Treatment-related toxicity in testicular germ cell tumors

INTRODUCTION — Testicular cancers, 95 percent of which are germ cell tumors, are among the most curable solid neoplasms. Testicular germ cell tumors (GCTs) are more sensitive to systemic chemotherapy than any other adult solid tumor. Conventional cisplatin-based regimens can cure up to 80 percent of patients with disseminated GCTs, including those with widespread visceral metastases [1]. An additional group of patients who relapse or have refractory disease can also be cured with further systemic therapy. Since most males with testicular GCTs are long-term survivors, minimizing treatment-related toxicity is a primary concern.

The adverse effects of conventional doses of commonly used chemotherapeutic agents in testicular GCTs are discussed in this topic. The management of long-term survivors and the late effects of radiation therapy are discussed separately. (See "Approach to the care of long-term testicular cancer survivors".)

IMPACT OF CISPLATIN-BASED CHEMOTHERAPY — The long-term disease-free survival for testicular germ cell tumor patients is approximately 95 percent, and these results rely heavily on the use of cisplatin-based chemotherapy regimens for patients with advanced disease. However, cisplatin-based chemotherapy is associated with clinically important long-term toxicities.

An extensive study of the impact of cisplatin chemotherapy on testicular cancer survivors comes from the multi-institutional Platinum Study Group, which assessed a wide range of adverse health outcomes in 952 males [2]. All study participants had been treated with cisplatin-based chemotherapy (predominantly bleomycin, etoposide, and cisplatin [BEP] for three or four cycles or etoposide plus cisplatin [EP] for four cycles). None had received radiation therapy or salvage chemotherapy, and all were disease-free at the time of assessment. The median age was 37 years, and the median time following chemotherapy was 4.3 years. Patients were assessed with a brief physical examination, audiometric testing, and a detailed questionnaire regarding selected health outcomes.

No adverse health outcomes were detected or reported in 20 percent, one or two in 42 percent, three or four in 25 percent, and five or more in 13 percent of cases. The most commonly reported adverse health outcomes were tinnitus, hearing impairment, and peripheral neuropathy in 37, 32, and 27 percent of cases, respectively. A combination of peripheral neuropathy and ototoxicity was observed in 16 percent. The patterns of toxicity were similar with the BEP and EP regimens, except that Reynaud phenomenon and obesity were more common with BEP (12 versus 21 and 26 versus 33 percent, respectively), while peripheral neuropathy was more common with EP (29 versus 21 percent).

Of note, ototoxicity was significantly more frequent when assessed with formal audiometric testing [3]. (See 'Ototoxicity' below.)

HEMATOLOGIC — For males with good-risk testicular germ cell tumors (GCTs), standard dose chemotherapy (three cycles of bleomycin, etoposide, and cisplatin [BEP (table 1)], or four courses of etoposide and cisplatin [EP]) is generally well tolerated. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Good risk'.)

Following each course of chemotherapy, the hematologic nadir will generally occur in week 2 or 3 and may extend into the beginning of the subsequent cycle. A low white blood cell count at the beginning of a subsequent course of chemotherapy does not mandate dose reduction or treatment delay unless the previous cycle was a complicated and significant clinical event, such as febrile neutropenia.

The concept that full doses should be administered at the scheduled time, regardless of the white blood cell count, is important; the curative potential of systemic chemotherapy may otherwise be compromised. While we do not use prophylactic hematopoietic growth factors (eg, granulocyte colony stimulating factors [G-CSF]) at the start of treatment, we recommend initiation of G-CSF in patients who develop low blood cell counts (on day 1 of the subsequent cycle) and those who had a complicated neutropenic event (eg, febrile neutropenia).

In patients treated with first-line chemotherapy who relapse and are subsequently treated with paclitaxel, ifosfamide, and cisplatin (TIP) (table 2), primary prophylaxis with G-CSF is indicated, given the high risk of neutropenic fever with this regimen. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Treatment after three or four cycles of cisplatin-based chemotherapy' and "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".)

PULMONARY

Bleomycin toxicity — The most serious pulmonary toxicities associated with chemotherapy for testicular germ cell tumors (GCTs) are the pneumonitis and pulmonary fibrosis attributed to bleomycin. The incidence of bleomycin lung injury is cumulative, increasing significantly above 450 units. Predictive factors for the development of pulmonary toxicity include advanced age, prior or concurrent thoracic radiation therapy (RT), and renal dysfunction (particularly due to concomitant cisplatin). (See "Bleomycin-induced lung injury".)

Approximately one-half of all treatment-related deaths in males treated with chemotherapy for testicular cancer are due to bleomycin-induced pulmonary fibrosis, which is fatal in 50 percent of patients [1]. The incidence of fatal bleomycin lung toxicity with four cycles of bleomycin, etoposide, and cisplatin (BEP) is 1 to 2 percent, but is less than 1 percent when BEP is limited to three cycles [1,4-8]. This low risk may be due to the fact that bleomycin is generally discontinued if patients show early signs of pneumonitis, although this is unproven.

Signs and symptoms suggestive of early lung toxicity include a non-productive cough, exertional dyspnea, and bibasilar crackles. Pulmonary nodules may be seen on chest imaging studies, although findings do not correlate with long-term damage [9]. Nevertheless, it is standard practice to eliminate further bleomycin if radiographic changes are observed during treatment.

Although pulmonary function tests (PFTs) are neither sensitive nor specific for bleomycin lung toxicity, the best diagnostic tool for early detection is measurement of the diffusing capacity for carbon monoxide (DLCO) [10]. A decline in DLCO may be the earliest sign of lung injury. At most centers, baseline PFTs are established prior to chemotherapy and are then repeated at the start of each new cycle. Several authors recommend that bleomycin be discontinued if the DLCO falls by 40 percent or if it falls to less than 60 percent of an individual's baseline value [11-13]. (See "Bleomycin-induced lung injury".)

Despite the potential for fatal pulmonary toxicity from bleomycin, three or four courses of BEP or cisplatin, vinblastine, and bleomycin (PVB) chemotherapy in males with testicular cancer does not appear to lead to long-term impairment of pulmonary function. The most extensive data come from a series of 565 patients who were evaluated with PFTs before or after treatment [14]. Although DLCO decreased during treatment, it rebounded to normal in most patients with long-term follow-up. Patients who had had pulmonary surgery or a pulmonary embolus, and those in the International Germ Cell Consensus Classification (IGCCC) poor prognostic group were at increased risk for late pulmonary impairment.

Late chemotherapy toxicity — High cumulative doses of cisplatin chemotherapy may also be associated with late impairment of pulmonary function and restrictive lung disease.

Pulmonary function and symptoms were analyzed with spirometry and a symptom questionnaire in a cohort of 1049 five-year survivors who had been treated in Norway between 1980 and 1994 [15]. Patients were divided into five treatment cohorts: orchiectomy only, RT, cisplatin cumulative dose ≤850 mg, cisplatin cumulative dose >850 mg, and cisplatin (any dose) with pulmonary surgery.

At a median observation time of 11 years, the incidence of restrictive physiology was significantly increased in patients treated with high doses of cisplatin or with cisplatin plus pulmonary surgery (18 and 17 percent, respectively, versus 7 percent in patients treated with orchiectomy alone). The observed changes in restrictive physiology were more closely correlated with cumulative cisplatin dose than bleomycin dose, suggesting that cisplatin may also have long-term important effects on pulmonary function.

Clinicians caring for long-term survivors of testicular cancer should be aware of the potential for chemotherapy to adversely affect pulmonary function in some patients.

Prevention of late pulmonary toxicity — Acute respiratory failure from adult respiratory distress syndrome has been reported following general anesthesia in patients previously treated with bleomycin [16,17]. It was suspected that exposure to high concentrations of oxygen could provoke latent pulmonary toxicity by increasing free radical formation in the lungs [4,16]. However, a review of 77 patients undergoing major surgery following bleomycin-containing chemotherapy failed to demonstrate a correlation between perioperative oxygen restriction and either postoperative pulmonary morbidity or survival [18]. These authors suggested that careful fluid management during surgery was more important than oxygen restriction.

Nevertheless, patients treated with bleomycin at any time in the past should not be exposed to high concentrations of inspired oxygen (either in the operating room or elsewhere) unless medically necessary to treat or prevent hypoxemia. When undergoing surgery, fluid balance must be carefully monitored, and intravenous fluids and blood products administered judiciously. These issues are discussed in detail elsewhere. (See "Bleomycin-induced lung injury", section on 'Supplemental oxygen and future perioperative management'.)

RENAL — The general aspects of renal toxicity associated with cisplatin are discussed in detail elsewhere. Here we will focus on the available data in males receiving cisplatin-based regimens for testicular cancer. (See "Cisplatin nephrotoxicity".)

Renal insufficiency — Despite prophylactic measures, such as large volume hydration and diuresis during drug administration, a reduction in the glomerular filtration rate (GFR) develops in a small percentage of patients receiving cisplatin. The incidence and severity of renal failure is correlated with the number of chemotherapy cycles and appears to be partially reversible after treatment is discontinued.

The most extensive data come from a database study of 1206 males treated with bleomycin, etoposide, and cisplatin (BEP) chemotherapy [19]. The GFR was measured prior to treatment, posttreatment, and at one, three, and five years. The decreases in posttreatment GFR for patients receiving 3, 4, or ≥5 cycles of BEP were 11, 15, and 26 percent, respectively. These changes were at least partially reversible. The study also observed a higher than expected incidence of cardiovascular disease and death, but acute changes in GFR did not correlate with the increase in late cardiovascular toxicity. (See 'Cardiovascular' below and 'Noncancer mortality' below.)

Electrolyte disorders — Persistent salt wasting is another manifestation of long-term renal toxicity. In two series, 20 to 30 percent of treated patients had evidence of persisting hypomagnesemia and/or hypophosphatemia an average of four years following chemotherapy [20,21]. One report suggests an even higher proportion of patients with persistent hypomagnesemia, although the clinical significance of this laboratory finding is unknown [22].

Reducing nephrotoxicity — Except for prophylactic measures, such as large volume hydration and diuresis during drug administration, there is no clinically useful method to minimize the risk of nephrotoxicity. Modifications in the treatment regimen that may be associated with a reduced potential for nephrotoxicity include infusional, rather than bolus, bleomycin, substitution of carboplatin for cisplatin, and the use of protective agents, such as amifostine.

Despite its more favorable toxicity profile, carboplatin should not be routinely used in the treatment of testicular GCTs. Although carboplatin is a less nephrotoxic drug than cisplatin, four large randomized trials directly comparing carboplatin with cisplatin in males receiving combination chemotherapy for testicular GCTs have all demonstrated an inferior outcome with carboplatin [23-26]. The use of renal protective agents, such as amifostine, has not been tested in males receiving cisplatin for testicular GCTs.

Drug-induced thrombotic microangiopathy — Drug-induced thrombotic microangiopathy (previously called hemolytic uremic syndrome) is a rare complication of cisplatin, either alone or with bleomycin or vinblastine. (See "Drug-induced thrombotic microangiopathy (DITMA)".)

GONADAL EFFECTS — Fertility issues are of concern for males with testicular cancer for several reasons. Testicular germ cell tumors (GCTs) are commonly associated with certain conditions resulting in impaired Sertoli cell function and spermatogenesis, such as cryptorchidism or testicular atrophy. Some patients develop testicular cancer as part of a developmental condition known as testicular dysgenesis, which is also characterized by hypospadias, cryptorchidism, and poor semen quality [27]. Furthermore, impaired sperm motility, azoospermia, or severe oligospermia is often present in patients with newly diagnosed testicular cancer prior to therapy [28]. (See "Epidemiology and risk factors for testicular cancer" and "Effects of cytotoxic agents on gonadal function in adult men", section on 'Testicular cancer'.)

Spermatogenesis — Orchiectomy may lead to further deterioration in spermatogenesis [29,30]. Cisplatin-based chemotherapy is associated with a dose-dependent impairment in fertility, with defects in spermatogenesis [21,31-35] but not sperm motility [36]. The probability of recovery of spermatogenesis is related to treatment intensity (both the number of cycles of chemotherapy and the administered dose), the age of the patient at the time of treatment, and the severity of pretreatment oligospermia [33,37,38].

●At least one report documents no evidence of long-term fertility impairment following two courses of bleomycin, etoposide, and cisplatin (BEP) chemotherapy administered in the adjuvant setting for stage I disease [39].

●In contrast, after three to four cycles of chemotherapy, most males develop a transient reduction in spermatogenesis that reaches a minimum 10 to 14 months after treatment [29,33,37,40]. Approximately three years later, sperm production recovers in approximately 70 percent of males [31,33,34,38,41-43]. In the largest series evaluating the time course of recovery of spermatogenesis, yearly sperm counts were assessed in 178 males after standard-dose chemotherapy for testicular GCTs [33]. Of the 89 males with normal pretreatment sperm counts, 64 percent were normal at one year. For all males, the probability of recovering some spermatogenesis was 48 and 80 percent at two and five years, respectively. At the same time points, the likelihood of achieving normal sperm counts was 22 and 58 percent, respectively. It should be noted that some males with persistent oligospermia following chemotherapy can successfully father children [32]. (See "Effects of cytotoxic agents on gonadal function in adult men" and "Treatments for male infertility".)

●Higher chemotherapy doses (>400 mg/m² or >850 mg total dose cisplatin) are associated with a higher incidence of persistent azoospermia (approximately 50 percent in several studies [31,38,44,45]).

Hormonal changes — Serum testosterone levels are usually normal before chemotherapy in males with testicular cancer, and they are not consistently altered in the short-term by standard chemotherapy doses [31,36,46-48].

Long-term changes in hormone levels, in contrast, are more prevalent [36,49-52]. In one of the largest series, over 300 testicular cancer survivors originally diagnosed between 1980 and 1994 (median age at diagnosis: 31.5) provided blood samples following orchiectomy at two time points: between 1998 and 2002 (survey I, median age: 42.3) and then between 2007 and 2008 (survey II, median age: 50.4) [52]. Treatment consisted of surgery only, chemotherapy with a platinum-based regimen, or radiation therapy (RT) in approximately 23, 35, and 42 percent of patients, respectively. At survey II, 50 percent of these males had at least one sex hormone level (testosterone, luteinizing hormone [LH], or follicle stimulating hormone [FSH]) outside the normal reference range. Compared with males who were treated with surgery only:

●Males treated with chemotherapy were at significantly higher risk of lower testosterone (odds ratio [OR] 5.2, 95% CI 3.5-7.9), higher FSH (OR 14.2, 95% CI 8.3-24.4), and higher LH levels (OR 3.6, 95% CI 2.4-5.3).

●Males treated with RT were also at significantly higher risk of lower testosterone (OR 3.3, 95% CI 2.3-4.7), higher FSH (OR 18.9, 95% CI 11-32.6), and higher LH levels (OR 4.4, 95% CI 3.1-6.5).

These data suggest that serial evaluation of hormone levels should be performed as part of the long-term follow-up of testicular cancer survivors. (See "Approach to the care of long-term testicular cancer survivors", section on 'Hypogonadism'.)

Other factors that may adversely affect reproductive capability in males with testicular cancer include RT and retroperitoneal lymph node dissection (RPLND). Although older RPLND techniques caused ejaculatory dysfunction in nearly all patients, improvements in surgical technique have reduced the frequency of this complication; furthermore, fewer males undergo RPLND than in the past. (See "Retroperitoneal lymph node dissection for early-stage testicular germ cell tumors" and "Treatment of stage I seminoma", section on 'Adjuvant radiation therapy'.)

Because of these issues, sperm banking is often recommended prior to initiating chemotherapy in young patients who may desire future fertility [53].

CARDIOVASCULAR — Accumulating evidence suggests that vascular toxicity is one of the most important late consequences of cisplatin-based chemotherapy in the treatment of males with advanced testicular germ cell tumors (GCTs). The major cardiovascular issues that have been studied include dyslipidemia, hypertension, early atherosclerosis and coronary artery disease (CAD), Raynaud phenomenon, and thromboembolic events.

Long-term survivors of testicular cancer have an increased risk of developing both an unfavorable cardiovascular risk profile and cardiovascular disease following treatment with chemotherapy [54-57]. Although the observed increase in toxicity may be due in part to these risk factors, other mechanisms, including direct vascular toxicity from the chemotherapy, may have a role [56,58,59].

An increased risk of cardiovascular disease has also been associated with radiation therapy (RT) in patients who receive both subdiaphragmatic and mediastinal RT [55,57]. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

In addition to the late consequences of chemotherapy, an increased risk of early cardiovascular events and cardiovascular mortality has been observed [60-62]. However, this association may be due to disease-related factors rather than a causal relationship linked to chemotherapy.

As an example, in a Surveillance, Epidemiology, and End Results (SEER) database study of 15,006 males treated for nonseminomatous GCT, mortality was significantly increased in those receiving chemotherapy (standardized mortality ratio [SMR] 1.36, 95% CI 1.03-1.78) but not in those treated with surgery alone (SMR 0.81, 95% CI 0.60-1.07). Excess mortality included both heart disease and cerebrovascular disease. The excess mortality was seen predominantly in the first year (SMR 5.31) and subsequently decreased (SMR 1.67 during years 1 to 4, and 1.20 between years 5 and 9).

The pathophysiologic mechanisms underlying cardiovascular toxicity have not been extensively studied [60,63]. While one study showed increased plasma renin and aldosterone activity following chemotherapy [63], others have found no correlation between hypertension and reduced renal function, or alterations in the renin-angiotensin-aldosterone system. (See "Overview of hypertension in acute and chronic kidney disease".)

The metabolic syndrome — The metabolic syndrome (hypertension, dyslipidemia, insulin resistance, and obesity) has been reported in many studies of survivors of testicular cancer and may be associated with the cumulative dose of chemotherapy [64-68]. This syndrome has been recognized as a proinflammatory, a prothrombotic state that is associated with elevated levels of C-reactive protein, interleukin (IL)-6, and plasminogen activator inhibitor-1, increasing the risk for subsequent cardiovascular disease and type 2 diabetes. The etiology of the metabolic syndrome in testicular cancer survivors is unclear. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)

Hyperlipidemia — Males receiving chemotherapy for testicular cancer have alterations in their lipid profiles, possibly due to endocrinologic disturbances [50,69,70]. In one series with a detailed lipid analysis, males previously treated with chemotherapy had a higher mean total cholesterol, a higher ratio of total to high-density lipoprotein (HDL) cholesterol, and more triglycerides compared with those undergoing orchiectomy alone [71]. The previously described study with 10-year follow-up after chemotherapy documented a mean increase in total cholesterol from 181 mg/dL pretreatment to 233 mg/dL posttreatment [72]. (See "Screening for lipid disorders in adults".)

Hypertension — Chemotherapy can increase blood pressure and cause hypertension [50,57,70-74]. This was illustrated by a series that compared 500 long-term survivors treated with cisplatin-containing chemotherapy with those treated with surgery alone (n = 242), RT (n = 547), or a control group of healthy males (n = 2847); those treated with chemotherapy had a higher prevalence of hypertension than surgically treated patients or controls [74]. The incidence of hypertension was higher in those patients who had received the highest cumulative doses of cisplatin (>850 mg).

Myocardial ischemia — Several large series have shown that there is an increased risk of ischemic events in long-term survivors of testicular GCTs [54,56,57,74,75]. In one report, the incidence of ischemic heart disease in 2512 long-term survivors in the Netherlands was compared with that of the general population [54]. The standardized incidence ratio for angina or myocardial infarction was 1.17 (95% CI, 1.04-1.31). Factors associated with an increased risk of myocardial infarction included mediastinal irradiation and the use of a cisplatin-containing chemotherapy regimen.

Raynaud phenomenon — The Raynaud phenomenon resulting from chemotherapy for GCTs was first described in 1977 [76]. Both bleomycin and cisplatin have been implicated as causes of secondary Raynaud phenomenon. The incidence is approximately 20 to 40 percent, depending on drug dose and regimen, methods of drug administration, electrolyte levels, and individual risk factors [72,77,78]. Although some series have suggested a correlation between hypomagnesemia and Raynaud phenomenon [79], others have failed to confirm this association [72,73]. In one report, hypertension, but not tobacco use, increased the risk of developing Raynaud phenomenon in association with chemotherapy for testicular cancer [72].

Symptoms may begin at any time during treatment and up to three years after the completion of chemotherapy. The particular chemotherapy regimen is of some importance. As an example, in one cohort of 60 males with testicular GCTs receiving chemotherapy, 37 percent developed Raynaud phenomenon within one year, and the incidence was higher with cisplatin, vinblastine, and bleomycin (PVB) compared with vinblastine and bleomycin (VB) without cisplatin (41 versus 21 percent) [79]. In a second series of 90 patients, the incidence of Raynaud phenomenon was significantly higher in males receiving PVB compared with cisplatin, etoposide, and bleomycin (PEB; 57 versus 25 percent) [72]. Furthermore, continuous infusion bleomycin was associated with a lower incidence than bolus infusion bleomycin [72]. There may be a role for calcium channel blockers in treatment of chemotherapy-induced Raynaud phenomenon [80]. The treatment of Raynaud phenomenon is discussed elsewhere. (See "Treatment of Raynaud phenomenon: Refractory or progressive ischemia".)

Thromboembolic events — The incidence of thromboembolic events, mainly deep vein thrombosis and pulmonary embolism, is increased in males who are undergoing cisplatin-based therapy for GCTs [81,82]. At least one report suggests that a high body surface area (>1.9 m²) and elevated serum levels of lactate dehydrogenase (LDH) predispose patients to thromboembolic events [82]. The risk of a thromboembolic event during therapy was 4 and 26 percent for males with no risk factors and those with at least one risk factor, respectively.

Rare arterial vascular events following treatment have been reported as well. However, the small number of cases and the limited duration of follow-up have prevented confirmation of this association [71,83].

Changes in body metabolism — It has been hypothesized that long-term cardiovascular side effects may be a result of metabolic changes rather than of the chemotherapy itself. Some data show that survivors of chemotherapy-treated testicular cancer have a disproportionate annual increase in body mass index (BMI) [65,70,74]. However, others suggest that this is related to hormonal and age-related changes rather than to chemotherapy [84]. In at least one report of long-term survivors, males undergoing orchiectomy alone for testicular cancer had similar increases in BMI to those who also received chemotherapy [56].

Patients cured of testicular cancer also have a greater than average level of physical activity, likely as a psychological consequence of their experience with cancer [85].

Summary — Males who have been treated for testicular GCTs require long-term follow-up that includes a focus on the potential for cardiovascular complications and interventions to reduce the risk of myocardial ischemia. Current guidelines recommend screening for hypertension every two years in individuals over the age of 20 and checking a lipid profile every five years. (See "Posttreatment follow-up for testicular germ cell tumors" and "Overview of established risk factors for cardiovascular disease".)

NEUROLOGIC — Neurologic toxicity is common during treatment. The main culprit is cisplatin, which causes both a distal, mainly sensory, neuropathy with motor sparing and ototoxicity.

Neuropathy

Cisplatin — Cisplatin causes an axonal neuropathy that affects predominantly large myelinated sensory fibers. The primary site of damage is the dorsal root ganglion, but the peripheral nerve is also affected. This topic is discussed in detail elsewhere. (See "Overview of neurologic complications of platinum-based chemotherapy", section on 'Cisplatin'.)

Most males experience some degree of neuropathy during chemotherapy for testicular cancer [86,87], and further deterioration in the three months following chemotherapy may occur [88]. Patients typically complain of paresthesias, dysesthesias, and disturbances in vibratory and position sense that begin in the toes and fingers, and spread proximally. Patients with mild neuropathy can continue to receive full doses of cisplatin; however, once the neuropathy becomes more severe and begins to interfere with neurologic function, the clinician must weigh the risk of potentially disabling neurotoxicity against the benefit of continued treatment.

The neuropathy eventually improves in most patients, although recovery is often incomplete [77]. Persistent symptomatic sensory neuropathy is reported in approximately 20 to 30 percent of cases [77,78]. Prophylactic strategies, such as pretreatment with amifostine, have been partially successful in delaying or preventing the development of cisplatin-induced neuropathy, but use of this agent is not routine in the treatment of testis cancer. (See "Overview of neurologic complications of platinum-based chemotherapy", section on 'Cisplatin'.)

Paclitaxel — Paclitaxel, as part of the TIP regimen for relapsed or refractory testicular germ cell tumors (table 2), is an antimicrotubule agent that can cause peripheral neuropathy. The most common neuropathy caused by paclitaxel involves sensory nerve fibers [89]. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Treatment after three or four cycles of cisplatin-based chemotherapy'.)

For patients without pre-existing neuropathy who are treated with TIP, the concurrent administration of cisplatin is a risk factor for developing paclitaxel-induced sensory neuropathy. Pre-existing neuropathy is also a risk factor for sensory neuropathy with paclitaxel, as some patients who are treated with TIP may already have sensory neuropathy from prior exposure to cisplatin during initial therapy. Further details on the risk factors for sensory neuropathy with paclitaxel are discussed separately. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Paclitaxel'.)

Vinblastine — Vinblastine is also a neurotoxin. Replacement of vinblastine with etoposide has reduced the incidence of treatment-related neuropathy [1]. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Other vinca alkaloids'.)

Ototoxicity — Another common cisplatin-related neurologic effect is ototoxicity, manifested by high-frequency sensorineural hearing loss and tinnitus. (See "Overview of neurologic complications of platinum-based chemotherapy", section on 'Ototoxicity'.)

Although some degree of hearing loss is reported by approximately one-half of patients undergoing chemotherapy for testicular cancer, audiometric hearing loss can be detected in almost 90 percent and is often accompanied by tinnitus [3]. Although hearing loss may partially resolve over time, audiometric testing has found that approximately 80 percent of survivors will still have significant hearing loss after four years based on audiometric criteria. The risk of cisplatin-induced ototoxicity is both dose- and schedule-dependent [3,90,91]. Other risk factors include the concurrent administration of other ototoxins and exposure to loud noise (including loud music) [90,92].

Cognitive functioning — Impaired cognitive function and structural changes on imaging have been observed in patients treated with cisplatin-based chemotherapy [93-96]. (See "Cognitive function after cancer and cancer treatment".)

SECOND MALIGNANCIES — Second primary cancers have emerged as a leading cause of death among testicular cancer survivors.

Solid tumors — The risk of developing or dying from a second malignancy is two to three times greater in survivors of testicular cancer than in the general population [55,75,97-100].

The largest study to date included 40,576 testicular cancer survivors from 14 population-based tumor registries in Europe and North America; more than 7800 were followed for 20 years, and 2065 were followed for 30 years [97]. Among the most important findings were:

●Among 10-year survivors diagnosed with testicular cancer at an average age of 35 years, the relative risk (RR) of developing a solid tumor relative to expected rates in males from the same registration area of similar age was 1.9 (95% CI 1.8-2.1). Risk remained significantly elevated for at least 35 years. The cumulative risk of developing a solid cancer by age 75 (ie, 40 years after treatment) for males with seminoma and nonseminoma histology was 36 and 31 percent, respectively, compared with 23 percent for the general population.

●Cancer of the lung (RR 1.5, 95% CI 1.2-1.7), colon (RR 2.0, 95% CI 1.7-2.5), bladder (RR 2.7, 95% CI 2.2-3.1), pancreas (RR 3.6, 95% CI 2.8-4.6), and stomach (RR 4.0, 95% CI 3.2-4.8) accounted for almost 60 percent of the total excess number of solid tumors. In contrast to other studies, this study found that risks were also elevated for mesothelioma (RR 3.4, 95% CI 1.7-5.9) and esophageal cancer (RR 1.7, 95% CI 1.0-2.6). Among males receiving radiation therapy (RT) alone, sites in typical infradiaphragmatic RT fields (ie, bladder, stomach, pancreas, kidney) accounted for 64 percent of the excess cancers.

●The RR and excess absolute risk of a second cancer decreased with increasing age at diagnosis of testicular cancer. As an example, a male diagnosed with seminoma at age 20 would have a 47 percent predicted cumulative risk of a solid cancer by age 75; the corresponding rates for a male diagnosed at age 35 or 50 would be 36 and 28 percent, respectively.

●Overall patterns were similar for seminoma and nonseminoma, although lower risks were observed for nonseminoma patients treated after 1975.

●An increased risk of second solid cancers was seen among males treated with RT alone (RR 2.0, 95% CI 1.9-2.2), chemotherapy alone (RR 1.8, 95% CI 1.3-2.5), and with both modalities (RR 2.9, 95% CI 1.9-4.2).

Leukemia — Males with testicular germ-cell tumors (GCTs) who undergo chemotherapy are also at an increased risk of developing leukemia. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

The contribution of RT to risk has not been well characterized. Contemporary studies evaluating large numbers of treated males suggest that the incidence of secondary leukemia is low, <0.5 percent, following a typical three- or four-cycle course of bleomycin, etoposide, and cisplatin (BEP), in which the cumulative etoposide dose is <2000 mg/m² [97,101].

In contrast, prolonged use of high doses of etoposide is associated with a significantly higher risk of secondary myelogenous leukemias that are highly refractory to treatment. Epipodophyllotoxin-induced leukemia is characterized by an onset two to three years following treatment and a hallmark chromosomal translocation involving the long arm of chromosome 11 (11q23) [102]. The risk of secondary leukemia may be as high as 5 percent in those receiving more than 2000 mg/m², representing a 336-fold increase in the likelihood of leukemia [101,103-109]. (See "Acute myeloid leukemia: Cytogenetic abnormalities".)

Combination chemotherapy cures a substantial number of males with advanced testicular GCTs, including 90 percent of those with good-risk advanced disease (see "Initial risk-stratified treatment for advanced testicular germ cell tumors"). Risk-benefit analyses have concluded that the benefit of standard-dose chemotherapy regimens in advanced GCTs outweighs the risk of treatment-related leukemia. In one review of 18,000 testis cancer survivors, it was estimated that, following standard-dose chemotherapy, 16 cases of secondary leukemia would be expected in 10,000 treated males.

Treatment outcome — Concerns exist that second malignancies in testicular cancer survivors might have a worse prognosis due to either late treatment effects preventing effective therapy or altered biology caused by the original treatment [110]. Despite these issues, testicular cancer survivors who develop a second primary malignancy appear to have a similar outcome to comparable patients with a first primary malignancy.

In a study of 29,356 males with testicular cancer from the Surveillance, Epidemiology, and End Results (SEER) database, 621 cases were identified with a second cancer of known stage [110]. These were compared with 12,420 males with a first primary malignancy; patients were matched for primary site, stage at diagnosis, year of diagnosis, and age. There was no significant increase in either cancer-related mortality (hazard ratio [HR] 1.05, 95% CI 0.90-1.23) or all-cause mortality (HR 1.09, 95% CI 0.96-1.23) compared with the control population.

The one exception was testicular cancer patients treated between 1973 and 1979, a period when substantially higher doses of RT were used, and RT often included treatment to the thorax. In that subset, there was a significant increase in both cancer-related mortality (HR 1.44, 95% CI 1.13-1.83) and overall mortality (HR 1.65, 95% CI 1.12-2.42).

Mitigating risk due to surveillance imaging — Guidelines for posttreatment surveillance of males with GCTs include numerous computed tomography (CT) scans over many years. As in other situations requiring repeated exposure to radiation, concern has been raised that the surveillance CT scans may themselves carry a risk of promoting malignancy [111,112]. (See "Radiation-related risks of imaging".)

●The theoretical added lifetime risk may range from 1 to 2 percent for survivors of GCTs, though this number is modeled not on clinical studies in testicular cancer but on data extrapolated from Hiroshima and other radiation exposure situations [113].

●In a targeted study of males with GCTs, no added risk of second malignancies was identified in over 2500 males, though with only limited follow-up [114].

Clinicians should take into account the age of patients undergoing surveillance when planning the frequency of imaging (particularly by CT), given concerns about second malignancies induced by radiation exposure. Attempts to lower the radiation exposure associated with CT scans with lower radiation dose CT scans or alternative use of magnetic resonance imaging (MRI) may be appropriate to diminish this risk. However, long-term data about the efficacy of these alternate approaches are not available. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Radiographic studies' and "Approach to the care of long-term testicular cancer survivors", section on 'Follow-up for long-term survivors of testicular cancer'.)

NONCANCER MORTALITY — Chemotherapy-related toxicity is associated with a small, but statistically significant, increase in late noncancer mortality [19,115]. This was illustrated by a multicenter tumor registry study involving almost 39,000 testicular cancer patients in which noncancer deaths exceeded that expected in the general population by 6 percent (standardized mortality ratio [SMR] 1.06, 95% CI 1.02-1.10) [115]. Although the magnitude of this risk is small, attention to cardiovascular risk factors is important. (See 'Cardiovascular' above.)

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: Testicular cancer".)

SUMMARY

●Late treatment-related toxicities in testicular GCTs – Testicular germ cell tumors (GCTs) are remarkably sensitive to multiple chemotherapy regimens and are curable in approximately 95 percent of patients. Since most males with testicular GCTs are long-term survivors, minimizing the late effects of treatment is a primary concern. Late treatment-related toxicities can affect multiple organ systems, such as:

•Pulmonary – Bleomycin can cause pneumonitis and pulmonary fibrosis. (See 'Pulmonary' above and "Bleomycin-induced lung injury".)

•Renal – Cisplatin is an integral component of the most effective chemotherapy regimens. Cisplatin is nephrotoxic and can be associated with a decrease in the glomerular filtration rate. (See 'Renal' above and "Cisplatin nephrotoxicity".)

•Fertility – Testicular GCTs are often associated with impaired spermatogenesis. Treatment (orchiectomy, chemotherapy, radiation therapy) can further impair spermatogenesis. (See 'Gonadal effects' above and "Effects of cytotoxic agents on gonadal function in adult men".)

•Cardiovascular – Vascular toxicity is one of the most important late consequences of cisplatin-based chemotherapy regimens. Major cardiovascular issues include dyslipidemia, hypertension, early atherosclerosis and coronary artery disease, Raynaud phenomenon, and thromboembolic events. (See 'Cardiovascular' above.)

•Neurotoxicity – Neurologic toxicity is common during treatment. This is primarily associated with cisplatin, which typically causes sensory neuropathy with motor sparing and ototoxicity, paclitaxel, and vinblastine. (See 'Neurologic' above and "Overview of neurologic complications of platinum-based chemotherapy" and "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Vinca alkaloids'.)

●Second malignancies – Both chemotherapy and radiation therapy have been associated with late secondary malignancies, which are more common in testicular GCT survivors than in the general population. (See 'Second malignancies' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William K Oh, MD, who contributed to earlier versions of this topic review.