The dose-response relationship of alkylating agents, and the effect of age, is a recurring theme in studies of fertility following chemotherapy. Amenorrhea and ovarian failure occur more commonly in adult women treated with cyclophosphamide and other alkylating agents than with adolescents, with pre-pubertal females tolerating cumulative cyclophos-phamide doses as high as 25 gm/m2 [11,23].In examining protocols with common chemotherapy, 86% of women >24-30 years have been shown to have ovarian failure, compared with 28-31 % of younger women [2,23].
Due to improved survivorship from childhood cancer noted as early as the 1970s to 1980s, large cohorts of female survivors have reached the 3rd and 4th decades of life, where the risk for infertility and premature menopause has been examined. Two large studies of these survivors demonstrated elevated risks for infertility and premature menopause [9,24]. A study of 2,498 female survivors, treated between 1945 and 1975, showed a 7% deficit in fertility, compared with siblings. Between ages 21 and 25 years, survivors had a risk of premature menopause four times greater than that of siblings. Treatment-related risk factors included radiotherapy alone (RR = 3.7), alkylating agents alone (RR = 9.2) or a combination of both (RR = 27). By age 31,42 % of these women had reached menopause, compared with 5% of siblings
. In a study of 719 survivors treated between 1964 and 1988,15.5% of women were unable to conceive. Women treated with abdominopelvic radiotherapy alone had a fertility deficit of 23%, compared with those treated with surgery. As with the previous study, the risk of infertility and premature menopause increased with increasing dose of abdomino-pelvic radiotherapy and amount of alkylating agent .
It is clear that the sterilizing effects of all alkylating agents are not equal. Mechlorethamine and procar-bazine together are perhaps the most damaging of the alkylating agents. Newer risk-adapted protocols in pediatric oncology have been developed to avoid mechlorethamine or procarbazine and to limit cumulative doses of alkylating agents, without negatively impacting the efficacy of the chemotherapy regimens. This is best illustrated by the development of risk-adapted protocols in Hodgkin disease, where avoidance of long-term toxicities is a primary study goal [25-27]. The substitution of cyclophosphamide for mechlorethamine and total dose reductions appear to have significantly reduced the risk of ovarian dysfunction [28-30].
However, the full impact of these risk-adapted protocols is yet to be felt, with respect to long-term ovarian function. Females treated with cyclophos-phamide with or without other alkylating agents are just now reaching the age where premature menopause was noted in earlier patient cohorts treated with mechlorethamine and procarbazine (in the 1960 s-80 s). Investigators are now starting to collect data on premature menopause in this group of women.
In recent years, ifosfamide, a congener of cyclo-phosphamide, has been used for a variety of solid tumors and lymphoma. The effects of ifosfamide on reproductive function are only beginning to be evaluated. An Italian study compared the residual ovarian function and fertility of two groups of female patients treated for osteosarcoma during different time periods with the same chemotherapy (ifosfamide, methotrexate, doxorubicin, cisplatin) at the same institution. Between 1997 and 2000, a group of 31 females treated with this chemotherapy, together with an oral contraceptive (OC), was compared with a group of 90 patients treated between 1974 and 1995 with the same drugs, but without any attempt to protect ovarian function. No protective effect on ovarian function was noted with the addition of the oral contraceptives . Data is now being collected on female patients treated with ifosfamide, with or without cyclophosphamide, during childhood and adolescence in North America during the 1980s and 1990s. It remains to be seen whether the gonadal toxicity of ifosfamide is similar to that already well documented with cyclophosphamide, and whether, and to what extent, the toxicity is additive in regimens where both agents are administered.
Similar to what has been done with conventional chemoradiotherapy protocols, transplant conditioning protocols without TBI are being utilized to avoid some of the associated adverse long-term sequelae. The use of high dose cyclophosphamide without TBI or other alkylating agents is associated with a lower risk of ovarian failure than conditioning regimens with TBI or multiple alkylating agents. In a study by Sanders, 100% of women (n = 15) younger than age 26 and three of nine older than age 26 who were treated with 200 mg/kg cyclophosphamide recovered normal gonadotropin levels and menstruation post-transplantation . However, many transplant protocols use high doses of alkylating agents together, most commonly busulfan and cyclo-phosphamide, which are associated with similar degrees of ovarian failure in females as protocols containing TBI [19,33,34].
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