Dose-Dense Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

Key Points

  • Pathologic response was observed in 57% of patients.
  • Presence of deleterious DDR gene alteration was associated with response and prolonged recurrence-free survival.

In a phase II trial reported in the Journal of Clinical Oncology, Iyer et al found that dose-dense neoadjuvant gemcitabine plus cisplatin produced a high response rate and was generally well tolerated in patients with planned radical cystectomy for muscle-invasive bladder cancer.

Study Details

In the study, 46 evaluable patients from 3 U.S. sites received gemcitabine 2,500 mg/m2 on day 1, cisplatin 35 mg/m2 on days 1 and 2 (planned dose intensity of 1.875 times and 1.5 times standard gemcitabine and cisplatin) and pegfilgrastim on day 3 every 2 weeks for 6 cycles followed by radical cystectomy.

The primary endpoint was pathologic downstaging to non–muscle-invasive disease (< pT2N0). Patients who did not undergo radical cystectomy were considered nonresponders.

Responses

Pathologic downstaging to < pT2N0 disease occurred in 26 patients (57%). Among the total of 41 patients undergoing radical cystectomy, patients with pathologic response had better 2-year recurrence-free (96% vs 52%, hazard ratio [HR] = 0.08, P = .004) and overall survival (96% vs 84% (HR = 0.15, P = .043). Next-generation sequencing of pretreatment tumors from 32 patients identified somatic deleterious DDR gene alterations in 9 patients, of whom 8 had pathologic response; the positive predictive value of a deleterious DDR gene alteration for response was 89%. No patient with a deleterious DDR gene alteration had experienced recurrence at median follow-up of 2 years.

Toxicity

Dose modifications due to toxicity occurred in 19 patients (39%), with 67% of patients completing all six planned cycles and no patient failing to undergo radical cystectomy due to drug-related toxicities. The most common grade 3 or 4 treatment-related adverse events were anemia (12% pre- and 12% post-surgery), decreased platelet count (6% pre-surgery), and hyperglycemia (6% pre-surgery).

The investigators concluded, “Six cycles of [dose-dense neoadjuvant gemcitabine plus cisplatin] is an active, well-tolerated neoadjuvant regimen for the treatment of patients with [muscle-invasive bladder cancer]. The presence of a putative deleterious DDR gene alteration in pretreatment tumor tissue strongly predicted for chemosensitivity, durable response, and superior long-term survival.”

The study was funded by the Zena and Michael A. Wiener Research and Therapeutic Program in Bladder Cancer, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Cycle for Survival, and National Cancer Institute.

Gopa Iyer, MD, of the Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

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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