INTRODUCTION — Testicular cancer is the most curable solid tumor and the most common malignancy in males between the ages of 18 and 35. Testicular cancer mortality has declined, with a relative overall survival rate after diagnosis and treatment exceeding 96 percent at 10 years. This improvement in survival is attributable in large part to treatment advances such as cisplatin-based chemotherapy. Following treatment for testicular cancer, oncologic follow-up is guided in part by the probability of relapse over time. Although most relapses occur within the first five years, late recurrences can occur.
During the period of oncologic follow-up, after active therapy or any time thereafter, patients with a history of testicular cancer may develop symptoms that affect quality of life or have abnormal findings on clinical examination [1]. The patient's clinicians and oncologists may be challenged with questions related to whether or not these symptoms or findings are due to prior treatment.
Because of the young age at which males with testicular cancer are diagnosed and success in treatment of testicular cancer, issues of cancer survivorship evolve as males mature. This topic will cover late treatment-related complications in testicular cancer survivors. The discussion is intended for the management of patients who have completed the active phase of cancer therapy and have transitioned to receiving almost all of their care from their other clinicians. Acute treatment-related toxicity and posttreatment follow-up of males treated for testicular cancer are discussed in more detail separately. (See "Treatment-related toxicity in men with testicular germ cell tumors" and "Posttreatment follow-up for men with testicular germ cell tumors".)
A general overview of cancer survivorship is discussed separately. (See "Overview of cancer survivorship care for primary care and oncology providers".)
OVERVIEW OF TREATMENT FOR TESTICULAR CANCER — In the United States, approximately 10,000 new cases of testicular cancer occur each year [2,3]. Testicular cancer usually presents as a nodule or painless swelling of one testicle, which may be noted incidentally by the patient or by their sexual partner [4]. The vast majority of testicular cancers are germ cell tumors, which are classified as either seminomas or nonseminomatous germ cell tumors (NSGCTs). Approximately 90 percent are detected with low-stage disease (stage I to IIB (table 1 and table 2)), and most (60 to 80 percent) will have clinical stage I disease [5].
Primary surgery — The primary treatment for testicular cancer is an inguinal orchiectomy. The information from pathology is used to determine pathologic tumor stage (table 1). Following diagnosis, treatment is based on the likelihood of recurrence in order to tailor treatment and minimize the long-term side effects.
Fertility preservation — When testicular cancer is suspected in males of reproductive age, counseling regarding sperm banking as a means of fertility preservation is routinely performed prior to initiation of any form of treatment. However, less than 30 percent of males actually choose to bank sperm and an even smaller proportion (10 percent) actually use banked sperm to father a child [6,7]. Despite this, many patients treated for testicular cancer go on to become fathers naturally with recovery of spermatogenesis achieved in 80 percent five years after diagnosis [8,9]. (See 'Hypogonadism' below.)
Primary treatment — Key elements used to determine the treatment plan include the following (see "Overview of the treatment of testicular germ cell tumors"):
●Histology (ie, seminoma versus NSGCT)
●Presence or absence of metastases
●Degree of elevation in serum tumor markers
The prognosis is excellent for most patients with testicular cancer, regardless of treatment. Treatment options after orchiectomy include the following:
●Surveillance – Active surveillance following orchiectomy is an option specifically for males with stage I seminoma or NSGCT. These patients have an extremely high cure rate following inguinal orchiectomy alone. (See "Active surveillance following orchiectomy for stage I testicular germ cell tumors".)
●Radiation therapy – Radiation therapy (RT) is an alternative option for males with stage I or II seminoma, although surveillance is the preferred approach for males with stage I disease. If administered to males with stage I seminoma, RT is directed to the para-aortic nodes to a dose of 20 Gy. For males with nonbulky stage II seminoma, 30 to 35 Gy RT to the para-aortic and ipsilateral iliac nodes may be used as an alternative to chemotherapy. (See "Treatment of stage II seminoma".)
●Chemotherapy – Chemotherapy is an option for males with testicular germ cell tumors regardless of disease stage. It is estimated that up to 20 percent of males will require primary chemotherapy for cure [8].
•Single-agent carboplatin can be administered to males with stage I seminoma who are not candidates for surveillance (ie, poorly compliant with medical follow-up) and is an alternative to RT.
•Combination cisplatin-based chemotherapy generally consists of bleomycin and etoposide plus cisplatin (BEP) or etoposide plus cisplatin (EP). It may be offered to males with stage II seminoma (as an alternative to RT) or to males with early stage NSGCT (stage IB to IIB).
•For males with advanced germ cell tumors, primary treatment consists of cisplatin-based combination chemotherapy (either BEP or EP). Surgery is often used to supplement chemotherapy in select patients with residual disease. (See 'Resection of residual disease following chemotherapy' below.)
●Retroperitoneal lymph node dissection – A primary retroperitoneal lymph node dissection (RPLND) is a treatment option for males with stage I and some patients with nonbulky stage II NSGCTs. (See "Retroperitoneal lymph node dissection for early-stage testicular germ cell tumors".)
Resection of residual disease following chemotherapy
●Seminoma – For males with seminomas, surgery of a residual mass may not be necessary. One-half of males with residual masses will have resolution of these findings during surveillance at a median of one year. However, the routine resection of larger residual masses (≥3 cm) is controversial. Positron emission tomography (PET) scans may be useful in detecting residual disease in this setting. This topic is discussed in detail elsewhere. (See "Treatment of stage II seminoma", section on 'Posttherapy residual masses'.)
For males with residual retroperitoneal adenopathy that demonstrates fludeoxyglucose uptake on PET at the end of treatment, postchemotherapy RPLND is sometimes performed, although this surgery should be restricted to specialized centers where a large number of testicular cancer patients are seen. Following resection of residual masses that contain viable tumor, at least two further courses of chemotherapy are generally advised. (See "Approach to surgery following chemotherapy for advanced testicular germ cell tumors", section on 'Role of adjuvant chemotherapy'.)
●Nonseminomatous germ cell tumors – Residual masses are commonly seen on postchemotherapy imaging studies in males with NSGCTs, and standard of care is to resect these lesions. Approximately 60 percent of patients with postchemotherapy residual masses will either have viable cancer or teratoma. As long as tumor markers have normalized, surgical resection is preferred over further chemotherapy. (See "Approach to surgery following chemotherapy for advanced testicular germ cell tumors", section on 'Retroperitoneal lymph node dissection'.)
FOLLOW-UP POSTTREATMENT — Follow-up care for males who have successfully completed therapy for testicular cancer consists of a surveillance schedule that includes history and physical examinations (including testicular examination), assessment of serum tumor markers (beta-human chorionic gonadotropin, alpha-fetoprotein [AFP], and lactate dehydrogenase) if indicated, and radiographic studies. (See "Active surveillance following orchiectomy for stage I testicular germ cell tumors", section on 'Active surveillance protocols' and "Posttreatment follow-up for men with testicular germ cell tumors", section on 'Guidelines for follow-up'.)
Factors that influence the nature and intensity of follow-up after completion of initial definitive therapy include the histology (seminoma versus nonseminomatous germ cell tumor [NSGCT]), original risk stratification group (for males presenting with advanced disease (table 2)), and treatment (particularly the use of surgery or radiation therapy to treat the retroperitoneal lymph nodes).
The intensity of follow-up is guided in part by the probability of relapse over time. For males with seminoma, the median time to relapse is 13 to 16 months. However, there is a wide range of relapse (between 2 and 108 months), with up to one-third of relapses occurring more than three years after completion of treatment [10,11]. By contrast, over 95 percent of relapses of NSGCTs occur within the first two years following orchiectomy [12].
Although most relapses occur within the first five years for both seminoma and NSGCT, late recurrences can occur [13-15]. Based on this type of observation, follow-up is most intensive during the first two years after treatment and then gradually decreases. Guidelines vary regarding the frequency of routine imaging or blood work for the long-term survivor of testicular cancer, particularly after the first five years have passed. However, most groups now recommend lifelong follow-up after completion of successful therapy because of the risk of late relapse. Therefore, cancer surveillance should be coordinated between the primary care clinician and the oncology team. (See "Posttreatment follow-up for men with testicular germ cell tumors".)
SIDE EFFECTS OF TREATMENT
Cumulative burden of morbidity — Cisplatin-based chemotherapy is essential for cure for patients with metastatic testicular germ cell tumors. Since the 1970s, a large number of testicular cancer survivors have been exposed to cisplatin-based chemotherapy as part of their initial treatment. This exposure to cisplatin results in a range of toxicities [16]. In addition, circulating serum platinum remains at detectable levels for at least 20 years after treatment and may continue to contribute to additional toxicity for prolonged periods [17]. In addition to the organ-specific toxicities discussed in the sections below, the use of cisplatin chemotherapy contributes to a cumulative burden of mortality in the testicular cancer survivors [18].
In a multi-institution cohort of 1214 testicular cancer survivors, the frequency and severity of specific adverse events was analyzed, and this information was combined into a cumulative burden of morbidity score [19]. All of the males in this cohort had received cisplatin-based chemotherapy as a component of their initial treatment and were undergoing routine follow-up at the time of study inclusion. The most frequently identified adverse health outcomes included obesity, sensory neuropathy, tinnitus, hearing damage, Raynaud phenomenon, and pain. At a median follow-up of 4.2 years after completion of chemotherapy, approximately 20 percent of males had a high, very high, or severe cumulative burden of morbidity score, and only 5 percent had no adverse health outcomes. A high cumulative burden of morbidity score was strongly associated with worse self-reported health.
Cardiovascular disease — Treatment with a platinum-based therapy regimen is associated with increased risk of hypertension and hypercholesterolemia [20]. Close cardiovascular follow-up in the first year following platinum-based chemotherapy is important to address modifiable cardiovascular risk factors in the long term [21,22]. (See "Treatment-related toxicity in men with testicular germ cell tumors", section on 'Cardiovascular' and "Cancer survivorship: Cardiovascular and respiratory issues".)
As examples:
●Contrary to prior studies that demonstrated a higher risk of long-term cardiovascular effects among testicular cancer survivors, the use of initial chemotherapy has been associated with increased cardiovascular mortality (due to both heart disease and cerebrovascular disease) in the first year after treatment [20,23]. As an example, one study of 15,006 patients identified using the Surveillance, Epidemiology, and End Results (SEER) program found that excess cardiovascular mortality was restricted to those treated with chemotherapy in the first year versus those treated with surgery. Similar cardiovascular risks were seen among those with more extensive disease and increasing age at diagnosis (particularly those older than 50) [23].
●In another observational study of 5185 patients with germ cell cancer, treatment with bleomycin and etoposide plus cisplatin (BEP) was associated with 44 percent increased risk of death from cardiovascular disease. In addition, the 20-year cumulative incidence of coronary heart disease or cerebrovascular accident after orchiectomy in patients undergoing surveillance, radiation therapy, and BEP was 6.6, 9, and 7.9 percent, respectively [20].
Metabolic syndrome — The metabolic syndrome (insulin resistance syndrome or syndrome X) represents a cluster of risk factors that result in an increased incidence of, and mortality from, cardiovascular disease.
●The prevalence of the metabolic syndrome in long-term testicular cancer survivors was evaluated in a study that included 251 testicular cancer survivors (cases) and 360 health subjects (controls) [24]. Among cases, 174, 57, and 20 males were previously treated with combination chemotherapy, single-agent carboplatin, or surgery alone, respectively. Main findings were as follows:
•Testicular cancer survivors had an almost twofold higher risk of metabolic syndrome compared with controls (14 versus 8 percent, respectively; odds ratio 1.9, 95% CI 1.1-3.2).
•Males treated with combination chemotherapy had the highest prevalence of metabolic syndrome (17 percent). However, the prevalence among males treated with surgery alone or single-agent carboplatin was similar to that of healthy controls (10 and 9 percent, respectively).
●A study of 486 testicular cancer survivors, all of whom had received first-line chemotherapy as a part of their initial treatment [25], found that the overall frequency of metabolic syndrome was similar in the testicular cancer survivors compared with a matched control group (21 versus 22 percent). However, cardiovascular risk factors were more often present among survivors, including hypertension and increased low-density lipoprotein, as well as hypogonadism and inflammation, but not low high-density lipoprotein and abdominal obesity.
Further discussion of the metabolic syndrome, including diagnostic criteria and an approach to treatment, is covered separately. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)
Gastrointestinal disorders — Fewer males are being treated with RT for testicular cancer now compared with previously, and as noted in one study, there is a slight increased risk of duodenal or gastric ulcers as a late complication in this population [26]. Biliary stenosis, a complication of radiation-induced retroperitoneal fibrosis, was also reported in another study [27]. Patients who received more than one line of treatment are at increased risk of late toxicity and death as a result of causes other than testicular cancer, including gastrointestinal toxicity [28].
Pulmonary toxicity — Testicular cancer survivors are at a slight increased risk of long-term pulmonary toxicity, especially those who received chemotherapy with either bleomycin or cisplatin. Pulmonary sequelae are of greatest concern in males who continue to use tobacco, and smoking cessation should be encouraged. (See "Treatment of alcohol use and smoking for cancer survivors".)
Bleomycin-induced lung injury — Bleomycin exerts its antitumor effect by inducing programmed cell death, by inhibiting angiogenesis, and by the formation of free radicals. The enzyme required to deactivate bleomycin, bleomycin hydrolase, is not present in lung tissue and results in pulmonary injury. Short-term pulmonary complications (defined as occurring within the first three years) of bleomycin are seen in up to 46 percent of patients but most are mild and self-limited; only a small fraction of bleomycin-treated patients develop pulmonary fibrosis [29]. However, the risk of fatality in patients who develop bleomycin-associated pulmonary fibrosis is on the order of 10 percent [29-31]. In one series of 835 males with testicular cancer who had been treated with a bleomycin-containing regimen, 57 males (7 percent) developed bleomycin pulmonary toxicity, and eight males (1 percent of those receiving bleomycin and 14 percent of those with bleomycin toxicity) died as a result [31]. (See "Bleomycin-induced lung injury".)
Cisplatin-induced restrictive lung disease — Cisplatin has also been associated with restrictive lung disease in testicular cancer survivors, which is discussed separately. (See "Treatment-related toxicity in men with testicular germ cell tumors", section on 'Late chemotherapy toxicity'.)
Hypogonadism — Males treated with chemotherapy or RT are at a long-term risk for chemical hypogonadism, which is associated with infertility and poor quality of life across multiple domains, including sexual, physical, and role function [32-35]. Patients with testicular dysgenesis, a developmental condition characterized by hypospadias, cryptorchidism, poor semen quality, and testicular cancer, may also experience hypogonadism after treatment for testicular cancer. (See "Treatment-related toxicity in men with testicular germ cell tumors", section on 'Gonadal effects' and "Effects of cytotoxic agents on gonadal function in adult men", section on 'Testicular cancer'.)
Infertility — Infertility is common in patients who have testicular cancer. The etiology of infertility in these males is not fully understood because testicular cancer and infertility often coexist, with many patients having evidence of impaired spermatogenesis prior to initiation of therapy. Therefore, patients with testicular cancer would benefit from evaluation of both their pre- and posttreatment reproductive status. The association between altered spermatogenesis and testicular cancer, as well as the assessment of treatment-induced infertility in males, is discussed separately. (See "Treatment-related toxicity in men with testicular germ cell tumors", section on 'Gonadal effects' and "Effects of cytotoxic agents on gonadal function in adult men", section on 'Testicular cancer' and "Effects of cytotoxic agents on gonadal function in adult men".)
The risk of infertility is dependent on the prior treatment received [36,37]. Males treated with chemotherapy, extended-field RT, and retroperitoneal lymph node dissection (RPLND) are at greatest risk for infertility. For example, chemotherapy and RT damage spermatogenesis, whereas non-nerve-sparing RPLND impairs ejaculatory function due to surgical disruption of crucial sympathetic nerve complexes [37]. Approaches that reduce the risk of infertility include minimizing chemotherapy and RT cumulative dosing and performing nerve-sparing RPLND techniques. (See "Effects of cytotoxic agents on gonadal function in adult men", section on 'Cisplatin and testicular cancer' and "Radiation therapy techniques in cancer treatment", section on 'Radiation side effects' and "Retroperitoneal lymph node dissection for early-stage testicular germ cell tumors", section on 'Infertility'.)
In light of the significant infertility risk, sperm banking prior to the initiation of therapy is routinely discussed. (See 'Fertility preservation' above.)
Sexual dysfunction — Sexual function may be affected in testicular cancer survivors due to hypogonadism and other factors, including increasing age, lack of a partner, and heightened anxiety [37-40].
Sexual dysfunction is a poorly understood problem in testicular cancer survivors and needs further study. Data are conflicting on the frequency of sexual dysfunction in these patients. As an example, in one study, the majority (approximately three-quarters) of young males diagnosed with testicular cancer did not report sexual dysfunction or reproductive concerns two years after diagnosis [41]. In contrast, another study of approximately 1200 testicular cancer survivors reported a fourfold higher risk of erectile dysfunction; additionally, the long-term risk for erectile dysfunction was higher in patients treated with combination therapies directed at testicular cancer [19].
Renal impairment — Although the greatest risk to the kidneys is during active treatment with nephrotoxic agents (eg, cisplatin), testicular cancer survivors with such exposure are at risk for long-term chronic renal insufficiency, with the prevalence of stage 3 chronic kidney disease estimated at approximately 10 to 20 percent in one study [42]. Further details on cisplatin nephrotoxicity are discussed separately. (See "Cisplatin nephrotoxicity".)
Neurotoxicity — Patients with testicular cancer are at increased risk for persistent peripheral neuropathy and ototoxicity, particularly if they were previously treated with a platinum-based regimen. A 2011 evaluation showed that residual platinum could be detected more than a decade following treatment and that the risk of neurotoxicity was associated with higher levels of residual platinum [43].
Impaired cognitive function and structural changes on imaging have been observed in patients treated with cisplatin-based chemotherapy [44-47]. (See "Cognitive function after cancer and cancer treatment".)
Peripheral neuropathy — Patients treated with cisplatin are at risk for neuropathy that may persist long after treatment has completed. This was illustrated in a cross-sectional study of 1409 testicular cancer survivors followed for a median of 11 years [48]. Of those treated with chemotherapy, 29 percent reported paresthesias in the hands or feet. Peripheral nerve damage is a rare complication following RT [49].
Combination chemotherapy is associated with a wide range of adverse health outcomes. A study in 952 testicular cancer survivors from the Platinum Study Group found that approximately 80 percent of males had one or more treatment-related adverse events at least one year after completing therapy [16]. The most common side effects included peripheral neuropathy. (See "Treatment-related toxicity in men with testicular germ cell tumors", section on 'Impact of cisplatin-based chemotherapy'.)
Ototoxicity — Patients treated with cisplatin display evidence of cochlear toxicity manifested by high-frequency hearing loss (3 to 8 kHz) and tinnitus [50]. In a mail survey of testicular cancer survivors 35 to 44 years of age, the reported incidence of hearing loss was twice the national average for this age range [51].
The prevalence of hearing loss in testicular cancer survivors is illustrated in the following studies:
●In a cross-sectional study of 1319 testicular cancer survivors, 21 percent reported hearing impairment, and 22 percent reported tinnitus [48]. Patients who received chemotherapy were more likely to have hearing impairment and tinnitus than those who did not, and there was greater risk for those who received more than five cycles of chemotherapy.
●Audiometric testing of 488 male germ cell tumor survivors found a hearing loss of 20 dB or greater in 80 percent of cases, and 18 percent had severe profound hearing loss [52]. Tinnitus was correlated with reduced hearing.
●A detailed study in 952 testicular cancer survivors from the Platinum Study Group found that approximately 80 percent of males had one or more treatment-related adverse events at least one year after completing therapy [16]. The most common side effects included tinnitus and hearing impairment. (See "Treatment-related toxicity in men with testicular germ cell tumors", section on 'Impact of cisplatin-based chemotherapy'.)
Further details on ototoxicity related to platinum-based chemotherapy are discussed separately. (See "Overview of neurologic complications of platinum-based chemotherapy", section on 'Ototoxicity'.)
Nontraumatic osteonecrosis — Nontraumatic osteonecrosis is most commonly seen as a complication of prolonged corticosteroid use. However, it has been reported as a rare complication of chemotherapy, particularly in males treated for testicular cancer. A 2008 literature review identified 54 cases of nontraumatic osteonecrosis, with 70 percent of these reported in testicular cancer survivors, all of whom were treated with cisplatin, bleomycin, vinblastine, and/or etoposide [53]. In these reports, the femoral head was most often affected, with 75 percent experiencing bilateral involvement. However, the overall prevalence appears to be on the order of 1.5 to 4 percent [54,55].
SECONDARY MALIGNANCIES — Testicular cancer survivors have an increased risk of secondary malignancies (ie, subsequent primary cancers), including solid tumors, nonmelanoma skin cancers, and leukemias [56,57]. Contralateral testicular cancers may occur but are not common. (See "Overview of cancer survivorship care for primary care and oncology providers", section on 'Risk of subsequent primary cancer'.)
Solid tumors — Males treated for testicular cancer have at least a twofold increased risk of developing a second solid tumor in their lifetime, especially if prior treatment consisted of both chemotherapy and radiation therapy (RT) [58-62]. This was demonstrated in one study involving 40,576 males [58]. For patients who survived at least 10 years after diagnosis, the relative risk (RR) of developing a solid tumor compared with the general population was reported as follows:
●For patients treated with RT, the RR was 2.0 (95% CI 1.9-2.2).
●For patients who received both RT and chemotherapy, the RR was 2.9 (95% CI 1.9-4.2).
The most common solid tumors arose from the lung, colon, bladder, pancreas, and stomach. The risk of developing a solid tumor increased over time and persisted for at least 30 years after treatment.
The risk of a second malignancy after chemotherapy as a single-modality therapy for testicular cancer appears to be elevated and remains so for years after treatment has completed. This was shown in a population-based study involving almost 13,000 males treated for testicular nonseminomatous germ cell tumors treated with either cisplatin-based chemotherapy or surgery without RT [63]. While there was no increased risk of solid tumors among males treated with surgery, treatment with chemotherapy was associated with the following:
●A significantly increased risk of a solid cancer (standardized incidence ratio [SIR] 1.43, 95% CI 1.18-1.73), with a median latency of 12.5 years
●An increased risk that persisted to more than 20 years after treatment had completed
●An increased risk primarily for thyroid, renal, and soft tissue malignancies
Skin cancers — Testicular cancer survivors are at risk for nonmelanoma skin cancers. This was illustrated in a study on the risk of second malignancies among 29,511 testicular cancer survivors [57]:
●The SIR for melanoma of the skin was 1.62 (95% CI 1.29-2.01).
●For nonmelanoma skin cancer, the SIR was 2.26 (95% CI 1.97-2.57).
In addition, a previous study suggested that testicular cancer survivors were at an increased risk of developing dysplastic nevi compared with healthy controls (37 versus 15 percent, respectively) [64]. In that same population, two testicular cancer survivors ultimately developed melanoma.
Hematologic malignancies — The risk of myelodysplastic syndrome and secondary acute leukemia is also increased after treatment for testicular cancer, particularly when the disease is diagnosed and treated at an early age [65]. In one study involving 18,567 males treated between 1970 and 1993, 36 males (0.2 percent) developed a secondary leukemia [66]. Compared with matched controls, males who developed a secondary leukemia had received a higher total dose of radiation and were more likely to have received a cisplatin-based regimen.
Contralateral testicular cancer — Males with a prior history of testicular cancer are at increased risk for contralateral testicular cancer, although the overall risks are low. In several studies, this risk ranged from 1 to 3 percent over 10 to 20 years of follow-up [67-69]. Therefore, all patients should be instructed to return to their clinician as soon as possible if a contralateral testicular mass is detected. For patients in whom a contralateral testicular cancer is detected, the psychosocial impact may be significant.
CHRONIC FATIGUE — Chronic fatigue, characterized as a subjective sense of tiredness that interferes with usual functioning, has been reported in long-term testicular cancer survivors [70,71]. In one study of 1431 testicular cancer survivors followed for an average of 11 years posttreatment, chronic fatigue was noted in 17 percent compared with 10 percent among 1080 age-matched controls [71]. Chronic fatigue was associated with poor quality of life, psychosocial and somatic problems, and neuroticism. In another study, chronic fatigue was also more common in males who were less physically active and those who smoked [72]. Discussion on chronic fatigue in cancer patients and chronic fatigue syndrome, also known as myalgic encephalomyelitis/chronic fatigue syndrome, are covered separately. (See "Cancer-related fatigue: Treatment" and "Treatment of myalgic encephalomyelitis/chronic fatigue syndrome".)
PSYCHOLOGIC DISTRESS — Various studies highlight the importance of longitudinal follow-up for psychologic distress in long-term testicular cancer survivors [73,74].
Long-term survivors of testicular cancer have been noted to have a higher incidence of anxiety disorder than seen in the general population, but they are not at an increased risk for depression [72,75]. This was illustrated in a study of 1400 testicular cancer survivors evaluated for anxiety and depression using the Hospital Anxiety and Depression Scale [75]. Compared with age-adjusted norms, testicular cancer survivors reported a higher risk of anxiety (relative risk [RR] 1.5, 95% CI 1.3-1.7) but not depression (RR 0.96, 95% CI 0.81-1.14). Factors associated with increased anxiety included: young age, presence of peripheral neuropathy, economic problems, alcohol problems, relapse anxiety, and prior treatment for psychologic problems.
Several observational studies suggest that males with testicular cancer are at increased risk of suicide at long-term follow-up [76,77]. As an example, in one study of over 9000 males treated for stage I seminoma, at a median follow-up of 12 years, 915 (10 percent) of the males had died, and of these, 39 (4 percent) had committed suicide, making it the fifth most common cause of death in these patients [76]. Compared with an age-adjusted general male population, this represented a significantly elevated risk of death due to suicide (standardized mortality ratio 1.45, 95% CI 1.06-1.98).
SURVIVORS AFTER SALVAGE THERAPY — Patients who have relapsed after their initial therapy can often be salvaged and remain disease-free with second or subsequent lines of therapy. However, subsequent lines of therapy are associated with significantly increased toxicity in long-term survivors.
In a retrospective study of 268 patients from the Danish Testicular Cancer database who relapsed after initial radiation therapy and/or chemotherapy, 136 patients eventually died of their germ cell tumor, and 132 were salvaged with one or more chemotherapy regimens [28]. For patients requiring second or subsequent salvage therapy, the risks of death from other causes, second cancer, gastric ulcer, renal failure, and neurologic disease were significantly increased compared with patients who were disease-free after treatment with one line of bleomycin, cisplatin, and etoposide therapy (hazard ratios [HRs] 1.7, 2.6, 3.6, 4.6, and 3.3, respectively).
FOLLOW-UP FOR LONG-TERM SURVIVORS OF TESTICULAR CANCER — In view of the number of possible long-term consequences of treatment for testicular cancer and the young age at which many males undergo treatment [78], long-term follow-up is suggested.
We suggest the following surveillance for long-term testicular cancer survivors, which are generally consistent with published guidelines, including those from the National Comprehensive Cancer Network (NCCN) [79]:
●Complete physical examination annually. Testicular cancer survivors should undergo a complete physical examination annually, with weight and blood pressure recorded. The examination should include a lymph node survey and examination of the contralateral testicle. An examination of the skin for dysplastic nevi should be performed. Particular attention should be paid to cardiovascular, pulmonary, and/or neurologic complaints. There should be a high index of suspicion for second cancers.
●Baseline lipid profile and counseling regarding cardiovascular risk factors.
●Renal function (serum creatinine), serum magnesium (for patients who received cisplatin-based chemotherapy), and serum tumor markers, including alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG), yearly.
●Serial assessment of hormonal function (ie, testosterone and luteinizing hormone levels) on a regular basis, particularly for males treated with chemotherapy or radiation therapy. There are no evidence-based guidelines to inform an optimal surveillance strategy, but a reasonable approach is to test hormonal function annually in long-term survivors, especially in males who may be hypogonadal based on symptoms (eg, poor energy, sexual dysfunction, depression, fatigue) or signs (obesity, small testicular size, poor muscular development).
●Surveillance imaging is typically not recommended beyond five years in asymptomatic patients. However, for testicular cancer survivors who self-report new symptoms, obtaining directed imaging studies based on the symptoms (such as computed tomography [CT] imaging [80] or an ultrasound of the remaining testicle), in addition to scheduled follow-up, may detect a secondary malignancy in these patients.
In a retrospective study of 1057 patients in long-term follow-up (consisting of yearly history, physical examination, germ cell tumor markers, abdominal CT scan, and chest radiograph), 57 males (5.4 percent) developed a secondary malignancy (after a median follow-up of 10 years) [81]. Of these, 54, 29, and 27 percent were detected by patients (or their relatives) due to new symptoms, by non-oncology providers (in the context of a scheduled clinical visit), and during oncologic follow-up, respectively. Symptoms or signs of a second cancer were present in 71 percent of cases. The diagnosis was made based on new findings on imaging in 30 percent.
In addition, patients should be:
●Counseled about the importance of reporting new symptoms early.
●Encouraged to adopt a healthy lifestyle, including a heart-healthy diet, regular exercise, and weight loss when needed to achieve a body mass index <25 [82,83].
●Encouraged to avoid smoking and excess alcohol intake [83]. (See "Treatment of alcohol use and smoking for cancer survivors".)
For those patients with persistent adverse effects from treatment:
●Males suspected of persistent otologic toxicity should be counseled to avoid loud noise. An audiogram should be performed in patients who report hearing loss or tinnitus, especially if there is a prior history of cisplatin therapy. However, clinicians should recognize that causes unrelated to treatment may be responsible for hearing impairment.
●Males with residual peripheral neuropathy should be counseled to avoid exposure to other potential neurotoxins such as alcohol. Our approach utilizes both complementary therapies (eg, physical therapy, massage, and acupuncture) and behavioral modifications aimed at helping patients recognize situations associated with increased symptoms and to avoid them. Pharmacologic options to treat neuropathic symptoms are discussed separately. (See "Overview of polyneuropathy", section on 'Treatment of symptoms and prevention of complications'.)
●Males who report difficulty with fertility issues should undergo a semen analysis and prompt referral to a reproductive endocrine specialist or urologist.
●Males with symptoms of anxiety or distress should be referred for treatment if indicated. Anxiety disorder is somewhat more prevalent in testicular cancer survivors.
●Males with hypogonadism should be offered testosterone treatment. (See "Testosterone treatment of male hypogonadism".)
Oncologic follow-up (with serum tumor markers, chest radiograph, and CT scan of the abdomen or abdomen and pelvis as indicated) should be coordinated between the primary oncology team and the patient's other clinical providers to ensure that services are not duplicated. For long-term cancer survivors, we offer lifelong follow-up at least annually due to the risk of late relapses [4,84,85]. The decision to extend cancer follow-up beyond 5 to 10 years with the oncology care team should be based on patient preference, risk factors for recurrence (eg, histology, risk stratification at diagnosis, treatment exposures, age, and family history, among others), availability of a cancer survivorship program, and discussion with the oncology team.
Surveillance for at least the first five years is discussed separately. (See "Posttreatment follow-up for men with testicular germ cell tumors", section on 'Guidelines for follow-up' and "Overview of cancer survivorship care for primary care and oncology providers", section on 'Coordination of care'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathic pain" and "Society guideline links: Testicular cancer".)
SUMMARY AND RECOMMENDATIONS
●Prognosis – The prognosis for males with testicular cancer is excellent. Nonetheless, compared with the general population, testicular cancer survivors face a higher risk of death from non-cancer causes and long-term complications that may affect long-term quality of life. (See 'Introduction' above.)
●Cardiovascular disease – Testicular cancer survivors are at an increased risk for cardiovascular disease, particularly among males who received chemotherapy or were treated with mediastinal radiation therapy (RT). (See 'Cardiovascular disease' above.)
●Pulmonary toxicity – Testicular cancer survivors are at a slight increased risk of long-term pulmonary toxicity, especially in those who received bleomycin and/or cisplatin and continue to use tobacco. (See 'Pulmonary toxicity' above.)
●Hypogonadism – Hypogonadism can be seen as a potential long-term complication from treatment of testicular cancer, particularly among males treated with extended-field RT or cisplatin-based chemotherapy. It can result in infertility and issues related to sexual dysfunction. (See 'Hypogonadism' above.)
●Renal impairment and neurotoxicity – Males treated with cisplatin-based chemotherapy are at increased risk for both renal dysfunction and neurotoxicity. Renal function (with creatinine and magnesium levels) should be assessed annually in males who received cisplatin-based chemotherapy. (See 'Renal impairment' above and 'Neurotoxicity' above.)
●Secondary malignancy – Males treated for testicular cancer have an increased risk of developing a second malignancy in their lifetime, especially if prior treatment consisted of both chemotherapy and RT. (See 'Secondary malignancies' above.)
●Follow-up – Testicular cancer survivors should undergo a complete physical examination with serum tumor markers annually, with weight and blood pressure recorded. Particular attention should be paid to cardiovascular or neurologic complaints. (See 'Follow-up for long-term survivors of testicular cancer' above.)
•Oncologic follow-up within the first five years following diagnosis should be coordinated between the primary oncology team and the patient's other health care providers to ensure that services are not duplicated. (See 'Follow-up posttreatment' above and "Posttreatment follow-up for men with testicular germ cell tumors", section on 'Guidelines for follow-up'.)
•We offer lifelong annual follow-up for all testicular cancer survivors due to the risk of late disease relapse and second cancers. The decision to extend cancer follow-up with the oncology team beyond 5 to 10 years from diagnosis should be based on patient preference, risk factors for recurrence, availability of a cancer survivorship program, and a discussion with the primary oncology team. (See 'Follow-up for long-term survivors of testicular cancer' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Clair Beard, MD, who contributed to an earlier version of this topic review.
