A neoadjuvant dose-dense regimen consisting of gemcitabine and cisplatin was active and well tolerated among patients with muscle-invasive bladder cancer (MIBC), allowing downstaging of most patients before radical cystectomy (RC), according to a phase II trial.
“Neoadjuvant chemotherapy has been underused predominantly because of concerns that clinical benefit is restricted to a subset of patients while all patients are exposed to chemotherapy toxicity,” wrote study authors led by Gopa Iyer, MD, of Memorial Sloan Kettering Cancer Center in New York. Previous studies have shown the benefit of a dose-dense approach to adjuvant chemotherapy in MIBC, but the optimal neoadjuvant regimen was previously unknown.
The new phase II study included 49 MIBC patients at 3 institutions; they had a median age of 64 years, and most were men (82%). They were treated with a regimen of gemcitabine 2,500 mg/m2 on day 1 and cisplatin 35 mg/m2 on days 1 and 2, every 2 weeks for 6 cycles, prior to undergoing RC. Results were published in the Journal of Clinical Oncology.
The primary endpoint of the trial was met, with 57% of patients deemed responders to the medication and were downstaged to < pT2N0 disease prior to RC. Among 41 patients who underwent RC, the chemotherapy responders had a significantly better recurrence-free survival (RFS) than the nonresponders, with a hazard ratio (HR) of 0.088 (95% CI, 0.01–0.73; P = .004). The 2-year RFS rate for responders was 96%, compared with 52% among the nonresponders. For overall survival, the 2-year rates were 96% and 84%, respectively, for an HR of 0.15 (95% CI, 0.02–1.26; P = .043).
A total of 19 patients (39%) required dose modifications or discontinuations due to toxicity. Dose delays or reductions were most commonly due to thrombocytopenia (18%) and creatinine elevation (6%). Treatment-related adverse events of grade 3 or 4 were reported in 37% of the cohort, with anemia (12%) as the most common. No patient failed to undergo RC because of treatment-related toxicity.
Tumor and germline DNA analysis was possible in 32 of the patients. The presence of a deleterious alteration in DNA damage repair (DDR) genes had a predictive value of 89% for response to the therapy, and the 2-year RFS rate was higher in those with a deleterious DDR mutation than in those without one (100% vs 61%; P = .07).
“These results challenge the orthodoxy that bladder extirpation is required for all patients with MIBC,” the authors wrote. They noted that larger studies are needed to determine whether chemosensitivity related to DDR gene alterations varies based on the details of these mutations, and in order to incorporate a comparator arm for this regimen.