Neoadjuvant Dose-Dense MVAC Demonstrates Superior Survival Outcomes in Bladder Cancer

Charles C. Peyton, MD

Neoadjuvant chemotherapy with a dose-dense, or accelerated, course of methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) was more likely to produce a complete pathologic response (pCR) and extend overall survival (OS) than any other chemotherapy regimen in patients with bladder cancer treated with cystectomy, according to a study published inJAMA Oncology.

Despite published reports on the efficacy of MVAC, gemcitabine plus cisplatin has become the standard neoadjuvant chemotherapy regimen for patients with muscle-invasive bladder cancer preceding surgical resection. This is owing, in part, to its favorable toxicity profile and published clinical trial results showing comparable results between the 2 regimens in patients with metastatic disease.

Regular administration of MVAC has been shown to have a serious toxicity profile with more than 50% of patients experiencing myelosuppression and mucositis in some published reports. However, using a dose-dense administration period is well tolerated, considered safe, and has response rates similar to gemcitabine plus cisplatin.

The investigators, led by Charles C. Peyton, MD, a urologic oncology fellow at Moffitt Cancer Center, performed a retrospective analysis of 1113 patients who underwent cystectomy for bladder cancer at the Moffitt Cancer Center in Tampa, Florida to compare neoadjuvant chemotherapy regimens. Patients undergoing cystectomy who did not receive any type of chemotherapy were included as controls.

Primary outcome measures included pathologic downstaging of disease, defined as either any decrease in disease stage or pCR, and OS, defined as date of cystectomy to date of last follow up or death from any cause. Clinical staging was determined mostly by pathologic findings on resection of the bladder tumor and was supplemented with radiographic images. Time to cystectomy was examined as a secondary outcome across chemotherapy subgroups.

Out of a total of 824 patients with advanced or invasive disease (defined as clinical stage ≥T2N0M0), 332 patients were treated with neoadjuvant chemotherapy, 329 received no chemotherapy, and 163 received induction or adjuvant chemotherapy. In the neoadjuvant chemotherapy group, 204 (61.4%) received gemcitabine plus cisplatin, 46 (14%) received ddMVAC, 32 (10%) received gemcitabine plus carboplatin, and 50 (15.1%) received other agents including etoposide, fluorouracil, and paclitaxel regimens. Standard MVAC was included in the other neoadjuvant chemotherapy regimens group and accounted for 3 patients. A 6- to 8-week administration period was used to distinguish dose-dense from standard MVAC regimens.

Patient characteristics based on chemotherapy regimen were similar between groups. The number of cycles of chemotherapy received were similar across regimens with 146 patients (73.7%) receiving gemcitabine plus cisplatin and 42 (91.3%) receiving ddMVAC having 3 or more cycles of chemotherapy. Clinical-stage distributions were similar between the two groups. Median follow-up times for each group were 15 months (95% CI, 12.6-21.0) for gemcitabine plus cisplatin, 12 months (95% CI, 8.2-19.4) for gemcitabine plus carboplatin, 11 months (95% CI, 6.3-18.0) for ddMVAC, and 15.8 months (95% CI, 12.2-23.6) for patients receiving all other regimens.

Downstaging was observed in 52.2% of patients receiving ddMVAC, 41.3% of patients receiving gemcitabine plus cisplatin, and 27% of patients taking carboplatin plus gemcitabine. The rates of pCR were 41.3%, 24.5%, and 9.4% of patients in each group, respectively. Notably, the rate of pCR for patients without neoadjuvant chemotherapy was 10.7% which is similar to the rate observed in patients receiving neoadjuvant carboplatin plus gemcitabine.

Median OS was higher for patients in the ddMVAC group compared with those treated with other regimens. The 2-year Kaplan-Meier survival probability estimates were 73.3% for ddMVAC (95% CI, 48%-89.1%), 62% for gemcitabine plus cisplatin (95% CI, 53.4%-69.9%), and 34.8% for gemcitabine plus carboplatin (95% CI, 18.8%-55.1%;P= .002).

Achieving pCR was also a significant predictor of OS regardless of the chemotherapy agent(s) used. Seventy-eight patients (92.8%) who achieved pCR were still alive 2 years following surgery and these results were consistent across neoadjuvant chemotherapy subgroups. All patients receiving both ddMVAC (n = 19) and gemcitabine plus carboplatin (n = 3) who had achieved pCR were still alive at 2 years. Forty-six patients (92%) receiving gemcitabine plus cisplatin and 10 patients (83.3%) on other chemotherapy regimens who had initially achieved pCR were also alive at 2 years.

Median treatment time for patients taking ddMVAC was 35 days (range 28-46). The average time from the start of neoadjuvant chemotherapy to cystectomy in patients taking ddMVAC was 95 days; for patients taking gemcitabine plus cisplatin the average was 119 days versus 134 days for gemcitabine plus carboplatin (P<.001).

The most common grade 1/2 adverse event (AE) reported was fatigue in 26 patients taking ddMVAC. There were no grade 4 AEs reported and the toxicity profile reported in this study was consistent with those previously published for ddMVAC.

Trial investigators said adjustments to administering MVAC &ldquo;have led to better tolerability, and as a result, 3 cycles of neoadjuvant MVAC can be safely and effectively delivered over a 6-week period.&rdquo;

Reference:

Peyton CC, Tang D, Reich RR, et al. Downstaging and survival outcomes associated with neoadjuvant chemotherapy regimens among patients treated with cystectomy for muscle-invasive bladder cancer.JAMA Oncol. 2018;4(11):1535-1542. doi: 10.1001/jamaoncol.2018.3542.