Side Effects of Adjuvant Treatment of Breast Cancer
Charles L. Shapiro, M.D. and Abram Recht, M.D.

N Engl J Med 2001; 344:1997-2008

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The side effects of irradiation of the breast, chest wall, and regional lymph nodes are listed above. As with chemotherapy, much of the information on the side effects of radiation therapy, such as cardiac toxic effects and second cancers, is confounded by treatment received decades ago with outmoded radiation techniques. Current radiation therapy, administered with the use of higher-energy sources, lower daily doses (or smaller fractions), and field arrangements that limit the exposure of normal tissue, is associated with lower rates of toxic effects.

Cardiac Toxicity

Acute and subacute cardiac complications of radiation therapy for breast cancer, such as pericarditis and cardiac failure, are rare. Meta-analyses and registry-based studies have shown small long-term increases in mortality from cardiac causes, probably involving coronary artery disease; however, most of the women in these studies received radiation therapy with outmoded techniques that exposed the heart to high doses of radiation. Studies with a median follow-up time of 10 to 20 years have not found an increased risk of cardiac disease in women treated with modern techniques that limit the exposure of the heart to radiation. However, even when radiation fields are limited to the breast, there still may be a risk of cardiac toxicity when the daily doses are high.

Many women with breast cancer are treated with both doxorubicin and irradiation of the breast or chest wall, but few long-term data are available on the interaction between chemotherapy and radiation therapy administered with current techniques. In several studies, there was no additional short- or long-term cardiac toxicity in women who received radiation therapy in combination with a standard dose of doxorubicin (60 mg per square meter) given for four cycles.However, treatment by radiation with a higher dose of doxorubicin (75 mg per square meter) given for four cycles administered concurrently,or by higher cumulative doses of doxorubicin (450 mg per square meter) with sequentially administered radiation,increased the risk of cardiac toxicity.

Second Cancers

Several registry-based case–control studies found that the risk of contralateral breast cancer was slightly increased among women who had been treated with radiation after mastectomy, probably as a result of the small dose of "scatter" radiation to the other breast.The increased risk seems to be confined to women younger than 40 to 45 years of age at the time of treatment, a finding that is consistent with increased risks among women with other types of radiation-associated breast cancer, such as survivors of the atomic explosions in Hiroshima and Nagasaki and women who have been treated for Hodgkin's disease.The dose of radiation to the contralateral breast can be reduced by technical measures when young women receive radiation treatment.

Sarcomas are very rarely caused by radiation. The 10-, 20-, and 30-year actuarial incidences of soft-tissue sarcomas in patients who have undergone chest-wall irradiation after mastectomy are 0.2 percent, 0.4 percent, and 0.8 percent, respectively.Likewise, angiosarcoma of the skin of the irradiated breast occurs in 0.1 percent to 0.5 percent of patients. The risks of acute myeloid leukemia and myelodysplasia are related to the total dose of radiation, the volume of bone marrow irradiated, and the use or nonuse of alkylating agents. Very small increases in the rate of acute myeloid leukemia after chest-wall and nodal irradiation have been noted in some, but not all, studies.In case–control studies that were mainly limited to smokers, there were very small excess risks of ipsilateral lung cancer and possibly of esophageal cancer among women treated with now-outmoded radiation techniques.

Pneumonitis

Symptomatic radiation pneumonitis is characterized by cough, fever, and shortness of breath occurring two to nine months after the completion of radiation therapy. The condition occurs in less than 1 percent of women who undergo irradiation of the breast or chest wall alone; however, the incidence is higher when chemotherapy and radiation therapy are given concurrently or when a supraclavicular or full axillary field is treated in addition to breast tangential fields.The symptoms of radiation pneumonitis usually resolve without treatment in a few weeks or months, and most patients do not require glucocorticoid therapy.

Lymphedema, Brachial Plexopathy, and Rib Fractures

The incidence of lymphedema ranges from 5 percent to 25 percent, depending on the extent of axillary irradiation and surgery.Lymphedema is a distressing side effect that should be treated early. Effective treatments include specialized massage (called complete decongestive physiotherapy) and elastic pressure sleeves.

The total and daily doses of radiation, as well as the use of chemotherapy, affect the development of brachial plexopathy. The risk of brachial plexopathy and rib fractures is 1 to 2 percent in series of women treated with modern radiation techniques.