Cardiovascular death and second non–breast cancer malignancy after postmastectomy radiation and doxorubicin-based chemotherapy

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Purpose To assess the incidence of long-term toxicity after postmastectomy radiation and doxorubicin-based adjuvant chemotherapy. Methods Records of 470 patients treated with mastectomy, doxorubicin-based chemotherapy, and postmastectomy radiation in five institutional prospective trials were retrospectively reviewed. Actuarial toxicity rates were compared with those of 1031 patients treated with mastectomy and doxorubicin-based chemotherapy who did not receive postmastectomy radiation. For those treated with radiation, the chest wall received a median dose of 55 Gy with Co-60 (42%) or electrons (51%). Adjuvant chemotherapy consisted of a doxorubicin-based regimen, often followed by 2 years of cyclophosphamide, methotrexate, and fluorouracil. Results Median follow-up was 10 years. The overall 10-year actuarial rates of RTOG toxicity Grade >1 and ≥3 after radiation were 4% and 2%, respectively. The overall 10- and 15-year actuarial rates of second non–breast cancer malignancy were 3.8% and 7%, respectively. There was no statistical difference between the rates of non–breast cancer second malignancy in the radiated and unirradiated cohorts (3.4% vs. 4.7% 10-year actuarial rates). Increasing age and treatment with >10 cycles of chemotherapy were associated with higher rates of second malignancy ( p = 0.025, p = 0.016). The 10-year actuarial rate of death from myocardial infarction (MI) was 2.4% (eight events) and 0.5% (five events) in the radiated and unirradiated groups, respectively ( p = 0.058). Of the 8 irradiated patients who died of MI, 2 patients had left-sided breast cancer. Conclusions We found very low rates of serious sequelae after postmastectomy radiation, including death from myocardial infarction and non–breast cancer second malignancy. The rate of second non–breast cancer malignancy was increased among patients treated with >10 cycles of cyclophosphamide-containing chemotherapy.