Neoadjuvant Dose-Dense Methotrexate, Vinblastine, Doxorubicin, Cisplatin With Pegfilgrastim: Safe and Effective in Muscle-Invasive Urothelial Cancer


Key Points

  • Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin produced pathologic response of ≤ pT1,N0,M0 in 49% of patients and was well tolerated.
  • The median time to surgery was 6 weeks after completion of chemotherapy.

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.


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.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.