We have known for some time, from data from the Childhood Cancer Survivor Study, that the risk of ever becoming pregnant is decreased for female childhood cancer survivors. It is reduced similarly for male childhood cancer survivors….— Daniel A. Mulrooney, MD, MS
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“Estimates suggest that by the year 2020, there will be over 500,000 adult survivors of childhood cancer in the United States,” Daniel A. Mulrooney, MD, MS, of the Division of Cancer Survivorship, St. Jude Children’s Research Hospital, Memphis, reported at the 10th Oncofertility Conference in Chicago.1 “I would like to suggest that that is probably an underestimate,” he added. “This population may increase more rapidly than we ever realized.”
The advances in cancer treatment that led to improved survival rates, particularly for children, can also cause long-term effects related to the therapy. These long-term effects cover the “spectrum from life-altering to life-threatening,” Dr. Mulrooney noted, but most of them involve only the individual cancer survivor. “Infertility is different from the others in that it not only involves the individual, but also a partner, a spouse, or other family members,” he explained.
Cancer Treatment Affecting Fertility
Fertility can be affected by radiation to the hypothalamus/pituitary (head/brain/total-body irradiation), the ovaries/uterus (abdominal/pelvic/total-body irradiation), and the testis (pelvic/gonadal/total-body irradiation); by chemotherapy with alkylating agents; and by surgery to remove reproductive organs or abdominal-pelvic staging procedures, which damage pelvic nerves.
“We have known for some time, from data from the Childhood Cancer Survivor Study,2 that the risk of ever becoming pregnant is decreased for female childhood cancer survivors. The relative risk is 0.8,” Dr. Mulrooney reported. “It is reduced similarly for male childhood cancer survivors, a relative risk of 0.6.”3
More recently, “a great deal of studies have been presented within the past year” concerning fertility outcomes among pediatric cancer survivors, Dr. Mulrooney said. He focused on three of those studies in particular.
Risk for Nonsurgical Premature Menopause
The risk for nonsurgical premature menopause, defined as cessation of menses before the age of 40 and not secondary to resection of reproductive organs, was highest among female cancer survivors who received alkylating agents at a cyclophosphamide equivalent dose > 6,000 mg/m2 or > 5 Gy radiation therapy to the ovaries, according to a study among 2,930 female cancer survivors enrolled in the original Childhood Cancer Survivor Study cohort.4 All patients were 18 or older at last follow-up. Almost half (49%) had chemotherapy and radiation therapy; 33% had chemotherapy alone; 11% had surgery alone; and 7% had radiation alone.
The study included a comparison group of 1,399 siblings. The median age at the time of the study was 34.3 years for survivors and 38 years for siblings. “Outcomes were self-reported menstrual and reproductive status. Pregnancy and live-birth rates were compared between survivors with and without nonsurgical menopause,” Dr. Mulrooney said.
Among the 110 survivors who had nonsurgical premature menopause, the median age was 32 years, with a prevalence of nonsurgical premature menopause of 9.1% at age 40 and a relative risk of 10.5 compared with siblings, who had a prevalence of 0.9% at age 40. In addition to higher exposure to alkylating agents, being older than age 14 at diagnosis also increased the risk for nonsurgical premature menopause. Survivors who developed nonsurgical premature menopause were less likely to ever be pregnant or to have a live birth after age 31.
Reassuring Female Survivors
“Greater doses of contemporary alkylating drugs and cisplatin were associated with a decreased likelihood of siring a pregnancy in male survivors of childhood cancer,” according to a study involving a Childhood Cancer Survivor Study subset of 10,938 survivors of the most common types of childhood cancer and extracting information from medical records about doses of 14 chemotherapy agents.5 “However, our findings should provide reassurance to most female survivors treated with chemotherapy without radiotherapy to the pelvis or brain, given that chemotherapy-specific effects on pregnancy were generally few,” Chow et al wrote in The Lancet Oncology.5 “Nevertheless, consideration of fertility preservation before cancer treatment remains important to maximise the reproductive potential of all adolescents newly diagnosed with cancer.”
The 14 chemotherapy agents were “mostly alkylating agents or DNA interstrand cross-linking drugs,” Dr. Mulrooney explained. “This is one of the first times we’ve looked closely at the platinum agents as well as the other alkylators.”
The survivors and 3,949 siblings in the comparison group were in the reproductive age range of 15 to 44 years old. The survivors had not been exposed to pelvic or cranial radiotherapy. Among the survivors, 4,149, or 38%, reporting siring or having a pregnancy and 3,453, or 83%, of these individuals reported at least 1 live birth. Among the siblings, 2,445 (62%) reported siring or having a pregnancy, and 2,201, or 90%, of those individuals reported at least 1 live birth.
In multivariate analysis, survivors were less likely to sire or have a pregnancy than were siblings and less likely to have a live birth. Among male survivors, a reduced likelihood of siring a pregnancy was associated with upper-tertile doses of cyclophosphamide, ifosfamide, procarbazine, and cisplatin. Among female survivors, only busulfan and doses of lomustine ≥ 411 mg/m2 were significantly associated with reduced pregnancy. “Results for live birth were similar to those for pregnancy,” the study authors reported.
The highest doses of cyclophosphamide exposure (≥ 7,412 mg/m2) “reduce the risk of ever siring a pregnancy,” Dr. Mulrooney elaborated. Ifsofamide doses higher than 53,000 mg/m2 “also significantly reduced the risk for these males to sire a pregnancy.” Procarbazine “in all dose ranges but particularly in the higher tertile (≥ 5,060 mg/m2) reduced the risk of siring a pregnancy.” It has been “known to be toxic to males for some time,” he added.
St. Jude Lifetime Cohort Study
In the “largest study evaluating sperm concentration in adult survivors of childhood acute lymphoblastic leukemia,” risk factors for azoospermia were determined to be higher exposure to chemotherapy, “particularly” a cyclophosphamide equivalent dose ≥ 8 g/ m2, Dr. Mulrooney said, and age of 5 to 9 years at the time of diagnosis.
“To be eligible for this study, participants had to be diagnosed with a pediatric malignancy and treated at St. Jude Children’s Research Hospital. They had to survive greater or equal to 10 years from the time of diagnosis, and their current age had to be greater or equal to 18. So this was to enroll an adult population of survivors of childhood cancer,” Dr. Mulrooney explained. These individuals are invited back to the institution, he continued, and return for a comprehensive on-campus medical evaluation.
Chemotherapy and Sperm Concentration
The St. Jude Lifetime Cohort Study involved two separate analyses. “The first investigation was to look particularly at chemotherapy exposure and to drill down a little bit into the alkylating agent exposure, as well as including the platinum agents,” Dr. Mulrooney said. “To look more carefully at chemotherapy,” patients were ineligible if they had a vasectomy, bilateral orchiectomy, or radiation exposure or were currently receiving androgen therapy.
Among the 214 men who agreed “to contribute a sample,” Dr. Mulrooney said, the median age at diagnosis was 7.7 years, the median age at evaluation was 29 years, and the median time since diagnosis was a median of 21 years. “Compared to nonparticipants, participants were younger at cancer diagnosis and less likely to have children,” he revealed. There was “some element of bias,” he noted, since those who already sired a pregnancy were less likely to contribute semen for analysis.
Sperm analysis showed that 48% were normospermic, defined as “greater than or equal to 15 million sperm/ mL”; 27% were oligospermic, defined as “greater than 0 and less than 15 million sperm/ mL”; and 25% were azoopspermic, defined as having “no viable sperm.”
Nearly 90% of those in the lowest cyclophosphamide equivalent-dose category (< 4,000 mg/m2) were found to be normospermic, but there is “no dose category beyond which everyone is azoospermic,” Dr. Mulrooney reported. Although “those with a higher cyclophosphamide equivalent-dose exposure were more likely to be oligospermic or azoospermic,” he added, there is a “tremendous amount of overlap between all categories.” There was no significant association between oligospermia or azoospermia and age at diagnosis or at evaluation.
Cranial Radiation Therapy
A second, separate analysis was conducted “to determine the association between lower-dose cranial radiation therapy and sperm concentration,” Dr. Mulrooney said. “Focused largely on male survivors of acute lymphoblastic leukemia, it included those who had no radiation therapy or cranial radiation therapy only.”
During on-campus visits, 173 men agreed to contribute a semen sample for this analysis. The investigators found that 35.8% were normospermic, 26.6% were oligospermic, and 37.6% were azoospermic.
“Those who had no radiation exposure and were in the lowest category for cyclophosphamide equivalent dose were the most likely to have normal sperm samples. And those who were at higher doses of cyclophosphamide equivalent dose, almost regardless of the radiation therapy exposure, were found to be more likely azoospermic,” Dr. Mulrooney reported. “In a multivariate analysis, there were significant associations with those men diagnosed between 5 to 9 years of age compared with those men diagnosed at a younger age and associations, as you might expect, with higher cyclophosphamide equivalent-dose exposure” and azoospermia or oligospermia.
In summary, Dr. Mulrooney said, the risk factors for azoospermia were “particularly” cyclophosphamide equivalent dose ≥ 8 g/m2 and age at diagnosis of 5 to 9 years. Cranial radiation therapy at either > 0 to < 20 Gy or ≥ 20 to < 26 Gy was not a significant risk factor for azoospermia/oligospermia among the patients also treated with an alkylating agent. ■
Disclosure: Dr. Mulrooney reported no potential conflicts of interest.
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