Special Feature

Reproductive Potential After Cancer Treatment

By David M. Gershenson, MD

With advances in the surgical, chemotherapeutic, and radiotherapeutic treatment of cancer over the past three decades, the prognosis for children and young adults afflicted with a malignancy has dramatically improved. It is now estimated that at least two- thirds of all children with a cancer diagnosed before age 15 will survive at least five years. For many childhood cancers, including acute lymphoblastic leukemia, Hodgkin’s disease, Wilms’ tumor, and malignant ovarian germ cell tumors, the five-year survival rates exceed 70%. As the number of adult survivors of childhood or young adult cancers has increased over the past 15 years, there has been a heightened interest in the late effects of treatment—particularly chemotherapy treatment. Much attention has been focused on long-term therapy effects on gonadal function, including the nature and frequency of chemotherapy-induced amenorrhea, other forms of menstrual dysfunction, premature menopause, infertility, pregnancy outcomes, and the incidence of congenital anomalies or cancer in the offspring of cancer survivors.

The primary lesion in females receiving chemotherapy appears to be follicle destruction plus ovarian stromal fibrosis, resulting in elevation of serum LH and FSH with a concomitant decrease in serum estradiol. Clinical findings include anovulatory cycles with irregular bleeding, progressing to oligomenorrhea, and eventually amenorrhea in the most severe form. Premature menopause may also occur. The long-term effects of abdominal surgery on reproductive function have not been well studied. After abdominal or pelvic surgery for cancer, the patient’s future fertility may be affected by compromise of the blood supply to the ovary, the formation of peritoneal adhesions, or ovarian failure associated with biopsy or wedge resection. We have known for quite some time that ionizing radiation causes damage to oocytes. The degree of damage is dependent on several factors, including the type of beam, dose rate, fractionation, and the total dose delivered. Studies have suggested that there may be an inverse relationship between age at treatment with radiotherapy and dose necessary to induce ovarian failure. Ovarian dysfunction is increasingly more common at doses above 1.5 Gy—at doses of 5-6 Gy, most women develop permanent ovarian failure.

In a large multi-institutional study sponsored by the National Cancer Institute, Byrne et al interviewed 2283 long-term survivors of childhood or adolescent cancer diagnosed in the period from 1945 through 1975.1 Eligibility requirements for the study were diagnosis before age 20, survival for at least five years, and attainment of the age of 21. They also interviewed 3270 control subjects selected from among the survivors’ siblings. They noted an overall fertility deficit of 15% among survivors. Among the women, Byrne et al noted no apparent effect of alkylating agent chemotherapy alone and only a moderate fertility deficit associated with the combined treatment of alkylating agent therapy and radiation below the diaphragm.

Several studies have documented successful pregnancies in young women who have undergone treatment for hematologic malignancies, including Hodgkin’s disease,2,3 non-Hodgkin’s lymphomas,4 and leukemias.5 Breast cancer is the most common cancer in American women. Approximately 25% are premenopausal at the time of diagnosis. Historically, there has been considerable concern about the potential deleterious effects of subsequent pregnancy on the incidence of recurrence and overall survival of breast cancer patients. Several investigators, however, have actually observed an improved survival in women who become pregnant after treatment for breast cancer. It is generally believed that this superior survival is related to a selection process by which patients who have less aggressive tumors or who "feel good" after breast cancer treatment are more likely to become pregnant. In a review article, Danforth concluded that pregnancy after treatment for breast cancer does not alter the outcome of the tumor.6 Nevertheless, he recommended that pregnancy be delayed for 2-3 years after completion of treatment. This recommendation was made not because of any adverse influence of pregnancy on the breast cancer but to defer pregnancy until after the period of greatest risk of recurrence.

Although early reports suggested that pregnancy had a deleterious effect on the clinical course and survival of women with melanoma, other studies have indicated that the association of pregnancy and melanoma does not adversely influence survival.7 Nevertheless, this issue remains controversial. On the other hand, there is fairly uniform agreement about the effect of pregnancy subsequent to the diagnosis and treatment of melanoma. Studies to date have shown that a subsequent pregnancy has no adverse effects on recurrence or survival rate.

Of course, most of my personal experience in this area is with women treated for gynecologic malignancies. Invasive cancer of the cervix occurs not infrequently in young women. Women who receive pelvic radiation (including those with bulky early stage disease or essentially all with advanced-stage disease) can expect permanent sterilization. For patients who undergo ovarian transposition prior to pelvic radiotherapy or who undergo radical hysterectomy and maintain their ovaries, there is the potential for subsequent oocyte retrieval, fertilization with the partner’s sperm, and implantation into a surrogate’s uterus. In addition, there are already several reports of selected young patients with superficially invasive cervical cancer being successfully treated with conization alone, with preservation of fertility.8,9

Selected young women with ovarian cancer may anticipate normal menstrual function and the potential for normal pregnancies following treatment. There are several subsets of patients for whom such concerns are realistic. Young patients with either malignant ovarian germ cell tumors (treated with surgery plus chemotherapy) or sex cord-stromal tumors (treated with either surgery alone or surgery plus chemotherapy) have unilateral ovarian involvement in more than 95% of cases, with the exception of pure dysgerminoma in which the incidence of bilaterality is 15%. Also, young patients with borderline ovarian tumors (usually treated with surgery alone) are likely to have their fertility preserved. Even in cases of bilateral ovarian involvement, ovarian cystectomy is an option. Several reports have documented successful pregnancies in women previously treated for various types of ovarian cancer.10,11 In my personal experience, more than 75% of young women treated with conservative surgery and chemotherapy for ovarian cancer may expect normal menses and the potential for a successful pregnancy.

Both ionizing radiation and chemotherapy are potentially mutagenic. In recent years, concern regarding congenital anomalies and malignancy among the offspring of survivors has mounted. Hawkins analyzed data on 2286 survivors of childhood cancer and found no effect of prior cancer treatment on incidence of major birth defects.12 Green et al reviewed the medical records of 306 men and women previously treated for childhood or adolescent cancer, and 100 reported 202 pregnancies.13 Green et al conclude that the findings suggested that treatment of children and adolescents with chemotherapy does not increase the risk of congenital anomalies in the offspring. In a multicenter cohort study of long-term survivors of childhood and adolescent cancer, Mulvihill et al found no increase in cancer cases among the offspring over the expected number in the normal population.14

In summary, I believe that, with much more emphasis on quality of life and late effects of cancer treatment, the prospect for many survivors of childhood, adolescent, and young adult cancer is bright regarding future reproductive potential. As we learn more about the biology of certain cancers and become more sophisticated about our selection of treatment depending on individual characteristics of the tumor and the patient, this situation should continue to improve. In the meantime, young patients newly diagnosed with cancer and their family members should be seeking information from their oncologist about the potential effects of cancer treatment on reproductive function.

References

1. Byrne, et al. N Engl J Med 1987;317:1315-1321.

2. Holmes GE, Holmes FF. Cancer 1978;41:1317-1322.

3. Horning SJ, et al. N Engl J Med 1981;304:1377-1382.

4. Schapira DV, et al. Cancer 1984;54:800-803.

5. Sanders JE, et al. J Clin Oncol 1989;6:813-818.

6. Danforth. Oncology 1991;5:23-30.

7. Levene A. Clin Oncol 1982;8:191-193.

8. Morris M, et al. Gynecol Oncol 1993;51:193-196.

9. Ueki M, et al. Gynecol Oncol 1994;53:109-113.

10. Gershenson DM. J Clin Oncol 1988;6:270-275.

11. Lim-Tan Sk, et al. Obstet Gynecol 1988;72:775-781.

12. Hawkins. J Natl Cancer Inst 1991;83:1643-1650.

13. Green, et al. N Engl J Med 1991;325:141-146.

14. Mulvihill, et al. Lancet 1987;2:813-817.