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Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version - National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version

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Late Effects of the Reproductive System

Surgery, radiation therapy, or chemotherapy that negatively affects any component of the hypothalamic-pituitary axis or gonads may compromise reproductive outcomes in childhood cancer survivors. Evidence for this outcome in childhood cancer survivors is limited by studies characterized by small sample size, cohort selection and participation bias, cross-sectional assessment, heterogeneity in treatment approach, time since treatment, and method of ascertainment. In particular, the literature is deficient regarding hard outcomes of reproductive potential (e.g., semen analysis in men, primordial follicle count in women) and outcomes after contemporary risk-adapted treatment approaches.[1,2]
The risk of infertility is generally related to the tissues or organs involved by the cancer and the specific type, dose, and combination of cytotoxic therapy.
  • Orchiectomy or oophorectomy performed for the management of pediatric germ cell tumors may reduce germ cell numbers.
  • Alkylating agents and similar DNA interstrand cross-linking agents used in the treatment of pediatric cancers are the primary chemotherapeutic agents associated with a high risk of infertility. Factors influencing the risk of gonadal injury in children treated with alkylating agent chemotherapy include the following:
    • Cumulative dose.
      Earlier studies used the alkylating agent dose to define dose levels associated with the risk of gonadal toxicity within a specific study cohort. Childhood Cancer Survivor Study (CCSS) investigators developed the cyclophosphamide equivalent dose, which is a metric for normalization of the cumulative doses of various alkylating agents that is independent of the study population. The alkylating agent dose and cyclophosphamide equivalent dose perform similarly when used in several models for different survivor outcomes that include treatment exposures, but only the cyclophosphamide equivalent dose permits comparison across variably treated cohorts. Investigations that evaluate risk factors for gonadal toxicity vary in the use of cumulative doses based on individual alkylating agents, the alkylating agent dose, and the cyclophosphamide equivalent dose.[3]
    • The specific alkylating agent.
    • The length of treatment.
    • Age at treatment.
    • Sex.
  • The risk of radiation injury to the hypothalamic-pituitary axis or gonads is related to the treatment volume, total dose, fractionation schedule, and age at treatment.
In addition to anticancer therapy, age at treatment, and sex, it is likely that genetic factors influence the risk of permanent infertility. It should be noted that pediatric cancer treatment protocols often prescribe combined-modality therapy; thus, the additive effects of gonadotoxic exposures may need to be considered in assessing reproductive potential. Detailed information about the specific cancer treatment modalities including specific surgical procedures, the type and cumulative doses of chemotherapeutic agents, and radiation treatment volumes and doses are needed to estimate risks for gonadal dysfunction and infertility.

Testis

Cancer treatments that may impair testicular and reproductive function include the following:

Surgery affecting testicular function

Patients who undergo unilateral orchiectomy for testicular torsion may have subnormal sperm counts at long-term follow-up.[4,5] Retrograde ejaculation is a frequent complication of bilateral retroperitoneal lymph node dissection performed on males with testicular neoplasms,[6,7] and erectile dysfunction may occur after extensive pelvic dissections to remove a rhabdomyosarcoma of the prostate.[8,9]

Radiation affecting testicular function

Among men treated for childhood cancer, the potential for gonadal injury exists if radiation treatment fields include the pelvis, gonads, or total body. The germinal epithelium is more sensitive to radiation injury than are the androgen-producing Leydig cells. A decrease in sperm counts can be seen 3 to 6 weeks after such irradiation, and depending on the dosage, recovery may take 1 to 3 years. The germinal epithelium is damaged by much lower dosages (<1 Gy) of radiation than are Leydig cells (20–30 Gy). Irreversible germ cell failure may occur with fractionated radiation doses of greater than 2 Gy to 4 Gy.[10] Administration of higher radiation doses, such as 24 Gy, which was used for the treatment of testicular relapse of acute lymphoblastic leukemia (ALL), results in both germ cell failure and Leydig cell dysfunction.[11]
Radiation injury to Leydig cells is related to the dose delivered and age at treatment. Testosterone production may be normal in prepubertal boys treated with less than 12 Gy fractionated testicular irradiation, but elevated plasma concentrations of luteinizing hormone observed in this group suggest subclinical injury. Gonadal failure typically results when prepubertal boys are treated with more than 20 Gy of radiation to the testes; androgen therapy is required for masculinization. Leydig cell function is usually preserved in sexually mature male patients if radiation doses do not exceed 30 Gy. Although available data suggest that Leydig cells are more vulnerable when exposed to radiation before puberty, confounding factors, such as the age at testing and the effects of both orchiectomy and chemotherapy, limit the reliability of this observation.[12]

Chemotherapy affecting testicular function

Cumulative alkylating agent (e.g., cyclophosphamide, mechlorethamine, dacarbazine) dose is an important factor in estimating the risk of testicular germ cell injury, but limited data are available that correlate results of semen analyses in clinically well-characterized cohorts.[13] In general, Leydig cell function is preserved, but germ cell failure is common in men treated with high cumulative doses of cyclophosphamide (7,500 mg/m2 or more) and more than 3 months of combination alkylating agent therapy. Most studies suggest that prepubertal males are not at lower risk for chemotherapy-induced testicular damage than are postpubertal patients.[14-17]
Studies of testicular germ cell injury, as evidenced by oligospermia or azoospermia, after alkylating agent administration with or without radiation therapy, have reported the following:
  • Cyclophosphamide:
    • Male survivors of non-Hodgkin lymphoma who received a cumulative cyclophosphamide dose of greater than 9.5 g/m2 and underwent pelvic radiation therapy were at increased risk for failure to recover spermatogenesis.[18]
    • In survivors of Ewing sarcoma and soft tissue sarcoma, treatment with a cumulative cyclophosphamide dose of greater than 7.5 g/m2 was correlated with persistent oligospermia or azoospermia.[19]
    • Cyclophosphamide doses exceeding 7.5 g/m2 and ifosfamide doses exceeding 60 g/m2 produced oligospermia or azoospermia in most exposed individuals.[20-22]
    • A small cohort study reported normal semen quality in adult long-term survivors of childhood ALL treated with 0 to 10 g/m2 of cyclophosphamide and cranial irradiation, whereas no spermatozoa were detected in semen samples from survivors treated with more than 20 g/m2 of cyclophosphamide.[23]
    • Treatment with a cyclophosphamide equivalent dose of less than 4 g/m2 results in infrequent azoospermia or oligospermia, with 88.6% of 31 men treated being normospermic.[24]
    • Spermatogenesis was present in 67% of 15 men who received 200 mg/kg of cyclophosphamide before undergoing HSCT for aplastic anemia.[25]
  • Dacarbazine:
    • The combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) produced oligospermia or azoospermia in adults frequently during the course of treatment. However, recovery of spermatogenesis occurred after treatment was completed, in contrast to the experience reported after treatment with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP).[26]
  • Alkylating agent plus procarbazine:
    • Most studies suggest that combination chemotherapy with an alkylating agent and procarbazine causes severe damage to the testicular germinal epithelium that is irreversible at high cumulative doses.[14,27-30]
    • Azoospermia occurred less frequently in adults after treatment with two, rather than six, cycles of MOPP.[31]
    • Elevation of the basal follicle-stimulating hormone (FSH) level, which may reflect impaired spermatogenesis, was less frequent among patients receiving two courses of vincristine, procarbazine, prednisone, and doxorubicin (OPPA) than among those who received two courses of OPPA in combination with two or more courses of cyclophosphamide, vincristine, procarbazine and prednisone (COPP).[32]
  • Low-dose cranial radiation plus alkylating agents:
    • In a cross-sectional study that included male adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without cranial radiation, St. Jude Children's Research Hospital investigators demonstrated that cranial radiation at doses lower than 26 Gy has no demonstrable independent effect on spermatogenesis.[33]

Testicular function after hematopoietic stem cell transplantation (HSCT)

The risk of gonadal dysfunction and infertility related to conditioning with total-body irradiation (TBI), high-dose alkylating agent chemotherapy, or both is substantial. Because transplantation is often undertaken for relapsed or refractory cancer, previous treatment with alkylating agent chemotherapy or hypothalamic-pituitary axis or gonadal radiation therapy may confer additional risks. Age at treatment also influences the risk of gonadal injury. Young boys and adolescents treated with high-dose cyclophosphamide (200 mg/kg) will generally maintain Leydig cell function and testosterone production, but germ cell failure is common. After TBI conditioning, most male patients retain their ability to produce testosterone but will experience germ cell failure.[34]
Limited data suggest that a greater proportion of boys will retain germinal function or recovery of spermatogenesis (based on pubertal progress and gonadotropin levels) after reduced-intensity conditioning with fludarabine/melphalan than will those treated with myeloablative conditioning with busulfan/cyclophosphamide.[35]

Recovery of gonadal function

Recovery of gonadal function after cytotoxic chemotherapy and radiation therapy is possible. Dutch investigators used inhibin B as a surrogate marker of gonadal function in a cross-sectional, retrospective study of 201 male survivors of childhood cancer, with a median follow-up of 15.7 years (range, 3–37 years) from diagnosis. The median inhibin B level among the cohort increased based on serial measurements performed over a median of 3.3 years (range, 0.7–11.3 years). The probability of recovery of the serum inhibin B level was significantly influenced by baseline inhibin B level, but not age at diagnosis, age at study evaluation, interval between discontinuation of treatment and study evaluation, gonadal irradiation, and alkylating agent dose score. These results suggest that recovery can occur but not if inhibin B is already at a critically low level.[36]
Inhibin B and FSH levels are correlated with sperm concentration and often used to estimate the presence of spermatogenesis; however, limitations in the specificity and positive predictive value of these tests have been reported.[37] Hence, male survivors should be advised that semen analysis is the most accurate assessment of adequacy of spermatogenesis.

Leydig cell function in long-term survivors of childhood cancer

Leydig cell function in childhood cancer survivors has not been well studied. St. Jude Lifetime Cohort investigators evaluated the prevalence of and risk factors for Leydig cell failure and Leydig cell dysfunction in 1,516 men (median age, 30.8 years; median time from diagnosis, 22 years).[38]
  • The prevalence of Leydig cell failure (defined as testosterone <250 ng/dL and luteinizing hormone >9.85 IU/L) was 6.9%.
  • The prevalence of Leydig cell dysfunction (defined as testosterone ≥250 ng/dL and luteinizing hormone >9.85 IU/L) was 14.7%.
  • Independent risk factors for Leydig cell failure included attained age of 26 years or older at assessment, testicular radiation therapy at any dose, and alkylating agents at cyclophosphamide equivalent doses of 4,000 mg/m2 or higher.
  • Unilateral orchiectomy and similar risk factors for Leydig cell failure were associated with Leydig cell dysfunction.
  • The risk of Leydig cell failure and dysfunction increased with older age, higher radiation doses, and increased alkylating agent exposure.
  • Adverse outcomes significantly associated with Leydig cell failure (but not Leydig cell dysfunction) included abdominal obesity, diabetes mellitus, erectile dysfunction, muscle weakness, and all-cause mortality.

Ovary

Cancer treatments that may impair ovarian function/reserve include the following:
  • Surgery (oophorectomy).
  • Radiation therapy (exposing the hypothalamic-pituitary axis or ovaries).
  • Chemotherapy (alkylating agents, similar DNA interstrand cross-linking agents like procarbazine).
  • HSCT.

Surgery affecting ovarian function

Oophorectomy performed for the management of germ cell tumors may reduce ovarian reserve. Contemporary treatments utilize fertility-sparing surgical procedures combined with systemic chemotherapy to reduce this risk.[39]

Radiation affecting ovarian function

In women treated for childhood cancer, the potential for primary gonadal injury exists if treatment fields involve the lumbosacral spine, abdomen, pelvis, or total body. The frequency of ovarian failure after abdominal radiation therapy is related to both the age of the woman at the time of irradiation and the radiation therapy dose received by the ovaries. The ovaries of younger individuals are more resistant to radiation damage than are those of older women because of their greater complement of primordial follicles.
Whole-abdomen irradiation at doses of 20 Gy or greater is associated with the highest risk of ovarian dysfunction. Seventy-one percent of women in one series failed to enter puberty, and 26% had premature menopause after receiving whole-abdominal radiation therapy doses of 20 Gy to 30 Gy.[40] Other studies reported similar results in women treated with whole-abdomen irradiation [41] or craniospinal irradiation [42,43] during childhood.

Chemotherapy affecting ovarian function

Ovarian function may be impaired after treatment with combination chemotherapy that includes an alkylating agent and procarbazine. In general, girls maintain gonadal function at higher cumulative alkylating agent doses than do boys. Most female childhood cancer survivors who are treated with risk-adapted combination chemotherapy retain or recover ovarian function. However, the risk of acute ovarian failure and premature menopause is substantial if treatment includes combined-modality therapy with alkylating agent chemotherapy and abdominal or pelvic radiation therapy or dose-intensive alkylating agents for myeloablative conditioning before HSCT.[44-48]

Premature ovarian failure

Premature ovarian failure is well documented in childhood cancer survivors, especially in women treated with both an alkylating agent and abdominal radiation therapy.[44,48-50]
Studies have associated the following factors with an increased rate of premature ovarian failure (acute ovarian failure and premature menopause):
  • Age at the time of treatment and attained age.
  • Increasing doses of abdominal-pelvic radiation therapy.
  • Exposure to alkylating agents and/or procarbazine.
  • Oophorectomy.
The presence of apparently normal ovarian function at the completion of chemotherapy should not be interpreted as evidence that no ovarian injury has occurred.
Evidence (acute ovarian failure and premature menopause in childhood cancer survivors):
  1. Of 3,390 eligible participants in the CCSS, 215 (6.3%) developed acute ovarian failure (defined as never having menses or ceased having menses within 5 years of diagnosis).[45]
    • Survivors with acute ovarian failure were older (aged 13–20 years vs. aged 0–12 years) at cancer diagnosis and more likely to have been diagnosed with Hodgkin lymphoma or to have received abdominal or pelvic radiation therapy than were survivors without acute ovarian failure.
    • Of survivors who developed acute ovarian failure, 75% had received abdominal-pelvic radiation therapy. Radiation doses to the ovary of at least 20 Gy were associated with the highest rate of acute ovarian failure, with over 70% of such patients developing acute ovarian failure.
    • In a multivariable logistic regression model, increasing doses of ovarian radiation, exposure to procarbazine at any age, and exposure to cyclophosphamide at ages 13 to 20 years were independent risk factors for acute ovarian failure.
  2. The menopausal status of 2,930 survivors participating in the CCSS was compared with that of 1,399 siblings. Nonsurgical premature menopause was defined as sustained menses cessation occurring for more than 6 months beginning 5 years after the cancer diagnosis but before age 40 years that was not caused by pregnancy, surgery, or medications. In 110 survivors who developed nonsurgical premature menopause, the prevalence was 9.1% at age 40 years in a population with a median age of 34 years.[48]
    • In multivariable analyses, significant independent risk factors for the development of nonsurgical premature menopause were exposure to a dose of procarbazine greater than 4,000 mg/m2 (odds ratio [OR], 8.96; 95% confidence interval [CI], 5.02–16.00 [P < .0001]), any dose of radiation therapy to the ovaries (OR, 2.73 [95% CI, 1.33–5.61; P = .0062] for a dose of less than 500 cGy and OR, 8.02 [95% CI, 2.81–22.85; P < .0001] for a dose of greater than 500 cGy), and receipt of stem cell transplant (OR, 6.35; 95% CI, 1.19–33.93 [P = .0307]). A cyclophosphamide equivalent dose of 6,000 mg/m2 or higher that included procarbazine was significant in the univariate analysis, but did not achieve significance in the multivariable analysis.
    • For survivors who received more than 4,000 mg/m2 of procarbazine, the prevalence of nonsurgical premature menopause at age 40 years was 39.7%, compared with 4.2% among those who did not receive any procarbazine (P < .0001). Radiation exposure to the ovaries of greater than 500 cGy resulted in a prevalence of nonsurgical premature menopause at age 40 years of 24.1%, compared with a prevalence of 3.0% in those who did not receive radiation (P < .0001).
    • Cyclophosphamide exposure (at any dose), unilateral oophorectomy, smoking status, and body mass index (BMI) were not found to be significant for the risk of nonsurgical premature menopause.
    • Compared with survivors who did not develop nonsurgical premature menopause, those who developed nonsurgical premature menopause were less likely to ever be pregnant or to have a live birth between the ages of 31 and 40 years. There was no difference in the pregnancy and live birth rates before the age of 30 years for survivors who ultimately developed nonsurgical premature menopause and those who do not.
  3. A French cohort study of 1,109 female survivors of childhood solid cancer identified the following risk factors for nonsurgical menopause:[50]
    1. Exposure to and dose of alkylating agents, especially during adolescence.
    2. Radiation dose to the ovaries.
    3. Oophorectomy.
    • Women treated with alkylating agents after the onset of puberty, either alone (relative risk [RR], 9.0; 95% CI, 2.7–28.0; P = .0003) or associated with even a low dose of radiation to the ovaries (RR, 29; 95% CI, 8–108; P < .0001), had the highest risk ratio for nonsurgical menopause.
    • The overall rate of nonsurgical menopause by age 40 years was only 2.1% and substantially lower than the CCSS and European Organization for Research and Treatment of Cancer cohort studies that include survivors of hematological malignancies.
    • Unilateral oophorectomy was associated with a 7-year-earlier age at menopause.
  4. 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.[49]
    • 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.
  5. St. Jude Lifetime Cohort investigators evaluated the prevalence of and risk factors for premature ovarian insufficiency in 921 female childhood cancer survivor participants. Premature ovarian insufficiency was clinically assessed and defined by persistent amenorrhea combined with an FSH level of 30 IU/L or higher before age 40 years.[51]
    • The prevalence of premature ovarian insufficiency was 10.9% among women who were a median age of 31.7 years at study assessment and a median 24 years from cancer diagnosis.
    • Independent risk factors for premature ovarian insufficiency included ovarian radiation therapy at any dose and cyclophosphamide equivalent dose of 8,000 mg/m2 or higher.
    • Obesity (BMI of 30 kg/m2 or higher) at assessment was associated with a lower risk of premature ovarian insufficiency (HR, 0.36). Survivors with premature ovarian insufficiency had increased odds of low bone mineral density (OR, 5.07) and frailty (OR, 3.5) than did those without premature ovarian insufficiency.

Ovarian function after HSCT

The preservation of ovarian function among women treated with HSCT is related to age at treatment, receipt of pretransplant alkylating agent chemotherapy and abdominal-pelvic radiation therapy, and transplant conditioning regimen.[46,52]
Evidence (ovarian function among women treated with HSCT):
  1. Girls and young women conditioned with TBI or busulfan-based regimens appear to be at equally high risk of declining ovarian function and premature menopause compared with patients conditioned with cyclophosphamide only.[46] All women who received high-dose (50 mg/kg/day x 4 days) cyclophosphamide before HSCT for aplastic anemia developed amenorrhea after transplantation.
    • In another series, 36 of 43 women with aplastic anemia conditioned with cyclophosphamide (200 mg/kg) had recovery of normal ovarian function 3 to 42 months after transplantation, including all of the 27 patients who were between ages 13 and 25 years at the time of HSCT.[47]
  2. TBI is especially damaging when given in a single fraction.[46] Most postpubertal women who receive TBI before HSCT develop amenorrhea.
    • In one series, recovery of normal ovarian function occurred in only 9 of 144 patients and was highly correlated with age at time of radiation therapy in patients younger than 25 years.[47]
  3. Among women with leukemia, cranial irradiation before transplantation further decreased the possibility of retaining ovarian function.[46]
  4. Ovarian function may be better preserved (based on pubertal progress and gonadotropin levels) in females undergoing HSCT with reduced-intensity conditioning using fludarabine/melphalan than in those undergoing conditioning with myeloablative busulfan/cyclophosphamide.[35]

Fertility

Infertility remains one of the most common life-altering treatment effects experienced by long-term childhood survivors. Pediatric cancer cohort studies have demonstrated the impact of cytotoxic therapy on reproductive outcomes. CCSS investigations have elucidated factors contributing to subfertility among childhood cancer survivors.[53,54]
Fertility was evaluated in 10,938 CCSS participants (5,640 males, 5,298 females) and 3,949 siblings.[53]
  • At a median follow-up of 8 years from cohort entry, 38% of survivors reported having or siring a pregnancy, resulting in at least one live birth in 83% of those survivors. Among siblings monitored for a median of 10 years, 62% reported having or siring a pregnancy, resulting in at least one live birth in 90% of those siblings. Multivariable analysis confirmed that survivors had significantly decreased likelihood of siring or having a pregnancy (hazard ratio [HR], 0.63 in males and 0.87 in females) or of having a live birth (HR, 0.63 in males and 0.82 in females) than did siblings.
  • Greater doses of alkylating drugs (HR, 0.82 per 5,000 mg/m2 increments) and cisplatin reduced the likelihood of siring pregnancy among male survivors, but only busulfan and higher doses (>411 mg/m2) of lomustine significantly reduced pregnancy among females. Reassuringly, the risk of reduced likelihood of pregnancy in women was observed only at the highest cyclophosphamide equivalent dose (HR, 0.85 for upper quartile [≥11,295 mg/m2] vs. no exposure).
  • HRs (95% CIs) for the likelihood of reporting first pregnancy by cyclophosphamide equivalent dose for male and female survivors are summarized in Table 14:
    Table 14. Cyclophosphamide Equivalent Dose by Tertile and Sex
    Cyclophosphamide Equivalent Dose by TertileMaleFemale
     HR (95% CI)P ValueHR (95% CI)P Value
    CI = confidence interval; HR = hazard ratio.
    Lower (<4,897 mg/m2)1.14 (1.00–1.30).0450.97 (0.86–1.08).55
    Middle (4,897–9,638 mg/m2)0.79 (0.68–0.91).00100.98 (0.87–1.11).76
    Upper (≥9,639 mg/m2)0.55 (0.47–0.64)<.00010.90 (0.79–1.01).07
  • Similar relationships were observed for live birth outcomes.
Fertility may be impaired by factors other than the absence of sperm and ova. Conception requires delivery of sperm to the uterine cervix, patency of the fallopian tubes for fertilization to occur, and appropriate conditions in the uterus for implantation.[6,7,55]
  • Retrograde ejaculation occurs with a significant frequency in men who undergo bilateral retroperitoneal lymph node dissection.[6,7]
  • Uterine structure may be affected by abdominal irradiation. A study demonstrated that uterine length was significantly shorter in ten women with ovarian failure who had been treated with whole-abdomen irradiation. Endometrial thickness did not increase in response to hormone replacement therapy in three women who underwent weekly ultrasound examination. No flow was detectable with Doppler ultrasound through either uterine artery of five women, and through one uterine artery in three additional women.[55]
In a study of menopausal status on reproductive outcomes in 2,930 survivors from the CCSS, investigators found that for those who ultimately developed nonsurgical premature menopause, rates of pregnancy and live birth were substantially reduced before nonsurgical premature menopause between the ages of 31 and 40 years. However, pregnancy and live birth rates did not differ for those aged 21 to 30 years on the basis of ultimate menopausal status. Treatment variables significant for developing nonsurgical premature menopause by multivariable analyses included exposure to procarbazine doses higher than 4,000 mg/m2, any ovarian irradiation, and stem cell transplant.[48] A cyclophosphamide equivalent dose of 6,000 mg/m2 or higher that included procarbazine was significant in the univariate analysis, but did not achieve significance in the multivariable analysis.[48]

Reproduction

For survivors who maintain fertility, numerous investigations have evaluated the prevalence of and risk factors for pregnancy complications in adults treated for cancer during childhood. Pregnancy complications including hypertension, fetal malposition, fetal loss/spontaneous abortion, preterm labor, and low birth weight have been observed in association with specific diagnostic and treatment groups.[56-60]
Evidence (pregnancy complications in adults treated for childhood cancer):
  1. In a study of 4,029 pregnancies among 1,915 women followed in the CCSS, there were 63% live births, 1% stillbirths, 15% miscarriages, 17% abortions, and 3% unknown or in gestation.[56]
    • Risk of miscarriage was 3.6-fold higher in women treated with craniospinal irradiation and 1.7-fold higher in those treated with pelvic irradiation. Chemotherapy exposure alone did not increase risk of miscarriage.
    • Survivors were less likely to have live births, more likely to have medical abortions, and more likely to have low-birth-weight babies than were siblings.
    • Disruption of normal uterine function after radiation therapy or other treatment that results in reduced uterine volume and impaired uterine blood flow appears to be the underlying pathophysiology for many of these adverse obstetrical events.[61]
  2. In the National Wilms Tumor Study, records were obtained for 1,021 pregnancies of more than 20 weeks duration. In this group, there were 955 single live births.[62]
    • Hypertension complicating pregnancy, early or threatened labor, malposition of the fetus, lower birth weight (<2,500 g), and premature delivery (<36 weeks) were more frequent among women who had received flank irradiation, in a dose-dependent manner.
  3. Another CCSS study evaluated pregnancy outcomes of partners of male survivors.[57]
    • Among 4,106 sexually active males, 1,227 reported they sired 2,323 pregnancies, which resulted in 69% live births, 13% miscarriages, 13% abortions, and 5% unknown or in gestation at the time of analysis.
    • Compared with partners of male siblings, there was a decreased incidence of live births (RR, 0.77), but no significant differences of pregnancy outcome by treatment.
  4. Results from a Danish study confirm the association of uterine irradiation with spontaneous abortion, but not other types of abortion. Thirty-four thousand pregnancies were evaluated in a population of 1,688 female survivors of childhood cancer in the Danish Cancer Registry. The pregnancy outcomes of survivors, 2,737 sisters, and 16,700 comparison women in the population were identified.[58]
    • No significant differences were seen between survivors and comparison women in the proportions of live births, stillbirths, or all types of abortions combined.
    • Survivors with a history of neuroendocrine or abdominal radiation therapy had an increased risk of spontaneous abortion.
    • Thus, the pregnancy outcomes of survivors were similar to those of comparison women with the exception of spontaneous abortion.
  5. In a retrospective cohort analysis from the CCSS of 1,148 men and 1,657 women who had survived cancer, there were 4,946 pregnancies.[59]
    • Irradiation of the testes in men and pituitary gland in women and chemotherapy with alkylating drugs were not associated with an increased risk of stillbirth or neonatal death.
    • Uterine and ovarian irradiation significantly increased the risk of stillbirth and neonatal death at doses higher than 10 Gy.
    • For girls treated before menarche, irradiation of the uterus and ovaries at doses as low as 1 Gy to 2.49 Gy significantly increased the risk of stillbirth or neonatal death.
  6. Most pregnancies reported by HSCT survivors and their partners result in live births.[60]
    • In female HSCT survivors who were exposed to TBI, there appears to be an increased risk of preterm delivery of low-birth-weight infants.
    • Female HSCT survivors are at higher risk of needing cesarean delivery than are the normal population (42% vs. 16%).
  7. Preservation of fertility and successful pregnancies may occur after HSCT, although the conditioning regimens that include TBI, cyclophosphamide, and busulfan are highly gonadotoxic. One study evaluated pregnancy outcomes in a group of females treated with HSCT.[63]
    • Among 708 women who were postpubertal at the time of transplant, 116 regained normal ovarian function and 32 became pregnant.
    • Among 82 women who were prepubertal at the time of transplant, 23 had normal ovarian function and nine became pregnant.
    • Of the 72 pregnancies in these 41 women, 16 occurred in those treated with TBI and 50% resulted in early termination.
    • Among the 56 pregnancies in women treated with cyclophosphamide without either TBI or busulfan, 21% resulted in early termination.
    • There were no pregnancies among the 73 women treated with busulfan and cyclophosphamide, and only one retained ovarian function.
  8. A German study demonstrated that the rate of childbearing for female survivors of Hodgkin lymphoma was similar to that of the general population, although the rate of childbearing was lower for survivors who received pelvic radiation therapy.[64]
  9. British CCSS investigators evaluated pregnancy and labor complications among female survivors of childhood cancer treated with abdominal radiation by linking British CCSS cohort data to a national hospital registry.[65]
    • Survivors treated with abdominal radiation had a significantly higher risk (RR, 2.1) of pregnancy complications than did survivors who did not receive abdominal radiation.
    • Risks were elevated for hypertension complicating pregnancy among Wilms tumor survivors (RR, 3.29) treated with abdominal radiation and for gestational diabetes mellitus (RR, 3.35) and anemia (RR, 2.10) among all survivors treated with abdominal radiation.
  10. A systematic review compared the data from published pregnancy and child health outcomes for pediatric and young adult leukemia and lymphoma survivors with the data from controls who did not have a history of cancer.[66]
    • No higher risks of spontaneous abortions, maternal diabetes and anemia, stillbirth, birth defects, or childhood cancer in offspring were observed in survivors compared with controls.
    • Live birth rates were lower, while risks of preterm birth and low birth weight were modestly higher in survivors than in controls.

Fertility preservation

Progress in reproductive endocrinology has resulted in the availability of several options for preserving or permitting fertility in patients about to receive potentially toxic chemotherapy or radiation therapy.[67] For males, cryopreservation of spermatozoa before treatment is an effective method to circumvent the sterilizing effect of therapy. Although pretreatment semen quality in patients with cancer has been shown to be less than that noted in healthy donors, the percentage decline in semen quality and the effect of cryodamage to spermatozoa from patients with cancer is similar to that of normal donors.[68,69] For those unable to bank sperm, newer technologies such as testicular sperm extraction may be an option. Further micromanipulative technologic advances such as intracytoplasmic sperm injection and similar techniques may be able to render sperm extracted surgically, or even poor-quality cryopreserved spermatozoa from cancer patients, capable of successful fertilization.[70]
For females, the most successful assisted-reproductive techniques depend on harvesting and banking the postpubertal patient’s oocytes and cryopreserving unfertilized oocytes or embryos before gonadotoxic therapy.[71] Options for prepubertal patients are limited to investigational ovarian tissue cryopreservation for later autotransplantation, which may be offered to girls with nonovarian, nonhematologic cancers.[72]

Offspring of childhood cancer survivors

For childhood cancer survivors who have offspring, there is concern about congenital anomalies, genetic disease, or risk of cancer in the offspring. Children of cancer survivors are not at significantly increased risk for congenital anomalies stemming from their parents' exposure to mutagenic cancer treatments.
Evidence (children of cancer survivors not at significantly increased risk of congenital anomalies):
  1. A retrospective cohort analysis of validated cases of congenital anomalies among 4,699 children of 1,128 male and 1,627 female participants of the CCSS observed the following:[73]
    • No significant associations between gonadal radiation therapy or cumulative exposure to alkylating agents and congenital anomalies in offspring.
  2. A study compared 2,198 offspring of adult survivors treated for childhood cancer between 1945 and 1975 with 4,544 offspring of sibling controls.[74]
    • There were no differences in the proportion of offspring with cytogenetic syndromes, single-gene defects, or simple malformations.
    • There was similarly no effect of type of childhood cancer treatment on the occurrence of genetic disease in the offspring.
  3. A population-based study of 2,630 live-born offspring of childhood cancer survivors versus 5,504 live-born offspring of the survivors' siblings found no differences in proportion of abnormal karyotypes or incidence of Down syndrome or Turner syndrome between survivor and sibling offspring.[75]
    In the same population-based cohort, survivors treated with abdominal radiation therapy and/or alkylating agents did not have an increased risk of offspring with genetic disease, compared with survivors not exposed to these agents.
  4. In a study of 5,847 offspring of survivors of childhood cancers treated in five Scandinavian countries, in the absence of a hereditary cancer syndrome (such as hereditary retinoblastoma), there was no increased risk of cancer.[76] Data from the five-center study also indicated no excess risk of single-gene disorders, congenital malformations, or chromosomal syndromes among the offspring of former patients compared with the offspring of siblings.[77]
  5. In a study that evaluated pregnancy outcomes in 19,412 allogeneic and 17,950 autologous transplant patients, European Group for Blood and Marrow Transplantation investigators did not observe an increased risk of birth defects, developmental delay, or cancer among offspring of male and female HSCT recipients.[60]
  6. A nationwide Finnish population-based registry study compared the risk of congenital anomalies in the offspring of 6,862 long-term survivors of childhood, adolescent, and young adult cancer treated between 1953 and 2004 with the risk of congenital anomalies in the offspring of 35,690 siblings.[78]
    • The study did not find a significant excess risk of congenital anomalies among childhood and adolescent survivors (prevalence ratio [PR], 1.17; 95% CI, 0.92–1.49) and young adult survivors (PR, 1.17; 95% CI, 0.83–1.23) compared with siblings.
    • There was an association between parent cancer and congenital anomalies in the offspring of survivors who were diagnosed in the earlier decades (1955–1964: PR, 2.77; 95% CI, 1.26–6.11; and 1965–1974: PR, 1.55; 95% CI, 0.94–2.56).
Table 15 summarizes reproductive late effects and the related health screenings.
Table 15. Reproductive Late Effectsa
Predisposing TherapyReproductive Late EffectsHealth Screening
AMH = anti-mullerian hormone; FSH = follicle-stimulating hormone; LH = luteinizing hormone.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer.
Alkylating agents; gonadal irradiationTesticular hormonal dysfunction: Testosterone deficiency/insufficiency; delayed/arrested pubertyTanner stage
Morning testosterone
LH
Impaired spermatogenesis: Reduced fertility; oligospermia; azoospermia; infertilitySemen analysis
FSH
Inhibin B
Ovarian hormone deficiencies: Delayed/arrested puberty; premature ovarian insufficiency/premature menopause. Reduced ovarian follicular pool: Diminished ovarian reserve; infertility.Tanner stage
Menstrual cycle history
Estradiol
FSH
LH
AMH
Antral follicle count
Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer for reproductive late effects information including risk factors, evaluation, and health counseling.
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