related death. One-year DFS was 89% versus 67% for patients who achieved PaR compared with those who did not (hazard ratio [HR], 2.6; 95% CI, 0.8 to 8.1; P = .08) and 86% versus 62% for patients who achieved RaR compared with those who did not (HR, 4.1; 95% CI, 1.3 to 12.5; P = .009). We found no association between serum tumor markers or ERCC1 expression with response or survival.

Conclusion: In patients with MIUC, neoadjuvant ddMVAC was well tolerated and resulted in significant pathologic and radiologic downstaging.

Trial registration: ClinicalTrials.gov NCT00808639.

Fig 1.

Gadolinium-enhanced magnetic resonance imaging (MRI) of radiologic (A, B) responder versus (C, D) nonresponder. (A, B) Significant adiologic response (RaR) after neoadjuvant dose-dense treatment in 49-year-old woman with muscle-invasive urothelial cancer (MIUC). T1W, fat-suppressed, gadolinium-enhanced MRI (A) at baseline and (B) after neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) demonstrated resolution of tumor bulk, thickness, and enhancement of left posterolateral bladder wall (arrow) at left ureterovesical junction, with no residual wall thickening or enhancement after treatment (arrow). At time of cystectomy, complete pathologic response was observed. (C, D) Absent RaR after neoadjuvant dose-dense treatment in 67-year-old man with MIUC and no RaR to therapy. T1W, fat-suppressed, gadolinium-enhanced MRI (A) at baseline and (B) after neoadjuvant ddMVAC demonstrated persistence of tumor bulk, thickness, and enhancement involving anterior bladder wall (arrows), with stranding extending into anterior perivesical fat. At time of cystectomy, tumor had invaded perivesicular tissue microscopically (stage ypT3aN0 disease).

Fig 2.

Association between disease-free survival and pathologic response. HR, hazard ratio.

Fig 3.

Association between disease-free survival and radiologic response. HR, hazard ratio.