234235Reproductive Considerations and Long-Term Complications of Therapy
Testicular cancer accounts for 1% of all cancers in men and is the most common cancer in men between the ages of 15 and 35. Ninety-five percent of testicular carcinoma is germ cell tumor that can further be divided into seminoma and nonseminomatous germ cell tumor. Testicular carcinoma is one of the most curable cancers and with advances in treatment the overall survival is beyond 10 years in more than 95% of patients. Treatment of testicular cancer is multimodal with radical inguinal orchiectomy followed by surveillance versus chemotherapy and/or radiation therapy (RT) depending on the cancer stage. Given that the majority of patients are young and the cure rate is high, survivors of testicular cancer are faced with challenges of long-term adverse effects of various modalities of treatment.
REPRODUCTIVE CHALLENGES IN TESTICULAR CANCER
Infertility is a major concern since testicular cancer affects men in their reproductive years. Testicular cancer patients are at high risk for infertility and hypogonadism even before the treatment is started due to endocrine and metabolic effects of cancer, autoimmune effects, dysgonadogenesis, and congenital malformation of the testis such as cryptorchidism and hypospadias (1).
236INTRINSIC EFFECTS OF TESTICULAR CANCER ON FERTILITY
Multiple studies have shown that more than 30% of testicular cancer patients have azoospermia or oligospermia prior to undergoing orchiectomy, and 50% have decreased sperm motility (2). Systemic effects of cancer such as fever and cytokine production can affect spermatogenesis. Cytokines also disturb normal endocrine pathways including the hypothalamic-pituitary-gonadal axis (3). In addition, hormone-producing testicular tumors affect spermatogenesis and cause changes in sex hormones. De Bruin et al have reported that patients with beta human chorionic gonadotropin (HCG)–producing testicular cancers have higher testosterone and estradiol, and lower follicle stimulating hormone (FSH), luteinizing hormone (LH), and sperm counts (4).
EFFECTS OF CANCER TREATMENT ON FERTILITY
The testis is highly susceptible to the toxic effects of radiation and chemotherapy since spermatogenesis involves rapid cell division. Cytotoxic chemotherapy and radiotherapy may produce long-lasting or persistent damage to primordial sperm cells, leading to oligo- or azoospermia. The risk of infertility is dependent on pubertal status at the start of treatment, the type of treatment used, the chemotherapy agent(s) administered, and number of cycles given. Men treated with chemotherapy and those treated with extended-field RT are at the highest risk. Standard treatment of advanced testicular cancer includes combination chemotherapy with cisplatin, bleomycin, and etoposide. A large European study involving 1,433 patients demonstrated that patients who received high-dose cisplatin (total dose >850 mg) had the lowest incidence of successful conception (38%) compared to surveillance (81%), low-dose cisplatin (62%), RT (61%), and retroperitoneal lymph node dissection (RPLND) (77%) (5). The type of surgery patients receive can also affect fertility and sexual dysfunction. Nonnerve sparing RPLND has the highest risk of sexual dysfunction, retrograde ejaculation, and anejaculation. Patients with dry ejaculation after treatment are the least likely to conceive. In addition, 0.6% of testicular cancer patients have synchronous tumors 237on the contralateral side and require bilateral orchiectomy. Psychosocial effects of cancer itself and treatment and anxiety also further diminish the chances of successful conception.
In light of the significant infertility risk in testicular cancer patients, discussion of infertility risk and methods of fertility preservation should be routinely incorporated in their care. Semen cryopreservation is considered the standard practice, and referral to a fertility specialist should be made before starting any treatment. If possible, baseline sperm count and sperm banking should be performed prior to the radiographic diagnostic evaluation in order to avoid radiation exposure of the sperm. Improvements in assisted reproductive techniques and cryopreservation have increased fertility rates; however, fewer than 30% of patients utilize sperm banking and testing before starting treatment. Reports show less than 10% proceed to conception with cryopreserved sperm. (6) Barriers to fertility preservation include lack of financial support, lack of proper knowledge of risks and benefits, lack of desire, and fear of delaying treatments. Despite multiple challenges hindering fertility and low use of fertility preservation methods, approximately 50% of testicular patients recover spermatogenesis in 2 years and 80% after 5 years. Cumulative posttreatment paternity rate is about 71% in a large European cohort described earlier (5).
TREATMENT-RELATED ADVERSE EFFECTS AND LONG-TERM COMPLICATIONS OF THERAPY
In addition to fertility challenges, testicular cancer survivors are at a higher risk of developing complications in multiple organs and systems following multimodality treatment.
Compared to the general population, testicular cancer survivors are not only at high risk of developing unfavorable cardiovascular risk factors such as metabolic syndrome, but also at higher risk of developing cardiovascular events 238such as coronary artery disease and thromboembolism. Factors associated with highest risk include mediastinal radiation and combination chemotherapy with cisplatin. The etiology of metabolic syndrome in testicular cancer is unclear.
Bleomycin is an integral part of testicular cancer treatment. In a cohort of 835 patients, bleomycin-induced pulmonary toxicity was seen in 7% and 1% died as a result (7). Short-term bleomycin-induced pulmonary toxicity occurs in up to 46% of patients within 3 years of treatment and is usually mild and self-limited. A small number of patients develop long-term complications such as pulmonary fibrosis with mortality up to 10%. Patients who are treated with bleomycin are at risk of provoking pulmonary toxicity and respiratory failure when exposed to high oxygen levels in general anesthesia. Thus, it is important to educate patients and alert health care personnel of prior bleomycin use to avoid high oxygen concentration if possible. High cumulative dose of cisplatin has also been associated with restrictive lung disease in long-term survivors.
Renal dysfunction is seen during active treatment with cisplatin, and hydration is of utmost importance. In a prospective study following 85 patients over 14 years, the incidence of long-term renal dysfunction is seen in 29% of patients treated with multiagent chemotherapy (8).
Patients treated with cisplatin are at risk of developing peripheral neuropathy and ototoxicity. Neuropathy may persist for up to a decade after treatment. Cisplatin-induced ototoxicity manifests as hearing impairment, tinnitus, and high-frequency hearing loss.
Patients treated with RT are at increased risk of late gastric and duodenal ulcers. Decreased bone mineral density and 239osteoporosis are also seen as a result of hypogonadism and late complications of chemotherapy and RT.
RISK OF SECONDARY MALIGNANCY
Testicular cancer survivors are more likely to develop second malignancies when compared to the general population. In the largest study to date, including 40,576 patients, there was an increased risk of solid cancers in men treated with RT (relative risk [RR] = 2), chemotherapy (RR =1.8), and with combined radiation and chemotherapy (RR = 2.9) (9). The most common second malignancies included lung, colon, bladder, pancreas, and stomach, which account for 60% of all solid tumors (9). Patients treated with combined chemotherapy are at increased risk of developing leukemia, but the incidence is less than 0.5%. Etoposide is a topoisomerase II inhibitor and is known to cause characteristic myeloid malignancy/leukemia involving chromosome translocation 11q23, and typically occurs within 1 to 3 years following treatment.
RISK OF RADIATION EXPOSURE
Testicular cancer patients are exposed to numerous imaging studies throughout the course of the disease and for many years thereafter for surveillance. Increased exposure to radiation has raised concerns over contributing to secondary malignancy. A Canadian study observed 2,569 testicular cancer patients over a median follow-up of 11 years. The median number of CT scans in the first 5 years was 10, and 14 patients developed secondary malignancy in this cohort. Radiation exposure was not associated with increased risk of secondary malignancy with hazard ratio (HR) 0.99 (95% confidence interval [CI] 0.95–1.04) (10). However, follow-up in this study was short and limited. Clinicians should always take into consideration a patient’s age and the risk of excessive radiation in young survivors when planning for imaging.