The presence of apparently normal ovarian function at the completion of chemotherapy should not be interpreted as evidence that no ovarian injury has occurred. Premature menopause is well documented in childhood cancer survivors, especially in women treated with both an alkylating agent and abdominal irradiation.[47,48,49,50] A total of 126 childhood cancer survivors and 33 control siblings who participated in the CCSS developed premature menopause. Of these women, 61 survivors (48%) and 31 siblings (94%) had surgically-induced menopause (relative risk [RR], 0.8; 95% confidence interval [CI], 0.52-1.23). However, the cumulative incidence of nonsurgical premature menopause was substantially higher for survivors than for siblings (8% vs. 0.8%; RR, 13.21; 95% CI, 3.26-53.51; P < .001).
Figure 6. Cumulative incidence curves of nonsurgical premature menopause in survivors (solid line) compared with siblings (broken line). Vertical bars indicate 95% confidence intervals. Sklar C A et al. JNCI J Natl Cancer Inst 2006;98:890-896. ©Sklar 2006. Published by Oxford University Press.
A multiple Poisson regression model showed that risk factors for nonsurgical premature menopause included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent dose score, and a diagnosis of Hodgkin lymphoma. For survivors who were treated with alkylating agents plus abdominal-pelvic radiation, the cumulative incidence of nonsurgical premature menopause approached 30%.
In Europe, survivors of Hodgkin lymphoma treated between the ages 15 years and 40 years and who were not receiving hormonal contraceptives were surveyed for the occurrence of premature ovarian failure. In 460 women, premature ovarian failure was mainly influenced by alkylating chemotherapy use with a linear dose relationship between alkylating chemotherapy and premature ovarian failure occurrence. Premature ovarian failure risk increased by 23% per year of age at treatment. In women treated without alkylating chemotherapy before age 32 years and at age 32 years or older, cumulative premature ovarian failure risks were 3% and 9%, respectively. If menstruation returned after treatment, cumulative premature ovarian failure risk was independent of age at treatment. Among women who ultimately developed premature ovarian failure, 22% had one or more children after treatment, compared with 41% of women without premature ovarian failure who had one or more children after treatment. This report indicates that women with proven fertility after treatment can still face infertility problems at a later stage.