Hodgkin's Therapy Affects Later Breast Cancer Risk

The higher the radiation dose, the higher the risk, study says

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TUESDAY, July 22, 2003 (HealthDayNews) -- Women who received smaller doses of radiation to treat Hodgkin's disease have a lower risk of developing breast cancer later in life.

It's not clear, however, whether this conclusion applies to women who are receiving the newest treatment regimens, which involve chemotherapy with even lower radiation doses, says a study appearing in the July 23/30 issue of the Journal of the American Medical Association.

Hodgkin's disease (HD), a cancer that affects the lymphatic system, has a phenomenally high cure rate today: 85 percent of patients are survivors at the five-year mark. The downside, however, is that people who survive HD have a higher likelihood of developing a second cancer such as leukemia, sarcoma, breast, lung, and thyroid as a result of radiation therapy. These second cancers are the leading the cause of death among long-term survivors.

"The main issue with HD are the early-stage patients because they constitute the majority and this is where the cure rate is so high," says Dr. Joachim Yahalom, a radiation oncologist at Memorial Sloan-Kettering Cancer Center in New York City and author of an accompanying editorial in the same issue of the journal. "Now, after you cure most of them -- well over 80 percent -- you're concerned about the long-term side effects."

Women survivors of HD are at particular risk for developing breast cancer. According to previous studies, that increased risk starts appearing about 10 to 15 years after radiation therapy and continues for about 20 years. Women who were 30 years old or younger when treated for HD seem to be at an even greater risk for developing breast cancer.

The purpose of this study was to get a better handle on the factors that might contribute to the development of breast cancer among women who were treated for HD at age 30 or less. The study authors looked at 3,817 women who had been treated for HD. Within that group, 105 women had developed breast cancer after treatment were compared to 266 women who had been treated for HD but who had not developed breast cancer.

The authors focused specifically on the radiation dose given to the breast, the radiation dose given to the ovaries, the number of cycles of certain types of chemotherapy, alkylating agents (which inhibit cell growth), and treatment-related menopause.

Not surprisingly, the higher the radiation dose to the breast, the more likely the women was to develop breast cancer. Women treated with 4 gray (or Gy, a measure of radiation dosage) or greater were 3.2 times more likely to develop breast cancer than those treated with a lower dose. Those treated with 40 Gy were eight times more likely to develop breast cancer. These increased risks persisted 25 years after receiving the initial therapy and increased as the radiation dose increased.

"We roughly estimate that among 1,000 women treated for HD at age 30 years or younger with mantle radiotherapy alone using a dose of 40 Gy delivered to the breast and followed up for 25 years, an excess of 83 breast cancers in tissue exposed to this dose might be expected on the basis of our data," says study author Dr. Lois B. Travis, lead author of the study and a senior investigator with the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. "Radiation doses of 20 Gy and 10 Gy delivered to tissues might result in an excess of 42 and 21 breast cancers per 1,000 women, respectively." Travis emphasizes that these numbers are only estimates.

On the flip side, adding alkylating agents reduced the relative risk from 3.2 to 1.4. The risk of developing breast cancer decreased as the number of cycles of alkylating agents increased, and as the radiation doses to the ovaries increased. Women who received ovarian doses of 5 Gy or more had a lower risk of breast cancer, whether or not alkylating agent had been used, compared with those who received ovarian doses of less than 5 Gy.

It appears likely that alkylating agent therapy and radiation dose have this beneficial effect because they damage the ovaries and induce early menopause, thus altering the hormonal balance in the body.

"The study indicates to patients and [doctors] that the lower radiation doses and reduced fields currently used to treat HD are likely to result in lower breast cancer risks," Travis says. "For women who have been treated for HD at age 30 or less with chest radiotherapy in the past, the high radiation-related risk of breast cancer, 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. Although there are currently no consensus recommendations for women treated with chest radiotherapy for HD, several other investigators advocate yearly clinical breast examinations and annual mammography beginning five to eight years after irradiation."

The women included in this study received the more aggressive treatments of the past. And while radiation levels have been reduced in recent years, it's not clear whether that will also decrease the risk of a second cancer.

"The standard treatment nowadays is to follow the chemo with a small size of radiation field. The areas that are being treated now are relatively small and the dose really depends," Yahalom explains. "In the past, the treatment for this early stage was radiation alone and radiation was given to large areas because no chemotherapy was given. The dose was higher. It was the only treatment that was successful at that time. This treatment has changed, mostly because chemotherapy is now the primary treatment and radiation is just given to the selected area just to finish it up or to ensure the very high cure rate that we have."

"Although our results indicate that 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 these patients is needed to verify this prediction," Travis adds.

Yahalom's editorial addressed the issue of eliminating radiotherapy from the treatment of HD altogether. Two studies that looked into this were terminated, however, when the results of chemo alone turned out to be inferior to those of the combination. "Those with chemotherapy alone had too many relapses," he says. "We probably cannot do without radiation. At the same time, radiation has changed so much that probably the risk is very, very, very different."

Even so, the study authors emphasize that the benefits of radiotherapy and chemotherapy far outweigh the risks, including the risk of future breast cancer for women.

More information

For more on Hodgkin's disease, visit the National Cancer Institute or the American Cancer Society.

SOURCES: Lois B. Travis, M.D., senior investigator, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Md.; Joachim Yahalom, M.D., radiation oncologist, Memorial Sloan-Kettering Cancer Center, New York City; July 23/30, 2003, Journal of the American Medical Association
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