Women with Hodgkin’s disease who were treated with chest radiation alone before the age of 30 years have an increased risk for breast cancer, according to an article in the July 23rd issue of The Journal of the American Medical Association.

According to background information in the article, the leading cause of death in long-term survivors of Hodgkin’s disease is the development of a second cancer; there is an exceptionally high risk for breast cancer among women treated at a young age. Increased rates of breast cancer have been generally attributed to chest irradiation for Hodgkin’s disease, consistent with the known sensitivity of breast tissue to ionizing radiation at young ages.

In the current study, Lois B. Travis, MD, and her American colleagues analyzed risk of breast cancer among 3,817 women diagnosed with Hodgkin’s disease at age 30 years or younger (between June 1965 and December 1994) and provided estimates of relative and absolute excess risk in terms of radiation dose delivered to the breast and the number of cycles of chemotherapy with an alkylating agent.

As part of an international investigation, the researchers studied 105 patients with Hodgkin’s disease who developed breast cancer and matched them with 266 patients who did not develop breast cancer. They wrote, "A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 8-fold with a dose of more than 40 Gy. Radiation risk did not vary appreciably by age at exposure or reproductive history. Increased risks persisted for 25 or more years following radiotherapy [2.3-fold increased risk]."

Treatment with alkylating agents alone resulted in a 40-percent reduced risk of breast cancer. The combination of alkylating agents and radiotherapy produced a 1.4-fold increased risk. Risk of breast cancer decreased with increasing number of alkylating agent cycles. There was a 60-percent reduced risk among women who received 5 Gy or more delivered to the ovaries compared with women who received lower doses of pelvic radiation.

"In summary, young women with Hodgkin’s disease may receive treatments that both increase their risk of breast cancer (that is, radiation dose delivered to the breast) and treatments that decrease their risk of breast cancer (that is, selected alkylating-agent chemotherapy or radiation delivered to the ovary). The overall increase in risk may be due in part to the result of mutational changes that, after prolonged hormonal stimulation, develop into breast cancer. The decrease in risk is likely due to a reduction or cessation of ovarian function and accompanying diminution in hormonal stimulation of breast tissue," the authors wrote.

"Despite our quantification of this serious late effect, it is clear that the major gains and successes in the treatment of Hodgkin’s disease greatly outweigh the treatment-related risks of breast cancer and other late sequelae. Given current modifications in approaches to radiotherapy, in the future late effects should have less impact on the lives of women with Hodgkin’s disease. In the interim, for current survivors of Hodgkin’s disease, the high risk of radiation-associated breast cancer, which in our study did not diminish at the highest doses or in the longest follow-up, suggests the need for programs of clinician and patient awareness, lifetime surveillance, and possible prevention strategies," the authors concluded.

In an accompanying editorial, Joachim Yahalom, M.D., wrote that the "results reported by Travis et al clearly demonstrate the influence of radiation dose on the risk of breast cancer. Within the range of doses that have been used in the past, more radiation translates into a higher risk of developing breast cancer. This information, as well as data from earlier publications, supports the notion that 'lower is better' as long as the radiation dose used augments the cure rate for Hodgkin’s disease."

"The pendulum of therapy for Hodgkin’s disease that has swung from wide-field, full-dose radiation alone to full-dose chemotherapy and no radiation is likely to settle in the middle, providing a safer cure for Hodgkin disease by using brief chemotherapy and reduced radiation. The efficacy of this strategy already has been demonstrated, but determination of potential long-term toxicity will require more time," he concluded.