Adjuvant radiation therapy and/or chemotherapy introduce higher risks of infertility in patients with cancer. Sterility from these therapies may be temporary or permanent. The occurrence of this toxicity is related to a number of factors including the following:
- Age at the time of treatment.
- Type of therapeutic agent.
- Radiation field.
- Total dose.
- Single versus multiple agents.
- Length of time since treatment.
When treatment-related or disease-related dysfunction is a possibility, every effort should be made to provide adequate information and education on reproduction and fertility. Conveying such information can be complicated, especially in younger pediatric cancer patients. Children may be too young to comprehend the implications of treatment on fertility. Additionally, in some instances, parents may decide to shelter children from such discussions.
Existing literature suggests that only about half of men and women of child-bearing age receive the information they need from their health care providers about cancer-related infertility at the time of diagnosis and treatment planning. This lack of information is one of the most common reasons men give for failing to bank sperm. To address this issue, a computerized interactive educational tool for patients, families, and physicians called Banking on Fatherhood after Cancer is under development and will be viewable on CD-ROM or over the Internet.Chemotherapy
With regard to chemotherapy, the extent of damage to a patient's fertility depends on the agent administered, the doses received, and the patient's age at the time of treatment. Age is an important factor, and the possibility of gonadal recovery improves with the length of time off chemotherapy. The germinal epithelium of the adult testis is more susceptible to damage than that of the prepubertal testis. The evidence to date (largely from adjuvant studies) suggests that patients older than 35 to 40 years are most susceptible to the ovarian effects of chemotherapy. The ovaries of younger women can tolerate greater doses. Predicting the outcome for any individual patient is difficult, as the course of ovarian functioning following chemotherapy is variable. Relative risk of ovarian failure and testicular damage from cytotoxic agents has been studied, and the alkylating agents have subsequently been shown to be damaging to fertility. The following agents have been shown to be gonadotoxic: [3,5-8]
In addition to these alkylating agents, vinblastine, cytarabine, cisplatinum, and procarbazine have also been reported to be gonadotoxic in male and female patients.
Chemotherapy regimens for the treatment of non-Hodgkin lymphoma are generally less gonadotoxic than those used for Hodgkin lymphoma. The addition of adjuvant endocrine therapy in patients older than 40 years was more likely to result in permanent chemotherapy-related amenorrhea. The effects of chemotherapy on testicular function have also been widely studied in patients with testicular cancer. One review reported that more than half of the patients with testicular germ cell cancer showed impaired spermatogenesis before undergoing cytotoxic treatment. Permanent infertility is ultimately defined by dose of cisplatin in these patients. At doses lower than 400 mg/m2, long-term effects on endocrine function and sperm production are unlikely to occur. Higher doses would be expected to cause long-term endocrine-gonadal dysfunction.
Although chemotherapy causes ovarian damage, there appears to be no risk of toxicity to future offspring of women treated with these agents before pregnancy.Radiation
When the testes are exposed to radiation, sperm count begins to decrease and, depending on the dosage, temporary or permanent sterility may result. Men who receive radiation to the abdominal or pelvic region may still regain partial or full sperm production, depending on the extent of injury to the testes. Unlike the germinal epithelium, Leydig cell function may be more prone to damage from irradiation in prepubertal life than in adulthood. Testicular radiation with doses higher than 20 Gy is associated with Leydig cell dysfunction in prepubertal boys, while Leydig cell function is usually preserved with doses of as much as 30 Gy in sexually mature males. Exposing the testes to ionizing radiation at a dose lower than 6 Gy causes disturbances of spermatogenesis and altered spermatocytes with recovery periods dependent on dose; doses higher than 6 Gy cause permanent infertility by killing off all stem cells.
For patients with testicular germ cell cancer, using modern radiation techniques (radiation doses <30 Gy to the para-aortic field) and testis shielding providing testis scatter radiation (<30 Gy), radiation-induced impairment of fertility is very unlikely. Sperm counts are typically lowest at 4 to 6 months posttreatment; return to pretreatment levels usually occurs in 10 to 24 months, with longer periods required for recovery after higher doses. Total-body irradiation (TBI) as a conditioning regimen for stem cell transplantation causes permanent gonadal failure in approximately 80% of men. For men, gonadal toxicity can be evidenced by the following three measurements:
- Testicular biopsy.
- Serum hormone assays (levels).
- Semen analysis.
When male infertility is the result of abnormal hormone production, the use of hormone manipulation may lead to the return of sperm production.
For women, a radiation dose of 5 Gy to 20 Gy administered to the ovary is sufficient to completely impair gonadal function, regardless of the patient’s age; a dose of 30 Gy provokes premature menopause in 60% of women younger than 26 years. In a study of children and adolescents diagnosed with cancer, female 5-year survivors were significantly less likely to have ever been pregnant when compared with their siblings. Survivors who received hypothalamic/pituitary radiation doses of 30 Gy or higher or ovarian/uterine radiation doses higher than 5 Gy and those who were treated with lomustine or cyclophosphamide were less likely to have ever been pregnant. Women who are older than 40 years when undergoing treatment have a smaller pool of remaining oocytes and require only 5 to 6 Gy to produce permanent ovarian failure. TBI, when used before stem cell transplantation, is associated with more than 90% permanent gonadal failure in women overall and an incidence of pregnancy less than 3%. The outlook for recovery of ovarian function before puberty is more favorable, particularly if radiation is delivered in several fractions. Measurement of gonadal toxicity in women is more difficult to assess due to the relative inaccessibility of the ovary to biopsy (which would require laparoscopy). Therefore, the criteria most commonly used to determine ovarian failure are the following:
- Menstrual and reproductive history.
- Measurements of serum hormone levels.
- Clinical evidence of ovarian function.
For women, studies  have shown that movement of the ovaries out of the field of radiation (ovariopexy)—laterally, toward the iliac crest, or behind the uterus—may help preserve fertility when high doses of radiation therapy are being applied. By relocating the ovaries laterally it is possible to shield them during radiation of the para-aortic and femoral lymph nodes. Pelvic radiation, however, still provokes an irradiation of the ovary of 5% to 10%, even if transposed outside the irradiation area. Similar prevention strategies are available for men. When possible, lead shields are used to protect the testes.Procreative Alternatives
When feasible and relative to the necessity of treatment, oncology professionals will discuss reproductive cell and tissue banking with patients, referring to a reproductive endocrinologist before chemotherapy and/or radiation. Men can store sperm from the following: [19-22]
- Semen ejaculate.
- Epididymal aspirate.
- Testicular aspirate.
- Testicular biopsy.
Women can store ovarian tissue, ovarian follicles, and embryos.[23,24][Level of evidence: II] In oocyte cryopreservation, which is still experimental, reproductive cells/tissue are cryopreserved for future use in artificial insemination for patients who wish to protect their reproductive capacity.
One published case report describes a live birth after in vitro fertilization of thawed cryopreserved ovarian cortical tissue into the ovaries of a 28-year-old woman who experienced ovarian failure secondary to high-dose chemotherapy for non-Hodgkin lymphoma.[Level of evidence: III] For this case, ovarian tissue (containing many primordial follicles) was harvested after administration of a second-line conventional therapy regimen and before treatment with high-dose chemotherapy. Since this time, work has continued to advance technology related to the preservation of unfertilized eggs and ovarian tissue cryopreservation.
More data have been published from clinics using preservation of unfertilized eggs, an important option for unpartnered, fertile women at the time of cancer diagnosis and treatment. The New York University (NYU) Fertility Center reported an ongoing/delivered pregnancy rate of 57% using oocyte cryopreservation. The authors state that this rate is better than the U.S. rate for conventional in vitro fertilization using fresh (as opposed to cryopreserved) oocytes. They also report that this success rate was similar to that for age-matched controls who underwent conventional in vitro fertilization at the NYU Fertility Center. There is likely a good deal of variability in the expertise and success rates of fertility centers using these newer strategies. When options for patients are being investigated, critical review is needed.
These options may not be appropriate for all patients. Counseling is an important part of the decision-making process for patients. Thinking through these decisions at a time when patients are struggling with issues of life and potential death are often difficult. Patients need to consider costs, stress, time, emotions, and potential inclusion of another individual in the pregnancy process (i.e., a surrogate). For many patients, the financial costs associated with in vitro fertilization and subsequent embryo cryopreservation is cost prohibitive. Consideration also needs to be given to the current rate of failure for in vitro fertilization procedures and the potential adverse effect of malignancy on sperm parameters.[Level of evidence: III] A retrospective analysis, with a limited sample size, reported that the oocytes from patients with malignant disorders were of a poorer quality and exhibited a significantly impaired fertilization rate compared with age-matched controls. Importantly, data on the outcome of pregnancies in cancer survivors [Level of evidence: III] have not shown any increase in genetically mediated birth defects, birth-weight effects, and sex ratios. Based on the evidence thus far, individuals treated with cytotoxic chemotherapy who remain fertile are not at an increased risk of having children with genetic abnormalities. For all patients who wish to be parents and who have permanent infertility, adoption is also a choice.
Men who are treated with sterilizing chemotherapy may have semen cryopreserved, yet utilization remains low.[Level of evidence: III] In a 15-year study of 776 men with a variety of malignancies, the cumulative rate of using the cryopreserved semen for assisted conception was less than 10% up to 8 years. Younger age at cryopreservation and a diagnosis of testicular cancer were associated with lower utilization.[Level of evidence: III] Despite poor postthawing sperm survival rates, intracytoplasmic sperm injection (ICSI) offers the possibility of a pregnancy even if only a single motile sperm is present after thawing.[Level of evidence: IV]
Cryopreservation of sperm is recommended even to oncological patients younger than 15 years (provided these patients can produce a semen sample), as overall success rates (defined as the observation of at least a single motile sperm after the thawing procedure) have been found to be similar to those observed in adults.[Level of evidence: III] For men who experience retrograde ejaculation after treatment and remain fertile, it is often possible to retrieve live sperm cells. An infertility specialist can retrieve sperm cells from the testicles and from urine. Testis sperm extraction incorporates the removal of testicular parenchyma with processing and isolation of individual sperm cells. This allows for ICSI in azoospermic men. In a retrospective study, 15 of 23 men who were azoospermic after receiving chemotherapy had retrievable testis sperm leading to successful fertilization. Pregnancies occurred in 31% of cycles. Future research is needed to address whether the offspring produced after ICSI techniques are at increased risk of genetic or congenital malformation.[Level of evidence: III]
Medication can sometimes be used to stimulate the remaining nerves around the prostate and seminal vesicles to convert a retrograde ejaculation to an antegrade ejaculation. In the United States, ephedrine sulfate is most often used; in Europe, imipramine is also used. Pharmacologic agents can also be used to induce an ejaculation (i.e., intrathecal neostigmine or subcutaneous physostigmine). When medication does not work, several other techniques are available and may be recommended, including vibratory stimulation, electroejaculation, direct aspiration of fluid from the vas deferens, perineal needle stimulation, and hypogastric-nerve stimulation. Further review of these treatments and information regarding treatment of infertility and assisted reproductive technology is available.[13,34]
Fertility outcomes after therapy of common cancer types (breast cancer, leukemia and lymphoma, cervical cancer, ovarian cancer, endometrial cancer, and testicular cancer) are available in a published review.Current Clinical Trials
Check NCI’s list of cancer clinical trials for U.S. supportive and palliative care trials about fertility assessment and management and cryopreservation that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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