Abstract: Over the past half century, advancements in treatment have led to cures in an overwhelming majority of patients with testicular germ cell tumors. Astute clinical decision-making, informed by the abundant data from published clinical trials, is essential for achieving a cure whenever possible and minimizing the toxicity of treatment. Important remaining challenges include reducing the risk of secondary malignancies and other late effects of chemotherapy and radiation therapy, and developing curative treatments for patients with cancer that is refractory to current therapies. This article reviews the current treatment landscape and highlights recent discoveries in diagnosis and staging, emerging biomarkers for disease, and treatment for relapsed/refractory disease. Treatment algorithms for testis cancer are complex and clinicians should apply them carefully, not only to optimize short-term, disease-related outcomes, but also to maximize long-term survival and quality of life.
Introduction
Although testis cancer represents less than 1% of all new cancer cases and 0.1% of all cancer deaths, it remains the most common cancer among young men in developed nations.1,2 Germ cell tumors (GCTs) are the predominant histology; less-common pathologies include lymphomas and sex cord–stromal tumors. Prognoses for patients with testicular cancer are generally favorable, and most patients with metastatic disease can be cured.3,4 Undertreatment can result in avoidable treatment failures, whereas overtreatment can result in unnecessary toxicity. We provide a clinically pragmatic review of GCTs in postpubertal males, including current management paradigms, recent advancements, and opportunities for future investigation.
Epidemiology and Biology
The vast majority of testicular GCTs in adolescent and adult males are type II testicular GCTs, which arise from germ cell neoplasia in situ and are associated with extra copies of the short arm of chromosome 12, often manifesting as isochromosome 12p.5 Type II testicular GCTs are thought to arise from primordial germ cells and can develop into multiple different histologies, including seminoma, embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma. When a tumor is 100% seminoma, it is referred to as a seminoma. If any other elements are present, even if the tumor is 99% seminoma, the tumor is referred to as a nonseminoma or nonseminomatous germ cell tumor (NSGCT). Seminomas represent 50% to 60% of testicular GCTs.6 Most NSGCTs represent a mix of different histologies and are sometimes referred to as mixed GCTs. GCTs are associated with the serum tumor markers alpha fetoprotein (AFP), beta human chorionic gonadotropin (β-HCG), and lactate dehydrogenase (LDH), but none of these are pathognomonic for testis cancer or GCTs. Seminomas do not produce AFP, and an elevated AFP thus indicates the presence of nonseminomatous elements. Type III testicular GCTs are referred to as spermatocytic tumors.7 They were previously labeled as spermatocytic seminomas, but they are biologically distinct from seminomas and have a much more benign natural history.8
Testis cancer is the most common cancer among adolescent and young adult males (typically between the ages of 15 and 40 years) in many Western nations. There is a significant incidence of testis cancer until age 60 years, after which it is rare. Great variation in incidence exists among different regions, with higher rates in Europe, North America, and Oceania than in Africa or Asia.9 Similarly, it is more common in more-developed than less-developed regions. Clearly identified risk factors include cryptorchidism, a personal or family history of testis cancer, and HIV/AIDS. Having a first-degree relative with testis cancer is associated with a substantially elevated risk, especially if the relative is a brother.10 Male infertility is also associated with an increased risk of developing testis cancer.5
Over the last century, the incidence of testis cancer has been rising substantially, albeit with great regional variation.9,11,12 The rate of increase is slowing significantly in developed nations but not in low- and middle-income countries.13 Testis cancer mortality has declined dramatically in developed countries owing to improvements in treatment, but remains high in the developing world. The incidence to mortality ratio is 2:1 in parts of Asia and Africa vs 26:1 in Northern Europe.13 Increases in incidence suggest an environmental cause, but specific environmental factors have not been definitively identified. The rise in testis cancer incidence has been accompanied by a rise in congenital genitourinary anomalies in baby boys as well as declining sperm counts. Common pathways have been hypothesized that focus on endocrine disrupters in the environment, such as phthalates and certain pesticides.14 However, no chemicals have been definitively linked to the risk of developing testis cancer.5 Because the suspected cell of origin for malignant GCTs is a primordial germ cell that is only present prior to birth, an association with prenatal environmental exposures has been suspected. The strong association between birth cohort and testis cancer incidence also supports the hypothesis that prenatal or early childhood exposures may be key.15
Diagnosis, Staging, and Prognostic Groups
Postpubertal males with testis cancer typically present with a testicular mass, but they may also present with testicular pain, testicular atrophy, or gynecomastia. They may also present with the signs, symptoms, or complications of metastatic disease, such as back pain (from retroperitoneal [RP] adenopathy) or thromboembolic disease. A male suspected of having testis cancer should undergo a transscrotal ultrasound. If a tumor is detected, an inguinal orchiectomy should be performed promptly to remove the involved testis and establish a histologic diagnosis. The serum tumor markers AFP, β-HCG, and LDH should ideally be measured before and after orchiectomy. Imaging studies should include a computed tomography (CT) or magnetic resonance imaging (MRI) scan, both with intravenous contrast of the abdomen and pelvis, and a chest CT scan. For seminomas, a chest x-ray is adequate for thoracic imaging if abdominal and pelvic imaging does not reveal metastatic disease. Sperm banking should be offered to patients prior to orchiectomy if the procedure will leave them with no functioning testicle as well as to all patients prior to undergoing chemotherapy, radiation therapy, or RP lymph node dissection.
There are 3 stages of testis cancer. Stage I GCTs are confined to the testis and epididymis (invasion of the spermatic cord or scrotum may be present), stage II GCTs include metastatic disease to the RP lymph nodes, and stage III GCTs are characterized by metastatic disease beyond the RP lymph nodes. However, NSGCTs with RP lymph node metastases are considered stage III rather than stage II if there are highly elevated postorchiectomy serum tumor markers (AFP >1000 ng/mL, β-HCG >5000 mU/mL, or LDH >1.5 times the upper limit of normal). In testis cancer, pelvic lymph node metastases are considered distant metastases because the testes’ lymphatic drainage is to the retroperitoneum.
It is essential to note that for staging purposes, it is the postorchiectomy values of serum tumor markers that matter. If the markers are elevated prior to orchiectomy and return to normal afterward, then they are considered normal for staging purposes. The biological half-life of AFP is less than 7 days, although that of β-HCG is less than 3 days. For patients undergoing treatment with chemotherapy, the serum tumor marker levels on day 1 of the first cycle of chemotherapy should be used for staging and risk stratification.16
The eighth edition of the American Joint Committee on Cancer staging manual included minor changes to pathologic staging. These changes included subdividing pure seminomas based on the size of the primary tumor (using a 3-cm cutoff), categorizing epididymal and hilar soft tissue invasion as pT2 disease, and considering discontinuous spermatic cord involvement as M1 disease.17 Although these changes may result in upstaging of disease, whether or not this upstaging should lead to changes in clinical practice remains unclear.18 Upstaging localized disease could result in more frequent administration of adjuvant therapy or treating localized disease as systemic disease. Most metastatic GCTs can be cured, so more aggressive treatment based on upstaging may expose more patients to treatment-related toxicity without improving overall prognosis.
The tumor markers AFP, β-HCG, and LDH are important in staging, risk stratification, diagnosis, and surveillance of GCTs. However, these tumor markers are not 100% sensitive nor 100% specific, as evidenced by the fact that roughly 25% of stage I NSGCTs and 18% of stage I seminomas relapse despite having had normal tumor markers prior to relapse, and a substantial proportion of patients have normal markers when metastatic disease is detected. Given these limitations, researchers are searching for improved biomarkers, with microRNAs as a leading candidate. MicroRNAs are noncoding RNAs involved in gene expression regulation and can become dysregulated in patients with cancer, contributing to carcinogenesis.19 For patients with GCTs, miR-371a-3p in particular has demonstrated promise, predicting active germ cell malignancy with high specificity and positive predictive value.20 In the largest prospective study to date involving 616 patients with testicular GCTs and 258 controls, Dieckmann and colleagues noted that serum levels of miRNA-371a-3p by polymerase chain reaction testing had a sensitivity of 90.1% and a specificity of 94% when used for the primary diagnosis of GCT, significantly outperforming conventional tumor markers. Notably, miR-371a-3p correlated with tumor size and stage, changed with treatment effects, and was elevated in recurrences.21 Several prospective clinical trials are underway that are examining this technology in a multitude of clinical scenarios.
Imaging
Ultrasound is the preferred imaging modality for detecting testicular masses. Staging of patients diagnosed with testis cancer should include CT scans of the abdomen and pelvis, and either a chest x-ray or CT scan of the chest. MRI scans can be used as an alternative for abdominopelvic imaging, but consistency of modalities should be maintained during surveillance.22-24 Outside of assessing postchemotherapy residual masses for patients with pure seminoma, positron emission tomography (PET) scans have limited value and should not be routinely performed. PET scans should not be used to assess treatment response for residual masses in patients with NSGCTs.
Stage I
Seminoma
The prognosis for stage I seminoma is excellent, and most patients are cured by the orchiectomy alone. Postoperatively, patients can be managed with surveillance, adjuvant radiation therapy, or adjuvant chemotherapy. Most major guidelines recommend surveillance as the preferred management for stage I seminoma.25-27 Multiple studies have reported 99% or higher disease-specific survival with surveillance. Surveillance offers the benefit of reducing the risk of exposure to radiation therapy or chemotherapy, both of which are associated with acute and late toxicities.28-30
For patients in whom surveillance is not preferable (eg, patient preference or concerns regarding adherence to surveillance schedule), we recommend single-agent carboplatin over radiation owing to studies reporting an increased mortality from secondary malignancies following radiation therapy.31-33 A randomized controlled trial comparing a single dose of carboplatin (area under the curve, 7 mg/mL per minute) to radiation therapy demonstrated similar relapse-free rates at 5 years (94.7% vs 96.0%) and a clear reduction in contralateral GCT (hazard ratio, 0.22; 95% CI, 0.05-0.95; P=.03) for patients treated with carboplatin.34
Several phase 2 studies reported consistently lower relapse rates with 2 doses of carboplatin, and we prefer 2 doses over a single dose.35 For example, the Spanish Germ Cell Cancer Group reported that 10-year disease-free survival was 97% and 10-year overall survival (OS) was 100% among 412 patients with clinical stage I seminoma who were at higher-than-average risk of relapse; these patients were treated with 2 doses of carboplatin (area under the curve, 7 mg/mL per minute) 21 days apart.36 (Carboplatin and other common chemotherapy regimens used to treat GCTs are listed in Table 1.) However, surveillance is the preferred approach for patients who are willing and able to undergo surveillance owing to the concern about the potential risk of secondary malignancies and other late toxicities from carboplatin.
Nonseminoma
For patients with clinical stage I nonseminoma and normal serum tumor markers, reasonable postoperative management options include surveillance, adjuvant chemotherapy, and nerve-sparing RP lymph node dissection (RPLND). The presence of lymphovascular invasion (LVI) or a predominance of embryonal carcinoma histology are risk factors for relapse, although LVI appears to be the strongest risk factor.37 One retrospective study of patients managed with active surveillance noted relapsed disease in 44% in patients with LVI vs 14% of those without LVI.38 Prospective trials using either 1 or 2 cycles of adjuvant bleomycin, etoposide, and cisplatin (BEP) have reduced recurrence rates to less than 5%.39,40 Although a German randomized trial demonstrated improved 2-year recurrence-free survival with adjuvant BEP over RPLND (99% vs 92%, respectively), the authors noted a relatively high rate of RP relapses in this community-based study, in contrast to only 1.2% of patients in a tertiary care–based single-arm study.40,41 Thus, although RPLND can be an appropriate treatment to reduce recurrence risk while avoiding toxicity from chemotherapy, consideration of a surgical team’s expertise is recommended. Although there can be toxicity and complications from adjuvant chemotherapy or RPLND, patients managed with surveillance who experience disease relapse will often require higher-intensity and longer-duration treatment. All options are appropriate, as disease-specific survival approaches 99% regardless of initial postoperative management. Most guidelines favor surveillance for low-risk disease but differ on the preferred option for high-risk disease.25-27 Shared decision-making is important, particularly for high-risk disease.42
If tumor markers are persistently elevated after orchiectomy and imaging studies show no metastatic disease, the disease is classified as stage IS and should be treated similar to metastatic NSGCTs based on risk stratification.
Stage II
Seminoma
Stage II seminoma is generally treated with either radiation therapy or chemotherapy (BEP × 3 or EP × 4). Historically, radiation therapy has been favored for less bulky disease (IIA and early stage IIB), although chemotherapy has been favored for bulkier disease.43 Cutoffs of 3 cm and 5 cm have been used to recommend chemotherapy over radiation therapy. The preference of chemotherapy for men with bulkier disease is based on studies showing high relapse rates after radiation in such patients.44,45 For patients with less bulky disease, chemotherapy and radiation therapy appear to have similar efficacy. However, in the absence of randomized controlled trials, it is impossible to definitively recommend one modality over the other. Numerous case series have reported the outcomes of chemotherapy and radiation therapy for stage II seminoma with varying results.44-49 A systematic review of studies published from 2010 to 2021 reported that relapse-free survival relapse rates were similar with radiation therapy (0%-4%) and chemotherapy (0%) in stage IIA disease, whereas the relapse rate was higher with radiation (9.5%-21.1%) than chemotherapy (0%-14.2%) in stage IIB disease.50 Five-year OS ranged from 90% to 100%. Although some studies have investigated combining carboplatin with involved-field radiation therapy, this approach remains investigational.51
Given the concerns for secondary malignancies and other significant treatment-related toxicity associated with both radiation and chemotherapy, RPLND continues to be explored in this population.52-54 Recent studies of RPLND have reported relapse rates as high as 30%, which is substantially higher than those for radiation therapy or chemotherapy. However, the benefit of reducing the risk of secondary malignancies and other late effects from those modalities may be greater than the benefit of a lower relapse rate.55-57 Depending on the results of ongoing studies of RPLND for stage II seminoma, it may become another standard treatment option in the future, but cannot be recommended outside of a clinical trial at this time. Stage IIC disease (any lymph node >5 cm) should be treated with primary chemotherapy only.
Nonseminoma
Stage IIA. Treatment options for stage II NSGCT include RPLND and chemotherapy (BEP × 3 or EP × 4). Treatment recommendations for stage II NSGCT are largely influenced by lymph node size. If RP lymph nodes are no larger than 2 cm across at their greatest diameter, primary RPLND can cure the majority of patients (80%-90%) and pathologically downstage some patients to stage I if tissue shows no active GCT in the RP nodes. This gives the patient a greater likelihood of avoiding the acute and late toxicity of chemotherapy. If RPLND reveals either pathologic stage I or IIA disease, then the standard practice is surveillance, though adjuvant chemotherapy can be considered for stage IIA disease. The risk of relapse for stage IIA disease is only approximately 10%, and a trial comparing adjuvant chemotherapy to surveillance for pathologic stage II disease reported no difference in OS. Adjuvant chemotherapy with 2 cycles of EP is recommended for patients with pathologic stage IIB or IIC disease because they are at much higher risk of relapse (approximately 50%), and adjuvant chemotherapy reduces that risk to approximately 1%.58,59
Stage IIB/C. If nodes are more than 2 cm across at their greatest diameter, primary chemotherapy (BEP × 3 or EP × 4) is generally preferred over RPLND because the relapse rates for bulky disease are higher. Nonrandomized data suggest improved outcomes when selecting primary treatment modality (chemotherapy vs RPLND) based on risk factors, such as lymph node size.60
Stage III
Unlike other solid tumor malignancies, GCTs tend to be very sensitive to platinum-based chemotherapy, and most patients with metastatic disease can be cured. Risk stratification using the International Germ Cell Consensus Classification staging system should guide treatment decisions.61 Stratification criteria appear in Table 2.
Good Risk
Good-risk disease should preferably be treated with 3 cycles of BEP. For patients at increased risk of bleomycin pulmonary toxicity (eg, >50 years of age, chronic kidney disease, or chronic obstructive pulmonary disease or other serious lung disease) or wanting to avoid exposure to bleomycin, an alternative is 4 cycles of EP. A randomized trial of 257 patients with good-risk metastatic NSGCTs reported more deaths in the EP arm (12 vs 5) and a slightly inferior event-free survival rate (86% vs 91%), but these differences were not statistically significant.62 Dose reductions should be avoided, given that a randomized trial of a deintensified BEP regimen resulted in inferior survival compared with standard BEP for good-risk nonseminomas.63 Similarly, carboplatin should not be substituted for cisplatin, given that carboplatin-based regimens have consistently been found to be inferior to cisplatin-based regimens.64-66 The prognosis for good-risk disease is favorable, with a 5-year OS of approximately 90%.61
Patients with good-risk disease includes those with seminoma whose metastases are limited to lymph nodes and lungs, regardless of serum tumor marker levels. However, many experts consider a very high β-HCG (eg, >1000 mU/mL) to be incompatible with pure seminoma, regardless of histopathologic findings, and an elevated AFP indicates that the tumor is not a pure seminoma. The question of whether to take LDH levels into account is harder to resolve because a recent international study reported that an LDH level greater than 2.5 times the upper limit of normal was associated with a worse prognosis among otherwise good-risk seminoma patients (3-year progression-free survival [PFS] and OS of 80% and 92%, respectively, vs 92% and 97% for other good-risk patients).67 Whether such patients should be treated as having intermediate-risk disease or with 3 cycles of BEP plus a fourth cycle with EP is an unresolved question.68
Intermediate and Poor Risk
Treatment paradigms for intermediate- and poor-risk disease are similar, with risk stratification affecting prognosis rather than clinical decision-making. The standard treatment is 4 cycles of BEP. For patients in whom bleomycin is contraindicated, etoposide, ifosfamide, and cisplatin (VIP) is an alternative regimen resulting in similar OS and PFS in both intermediate- and poor-risk disease.69,70 Although using VIP avoids bleomycin-induced pulmonary toxicity, VIP does result in increased hematologic toxicity. Based on historical data, the 5-year OS for intermediate- and poor-risk disease was 79% and 48%, respectively.61 However, these data are based on patients treated between 1975 and 1990. More recently, data from 1990 to 2013 found that patients with intermediate-risk seminomas had a 5-year OS of 88%, and a meta-analysis of patients with NSGCTs treated after 1989 reported pooled 5-year survival estimates of 83% (intermediate risk) and 71% (poor risk).67,71
Residual Masses After Chemotherapy
Seminoma
Residual masses in patients with seminoma are usually benign, and surveillance is a safe option.72,73 Based on data showing that the likelihood of viable residual seminoma increases with larger residual mass size,74 some advocate for surveillance of masses less than 3 cm and the use of a fluorodeoxyglucose (FDG) PET scan for masses 3 cm or larger.75 This is based on data from the SEMPET trial, which reported 100% accuracy for masses larger than 3 cm.76
However, subsequent studies have reported false-positive rates of approximately 75%, and enthusiasm for PET scans in this setting has greatly declined.77,78 For patients who have a positive PET scan, we recommend either repeating the PET scan at least 6 weeks later or performing resection or biopsy (biopsy should be extensive to mitigate sampling error) to confirm whether viable seminoma is present. Enlarging residual masses on surveillance should be treated as relapsed disease and managed with chemotherapy or, less frequently, resection, depending on the clinical circumstances. It is important to note that treated seminomas are often characterized by a dense scirrhous reaction that can make resection technically difficult and increase the rate of surgical complications.73,78,79
Nonseminoma
If tumor markers are normal, resection of all masses larger than 1 cm is the standard of care whenever feasible.80 There is no role for FDG-PET in the evaluation of residual masses in nonseminomas. For masses in the retroperitoneum, an RPLND is performed, and masses elsewhere (eg, lungs, liver, brain) should also be resected when feasible. Masses less than 1 cm should be observed closely. The histopathology of residual masses may show fibrosis and necrosis, teratoma, or residual GCT. If there is residual GCT, 2 cycles of adjuvant chemotherapy are recommended for patients who have previously received first-line but not second- or third-line chemotherapy.81
Relapsed Disease
Despite the significant advancements that have resulted in a cure for many patients with GCTs, a minority of patients will experience disease relapse. For patients with stage I disease who experience relapse in the retroperitoneum, RPLND can be considered for nonbulky disease (lymph nodes <2 cm) if tumor markers are normal. In one report of 45 patients undergoing surveillance for stage I NSGCT who experienced disease relapse in the retroperitoneum, RPLND alone (without further therapy) was curative in 82%.82
For most patients with relapsed disease, however, cytotoxic chemotherapy is the standard. The choice of regimen depends on prior exposure to chemotherapy, medical comorbidities, and contraindications to specific agents. For patients who are chemotherapy-naive or whose only prior chemotherapy was carboplatin (for stage I seminoma), chemotherapy selection should be determined by risk stratification criteria for de novo stage III disease (eg, good-risk: BEP × 3 or EP × 4, intermediate- or poor-risk: BEP × 4 or VIP × 4). For patients who received 1 or 2 cycles of BEP for stage I or pathologic stage II NSGCT, the chemotherapy regimen used for patients at standard risk should also be given, although we avoid exposing patients to more than 4 cycles of bleomycin-containing chemotherapy owing to the risk of pulmonary complications.
For patients who experience disease relapse after first-line chemotherapy for advanced-stage disease (eg, BEP × 3, EP × 4, BEP × 4, VIP × 4), treatment with either standard-dose or high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) are options. Paclitaxel, ifosfamide, and cisplatin (TIP)83 and vinblastine, ifosfamide, and cisplatin (VeIP)84 are both acceptable options for standard-dose chemotherapy, whereas carboplatin plus etoposide is the most commonly used high-dose chemotherapy regimen.85
HDCT with ASCT has demonstrated efficacy in heavily pretreated patients with relapsed GCTs. However, it is unclear whether or not to use HDCT with ASCT instead of standard-dose chemotherapy in the second line. Retrospective analyses have supported the use of HDCT with ASCT as the first salvage treatment for relapsed GCT. Based on a database of 1984 patients with relapsed GCT, one analysis found that HDCT was superior to standard-dose chemotherapy in both 2-year PFS (49.6% vs 27.8%) and 5-year OS (53.2% vs 40.8%).86 The international phase 3 TIGER trial is comparing salvage conventional-dose chemotherapy with HDCT with ASCT in the second line, with a primary endpoint of OS.87 As of December 2022, this trial has completed accrual and we await the results with anticipation.88
Prognosis is poor for patients with multiple disease relapses or platinum-refractory disease, although treatment with chemotherapy can still be beneficial. The combination of gemcitabine, oxaliplatin, and paclitaxel was shown to have efficacy in cisplatin-refractory disease or relapse after HDCT with ASCT. The overall response was 51%, with 5% achieving a complete response. Fifteen percent remained in remission after chemotherapy with or without residual tumor resection at a median follow-up of 5 months.89
The efficacy of checkpoint inhibitors for relapsed/refractory GCTs is disappointing. A single-arm phase 2 trial of pembrolizumab (Keytruda, Merck) demonstrated no responses in 12 patients who had received at least 2 prior lines of therapies.90 Thus, outside of a clinical trial or a biomarker-selected cohort (such as mismatch repair deficiency, microsatellite instability, or tumor mutation burden–high cancers), checkpoint inhibitors have no role at this time.
Personalized treatment of refractory GCTs based on molecular or genomic profiling has thus far been disappointing because targetable mutations are rarely identified; further studies in this area are needed to develop effective targeted therapies for patients with testis cancer.91
Survivorship
Although cisplatin-based chemotherapy has dramatically increased the cure rate for testicular GCTs, it has also resulted in toxicity that can compromise both quality and length of life.31,92-95 Radiation therapy for testis cancer has also been associated with decreased life expectancy.31,33 These findings have led to increased interest in expanding the role of surgery to reduce exposure to chemotherapy and radiation therapy. Chemotherapy side effects and late toxicities include peripheral neuropathy, high-pitch hearing loss, tinnitus, cardiovascular disease, reduced pulmonary and renal function, Raynaud phenomenon, hypogonadism, and infertility.94,96 Both radiation therapy and chemotherapy are associated with an increased risk of developing secondary malignancies, which have been associated with reduced life expectancy.31,32 Radiation therapy and chemotherapy have also both been associated with an increased incidence of erectile dysfunction.
Disclosures
Dr Wee is an advisory board consultant for Bayer and Janssen. Dr Gilligan has no disclosures.
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