Do Dose-Dense Neoadjuvant Chemo Regimens Improve Responses in Bladder Cancer?

A dose-dense neoadjuvant chemotherapy regimen yielded higher response rates compared with standard neoadjuvant chemotherapy in a cohort of patients with bladder cancer. Further evidence regarding potential survival benefits may still be necessary, though, for this approach to become clinically relevant.

“Neoadjuvant chemotherapy (NAC) given before cystectomy is a standard treatment for muscle-invasive bladder cancer,” wrote study authors led by Charles C. Peyton, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. “However, despite unequivocal evidence supporting its efficacy, the rates of adoption and routine use of NAC have been modest.”

The specific NAC approach that offers the best outcomes is still under investigation. Some phase II studies have suggested that a dose-dense regimen involving methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) could improve over a standard dosing. In the new study, researchers examined outcomes of 1,113 consecutive bladder cancer patients treated with cystectomy between 2007 and 2017. Of these, 332 received NAC: 204 patients (61.4%) received gemcitabine-cisplatin, 32 patients (10.0%) received gemcitabine-carboplatin, and 46 patients (14.0%) received ddMVAC. Results of the study were published in JAMA Oncology.

Among those treated with NAC, the median age was 66 years, which was significantly younger than the 68 years for those who did not receive NAC (P < .001). In the NAC cohort, most patients were male (72.9%) and white (93.7%), and most had stage II disease (68.7%). They were followed for a median of 13.8 months.

Complete pathologic responses were seen in 19 of 46 patients receiving dose-dense chemotherapy (41.3%), compared with 50 patients receiving standard-dose gemcitabine-cisplatin (24.5%) and 3 receiving gemcitabine-carboplatin (9.4%). A comparison of ddMVAC and gemcitabine-cisplatin significantly favored ddMVAC (P = .02). A multivariable analysis showed an odds ratio (OR) for complete pathologic response favoring ddMVAC over gemcitabine-cisplatin (OR, 2.67; 95% CI, 1.50–4.77).

The 2-year overall survival rate was 73.3% with ddMVAC, compared with 62% with gemcitabine-cisplatin, and 34.8% with gemcitabine-carboplatin (P = .002). An adjusted analysis, however, was not significant, with a hazard ratio for mortality of 0.42 (95% CI, 0.17–1.06; P = .07) when ddMVAC was compared with gemcitabine-cisplatin. It was significantly better than gemcitabine-carboplatin.

The most common grade 3 adverse event with ddMVAC was anemia requiring a blood transfusion, seen in 3 patients; there were no grade 4 adverse events. The most common grade 1/2 adverse event was fatigue, in 26 patients.

Jeffrey M. Holzbeierlein, MD, director of urologic oncology at Kansas University Medical Center in Kansas City, who was not involved with the research, noted that comparing the ddMVAC regimen with gemcitabine-carboplatin is not warranted at this time. “We know that gemcitabine-carboplatin is inferior to the other regimens and in fact is not recommended in the muscle-invasive bladder cancer guidelines,” he told Cancer Network.

Holzbeierlein also pointed out the lack of survival advantage shown here or in other studies of dose-dense regimens. “The reasons for this are complicated and it would likely require a large prospective trial” to show a survival advantage; one trial, the COXEN study, is currently enrolling patients. He added that, so far, it is mostly large academic centers that will use ddMVAC, given concerns about increased toxicity.

“Overall this is thought-provoking and interesting but without a clear survival advantage, it is unlikely to change practice much at this point,” he said. “We will see whether the results of the COXEN trial, especially since this will be correlated with biomarkers, changes the use of ddMVAC.”