Our findings may have implications for family planning after chemotherapy treatment for cancer. For women diagnosed with cancer during their reproductive years, reproductive impairment can significantly impact quality of life long after cancer treatment. In order to make informed decisions about fertility preservation at the time of treatment, patients should better understand their risk of future reproductive impairment.
In this study, we demonstrate that rates of acute ovarian failure alone likely underestimate the effect of chemotherapy on reproductive function in women of reproductive age. Previous studies have largely focused on amenorrhea as a primary reproductive impairment outcome after cancer treatment.13
We have shown here, however, that chemotherapy is additionally associated with infertility and early menopause, essentially narrowing the reproductive window, even in women whose menses resume after treatment.
The percentage of women reporting acute ovarian failure after chemotherapy in our study is consistent with previous work in our field. Among breast cancer patients, the 9% experiencing acute ovarian failure in our patient population is consistent with the rate of 7% in patients younger than age 35 reported by Kil and colleagues.14
In a prior study of 400 patients with Hodgkin’s disease, 7% reported acute ovarian failure, compared to 8% in our study.15
The relatively low rate of acute ovarian failure seen in leukemia is consistent with what has been learned from in vitro models, where it has been suggested the agents used to treat the most common types of leukemia portend to the least gonadotoxicity.16
Our age-specific proportions of acute ovarian failure are also similar to those seen by others. For instance, 55% of women who were 40 years old at diagnosis and treated with chemotherapy alone for breast cancer reported acute ovarian failure in our study. This is similar to Goodwin and colleagues’ reported rate of approximately 50%.17
While there is likely a significant biological component contributing to variability in rates of acute ovarian failure among disease and age-matched women,18
we have shown age to be a significant predictor. Our results, for instance, demonstrate that women who are 40 years old at the time of diagnosis for NHL are three times more likely to experience acute ovarian failure than women who are age 18 at diagnosis.
The majority of women who remain amenorrheic one year post-treatment will not regain ovarian function.14,19–21
When women do not become menopausal at treatment and continue to menstruate, infertility and early menopause continue to significantly impact reproductive function. While women age 18 at diagnosis for NHL have a 13% chance of acute ovarian failure, if they do continue to menstruate, they have an additional 9% chance of experiencing infertility and 60% probability of early menopause. It has been suggested that, since the majority of women younger than 35 years of age treated for breast cancer experience only temporary amenorrhea due to chemotherapy, many of these women can maintain fertility.22
In contrast, we found that at least 27% of all women with breast cancer in our study had infertility after treatment, despite the presence of menses.
Literature regarding the impact of chemotherapy on infertility is scarce. There have been numerous studies showing that women with prior diagnosis and treatment for cancer do
successfully have children.23
However, there is often no information on the number of women actually attempting
pregnancy. The percentage of 12-month infertility seen in all cancer types in our study was higher than the 7%, 12-month infertility seen in the United States population. Our results are consistent with rates of infertility seen in the Norwegian Cancer Registry, in which 25% of 184 women with similar time to follow-up for Hodgkin’s disease and attempting conception were unable to conceive.23
Notably, modern treatment for Hodgkin’s disease, which commonly includes AVBD (Adriamycin, Bleomycin, Vinblastine, and Dacarbazine) or Stanford V (Mechlorethamine, Adriamycin, Vinblastine, Vincristine, Bleomycin, Etoposide, and Prednisone), appears likely to have a significant and negative on impact fertility, in contrast to previous reports.24, 25
Our results suggest that fertility counseling for women who are nearer to 40 years old at the time of diagnosis could be different than for a woman who is 18. For instance, there appears to be a four- to five-fold increase in rates of infertility from age 18 to age 40 in women with Hodgkin’s disease. Seventy percent of reproductive age women are concerned about infertility after a cancer diagnosis, and almost one-third of women will adjust their treatment plans based on fertility concerns.3
Our data could contribute to an improved ability to counsel women about future risk of infertility, based on predictors like disease-type and age, and help to make more informed decisions about fertility preservation.
Women concerned about future fertility should also understand their risk of early menopause. Our results demonstrate age-specific rates of early menopause in women treated with chemotherapy for Hodgkin’s disease, non-Hodgkin lymphoma, and gastrointestinal malignancies. Consistent with the work of Partridge and colleagues, we have demonstrated that the closer in age one is to natural menopause at the time of diagnosis, the lower the chance that chemotherapy will induce early menopause.9
For instance, 18 year-old women with Hodgkin’s disease are at a two-fold increased risk of experiencing early menopause versus their 40 year-old counterparts. Although there are previous data alluding to the finding that younger aged patients exposed to chemotherapy are more likely to experience early menopause, this outcome is still quite surprising. Such results argue for the importance of counseling younger women about their risk of a shortened reproductive window. The reasons that young women may experience higher risks of early menopause yet lower risks of infertility and acute ovarian failure, while interesting, are beyond the scope of this paper and likely relate to duration of time elapsed since exposure.
This study has several important strengths and limitations. The outcomes chosen are comprehensive and inclusive, and not just focused on amenorrhea. However, despite controlling for cancer type at diagnosis, lack of clearly defined treatment type and duration for each patient requires us to make generalizations and assumptions about what chemotherapy regimens patients likely received. We are limited to making reasonable inferences about treatment, based on cancer type and practice patterns at that time, as has been done by others with success.26
It is also possible that other, unmeasured, factors may play a role in our findings. For example, women who receive cancer treatment may postpone childbearing, leaving them older at the time they are trying to conceive. Also, while discussing counseling, age is an important prognosticator, but not a perfect predictor of reproductive impairment. Even within a given age group, prior studies have shown wide-variability in individual’s ovarian reserve.18
Another limitation of this study has been the use of a retrospective, rather than prospective, survey, and using a historical cancer registry in which patients may be lost to follow-up.27
Nevertheless, as the National Cancer Institute’s working group for the improvement of care of gynecologic malignancies indicated, cancer registries offer an effective means of rapidly acquiring large amounts of data for important cancer issues.28
And our response rate was consistent with those from previously published studies.29,30
This study of a cancer registry has been most important in its ability to effectively identify a large sample of patients to demonstrate infertility as a missing metric in cancer survivorship research.
It is fundamental that patients understand their risk of future reproductive compromise – a risk that may include infertility and early menopause, in addition to acute ovarian failure. Counseling based on the risk of amenorrhea alone may give women an unrealistically low perception of their total risk of reproductive impairment - as we know that women can be menstruating and still be infertile. Patients should be given a chance to make an active decision about post-treatment family planning in the presence of the most comprehensive available information.