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Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity

Publication: J Clin Oncol. 2014 Jun 20, Volume 32, Issue 18, Pages 1895-1901


Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC); however, it is infrequently adopted in practice because of concerns regarding toxicity and delay to cystectomy. We hypothesized that three cycles of neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) would be safe, shorten the time to surgery, and yield similar pathologic complete response (pT0) rates compared with historical controls.

Patients and methods:
Patients with cT2-T4a and N0-N1 MIBC were eligible and received three cycles of AMVAC with pegfilgrastim followed by radical cystectomy with lymph node dissection. The primary end point was pT0 rate. Telomere length (TL) and p53 mutation status were correlated with response and toxicity.

Forty-four patients were accrued; 60% had stage III to IV disease; median age was 64 years. Forty patients were evaluable for response, with 15 (38%; 95% CI, 23% to 53%) showing pT0 at cystectomy, meeting the primary end point of the study. Another six patients (14%) were downstaged to non-muscle invasive disease. Most (82%) experienced only grade 1 to 2 treatment-related toxicities. There were no grade 3 or 4 renal toxicities and no treatment-related deaths. One patient developed metastases and thus did not undergo cystectomy; all others (n = 43) proceeded to cystectomy within 8 weeks after last chemotherapy administration. Median time from start of chemotherapy to cystectomy was 9.7 weeks. TL and p53 mutation did not predict response or toxicity.

AMVAC 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.

Commented by Maria Ribal

Neoadjuvant chemotherapy based on cisplatin is recommended with a level of evidence 1a in the current European Guidelines on  muscle invasive bladder cancer. The evidence derived from randomized trials and meta-analysis demonstrates an impact on overall survival of 5-8% in 5 years (Eur Urol. 2014 Apr;65(4):778-92. EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines)

The pioneering studies on the use of neoadjuvant chemotherapy in bladder cancer used the MVAC scheme. However, once lower toxicity of gemcitabine and cisplatin (GC) scheme in a metastatic patient is proved, this pattern was adopted in the neoadjuvant setting; although there are no randomized studies directly involving this therapeutic regimen. Despite the evidence supporting the use of neoadjuvant chemotherapy in invasive bladder cancer, the scheme is underused globally, without exception, although current trends show a slight increase in the rate of use of neoadjuvant chemotherapy. The main problems for the use of neoadjuvant scheme is the inability to detect responders patients from non-responders previously to therapy,  the possible resulting toxicity of treatment and the delay in the completion of radical cystectomy. We need to invest in research on therapeutic response markers, new therapeutic regimens tailored to the needs of patients, and new therapies that improve the outcomes we have today. Within this context the items selected in this section are framed; these studies propose a new administration regimen for MVAC that has shown to be safe in phase II trials, shortening the time to surgery and maintaining results of conventional schemes.