A Prospective Phase I trial of Concurrent Cisplatin (CIS) and Radiation Therapy (RT) in Women with Stage II and III Triple-negative Breast Cancer (TNBC)

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Patients with TNBC experience a higher rate of both in breast and regional nodal recurrence. CIS is an effective systemic chemotherapy in TNBC, and is also a radiation sensitizer. This prospective, phase Ib trial was designed to assess safety and toxicity and establish the recommended phase 2 dose of concurrent CIS with adjuvant RT for women with stage II and III TNBC. Eligible patients had stage II or III TNBC. Any prior preoperative or adjuvant chemotherapy was permitted except CIS or carboplatin. Patients receiving preoperative therapy could not have a complete pathologic response. CIS was initiated at 10 mg/m2intravenously once weekly, then escalated in a classic 3 + 3 design by 10 mg/m2at each dose level until a dose of 40 mg/m2, or maximum tolerated dose (MTD), was reached. Breast conservation (BCT) and mastectomy (M) patients were accrued in separate parallel cohorts in dose-escalation followed by a 10 patient expansion at the MTD for each group. During the escalation phase, all patients in each dose level were observed throughout the 8-week dose limiting toxicity (DLT) window prior to dose escalation. RT was delivered with conventional once-daily fractionation (1.8-2.0 Gy) to the breast or chest wall to 50-50.4 Gy followed by a 10 Gy lumpectomy site cone down (BCT) or 6-10 Gy incision boost (M) at the discretion of the radiation oncologist. Regional nodal radiation was also at the discretion of the treating physician (46-50.4 Gy). Fifty-five patients were accrued from 2013-2018. Four experienced a DLT. In the BCT cohort, one patient developed tinnitus at the maximum dose level of 40 mg/m2resulting in a cisplatin delay. This was therefore the BCT MTD. In the M cohort, three experienced a DLT. One patient, receiving 30 mg/m2CIS, was hospitalized for a grade 3 urinary infection. Two additional patients had DLTs at 40 mg/m2: one grade 3 neutropenia, and the other tinnitus, both resulting in delays in CIS. As a result, 30 mg/m2was the MTD for the M cohort. Two patients had breaks in radiation, (one day and three days; both hospitalized for infection). The most common adverse events in both cohorts were dermatitis (45% grade 2, 2% grade 3), leukopenia (15% grade 2, 15% grade 3), fatigue (15% grade 2), nausea (11% grade 2), ototoxicity and thrombocytopenia (each 7% grade 2). Only one patient (BCT cohort at 30 mg/m2) experienced grade 3 radiation dermatitis; there were no grade 4 skin reactions. CIS was held (16%) or discontinued early (7%) in 13 patients. Median follow-up was 29.1 months. Three-year disease-free survival was 71% in the BCT cohort, and 70% among M patients. Adjuvant radiation therapy with concurrent CIS is feasible with the MTD of 30 mg/m2and 40 mg/m2IV weekly in M and BCT patients, respectively. Additional study is necessary to determine the long-term benefits of concurrent treatment in this high-risk population.