International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationTreatment-related toxicity from a randomized trial of the sequencing of doxorubicin and radiation therapy in patients treated for early stage breast cancer
Introduction
Doxorubicin (DOX)-containing drug regimens are widely used for adjuvant treatment of patients with early-stage breast cancer. The dose of DOX given must be limited because of the associated risk of cardiotoxicity. Retrospective studies have indicated that the risk of developing cardiotoxicity, specifically congestive heart failure, increases with increasing cumulative doses of doxorubicin 1, 2.
Radiation therapy (XRT) has been associated with potential cardiotoxicity, specifically ischemic heart disease, in patients irradiated to the left breast 3, 4. The development of ischemic heart disease has been correlated with the volume of heart irradiated and the total radiation dose 5, 6, 7.
Although the mechanisms of injury for DOX-associated cardiotoxicity are thought to be different from those of XRT-associated cardiotoxicity, both ultimately appear to result in myocardial fibrosis. DOX-associated heart damage is characterized by destruction of the myofibrils rendering the myocytes nonfunctional 2, 8. This results in loss of the injured myocyte and subsequent myocardial fibrosis. While the myocytes appear to be relatively radioresistant, XRT appears to damage the endothelial cells of myocardial capillaries. The lesion results in damage to the microvascular network with subsequent ischemia and myocardial fibrosis 7, 9. Additionally, there is some evidence that XRT affects larger vessels such as the coronary arteries (10).
Animal and human studies have suggested an additive effect of DOX and XRT on the risk of cardiac damage 11, 12. This additive effect may be especially evident with concurrent administration DOX and XRT (13). However, the cardiotoxic effect of sequentially administered DOX and XRT in breast cancer patients is not well understood. Recently, we reported that there appeared to be an increased number of cardiac events among node-positive breast cancer patients who received a total cumulative dose of DOX of 450 mg per square meter and subsequent left-sided breast/chest wall XRT with moderate or large cardiac exposure (12). Interestingly, when 225 mg per square meter of DOX was given, there was no increase in the incidence of cardiac events observed in patients irradiated to the left side of the chest, when compared to patients not given XRT.
In this article, we report the rates of nonacute complications in a prospective randomized trial which was designed to evaluate optimal sequencing of chemotherapy and XRT. Clinical outcomes and acute complications in this trial have been previously reported (14). One specific goal of this study was to determine if there was an increased rate of cardiac events in patients treated with moderate total doses of DOX (180 mg per square meter) and XRT to the left breast, when compared to patients with right-sided breast cancer. In addition, we examined whether there were differences in the rate of other treatment-related toxicities based on the sequencing of XRT and CT.
Section snippets
Methods
From June 1984 to December 1992, 244 patients with clinical Stage I or II breast cancer were randomized following conservative surgery and axillary dissection to receive a 12-week course of CT either before or after XRT. Patients with a prior history of XRT or CT or serious co-existing illnesses were excluded from entry onto the protocol.
Of the 244 patients enrolled on the protocol, 231 were evaluable for cardiac evaluation in our review (113 patients in the XRT-first arm and 118 patients in
Results
There were no cardiac events among either the 121 left-sided or 110 right-sided breast cancer patients. Consequently, neither the sequencing of CT and XRT nor the side treated had any observed affect on cardiac toxicity (Table 1). One 35-year-old patient with left-sided breast cancer in the CT-first group developed angina 4 years following her original treatment. She had no risk factors for cardiac disease. Angiography identified a lesion in the proximal left anterior descending artery. This
Discussion
In this randomized trial testing the sequencing of XRT and DOX-based CT in breast cancer patients, we found no adverse cardiac events in patients treated to either the left or right breast. In addition, the sequencing of CT and XRT does not appear to affect other treatment related toxicities.
The total planned dose of DOX administered in this study (180 mg per square meter) is lower than the total dose commonly employed for adjuvant therapy today. In a previously-reported retrospective analysis
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Cited by (37)
Radiation complications and their management
2018, The Breast: Comprehensive Management of Benign and Malignant DiseasesElective Regional Nodal Irradiation in Patients With Early-Stage Breast Cancer
2011, Seminars in Radiation OncologyRadiation Complications and Their Management
2009, The Breast: Comprehensive Management of Benign and Malignant DiseasesSpecial focus on cardiac toxicity of different sequences of adjuvant doxorubicin/docetaxel/CMF regimens combined with radiotherapy in breast cancer patients
2009, Radiotherapy and OncologyCitation Excerpt :Modern radiation therapy techniques have helped to decrease the risk of cardiac toxicity [13–18]. The irradiated heart volume, pre-existing cardiac morbidity, the dose and fractionation or the use of adjuvant chemotherapy should be taken into account during radiotherapy [31]. The comparison of the left side versus the right side and the chest wall versus the breast is informative because it focuses on the impact of cardiac toxicity even though the number of patients is low due to the different chemotherapy regimens.
Radiation Therapy, Cardiac Risk Factors, and Cardiac Toxicity in Early-Stage Breast Cancer Patients
2007, International Journal of Radiation Oncology Biology PhysicsCitation Excerpt :Conflicting reports on this interaction have been published (15, 25–29). Although the mechanisms by which RT and chemotherapy may cause cardiotoxicity differ, both treatments may result in myocardial fibrosis (29). Studies by our group have shown that postmastectomy radiation is more likely to result in secondary radiation-induced malignancies of the lung (30) and esophagus (31).
Delaying radiotherapy for the delivery of adjuvant chemotherapy in the combined modality treatment of early breast cancer: Is it disadvantageous and could combined treatment be the answer?
2006, Clinical OncologyCitation Excerpt :Toxicity profiles for the two treatments were similar, although the granulocyte count of women receiving radiotherapy followed by chemotherapy were lower (P = 0.05), and the number of women requiring hospitalisation for fever and neutropenia was significantly increased (P = 0.02) [66]. A more recent update on the late toxicity experienced by women participating in this study has shown no significant difference between the treatment groups in terms of cardiac toxicity, cellulitis, lymphoedema or brachial plexopathy [68]. To date, only two published randomised studies have compared sequential with synchronous treatment [69,70].