What is the Impact of Pediatric Cancer Care on Future Fertility in Female Survivors?
Abstract & Commentary
By Robert L. Coleman, MD
Professor, University of Texas; M.D. Anderson Cancer Center, Houston
Dr. Coleman reports no financial relationships relevant to this field of study.
This article originally appeared in the September 2013 issue of OB/GYN Clinical Alert.
Synopsis: Women undergoing pediatric cancer care are significantly more likely than their siblings to have clinical infertility (≥ 12 months of non-conception despite desired attempts) and total infertility (clinically infertile women who also reported ovarian failure defined as never initiating menstruation or no periods 5 years before baseline questionnaire). Although infertile cancer survivors were no more likely to seek professional help for conception than their siblings, they were significantly less likely to receive drugs to assist with conception. They also had an increased time to achieve pregnancy. The report provides the first large-scale, comprehensive survey of infertility in childhood cancer survivors.
Source: Barton SE, et al. Infertility, infertility treatment, and achievement of pregnancy in female survivors of childhood cancer: A report from the Childhood Cancer Survivor Study cohort. Lancet Oncol 2013;Jul 12 [Epub ahead of print].
Previous studies have shown decreased pregnancy rates and early menopause in female cancer survivors; however, infertility rates and reproductive interventions have not been studied. This study investigated infertility and time to pregnancy in female childhood cancer survivors, and analyzed treatment characteristics associated with infertility and subsequent pregnancy. The primary dataset was developed by querying the Childhood Cancer Survivor Study (CCSS), a multinational (United States and Canada) cohort study enrolling 5-year cancer survivors who were younger than 21 years at the time of diagnosis between Jan. 1, 1970, and Dec. 31, 1986, and a sibling control group. Women aged 18-39 years who had ever been sexually active provided medical and reproductive data via a baseline questionnaire and underwent quantification of alkylating agent and radiation therapy exposure. The authors analyzed self-reported infertility, medical treatment for infertility, time to first pregnancy in survivors and siblings, and the risk of infertility in survivors by demographic, disease, and treatment variables. Overall, 3531 survivors and 1366 female sibling controls were evaluated. Compared with their siblings, survivors had an increased risk of clinical infertility (relative risk [RR], 1.48; 95% confidence interval [CI], 1.23-1.78; P < 0.0001), which was most pronounced at early reproductive ages (e.g., age 24 years; RR, 2.92; 95% CI, 1.18-7.20; P = 0.02, in participants ≤ 24 years). Despite being equally likely to seek treatment for infertility, survivors were significantly less likely than were their siblings to be prescribed drugs for treatment of infertility (RR, 0.57; 95% CI, 0.46-0.70; P < 0.0001). Increasing doses of uterine radiation and alkylating agent chemotherapy were strongly associated with infertility. Although survivors had an increased time to pregnancy compared with their siblings (P = 0.032), 292 of 455 participants (64%) with self-reported clinical infertility ultimately achieved a pregnancy. These data provide more comprehensive understanding of infertility after successful pediatric cancer care and avenues for counseling and decision-making about future conception attempts and fertility preservation.
Successful care in pediatric cancers has been a remarkable achievement over the past several decades. Overall, long-term survivorship is now the norm and many of these patients (male and female) have interest in achieving pregnancy. The CSS is a comprehensive, multinational, cohort study that enrolled patients with pediatric cancers and their unaffected siblings (controls) to evaluate interventions and outcomes.1 This latest report targeted reproductive history and fertility to better define expectations from treatment and significantly enhance the limited data on the topic to provide better counseling opportunities. Eligible malignancies were leukemia, CNS cancer, Hodgkin’s lymphoma, non-Hodgkin lymphoma, Wilms’ tumor, neuroblastoma, soft-tissue sarcoma, and bone tumors. Many of these malignancies are treated with partial or total body radiation and/or the use of alkylating agents, both of which have been linked to reproductive failure and infertility.2 By using a sibling cohort, the investigators were better able to estimate relative infertility in affected individuals by providing some control of shared familial and environmental risks. Previous studies of the participants in the CSS have documented no significant clinical or demographic differences in the cohorts.
Overall, the data are in line with expectations from these types of therapy. It has been known for many years that the ovaries are sensitive to radiation and fail at a higher rate than expected, even when transposed or blocked during therapy.2 In addition, alkylating agents are known to have a dose effect on ovarian failure, which was assessed in the current study by creating an index of total exposure based on dose, frequency, and number of courses of chemotherapy involving these agents. However, the new data demonstrate that the impact of therapy on clinical infertility is greatest early on (≤ 24 years of age) and diminishes over time, despite remaining more common in survivors compared to their siblings. This was manifested by increasing time to first pregnancy despite the similar rates of infertility specialist referral. Of some surprise was the lower use of fertility-enhancing drug therapies. The data did not address causes or reasons for the variance, but it was considered that there might be reluctance to use these agents due to subsequent cancer/medical risk or low confidence they would work. Although infertility care is much better today than during the time of exposure for the cohort (about a decade ago), these observations serve to enhance the discussions of health care providers with patients and caregivers in addressing the topic of fertility following therapy.
The topic is of increasing importance, as more and more cancer survivors are making it to the age of majority and are as interested in opportunities for childbearing as noncancer patients. For women who have already begun to ovulate and in whom preservation is still of interest ahead of planned additional therapy, many new options are available such as cryopreservation of oocytes, embryos, and even unstimulated ovarian cortical tissue. The American Society of Clinical Oncology recently updated its guidelines of fertility preservation, which will bring the discussion to the forefront of treatment planning.3
1.Robison LL, et al. Study design and cohort characteristics of the Childhood Cancer Survivor Study: A multi-institutional collaborative project. Med Pediatr Oncol 2002;38:229-239.
2.Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update 2001;7:535-543.
3.Loren AW, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013;31:2500-2510.