Neoadjuvant Dose-Dense Methotrexate, Vinblastine, Doxorubicin, Cisplatin With Pegfilgrastim: Safe and Effective in Muscle-Invasive Urothelial Cancer
In a phase II trial reported in the Journal of Clinical Oncology, Choueiri et al found that a neoadjuvant four-cycle/8-week regimen of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin was well tolerated and effective in patients with muscle-invasive urothelial cancer.
Study Details
In the study, 39 patients with cT2 to T4 and N0 to N1 muscle-invasive urothelial cancer received four 2-week cycles of methotrexate at 30 mg/m2, doxorubicin at 30 mg/m2, vinblastine at 3 mg/m2, and cisplatin at 70 mg/m2 plus pegfilgrastim (Neulasta) administered approximately 24 hours after the last dose of chemotherapy in each cycle, followed by radical cystectomy. The primary endpoint was pathologic response defined as downstaging to ≤ pT1, N0, M0. Secondary endpoints included disease-free survival, radiologic response, and associations of biomarkers, including ERCC1, with response.
Most patients (69%) were aged < 65 years, 72% were male, 100% were white, 92% had bladder cancer and 8% had other urothelial cancer, and 23% had carcinoma in situ. The majority of patients (92%) had Eastern Cooperative Oncology Group performance status of 0; disease stage was II in 33%, III in 18%, and IV in 46%; and clinical TNM stage was T2, N0 in 33%; T3, N0 in 18%; T4, N0 in 3%; T2 to T4, N1 in 43%; and unspecified in 3%.
Pathologic Responses
Median follow-up was 2 years. Pathologic response to ≤ pT1, N0, M0 was observed in 19 patients (49%, 80% confidence interval = 38%–61%), with the primary endpoint thus being achieved. Overall, 37 (95%) of 39 patients completed all four cycles of chemotherapy. Radiologic response was observed in 62% of patients. One-year disease-free survival was 89% vs 67% for patients who did vs did not achieve a pathologic response (hazard ratio [HR] = 2.6, P = .08) and 86% vs 62% for those who did vs did not achieve a radiologic response (HR = 4.1, P = .009). The median time to surgery was 6 weeks (range = 4–12 weeks) after the last dose of chemotherapy.
Toxicity
Grade 3 or 4 adverse events occurred in 10% of patients, consisting of hand-foot-skin reaction, mucositis, hypokalemia, and neutropenia in one patient each. Treatment was discontinued due to adverse events after three cycles in two patients (5%). No febrile neutropenia or treatment-related deaths were observed. Postoperative complications occurred in seven patients and were considered possibly related to chemotherapy in four (11%).
No associations between expression of ERCC1 or other serum tumor markers and response or survival were observed.
The investigators concluded, “In patients with [muscle-invasive urothelial cancer], neoadjuvant [dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin] was well tolerated and resulted in significant pathologic and radiologic downstaging.”
Toni K. Choueiri, MD, of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by the Dana-Farber Cancer Institute and by Amgen. Dr. Choueiri and Leonard J. Appleman, MD, PhD, receive research funding from Amgen.
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