Childhood cancer survivors, late effects, premature menopause. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
When girls who survive cancer grow up, they are 13 times more likely to experience menopause before age 40 than other women, according to a large study of childhood cancer survivors. The risk is highest for women whose childhood cancer treatment involved radiation to the ovaries and/or chemotherapy with
Journal of the National Cancer Institute, July 5, 2006 (see the journal abstract).
(JNCI 2006 Jul 5, 98;13: 890-896)
Nearly 300,000 people in the United States are alive after surviving childhood cancer, and the five-year survival rate for many types of childhood cancer approaches 80 percent. However, the same medical treatments that help children survive cancer can cause health problems down the road, known as late effects. Studies indicate that early menopause may be one of these late effects.
In the United States, women reach menopause on average at the age of 51. Menopause that occurs for any reason before the age of 40 is considered premature. Women who experience early menopause face more years without the protective effects of their own natural estrogen. This can increase the risk of osteoporosis and some types of heart disease. Those who undergo menopause early thus face a greater cumulative risk for adverse health effects than do women whose menopause comes later.
Exposure to a class of chemotherapy drugs called alkylating agents (for example, cyclophosphamide) has been linked to a risk of premature menopause, as has radiation therapy directed to the abdominal and pelvic areas, where a woman’s ovaries are located.
The Childhood Cancer Survivor Study (CCSS) was started in 1993 to better understand the magnitude and specifics of late effects. More than 14,000 childhood cancer survivors who were originally diagnosed between 1970 and 1986 and about 3,700 of their healthy siblings have been surveyed and followed for long-term health outcomes. The analysis described here is one of many substudies based upon the data gathered as part of the larger CCSS.
For this analysis, researchers looked at the occurrence of menopause before age 40 in 2,819 survivors and 1,065 comparison female siblings participating in the CCSS. The women in the survivors’ group had all continued to menstruate more than five years after their diagnosis; their median age was 29 at the time of the analysis, and 92 percent were age 40 or younger. The sibling controls were all older than 18 and had begun menstruating spontaneously.
The lead author on the premature menopause study is Charles A. Sklar, M.D., from the Memorial Sloan-Kettering Cancer Center in New York City.
Researchers used a statistic called cumulative incidence as the basis of their findings. Cumulative incidence measures how many cases (incidents) of a certain event occur in a group over a certain period of time. In this study, researchers were interested in knowing the cumulative incidence of menopause before the age of 40 among the survivors and siblings participating in the survey.
At the time the women were surveyed (between 2000 and 2001), 126 of the 2,819 survivors and 33 of the 1,065 siblings had developed premature menopause. The median age at which menopause occurred for these women was 37.
There was no statistically significant difference between cancer survivors and siblings in terms of those whose premature menopause was the result of surgery. By contrast, survivors experienced a higher cumulative incidence rate of nonsurgical premature menopause compared to their siblings: 8 percent compared to 0.8 percent by age 40. Overall, childhood cancer survivors were about 13 times more likely to develop premature menopause than their siblings.
The risk of early menopause was higher for those who had survived Hodgkin lymphoma, and lower for leukemia survivors. Radiation treatments to the ovary conferred the greatest risk, especially when the Hodgkin lymphoma patients were excluded from the analysis: even small doses of radiation to the stomach and pelvic region increased the risk significantly, and risk escalated with the total accumulated dose of radiation.
Chemotherapy during treatment for childhood cancer conferred a risk of premature menopause in patients who had significant exposure to alkylating agents. Patients receiving both radiation and alkylating drugs had a cumulative incidence of premature menopause approaching 30 percent.
Study author Sklar believes the “unique resource of the CCSS provides new information” on this important health question, and allowed his team to “provide more precise estimates of risk than previous studies.” Not only will this risk profile facilitate counseling for current survivors about their premature menopause risk, he said, but it “will assist researchers in designing new therapeutic protocols that aim to reduce late ovarian toxicity.”
“In addition to bone health and cardiovascular disease,” write Wendy Y. Chen, M.D., M.P.H, and JoAnn E. Manson, M.D., Dr.PH., of Harvard University in an editorial accompanying the published results, “quality-of-life issues are also important in this population.” They say that such women often struggle with the loss of fertility, citing research that shows lower ratings of perceived health and sexual functioning.
Taken together with other similar findings, they write, the study further “helps clinicians to identify women at increased risk” of premature menopause, “so that prevention, screening, and treatment strategies can be implemented at an earlier stage.”
“The key is to focus on those risks where women can take preventive action,” said Julia Rowland, Ph.D., director of the Office of Cancer Survivorship at the National Cancer Institute’s Division of Cancer Control and Population Sciences. “Osteoporosis is an ‘actionable risk’ we know that dietary calcium and weight-bearing exercise confer a protective effect.”
The same applies to cardiovascular disease, she explained. “Healthy lifestyles, physical activity, body-mass index, smoking habits all of these are factors a person can control, and thus counteract the increased risks from premature menopause.”
The study’s authors note that much of the data in the CCSS about menopausal status is self-reported, which could include some misclassification, particularly for women with surgically induced menopause. They also believe that the current young age of the cohort and the prevalent use of oral contraceptives among those who reported they were not menopausal could lead to an underestimation of the incidence of nonsurgical premature menopause.
Further, wrote Chen and Manson, “this study may still underestimate the true incidence of premature menopause because the median age at time of analysis was 29 years and only 10 percent of the cohort had reached 40 years.”
The CCSS is a retrospective cohort study, not a prospective clinical trial. (See Which Study Results Are the Most Helpful in Making Cancer Care Decisions? for an explanation of how observational and retrospective studies differ from other types of clinical studies.) Also, commented Rowland, patients in this study were diagnosed between 1970 and 1986. Since that time, both chemotherapy and radiation treatments have changed markedly. Thus the results of this study apply strictly to the survivors of that earlier era, and in some cases may have more limited implications for young patients treated since 1986.
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