Treatment-related toxicity from a randomized trial of the sequencing of doxorubicin and radiation therapy in patients treated for early stage breast cancer

doi:10.1016/S0360-3016(99)00127-3

International Journal of Radiation OncologyBiologyPhysics

Volume 45, Issue 1, 1 August 1999, Pages 69-72

Presented at the 38th Annual Meeting of the American Society of Therapeutic Radiology and Oncology.

https://doi.org/10.1016/S0360-3016(99)00127-3 Get rights and content

Abstract

Purpose: There is concern that breast cancer patients treated with left-sided radiation therapy (XRT) and doxorubicin (DOX) may have an increased risk of cardiac toxicity. In addition, the effect of different sequencing of XRT and chemotherapy (CT) on the likelihood of cardiotoxicity, as well as cellulitis, arm edema, or brachial plexopathy, is not well understood. We reviewed the records of patients treated on a randomized trial testing the sequencing of CT and XRT to determine if there was an increase in cardiac events or other complications in patients treated with a total dose of DOX of 180 mg/m² and XRT, comparing patients with treatment to the left breast and the right breast, and comparing patients treated with initial CT and initial RT.

Materials and Methods: From June 1984 to December 1992, 244 patients with clinical stage I or II breast cancer were randomized following conservative surgery to receive CT (4 cycles of CAMFP at 3 week intervals) either before or after XRT (45 Gy to the entire breast, followed by a boost of 16 Gy; nodal radiation therapy was optional). Two hundred thirty-one patients were evaluable for the development of cardiac toxicity. The median age at diagnosis was 45 years (range, 20–68). CT doses were: doxorubicin, 45 mg/m² IV bolus, d 3; methotrexate, 200 mg/m² IV, d 1 and 15; 5-fluorouracil, 500 mg/m² IV, d 1; cyclophosphamide, 500 mg/m² IV, d 1; prednisone 40 mg p.o., d 1-5. A cardiac event was defined as a myocardial infarction or clinical evidence of congestive heart failure. Median follow-up time was 53 months.

Results: No cardiac events were observed for patients with either left- or right-sided breast cancer. The sequencing of CT and XRT had no significant effect on the risk of cardiac toxicity, cellulitis, arm edema or brachial plexopathy.

Conclusions: We observed no evidence of an increased risk of cardiac toxicity from the addition of left breast tangential irradiation to DOX at a total dose of 180 mg/m². Additional follow-up is needed to exclude possible late events. In addition, the sequencing of CT and XRT does not appear to affect the risk of cellulitis, arm edema, or brachial plexopathy.

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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Clinical InvestigationTreatment-related toxicity from a randomized trial of the sequencing of doxorubicin and radiation therapy in patients treated for early stage breast cancer

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Int J Rad Oncol Biol Phys

Int J Rad Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Am J Cardiol

Ann of Oncol

Risk factors for doxorubicin-induced congestive heart failure

Ann Intern Med

Anthracycline cardiomyopathy monitored by morphologic changes

Cancer Treat Rep

Cause-specific mortality in long term survivors of breast cancer who participated in trials of radiotherapy

J Clin Oncol

Clinical Investigation
Treatment-related toxicity from a randomized trial of the sequencing of doxorubicin and radiation therapy in patients treated for early stage breast cancer