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Accelerated Methotrexate, Vinblastine, Doxorubicin, Cisplatin With Pegfilgrastim Is Effective, Well-Tolerated Neoadjuvant Therapy for Bladder Cancer

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Key Points

  • Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin was well tolerated and resulted in pathologic complete response in 38% of patients and downstaging in 53%.
  • All evaluable patients proceeded to cystectomy within 8 weeks of completing the accelerated regimen.

Although neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer, it is not widely used due to concerns over toxicity and delayed cystectomy. In a phase II trial reported in the Journal of Clinical Oncology, Plimack et al evaluated whether a neoadjuvant three-cycle/6-week course of accelerated methotrexate, vinblastine, doxorubicin, and cisplatin could safely shorten time to surgery without reducing achievement of pathologic complete response (pT0). The accelerated regimen was found to be well tolerated and to produce pT0 rates comparable to those achieved with standard 12-week methotrexate, vinblastine, doxorubicin, and cisplatin treatment in historical controls.

Study Details

In the trial, 44 patients with cT2 to T4a and N0 to N1 muscle-invasive bladder cancer received three cycles of accelerated methotrexate at 30 mg/m2, vinblastine at 3 mg/m2, doxorubicin at 30 mg/m2, and cisplatin at 70 mg/m2 with pegfilgrastim (Neulasta) over 6 weeks followed by radical cystectomy with lymph node dissection. Pegfilgrastim was administered 24 to 48 hours after completion of chemotherapy. The primary endpoint was pT0 rate. Telomere length and p53 mutation status were assessed for prediction of response and toxicity.

The study tested the null hypothesis that the pT0 rate among evaluable patients would be ≤ 23% vs the alternative hypothesis that the rate would be 43%. If there were ≥ 3 pT0s among the first 15 evaluable patients, up to an additional 27 patients would be accrued; otherwise, the trial would be stopped for lack of efficacy. The trial was to be declared a success if ≥ 15 pT0s were observed. The null hypothesis and success thresholds were based on response rates in historical controls for 12-week standard methotrexate, vinblastine, doxorubicin, and cisplatin and gemcitabine/cisplatin treatment.

Patients had a median age of 64 years (range = 44–83 years), 68% were male, and 91% were white. Eastern Cooperative Oncology Group performance status was 0 in 84% and 1 in 16%, and clinical TNM stage was T2, N0 in 36%; T3, N0 in 43%; T4a, N0 in 14%; and Tany, N1 in 7%.

Pathologic Complete Response

Four patients were not evaluable due to early discontinuation of therapy in the absence of grade > 2 toxicity or disease progression. Among the 40 evaluable patients, pT0 at cystectomy was observed in 15 (38%, 95% confidence interval = 23%–53%), with the primary endpoint of the study thus being met. In an additional six patients (14%), disease was downstaged to non–muscle invasive. In total, 37 patients (93%) completed all three cycles of chemotherapy.

Overall survival (P = .041) and relapse-free survival (P = .034) were significantly longer in patients with vs without pT0; differences in overall survival (P = .2) and relapse-free survival (P = .05) did not achieve significance.

Toxicity

Only grade 1 or 2 adverse events occurred in 82% of patients and grade 3 or 4 adverse events were observed in 12%. The only grade 3 adverse events occurring in > 2% of patients were anemia in 7%, fatigue in 7%, and lymphocytopenia in 5%; the only grade 4 adverse event occurring in > 2% was neutropenia in 5%. No grade 3 or 4 renal toxicity was observed, and there were no treatment-related deaths.

Time to Cystectomy

Among all 44 patients, one did not undergo cystectomy, due to early development of metastases. All other patients had cystectomy within 8 weeks of their last chemotherapy infusion; median time from start of chemotherapy to cystectomy was 9.7 weeks (range = 4.6–13 weeks). There were no apparent differences in incidence or severity of postoperative complications compared with historical controls.

There were no associations of telomere length or p53 mutation status with response or toxicity.

The investigators concluded, “[Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin] is well tolerated and results in similar pT0 rates with 6 weeks of treatment compared with standard 12-week regimens. Further analysis is ongoing to ascertain whether molecular alterations in tumor samples can predict response to chemotherapy.”

Elizabeth R. Plimack, MD, MS, of Fox Chase Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by grants from the American Cancer Society and National Cancer Institute. Timothy A. Brennan and Norma Palma, PhD, reported employment or leadership positions and stock ownership with Foundation Medicine.

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®.


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