Introduction

Fifty years ago, Hodgkin disease (HD, also known as Hodgkin's disease), a cancer of the lymphatic system*, was nearly uniformly fatal. With the introduction of effective treatment regimens, HD is now a potentially curable cancer, associated with an 85 percent five-year relative survival rate. There are currently about 120,000 survivors of HD in the United States alone. However, the success of these treatments is accompanied by an increased risk of second cancers, the leading cause of death among long-term survivors of HD. Survivors have an increased risk of leukemia, sarcoma (cancer that develops from connective tissue such as bone, cartilage, or muscle), and breast, lung, and thyroid cancers. Among female HD survivors, breast cancer is the most likely tumor to develop and is a major concern for these women.

Background

Previous studies have shown that increased breast cancer risk begins to be evident about 10 to15 years after radiation therapy for Hodgkin disease and continues for at least 20 years. It has also been reported that women who are age 30 years or less when treated with radiotherapy for Hodgkin disease are more likely to develop breast cancer than those treated at older ages.

JAMA Report

In a study published in the July 23, 2003, issue of the Journal of the American Medical Association, Lois B. Travis, M.D., from the National Cancer Institute in Bethesda, Md., and her colleagues looked more closely at female Hodgkin disease survivors in the United States, Canada, Denmark, Finland, Sweden, and the Netherlands, in an effort to evaluate factors that contribute to breast cancer development in young women. This large international case-control study was conducted among women who were treated for Hodgkin disease at age 30 or younger. The study included 105 women who developed breast cancer after treatment for HD and 266 matched controls who did not develop breast cancer (JAMA 2003;290:465).

The investigators focused on the following risk factors:
   •  The radiation dose to the breast;
   •  The radiation dose to the ovaries;
   •  The number of cycles of alkylating agents, a particular type of chemotherapy; and
   •  Treatment-related menopause.

In the course of their study, they estimated the radiation dose to the area of the breast where each patient's tumor developed and to a comparable location in the matched controls. They found that the higher the radiation dose to the breast, the more likely the women were to develop breast cancer. Specifically, compared with women receiving less than a 4 gray (Gy) dose to the breast, women treated with a breast dose of 4 Gy or greater were 3.2 times more likely to develop breast cancer, and those treated with a dose greater than 40 Gy were 8 times more likely to develop breast cancer. The increased risks associated with radiotherapy were still present after 25 years of follow-up, and increased with increasing dose of radiation to the breast.

They also found that treatment with alkylating agents reduced the breast cancer risk associated with radiotherapy. Whereas treatment with 4 Gy or greater of radiation resulted in a 3.2 times greater risk of breast cancer, adding alkylating agents to the radiation reduced this relative risk to 1.4. Breast cancer risk decreased with increasing number of cycles of alkylating agents.

Breast cancer risk also decreased with increasing radiation doses to the ovaries. Compared with those who received ovarian doses of less than 5 Gy, women who received ovarian doses of 5 Gy or greater had lower breast cancer risks, regardless of whether alkylating agents were used. The decreased breast cancer risk associated with both alkylating agent therapy and radiation dose to the ovaries is probably caused by their damaging effect on ovarian function, including the induction of premature menopause.

It is important to note that recent changes in the treatment of Hodgkin disease are not reflected in the current, multi-center study. Lower radiation doses and reduced fields (which result in a reduction of the amount of exposed breast tissue) have been introduced for selected patients, and alkylating agent-based chemotherapy regimens such as MOPP (mechlorethamine, vincristine [Oncovin], procarbazine, and prednisone) have been largely replaced by more modern regimens, including ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine), as initial therapy. ABVD is at least as effective as MOPP against most tumors, but has a negligible effect on fertility and is associated with a lower risk of leukemia.

Thus, most of the women in the current report were treated with the more aggressive radiotherapy regimens and alkylating agents of the past.

A recent study published in the Journal of the National Cancer Institute (JNCI 2003;95:971) included most of the Dutch patients in the current JAMA publication, but extended the group to older ages (eight additional cases) (< 41 years). The results supported the conclusions reported by Travis et al. (JAMA 2003;290:465).

Conclusions and Public Health Implications

Travis and colleagues drew the following conclusions:
   •  The high radiation-related breast cancer risk in Hodgkin survivors, which did not diminish at the highest doses or the longest follow-up, suggests the need for lifetime surveillance and programs of patient and public awareness.
   •  Ovarian stimulation appears to be important for the development of radiation-induced breast cancer, as evidenced by the reduced risk associated with ovarian damage from alkylating agents or radiation.
   •  Although there are no consensus recommendations for women treated with radiotherapy for Hodgkin disease, several investigators (cited by Travis and colleagues in the JAMA paper) advocate yearly clinical breast exams and annual mammography beginning five to eight years after irradiation.
   •  It is important to continue to minimize radiation doses and fields without compromising the current excellent cure rates.

Overall, Travis and colleagues emphasize that the benefits of radiotherapy and chemotherapy for Hodgkin disease patients far outweigh the treatment-related risks, including the increased risk of breast cancer for women.

Future Research Recommendations

Based on the results of this international study, Travis and her colleagues made the following recommendations:
   •  Although the lower radiation doses and reduced fields currently used for Hodgkin disease patients are likely to result in lower breast cancer risks, long-term follow-up of patients receiving reduced doses is needed to verify this prediction.
   •  Additional studies evaluating the risk of breast cancer following HD should include detailed information on hormonal and other established risk factors for breast cancer in addition to information on treatment for HD.

* The lymphatic system is a part of the body's immune system that helps fight disease and infection. It includes the bone marrow, spleen, thymus, and lymph nodes, and a network of thin tubes that branch, like blood vessels, into surrounding tissues. The network of vessels distributes lymph, a colorless watery fluid containing infection-fighting cells, to the body's tissues.

Published by the National Cancer Institute on July 22, 2003.