Long-term cardiac mortality after hypofractionated radiation therapy in breast cancer.

PURPOSE: To explore very-long-term mortality from ischemic heart disease (IHD) after locoregional radiation therapy of breast cancer (BC) in relation to degree of hypofractionation and other treatment variables. METHODS AND MATERIALS: Two hypofractionated regimens used for locoregional radiation therapy for BC from 1975 to 1991 were considered. Patients received 4.3 Gy × 2/week (10 fractions; target dose 43 Gy; n=1107) or 2.5 Gy × 5/week (20 fractions; target dose 50 Gy; n=459). To estimate cardiac doses, radiation fields were reconstructed in a planning system. Time to death from IHD was the endpoint, comparing the groups with each other and with age-matched, cancer-free control individuals, modeled with the Cox proportional hazards model. RESULTS: Patients given 4.3 Gy × 10 had an increased risk of dying of IHD compared with both the 2.5 Gy group (hazard ratio [HR] = 2.37; 95% confidence interval [CI]: 1.06-5.32; P=.036) and the control group (HR = 1.59; 95% CI: 1.13-2.23; P=.008). Photon beams for parasternal fields gave an increased risk of dying of IHD compared with electron beams (HR = 2.56; 95% CI: 1.12-5.84; P=.025). Multivariate analysis gave an increased risk for the 4.3-Gy versus 2.5-Gy regimen with borderline significance (HR = 2.90; 95% CI: 0.97-8.79; P=.057) but not for parasternal irradiation. CONCLUSIONS: The degree of hypofractionation and parasternal photon beams contributed to increased cardiac mortality in this patient cohort. Differences emerged after 12 to 15 years, indicating the need of more studies with observation time of 2 decades.

Dose Distribution in the Heart and Cardiac Chambers Following 4-field Radiation Therapy of Breast Cancer: a Retrospective Study.

PURPOSE: To evaluate cardiac doses in breast cancer patients with stage II/III treated with 4-field radiotherapy based on computed tomography (CT) dose planning. METHODS AND MATERIALS: Based on archived CT images, whole heart and cardiac chamber radiation doses were analyzed in 216 (111 left-sided and 105 right-sided) mastectomized or lumpectomized breast cancer patients treated at a single institution, the Norwegian Radium Hospital, between 2000-2002. Individual dose volume histograms for the whole heart and for the four cardiac chambers were obtained, and mean, median and maximum doses to these structures were calculated. The dose (Gy) delivered to the 5% of the volume of each cardiac structure (D5%), and the volume percentage of each structure receiving ≥ 25 Gy (V25Gy) were reported. Normal tissue complication probability (NTCP) calculations were used to estimate the risk for ischemic heart disease (IHD). RESULTS: Cohort-based medians of the whole heart mean dose (Dmean) for left- and right-sided tumors were 3.2 Gy and 1.3 Gy, respectively, with similar ventricular but lower atrial values. The atrial doses did not differ according to laterality of the breast tumor. In 13 patients with left-sided cancer, 5% of the heart volume was exposed to >25 Gy. The NTCP estimates were generelly low, with a maximum of 2.8%. CONCLUSIONS: During adjuvant CT-based locoregional radiotherapy of women with breast cancer, the cardiac radiation doses are, at the group level, below recommended threshold values (D5% < 25 Gy), though individual patients with left-sided disease may exceed these limits.

Thyroid function in women after multimodal treatment for breast cancer stage II/III: comparison with controls from a population sample.

PURPOSE: A possible association between thyroid diseases (TD) and breast cancer (BC) has been debated. We examined prevalence and development of TD in women after multimodal treatment for Stage II/III BC compared with women from a general population. Secondarily, we explored the impact of two different radiotherapy (RT) techniques (standardized field arrangements vs. computed tomography [CT]-based dose planning) on TD in BC patients examined 35-120 months after primary BC treatment. METHODS AND MATERIALS: A total of 403 BC patients completed a questionnaire about TD and had blood samples taken for analyses of thyroid function. All had undergone postoperative RT with or without (2%) adjuvant systemic treatment. The results in the BC patients were compared with a cancer-free, age-matched control group from a general population (CGr). RESULTS: There was higher prevalence of self-reported hypothyroidism in the BC patients as compared with the CGr (18% vs. 6%, p < 0.001). The raised prevalence was predominantly due to a substantial increase in the development of hypothyroidism after BC diagnosis, whereas the prevalence of hypothyroidism before BC diagnosis was similar to that observed in the CGr. Patients treated with CT-based RT showed a trend for increased post-BC development of hypothyroidism as compared with those treated with standardized field arrangements (p = 0.08). CONCLUSIONS: Hypothyroidism is significantly increased in women after multimodal treatment for Stage II/III BC. Radiation to the thyroid gland may be a contributing factor. BC patients should be routinely screened for hypothyroidism.

Late regional density changes of the lung after radiotherapy for breast cancer.

BACKGROUND AND PURPOSE: To investigate density changes in lung tissue, 3-4 years after postoperative adjuvant radiotherapy for breast cancer, based on dose dependence and regional differences. MATERIAL AND METHODS: Sixty-one breast cancer patients, who had received computed tomography (CT) based postoperative radiotherapy, were included. CT scans were performed 35-51 months after start of radiotherapy. Dose information and CT scans from before and after radiotherapy were geometrically aligned in order to analyse changes in air-filled fraction (derived from CT density) as a function of dose for different regions of the lung. RESULTS: Dose-dependent reduction of the air-filled fraction was shown to vary between the different regions of the lung. For lung tissue receiving about 50 Gy, the largest reduction in air-filled fraction was found in the cranial part of the lung. An increased air-filled fraction was observed for lung tissue irradiated to doses below 20 Gy, indicating compensatory response. CONCLUSIONS: The treatment-induced change in whole-lung density is a weighted response, involving the different regions, the irradiated volumes, and dose levels to these volumes. Simplistic models may therefore not be appropriate for describing the whole-lung dose-volume-response relationship following inhomogeneous irradiation.

Estimated risk for secondary cancer in the contra-lateral breast following radiation therapy of breast cancer.

PURPOSE: To facilitate a discussion about the impact of dose heterogeneity on the risk for secondary contralateral breast (CB) cancer predicted with linear and non linear models associated with primary breast irradiation. METHODS AND MATERIALS: Dose volume statistics of the CB calculated for eight patients using a collapsed cone algorithm were used to predict the excess relative risk (ERR) for cancer induction in CB. Both linear and non-linear models were employed. A sensitivity analysis demonstrating the impact of different parameter values on calculated ERR for the eight patients was also included in this study. RESULTS: A proportionality assumption was established to make the calculations with a linear and non-linear model comparable. ERR of secondary cancer predicted by the linear model varied considerably between the patients, while the predicted ERR for the same patients using the non-linear model showed very small variation. The predicted ERRs by the two models were indistinguishable for small doses, i.e. below approximately 3 Gy. The sensitivity analysis showed that the quadratic component of the radiation-induction pre-malignant cell term is negligible for lower dose level. The ERR is highly sensitive to the value of alpha(1) and alpha(2). CONCLUSIONS: Optimization of breast cancer radiation therapy, where also the risk for radiation induced secondary malignancies in the contralateral breast is taken into account, requires robust and valid risk assessment. The linear dose-risk model does not account for the complexity in the mechanisms underlying the development of secondary malignancies following exposure to radiation; this is particularly important when estimating risk associated with highly heterogeneous dose distributions as is the case in the contralateral breast of women receiving breast cancer irradiation.

Contralateral breast doses following radiotherapy of the breast and regional lymph nodes: Measurements and treatment planning calculations.

PURPOSE: To measure the dose distribution in the contralateral breast (CB) following radiotherapy of the breast and regional lymph nodes by a 4-field technique, and to examine whether related treatment planning calculations of CB doses reproduce the measurements. MATERIALS AND METHODS: CB doses were measured by thermoluminescence dosimetry on the surface of 8 patients and in an anthropomorphic phantom. Dose calculations at corresponding points of interest were performed by the treatment planning system Helax-TMS 6.1 using the pencil beam or the collapsed cone algorithm. RESULTS: The measured CB doses were typically between 1% and 15% of the prescribed dose. The dose decreased significantly both in the medial-lateral and cranial-caudal direction. The average ratio of the measured to the calculated CB dose was about 0.7 and 0.9 for the pencil beam and the collapsed cone algorithm, respectively. One of the treatment fields aimed at the regional lymph nodes and some of the chest wall gave the highest contribution to the CB dose. CONCLUSIONS: The dose distribution in the CB following locoregional radiotherapy of the breast and regional lymph nodes is quite inhomogeneous. The collapsed cone algorithm may be used for estimating doses to the CB. Some concern is raised regarding the current field arrangement and the consequences for the CB dose.