A phase II multicenter study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy with pegfilgrastim support in patients (pts) muscle-invasive urothelial cancer (MIUC): Safety, pathologic, radiologic, and molecular correlates.

Abstract

278 Background: ddMVAC is associated with high responses rate (RR) in advanced urothelial cancer (UC). We embarked on a study in MIUC to determine pathologic RR and its correlation with clinical and radiological outcomes as well as DNA excision repair pathway biomarkers (ERCC1, PAR, BRCA1, and BRCA2). Methods: Patients with cT2-T4, N0-1, M0 UC, and adequate kidney and marrow function were enrolled on a prospective multicenter phase II trial. Four cycles of ddMVAC were given followed by radical cystectomy (RC). The primary endpoint was pathologic downstaging to <pT1N0M0. The treatment would be considered effective if 17 of 37 eligible patients (46%) met the primary endpoint (85% power, 1-sided type I error 0.1). Secondary endpoints included safety, imaging response (by contrast-enhanced imaging, largely MRI), and biomarker correlates. Results: Between 12/08 and 4/12, 39 pts (cT2:42%; cT3:42%, cT4:16%, N1:45%) were enrolled. 91% had bladder primary, and 95% received 4 cycles of ddMVAC. Median follow up was 18 months. One patient developed distant metastases before RC. Of 39 eligible pts, 49% (90% CI 35-63) downstaged to <pT1N0M0 (pT0N0=26%), and the primary endpoint was met. 14/17 (82%) of pts with cN1 disease had pN0 at surgery; no pts with cN0 was found to have pN(+). Toxicities >Grade 3 related to chemotherapy were observed in 10% of pts and included mucositis, hand-foot skin reaction, hypokalemia and neutropenia. No neutropenic fevers were seen. Median and 18-month disease-free survival (DFS) is provided in Table. Tissue biomarker analyses will be presented. Conclusions: ddMVAC regimen is well tolerated and results in significant pathologic and radiologic downstaging in pts with MIUC. Clinical trial information: NCT00808639. [Table: see text]