A Prospective Longitudinal Study of Radiation Therapy–Induced Skin Toxicity and Long-term Fatigue in Breast Cancer Patients

Abstract

Cancer-related fatigue is believed to be due to peripherally elaborated inflammatory cytokines that can enter the brain and activate a central inflammatory response associated with fatigue. Radiotherapy (RT)-induced skin changes may trigger an inflammatory response increasing a patient’s risk for developing fatigue. We, therefore, conducted a prospective, longitudinal study of long-term fatigue in breast cancer patients to determine the relationship between fatigue and RT-induced skin toxicity, measured objectively with ultrasound tissue characterization, during and after whole breast RT. We prospectively followed 112 breast cancer patients before, during, 12 weeks and 1 year post-RT following lumpectomy. At each time point, ultrasound images of the irradiated and unirradiated breast were acquired. A skin thickness ratio (STRA) was calculated by determining the epidermal thickness in each quadrant of the irradiated breast and normalizing these measurements to those taken of the contralateral breast. Patients completed the Multidimensional Fatigue Inventory (MFI) and Inventory of Depressive Symptomatology-Self Report (IDS-SR) during each assessment. Univariate and multivariate analysis were conducted to determine predictors of higher MFI scores, proportional to fatigue, at 1 year. Mean MFI at 1 year was 43.48 (SD 15.8). In univariate analysis, MFI at 1 year was associated with baseline MFI scores, baselines and 1 year IDS-SR scores, supraclavicular irradiation in addition to whole breast RT, and STRA prior to, during, and at 12 weeks post-RT (all P<0.05). Age, race, menopausal status, body mass index, RT fractionation (standard vs. hypofractionation), prior chemotherapy treatment, and concurrent hormone therapy for breast cancer were not associated with MFI scores. Being a smoker or a diabetic also did not increase a patient’s risk for fatigue at 1 year. In multivariate analysis, skin thickening at baseline, during, and 12 weeks post-RT were independently predictive of higher MFI scores at 1 year in addition to pre-XRT MFI score (all P<0.05). Our prospective study of fatigue and RT-induced skin changes in breast cancer patients treated with whole breast RT found that baseline levels of fatigue predict for higher levels of long-term fatigue. Notably, treatment-related changes to the breast from surgery prior to RT (STRA at baseline) as well as RT (STRA during and 12 weeks after RT), itself, were also significantly associated with higher MFI scores 1 year post RT completion. These findings suggest that surgery and RT may have a long-lasting impact on both the physical and behavioral side effects of breast cancer treatment.