Initial risk-stratified treatment for advanced testicular germ cell tumors

INTRODUCTION — Testicular cancer has become one of the most curable solid neoplasms. Factors that have likely contributed to the declining mortality rate for testicular cancer over time include the development and use of effective chemotherapy, a trend toward earlier stage disease at presentation, and an increasing proportion of tumors that are pure seminomas [1]. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors" and "Epidemiology and risk factors for testicular cancer".)

The risk stratification of advanced testicular germ cell tumors (GCTs) and initial management based on risk will be reviewed here. The clinical manifestations, diagnosis, and staging of testicular GCTs are reviewed separately. In addition, chemotherapy protocols used in the management of GCTs are also covered separately.

●(See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors".)

GENERAL APPROACH TO ADVANCED DISEASE — The term "advanced" is used differently for GCTs compared with most other cancers, and it refers to stage IS, II, and III disease, based on the 2017 joint staging system of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) (table 1A-B).

Cisplatin-based combination chemotherapy is used with curative intent to treat advanced disease in several scenarios:

●"Advanced" or "disseminated" testicular GCTs typically are those that have metastasized to retroperitoneal lymph nodes or beyond. In most cases, advanced GCTs are either stage III or stage IIb to IIc (table 1A-B).

●Men with stage IS nonseminomas (abnormal tumor markers without radiographic evidence of metastases) are treated the same as stage III because they are assumed to have occult metastases. Stage IS seminomas are extremely rare, and management should be individualized.

●In addition, other groups treated for advanced disease include some men with stage IIa seminoma (if they are not treated with radiation therapy) and some with stage IIa nonseminoma (if they are not managed with retroperitoneal lymph node dissection).

●Patients with primary mediastinal or retroperitoneal GCTs are generally treated as having advanced-stage disease, even in the absence of metastatic lesions.

There is a delicate balance between too little and too much therapy in men with GCTs:

●Inadequate therapy can cause a missed opportunity for cure and an unnecessary patient death. It can also result in the need for more aggressive subsequent therapy, and consequently, increased side effects and complications.

●By contrast, overtreatment (or unnecessarily aggressive treatment) can result in potentially serious acute and delayed toxicities. Whenever possible, men with advanced testicular GCTs should be referred to centers with expertise in the management of such tumors. (See "Treatment-related toxicity in testicular germ cell tumors".)

The treatment of advanced GCTs is guided by risk stratification that is based on the following variables: histology (seminoma versus nonseminoma), the presence or absence of metastatic lesions to organs other than the lungs, serum tumor marker levels, and the location of the primary tumor (testis or retroperitoneum versus mediastinum).

DEFINITION OF RISK — The 2017 joint staging system of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) (table 1A-B) is used to stage men with testicular cancer [2,3]. For men with advanced disease, it is supplemented with a validated prognostic model that was developed by the International Germ Cell Cancer Collaborative Group (IGCCCG) [2].

In the IGCCCG prognostic classification system, patients with disseminated disease (stages IS and II to III) are divided into good-, intermediate-, and poor-risk groups for both progression-free and overall survival (table 2) [2,4]. It is based upon the histology of the tumor (seminoma versus nonseminoma), primary site of the GCT, metastatic sites of involvement, and levels of serum tumor markers (drawn on day 1 of the first cycle, prior to initiation of chemotherapy, and after radical orchiectomy has been performed for patients with testicular primaries).

The risk stratification system is important for the identification of appropriate treatment for men with GCTs. Risk stratification differs for seminomas and nonseminomatous germ cell tumors (NSGCTs).

Seminomas — Metastatic seminomas are classified as either good or intermediate risk. There is no poor-risk classification for pure seminomas.

Historically, the distinction between good- and intermediate-risk metastatic seminoma has been based upon whether or not metastases to organs other than the lungs or lymph nodes are present (table 2). Additionally, we treat men with metastatic good-risk seminoma and lactate dehydrogenase (LDH) greater than 2.5 times the upper limit of normal (ULN) using an approach similar to those with intermediate-risk seminoma; however, there is no consensus on whether treatment should be intensified in such patients. In one study of 2451 men with metastatic seminoma, elevation of LDH greater than 2.5 times ULN was independently associated with worse prognosis [5]. The authors of this study did not advocate changing the risk-stratification schema to include LDH elevation as a criterion for intermediate-risk disease but rather suggested distinguishing two different groups of good-risk patients based on LDH levels. Serum levels of beta-human chorionic gonadotropin (beta-hCG) and LDH were not used in assigning risk status to patients with seminoma, although one or both are often elevated. (See 'Seminoma' below.)

Serum beta-hCG and alpha-fetoprotein (AFP) are not listed as prognostic factors for metastatic seminoma. The diagnosis of seminoma is precluded by elevation of AFP or highly elevated beta-hCG. More specifically, beta-hCG levels are rarely elevated above 1000 ng/mL in pure seminomas: a beta-hCG above 5000 international units/L (the cut-off separating good- from intermediate-risk disease for NSGCT) would generally be interpreted as representing the presence of choriocarcinoma or embryonal carcinoma and hence a diagnosis of NSGCT. (See 'Nonseminomatous germ cell tumors' below.)

Because seminomas do not produce AFP, an elevated AFP indicates the presence of NSGCT unless another explanation for the AFP elevation is obvious. Trivial elevations of serum AFP (<30 ng/mL) should be interpreted cautiously, and for the purposes of classifying GCTs, any AFP less than 20 ng/mL should generally be considered normal, regardless of the reporting laboratory's normal range. (See 'Nonseminomatous germ cell tumors' below.)

Criteria used to define good and intermediate risk for men with advanced seminoma are described below:

●Good risk – Patients with advanced seminoma are classified as having good risk if metastases are limited to the lungs and/or lymph nodes, regardless of the primary site. However, their prognosis is less favorable if the serum LDH at the start of chemotherapy is greater than 2.5 times ULN.

●Good risk with LDH greater than 2.5 times ULN – These patients have a prognosis very similar to intermediate-risk patients.

●Intermediate risk – Patients with metastases at sites other than the lungs or lymph nodes are classified as having intermediate-risk disease.

●Those with AFP outside the normal range or beta-hCG >1000 international units/L are considered to have NSGCT and are stratified accordingly.

Nonseminomatous germ cell tumors — Men with advanced NSGCTs are divided into good-, intermediate-, and poor-risk categories (table 2).

While men with NSGCTs who have persistently elevated postorchiectomy serum tumor markers and normal imaging studies are categorized as having clinical stage IS disease (table 1A-B), the elevated markers generally indicate the presence of occult metastatic disease [6]. Therefore, these patients should be treated similarly to men with advanced disease (stage III).

Stratification is based upon the extent and location of metastatic disease, and the degree of elevation of serum tumor markers following orchiectomy (table 2).

Good risk — Patients with metastatic NSGCTs are categorized as good risk if they meet all of the following conditions:

●Testicular or retroperitoneal primary tumor

●Metastases limited to the lungs and/or lymph nodes

●Tumor markers on day 1 of the first cycle of chemotherapy:

•Serum AFP <1000 ng/mL

•Beta-hCG <5000 milli-international units/mL

•LDH <3 times ULN

Although published staging and risk-stratification tables list an LDH cutoff of 1.5 times ULN, we use a cutoff of 3 times ULN because LDH is not specific to GCTs or malignancy and can be elevated for many different reasons. Many GCT experts would not intensify a patient's treatment from good risk to intermediate risk if the only adverse prognostic factor were an LDH between 1.5 and 3 times ULN [7].

Intermediate risk — Patients with NSGCTs are considered intermediate risk if all of the following criteria are present:

●Testicular or retroperitoneal primary tumor.

●Metastases limited to the lungs and/or lymph nodes.

●Tumor markers on day 1 of cycle 1 of chemotherapy (one or more must be in the range defined below, and none can be higher than the upper limit of the ranges below):

•Serum AFP 1000 to 10,000 ng/mL

•Beta-hCG 5000 to 50,000 milli-international units/mL

•LDH 3 to 10 times ULN

Although published staging and risk-stratification tables list an LDH cutoff of 1.5 times ULN, we use a cutoff of three times ULN because LDH is not specific to GCTs or malignancy and can be elevated for many different reasons. Many GCT experts would not intensify a patient’s treatment from good risk to intermediate risk if the only adverse prognostic factor were an LDH between 1.5 and 3 times ULN.

Poor risk — Patients with NSGCTs are considered poor risk if any of the following are present:

●Mediastinal primary site, with or without metastases. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum".)

●Metastases to organs other than the lungs (eg, liver, bone, or brain metastases).

●Tumor markers on day 1 of cycle 1 of chemotherapy (at least one must be above the cutoff below):

•Serum AFP >10,000 ng/mL

•Beta-hCG >50,000 milli-international units/mL

•LDH >10 times ULN

TREATMENT OPTIONS — The treatment of advanced disease depends upon the prognostic risk group rather than on the histologic type alone (table 2 and algorithm 1). However, the type of GCT has prognostic implications and helps to inform appropriate follow-up at the end of treatment. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Guidelines for follow-up'.)

Good risk — For men with good-risk advanced GCTs, we recommend cisplatin-based combination therapy. We use bleomycin, etoposide, and cisplatin (BEP) rather than etoposide plus cisplatin (EP) in most patients, although both are acceptable regimens. For men at increased risk for pulmonary toxicity from bleomycin and for men over the age of 50, we prefer EP. If BEP is used, three cycles should be given. If EP is administered, four cycles must be given.

Men with metastatic seminoma with metastases limited to the lungs and/or lymph nodes and lactate dehydrogenase (LDH) greater than 2.5 times the upper limit of normal (ULN) were previously considered to have good-risk disease. However, one analysis reported that such men had outcomes similar to men with metastases to organs other than the lungs and lymph nodes, providing a rationale to treat such men as having intermediate-risk disease, rather than good-risk disease [5]. (See 'Seminoma' below.)

The evidence to support these recommendations is discussed below.

Bleomycin, etoposide, and cisplatin — For men with good-risk GCTs, we suggest three cycles of standard BEP (bleomycin 30 units on days 1, 8, and 15; etoposide 100 mg/m² on days 1 to 5; cisplatin 20 mg/m² on days 1 to 5) administered on a 21-day cycle. This regimen of BEP is associated with an excellent survival outcome with limited toxicity (table 3).

Three cycles of standard BEP result in similar activity and less toxicity compared with four cycles of BEP [8-11]. The largest study, conducted by the European Organisation for Research and Treatment of Cancer (EORTC), randomized 812 subjects to either three or four cycles of BEP. With a median follow-up of 25 months, it reported that two-year progression-free survival (PFS) was 90.4 percent with three cycles and 89.4 percent with four cycles [11]. There were 12 deaths in each arm. These results were confirmed in a 2008 systematic review, which reported that approximately 90 percent of men with good-risk GCTs had a durable complete remission with either regimen [8].

For men receiving BEP, dose intensity should be maintained throughout treatment because lowered chemotherapy doses are associated with worse outcomes. In a trial sponsored by the Australian and New Zealand Germ Cell Trial Group, 166 men were randomly assigned treatment using three cycles of standard BEP (table 3) or four cycles of a modified BEP regimen (bleomycin 30 units day 1; etoposide 120 mg/m² days 1 to 3; cisplatin 100 mg/m² day 1) every 21 days [12]. The trial was closed at interim analysis because the modified BEP arm was inferior to standard BEP. Compared with modified BEP dosing, standard BEP dosing was associated with significant improvement in overall survival (OS; hazard ratio [HR] for mortality 0.25, 95% CI 0.07-0.88). With 8.5 years median follow-up, eight-year OS was 92 percent with standard BEP and 83 percent with reduced-dose BEP [13].

Etoposide and cisplatin — Due to the association of bleomycin with occasional, but serious and potentially fatal, pulmonary toxicity, EP for four cycles has been evaluated as an alternative regimen to BEP (table 4). (See "Bleomycin-induced lung injury".)

While we prefer BEP as first-line therapy in men with good-risk GCTs, the available evidence suggests that EP represents a reasonable, albeit possibly slightly less effective, alternative:

●EORTC trial – The EORTC Genitourinary Tract Cancer Cooperative Group conducted a study of 395 men who were randomly assigned to treatment using four cycles of EP with or without bleomycin, with a lower dose of etoposide administered than what is now considered standard (360 mg/m² per cycle rather than the standard 500 mg/m² per cycle) [14]. Compared with EP, BEP resulted in:

•A significantly higher complete response rate (95 percent with BEP versus 87 percent with EP)

•Fewer deaths (7 [3 percent] with four cycles of BEP versus 12 [6 percent] with four cycles EP), although this difference was not statistically significant

•Significantly higher rates of pulmonary toxicity and neurotoxicity, including two deaths from pulmonary toxicity

●GETUG T93BP – In a trial conducted by the Groupe d'Etude des Tumeurs Uro-Genital (GETUG), 257 men were randomly assigned to BEP for three cycles or EP for four cycles (using standard doses) [15]. The overall response rate was equivalent between EP and BEP (97 versus 96 percent, respectively). At a median follow-up of 53 months, EP had a numerically lower four-year event-free survival rate (86 versus 91 percent) and a higher mortality rate (12 men treated with EP died versus 5 men treated with BEP), though neither result was statistically significant.

These studies suggest that EP (four cycles) results in similar, but possibly slightly inferior, outcomes in the treatment of good-risk testicular GCTs. We (and others [16]) prefer BEP rather than EP for men with good-risk GCTs. We reserve four cycles of EP for men with compromised pulmonary function, men with compromised renal function (which increases the risk of bleomycin-induced lung injury), and those over the age of 50 years. (See "Bleomycin-induced lung injury".)

Decreased efficacy with carboplatin — Despite the improved toxicity profile associated with carboplatin, we do not recommend substitution of carboplatin for cisplatin because it is associated with decreased survival [17-19].

In the largest trial, four cycles of modified BEP (bleomycin 30 units on day 2; etoposide 120 mg/m² on days 1 to 3; and cisplatin 20 mg/m² per day on days 1 to 5, or 50 mg/m² on days 1 and 2) administered every three weeks was compared with four cycles of CEB (bleomycin 30 units on day 2; etoposide 120 mg/m² on days 1 to 3; and carboplatin dosed at an area under the concentration x time curve [AUC] 5) [18]. The cisplatin combination was associated with significantly enhanced rates of three-year OS (97 versus 90 percent with the carboplatin regimen) and one-year recurrence-free survival (91 versus 77 percent).

In a separate trial, men were randomly assigned to treatment using three cycles of standard BEP or four cycles of CEB. The trial was terminated after 54 patients were accrued, due to a higher relapse rate (32 versus 13 percent) and a larger number of deaths (four versus one) in the carboplatin arm [19].

Chemotherapy-related toxicity — For men with good-risk disease, cisplatin-based chemotherapy is generally well tolerated, although both acute and late toxicities are a significant concern. (See 'Chemotherapy-related toxicity' below.)

Full doses should be administered at the scheduled time, regardless of the white blood cell count on day 1 of each cycle, to maximize the chances for cure. The risk of neutropenic fever and fatal infections is low in patients with good-risk disease. Therefore, for good-risk patients, we recommend use of granulocyte-colony stimulating factors (G-CSF) only if the prior cycle was complicated by febrile neutropenia.

When the prior cycle is complicated by febrile neutropenia or some other significant clinical event, a delay in treatment is recommended if necessary to allow the patient to recover. For example, for a patient with febrile neutropenia, additional chemotherapy should be delayed until the neutropenia has resolved and any identified infection is under control.

Intermediate- and poor-risk advanced disease — For men with intermediate- or poor-risk disease, we recommend four cycles of BEP rather than other platinum-based regimens (table 2 and algorithm 1). There are no data to support the use of three rather than four cycles of BEP in this population. In addition, there are no data supporting the use of more than four cycles.

BEP — The benefit of bleomycin, etoposide, and cisplatin (BEP) was demonstrated in a trial involving 244 men with advanced GCTs randomly assigned treatment with BEP versus vinblastine, etoposide, and cisplatin (PVB) [20]. Compared with PVB, BEP resulted in:

●A significantly higher complete response rate (77 versus 66 percent) among men with advanced disease (defined by the presence of extensive pulmonary disease, abdominal or visceral metastases, or central nervous system, bone, or extra-abdominal nodal involvement).

●Similar OS at two years (80 percent in each arm).

●Significantly less frequent serious (grade 3/4) toxicity, including paresthesias (4 versus 11 percent), abdominal cramps (2 versus 8 percent), and myalgias (0 versus 14 percent).

VIP — Although four courses of BEP remains the standard of care for men with intermediate- or poor-risk disease, the combination of ifosfamide, etoposide, and cisplatin (VIP) is an alternative to BEP in men who are not candidates for bleomycin (table 5). (See "Bleomycin-induced lung injury".)

This includes men with [21]:

●Underlying lung disease.

●Bulky lung metastases that may require postchemotherapy resection. (See "Approach to surgery following chemotherapy for advanced testicular germ cell tumors", section on 'Preoperative considerations'.)

●Extensive tumor burden in the lung.

●Men with primary mediastinal nonseminomatous germ cell tumors (NSGCTs), who typically undergo postchemotherapy resection of residual mediastinal disease and are, thus, at risk of perioperative bleomycin-related lung toxicity. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum".)

The data to support the use of VIP come from the following studies:

●Intergroup trial – In this trial, 299 men with poor-risk disease were randomly assigned to four cycles of either BEP or VIP [22,23]. With a median follow-up of 7.3 years, the following results were reported [23]:

•A similar rate of PFS (58 versus 64 percent with BEP and VIP, respectively) and OS (67 and 69 percent, respectively)

•A significantly lower rate of serious (grade 3/4) hematologic toxicity with BEP compared with VIP (73 versus 89 percent)

●A second, smaller trial included 84 men with intermediate-risk disease randomly assigned to treatment with VIP or BEP [24]. With a median follow-up of 7.7 years, the following results were reported:

•A similar PFS rate at five years (85 versus 83 percent with VIP and BEP, respectively)

•Rare patient deaths (one versus two, respectively)

•A significantly higher rate of grade 3/4 leukopenia with VIP (89 versus 37 percent with BEP)

Other therapeutic approaches for poor-risk disease have included escalation of the dose of cisplatin, dose intensification through the use of sequential or alternating non-cross-resistant chemotherapy regimens, and the use of high-dose chemotherapy protocols, but none has been shown to be superior to four cycles of either BEP or VIP [25-30]. Although there is interest in comparing four cycles of paclitaxel, ifosfamide, and cisplatin (TIP) with four cycles of BEP based on promising results with TIP in a phase II trial, TIP remains an experimental regimen in the first-line setting and has not been shown to be equal or superior to BEP. We do not recommend the use of any regimen other than four cycles of BEP or VIP in men with intermediate- or poor-risk advanced GCTs outside of clinical trials. We do encourage eligible men with poor-risk disease to enroll in clinical trials evaluating new treatment strategies.

The GETUG-13 trial suggested that changes in the tumor markers three weeks after the first dose of BEP can be used to individualize therapy for men with poor-prognosis NSGCT [30-32]. In the GETUG-13 trial, the 203 men who were classified as having an unfavorable decline in tumor markers were randomly assigned to treatment with three additional cycles of BEP or a complex dose-dense regimen that incorporated paclitaxel, cisplatin, etoposide, oxaliplatin, ifosfamide, and continuous-infusion bleomycin.

The results of the GETUG-13 trial were updated at the 2016 American Society of Clinical Oncology (ASCO) meeting [31]. There was a statistically significant improvement with the experimental regimen in five-year PFS compared with standard BEP for patients with an unfavorable decline in serum tumor markers (60 versus 47 percent, HR 0.65, 95% CI 0.43-0.97). However, the difference in OS at five years was not statistically significant (70 versus 61 percent, HR 0.69, 95% CI 0.43-1.11). This regimen is complex and is associated with increased toxicity, and we do not recommend it for routine use in these patients.

Chemotherapy-related toxicity — Men with poor-risk disease face a greater risk of chemotherapy-related neutropenic sepsis and bleomycin pneumonitis compared with men with good-risk disease, both of which can be fatal. Almost all patients will experience myelosuppression (particularly neutropenia), fatigue, hair loss, and at least mild to moderate nausea, and there is a significant rate of peripheral neuropathy, high-frequency hearing loss, and decline in measured renal and pulmonary function. Chronic and late toxicities include peripheral neuropathy, tinnitus, hearing loss, Raynaud phenomenon, cardiovascular disease, secondary malignancies, and reduced renal function [33]. (See "Treatment-related toxicity in testicular germ cell tumors".)

Despite these concerns, full doses should be administered at the scheduled time, regardless of the white blood cell count on day 1 of each cycle, to maximize the chances for cure. Given the substantial risk of neutropenic fever and fatal infections in intermediate- and poor-risk patients receiving VIP chemotherapy, we suggest administration of G-CSF as part of each cycle (ie, prophylactically). We do not recommend routine use of colony stimulating factors with BEP chemotherapy.

When the prior cycle is complicated by febrile neutropenia or some other significant clinical event, a delay in treatment is recommended if necessary to allow the patient to recover, and G-CSF should be used for subsequent cycles to prevent febrile neutropenia. If febrile neutropenia develops during a cycle in which G-CSF was administered, then we recommend reducing the dose of etoposide and (if VIP is being administered) ifosfamide by 20 percent for subsequent cycles while maintaining cisplatin at full dose.

MONITORING RESPONSE TO TREATMENT — Our approach to monitoring the response to chemotherapy for patients with advanced testicular GCT can be summarized as follows:

●Tumor markers on day 1 of each chemotherapy cycle (beta-human chorionic gonadotropin [beta-hCG], alpha-fetoprotein [AFP], and lactate dehydrogenase [LDH; cycle 1 only]).

●Computed tomography (CT) of the chest, abdomen, and pelvis with intravenous contrast should be performed prior to chemotherapy and at the completion of chemotherapy. Additional imaging during treatment is indicated only if there is a specific clinical indication.

●For patients with stage II/III seminoma, a positron emission tomography (PET)/CT is indicated six to eight weeks after the completion of chemotherapy if there is a residual mass on CT imaging ≥3 cm.

PROGNOSIS — For men with advanced testicular GCTs, data indicate that outcomes have improved substantially in the setting of remarkable treatment advances, with an expected five-year survival rate over 95 percent. Specific survival data for men with seminomas and nonseminomatous GCTs based on risk classification are discussed below.

Seminoma — The risk stratification of men with metastatic GCTs is derived from a multinational observational analysis of 5202 patients with nonseminomatous germ cell tumors (NSGCTs) and 660 men with seminoma diagnosed between 1975 and 1990 [2]. Of note, this seminal publication established the risk criteria for advanced testicular GCTs. (See 'Definition of risk' above.)

In this study, approximately 90 percent of men with advanced seminoma had good-risk disease and an excellent prognosis following orchiectomy alone, with five-year progression-free survival (PFS) and overall survival (OS) rates of 90 and 92 percent, respectively [2]. Among the approximately 10 percent of men with seminoma and intermediate-risk disease, five-year PFS and OS rates were 67 and 72 percent, respectively.

A subsequent observational study using data from the Surveillance, Epidemiology, and End Results (SEER) database evaluated 321 men with metastatic seminomas and 803 with metastatic nonseminomas treated between 2004 and 2015 in the United States. For patients with good- and intermediate-risk seminomas, five-year OS was 87 and 78 percent, respectively [34].

In another observational study of 2451 men with metastatic seminoma, both OS and PFS improved over time among patients with good-risk disease (five-year OS 86 to 95 percent; five-year PFS 82 to 89 percent) and intermediate-risk patients (five-year OS 72 to 88 percent; five-year PFS 67 to 79 percent) [5]. Additionally, among patients with good-risk disease, elevation of LDH >2.5 times the upper limit of normal (ULN) was independently associated with worse prognosis. In this study, among patients with good-risk disease, both OS and PFS was higher for those with LDH ≤2.5 times ULN versus those with LDH >2.5 times ULN (three-year OS 97 versus 92 percent; three-year PFS 92 versus 80 percent). For patients with intermediate-risk disease, three-year OS and PFS were 93 and 78 percent, respectively.

Nonseminomatous germ cell tumors — For patients with nonseminomatous GCTs, improvements in the treatment regimens have improved survival outcomes, particularly for patients with poor-risk disease.

In the multinational observational study discussed above that included 5202 patients with NSGCTs, approximately 56 percent of men had good-risk metastatic disease [2]. The five-year PFS and OS rates for these patients were 89 and 92 percent, respectively. Among the approximately 28 percent of men with NSGCTs and intermediate-risk disease, the five-year PFS and OS rates were 75 and 80 percent, respectively. Among the approximately 16 percent of men with NSGCTs and poor-risk disease, the five-year PFS and OS rates for these patients were 41 and 48 percent, respectively.

Subsequent studies have reported better results for patients with poor-risk disease, with five-year OS between approximately 60 and 70 percent [35,36]. As examples:

●A meta-analysis of 10 studies, which included data on 1775 patients with NSGCTs, reported that the pooled five-year OS rates were 94 percent for good-risk, 83 percent for intermediate-risk, and 71 percent for poor-risk disease [35]. A separate analysis of 1889 men with GCTs treated initially with bleomycin, etoposide, and cisplatin (BEP) chemotherapy between 1984 and 2007 in Denmark yielded similar OS results, with outcomes improving over time, particularly among those with poor-risk NSGCTs [37].

●Another study evaluated 321 men with metastatic seminomas and 803 with metastatic nonseminomas treated between 2004 and 2015 in the United States [34]. In this study, for men with nonseminomas, five-year OS was 89, 75, and 60 percent for good-, intermediate-, and poor-risk groups, respectively.

Long-term prognosis — Men with metastatic GCTs are generally followed on a surveillance schedule for at least five years after treatment. A large majority of patients relapse within the first two years of treatment completion. Not surprisingly, men who have a favorable response to first-line chemotherapy are less likely to relapse. (See "Posttreatment follow-up for testicular germ cell tumors" and "Approach to the care of long-term testicular cancer survivors".)

Data suggest that men who live for two years after diagnosis without relapsing have a high probability of being cured and a very low risk of dying of their cancer. In an analysis of 942 patients with metastatic testicular GCTs treated at five tertiary cancer centers between 1990 and 2012, the conditional OS rates were calculated for patients who were alive and disease-free at 24 months after diagnosis [36]. Within the study population, 26 percent of patients had seminoma, and 74 percent had nonseminomatous NSGCTs. For patients in the good-risk group, the two-year conditional OS rate improved from 97 percent at baseline to 99 percent at 24 months. In the intermediate-risk group, the two-year conditional OS rate increased from 94 to 99 percent at 24 months, and for those with high-risk disease, the two-year conditional OS rate increased from 71 to 93 percent.

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Testicular cancer (The Basics)" and "Patient education: Preserving fertility after cancer treatment in men (The Basics)")

●Beyond the Basics topics (see "Patient education: Testicular cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Prognosis for testicular cancer – Testicular cancers, 95 percent of which are germ cell tumors (GCTs), have become one of the most curable solid neoplasms because of remarkable treatment advances, with an expected five-year survival rate over 95 percent. (See 'Introduction' above and 'Prognosis' above.)

●Risk stratification – For all patients with advanced GCTs, stratification into good-, intermediate-, or poor-risk categories based upon their histology, primary tumor site, anatomic staging, and levels of serum markers following orchiectomy is necessary prior to treatment (table 2). This risk classification is used to plan treatment (algorithm 1). (See 'Definition of risk' above.)

●Good-risk disease – For patients with good-risk disease who are not at elevated risk for bleomycin lung toxicity, we suggest chemotherapy with three cycles of bleomycin, etoposide, and cisplatin (BEP) (table 3) rather than four cycles of etoposide plus cisplatin (EP) (Grade 2B).

•For men with good-risk GCTs who are at risk of bleomycin lung toxicity, including men with renal insufficiency or age greater than 50 years, we suggest four cycles of chemotherapy with EP (table 4) (Grade 2B). (See 'Good risk' above.)

•For men with good-risk seminoma (eg, metastases limited to lymph nodes and/or lungs) and a lactate dehydrogenase (LDH) level greater than 2.5 times the upper limit of normal (ULN), we treat using an approach similar to those with intermediate-risk seminoma (algorithm 1).

•We do not substitute carboplatin for cisplatin in the treatment of testicular GCTs because of the worse outcomes with carboplatin-based regimens. (See 'Decreased efficacy with carboplatin' above.)

●Intermediate- or poor-risk disease – For men with intermediate- or poor-risk GCTs who are not at elevated risk for bleomycin lung toxicity, we recommend four cycles of BEP (table 3) rather than other cisplatin-based combinations (Grade 2B). We do not administer prophylactic granulocyte-colony stimulating factors (G-CSF) for men receiving BEP. (See 'Intermediate- and poor-risk advanced disease' above.)

•For those at a significantly increased risk of bleomycin lung toxicity, we suggest four cycles of etoposide, ifosfamide, and cisplatin (VIP) (table 5) as an alternative regimen (Grade 2B). For men with intermediate- or poor-risk GCTs receiving four cycles of VIP, we recommend the administration of prophylactic G-CSF (Grade 1B). (See 'VIP' above.)

●Primary mediastinal nonseminomatous germ cell tumors – For men with primary mediastinal nonseminomatous GCTs, we recommend four cycles of VIP (table 5) (Grade 1A). (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum", section on 'Mediastinal nonseminomatous GCTs'.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Philip W Kantoff, MD, who contributed to an earlier version of this topic review.