Initial risk-stratified treatment for advanced testicular germ cell tumors

INTRODUCTION — 

Testicular cancer is one of the most curable cancers. Although most patients with testicular cancer present with early-stage disease, many patients with advanced-stage disease can also be successfully treated with chemotherapy. (See "Epidemiology and risk factors for testicular cancer".)

The risk stratification and initial management of advanced testicular germ cell tumors (GCTs) is presented here. The clinical manifestations, diagnosis, and staging as well as an overview of the treatment of testicular GCTs are discussed separately. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors" and "Overview of the treatment 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).

●Males 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 males with stage IIa seminoma (if they are not treated with radiation therapy [RT]) 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 males 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, males 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).

RISK STRATIFICATION — 

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 males with testicular cancer [1,2]. For males with advanced disease, it is supplemented with a validated prognostic model that was developed by the International Germ Cell Cancer Collaborative Group (IGCCCG) [1].

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 (OS) (table 2) [1,3]. 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 closest to (but prior to) the start of chemotherapy (ie, drawn on day 1 of the first cycle but 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 males 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. Risk criteria for advanced seminoma are as follows:

●Good risk – Patients with advanced seminoma are classified as having good-risk disease 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 lactate dehydrogenase (LDH) at the start of chemotherapy is greater than 2.5 times upper limit of normal (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.

The distinction between good- and intermediate-risk metastatic seminoma is based upon whether or not metastases to organs other than the lungs or lymph nodes are present (table 2). Additionally, we treat males with metastatic good-risk seminoma and LDH greater than 2.5 times the 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 males with metastatic seminoma, elevation of LDH greater than 2.5 times ULN was independently associated with worse prognosis [4]. 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 used as prognostic factors for advanced and metastatic seminoma. The diagnosis of seminoma may be precluded based on specific levels of AFP or highly elevated beta-hCG.

●Seminomas do not produce AFP. Patients with seminoma and elevated levels of serum AFP (typically >30 ng/mL) are classified and treated as an NSGCT. 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 stable or fluctuating 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.)

●Some patients with pure seminomas may have elevated levels of beta-hCG (15 to 20 percent) but these elevations are typically modest (<200 IU/L) and rarely above 1000 IU/L. For those with advanced seminoma, a postorchiectomy serum beta-hCG level that is greater than 1000 IU/L indicates that nonseminomatous components are likely present, and a level greater than 5000 IU/L (the cut-off that separates good- from intermediate-risk disease for NSGCT (table 2)) would generally be interpreted as the presence of choriocarcinoma or embryonal carcinoma and hence a diagnosis of NSGCT. (See 'Nonseminomatous germ cell tumors' below.)

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

While males 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 [5]. Therefore, these patients should be treated similarly to males 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 [6], 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]. Alternatively, some experts prefer an LDH cutoff of 2.5 times ULN. This is based on data from the IGCCCG update consortium that an LDH of 2.5 times ULN or more is associated with a worse prognosis [8].

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 drawn closest to the start of chemotherapy and after any prechemotherapy surgical intervention (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 lower-bound cutoff of 1.5 times ULN [6], we use a lower-bound 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 [7,8].

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 disease — Males with good-risk advanced GCTs are treated with cisplatin-based combination therapy.

●For patients who are not at increased risk of bleomycin pulmonary toxicity, we suggest either three cycles of bleomycin, etoposide, and cisplatin (BEP) or four cycles of etoposide plus cisplatin rather than other platinum-based regimens. (See 'Bleomycin, etoposide, and cisplatin' below and 'Etoposide and cisplatin' below.)

●For patients at increased risk of bleomycin pulmonary toxicity (eg, those who are 50 years of age or older, those with compromised kidney or pulmonary function, those who actively smoke, and/or those who have previously had chest radiation therapy [RT]), we suggest four cycles of EP rather than three cycles of BEP. (See 'Etoposide and cisplatin' below.)

Males 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 males had outcomes similar to males with metastases to organs other than the lungs and lymph nodes, providing a rationale to treat such males as having intermediate-risk disease, rather than good-risk disease [4]. (See 'Seminoma' below.)

Bleomycin, etoposide, and cisplatin — For males with good-risk GCTs, one option for initial therapy is 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 [9-12]. One 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, two-year progression-free survival (PFS) was 90.4 percent with three cycles and 89.4 percent with four cycles [12]. There were 12 deaths in each arm. These results were confirmed in a 2008 systematic review, which reported that approximately 90 percent of males with good-risk GCTs had a durable complete remission with either regimen [9].

For males 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 males 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 [13]. 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 [14].

Etoposide and cisplatin — Four cycles of EP are an option for patients with good-risk disease [7], and it is the preferred option for those with risk factors for bleomycin toxicity (50 years of age or older, compromised kidney or pulmonary function, actively smoking, and/or prior chest RT). (See "Bleomycin-induced lung injury".)

EP has been compared to BEP since bleomycin can cause occasional, but serious and potentially fatal, pulmonary toxicity. In randomized trials of patients with good-risk testicular GCT, four cycles of EP (table 4) is similarly effective to three cycles of BEP, with similar to less toxicity, although there was a nonsignificant trend toward higher OS with BEP. Data are as follows:

●In a trial conducted by the Groupe d'Etude des Tumeurs Uro-Genital (GETUG), 257 males with good-risk NSGCT 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, compared with BEP, EP had a numerically lower four-year event-free survival rate (86 versus 91 percent) and a higher mortality rate (12 males treated with EP died versus 5 males treated with BEP; four-year OS 97 versus 93 percent with BEP and EP, respectively), though the differences were not statistically significant. Of note, in those treated with EP, there was a lower dose intensity for cisplatin and etoposide as well as more treatment delays.

●The EORTC Genitourinary Tract Cancer Cooperative Group conducted a study of 395 males with good-risk testicular NSGCT 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 considered standard (360 mg/m² per cycle rather than the standard 500 mg/m² per cycle) [16]. 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.

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 a randomized clinical 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, males 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 more deaths (four versus one) in the carboplatin arm [19].

Chemotherapy-related toxicity — For males with good-risk disease, cisplatin-based chemotherapy is generally well tolerated, although both acute and late toxicities are a significant concern. (See "Treatment-related toxicity in testicular germ cell tumors".)

In general, chemotherapy dose reductions and delays for myelotoxicity should be minimized or avoided since treatment intent is curative.

For patients who are receiving EP (table 4) for good-risk disease, the decision to administer prophylactic granulocyte-colony stimulating factor (G-CSF) is individualized and discussed with patients since the rate of febrile neutropenia ranges from 10 to 20 percent [7,20]. For such patients who are age 50 years or older, we offer prophylactic G-CSF, as the risk of neutropenic fever with EP is higher in this population (approximately 40 percent) [21].

For patients who are receiving BEP (table 3) for good-risk disease, the decision to administer prophylactic G-CSF is individualized, since the rate of febrile neutropenia ranges from 10 to 20 percent [20]. For such patients who are age 50 or older or have previously received radiation therapy, we offer prophylactic G-CSF since these factors are associated with an increased risk of febrile neutropenia [21,22]. We avoid administering G-CSF on the day of a bleomycin infusion.

For patients receiving either EP or BEP, when the prior cycle is complicated by febrile neutropenia or some other significant clinical event, a delay in treatment may be warranted 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. If prophylactic G-CSF was not administered during the cycle in which neutropenic fever occurred, prophylactic G-CSF should be administered for subsequent cycles to prevent febrile neutropenia. For patients who experience neutropenic fever despite G-CSF prophylaxis, UpToDate contributors administer antibiotic prophylaxis for future cycles. We do not advise dose reduction of chemotherapy for febrile neutropenia. Such dose reductions can lead to inferior cancer-specific outcomes [14], which are more likely to occur than severe sepsis from subsequent cycles without dose reduction. Patients with life-threatening febrile neutropenia (eg, those who require intensive care unit admission) who are able to resume testicular cancer chemotherapy may be evaluated for a dose reduction or an alternative regimen.

Further details on the prevention of febrile neutropenia due to chemotherapy with G-CSF prophylaxis are discussed separately. (See "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".)

Intermediate- or poor-risk disease — For males with intermediate- or poor-risk disease who are not at increased risk for bleomycin pulmonary toxicity, we suggest four cycles of BEP rather than other platinum-based regimens (table 2 and algorithm 1). For patients who are not candidates for bleomycin, four cycles of VIP are an appropriate alternative.

BEP — The benefit of bleomycin, etoposide, and cisplatin (BEP) was demonstrated in a trial involving 244 males with advanced GCTs randomly assigned treatment with BEP versus cisplatin, vinblastine, and bleomycin (PVB) [23]. Compared with PVB, BEP resulted in:

●A significantly higher complete response rate (77 versus 66 percent) among males 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).

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 of BEP.

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

This includes males with [24]:

●Underlying lung disease such as emphysema/chronic obstructive pulmonary disease (COPD) or interstitial lung disease.

●Bulky lung metastases that may require postchemotherapy resection. (See "Management of residual masses in advanced testicular germ cell tumors following initial systemic therapy", section on 'Preoperative considerations'.)

●Extensive tumor burden in the lung.

●Some centers prefer VIP for males 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. However, VIP is associated with greater hematologic toxicity so there are advantages and disadvantages to each regimen in this setting. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum".)

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

●In an Intergroup trial, 299 males with poor-risk disease were randomly assigned to four cycles of either BEP or VIP [25,26]. With a median follow-up of 7.3 years, the following results were reported [26]:

•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)

●Another randomized trial included 84 males with intermediate-risk disease randomly assigned to treatment with VIP or BEP [27]. 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)

Regimens not used — We do not offer any systemic regimen other than four cycles of BEP or VIP in males with intermediate- or poor-risk advanced GCTs. For patients who are interested in other approaches, clinical trial enrollment is encouraged where available.

In randomized trials of intermediate- and poor-risk advanced testicular GCT, initial regimens that failed to show superior efficacy to either four cycles of BEP or four cycles of VIP include paclitaxel, ifosfamide, and cisplatin (TIP) [28,29]; risk-stratified chemotherapy on the basis of tumor marker decline using a complex dose-dense regimen that incorporated paclitaxel, cisplatin, etoposide, oxaliplatin, ifosfamide, and continuous-infusion bleomycin [30-32]; the addition of paclitaxel to BEP [33]; dose-escalated cisplatin, dose intensification through the use of sequential; or alternating non-cross-resistant chemotherapy regimens; and high-dose chemotherapy [34-38].

Chemotherapy-related toxicity — Males with poor-risk disease face a greater risk of chemotherapy-related neutropenic sepsis and bleomycin pneumonitis compared with males 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 kidney and pulmonary function. Chronic and late toxicities include peripheral neuropathy, tinnitus, hearing loss, Raynaud phenomenon, cardiovascular disease, secondary malignancies, hypogonadism, infertility, and reduced kidney function [39]. (See "Treatment-related toxicity in testicular germ cell tumors".)

In general, chemotherapy dose reductions and dose delays for myelotoxicity should be minimized or avoided since treatment intent is curative.

For patients receiving BEP (table 3) who have poor-risk disease, are age 50 or older, or have previously received radiation therapy, we offer prophylactic G-CSF since these factors are associated with an increased risk of febrile neutropenia [21,22]. We avoid administering G-CSF on the day of a bleomycin infusion [25,26].

For patients receiving VIP (table 5) who have intermediate- or poor-risk disease, we offer prophylactic administration of G-CSF as part of each cycle due to the substantial risk of febrile neutropenia and fatal infections.

For either VIP or BEP, when the prior cycle is complicated by febrile neutropenia or some other significant clinical event, a delay in treatment may be warranted 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. If prophylactic G-CSF was not administered during the cycle in which neutropenic fever occurred, G-CSF should be administered for subsequent cycles to prevent febrile neutropenia. For patients who experience neutropenic fever despite G-CSF prophylaxis, UpToDate contributors administer antibiotic prophylaxis for future cycles. We do not advise dose reductions of chemotherapy for febrile neutropenia. Such dose reductions can lead to inferior cancer-specific outcomes [14], which are more likely to occur than severe sepsis from subsequent cycles without dose reduction. Patients with life-threatening febrile neutropenia (eg, those who require intensive care unit admission) who are able to resume testicular cancer chemotherapy may be evaluated for a dose reduction or an alternative regimen.

Further details on the prevention of febrile neutropenia due to chemotherapy with G-CSF prophylaxis are discussed separately. (See "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".)

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]).

●Contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis 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.

●The management of patients with testicular GCT and residual masses on imaging studies after initial systemic therapy is discussed separately. (See "Management of residual masses in advanced testicular germ cell tumors following initial systemic therapy".)

PROGNOSIS — 

For males with advanced testicular GCTs, data indicate that outcomes have improved substantially in the setting of remarkable treatment advances. For patients with good-risk disease, five-year overall survival (OS) is typically 90 percent or higher. For those with intermediate-risk disease, five-year OS ranges between 70 to 90 percent. For those with poor-risk disease, five-year OS ranges between 50 to 70 percent. Specific survival data for males with seminomas and nonseminomatous germ cell tumors (NSGCTs) based on risk classification are as follows:

Seminoma — The risk stratification of males with metastatic GCTs is derived from a multinational observational analysis of 5202 patients with NSGCTs and 660 males with seminoma diagnosed between 1975 and 1990 [1]. Of note, this seminal publication established the risk criteria for advanced testicular GCTs. (See 'Risk stratification' above.)

In this study, approximately 90 percent of males with advanced seminoma had good-risk disease and an excellent prognosis following orchiectomy alone, with five-year progression-free survival (PFS) and OS of 90 and 92 percent, respectively [1]. Among the approximately 10 percent of males with seminoma and intermediate-risk disease, five-year PFS and OS were 67 and 72 percent, respectively.

A subsequent observational study using data from the Surveillance, Epidemiology, and End Results (SEER) database evaluated 321 males 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 [40].

In another observational study of 2451 males 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) [4]. 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 germ cell tumors (NSGCTs), 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 males had good-risk metastatic disease [1]. The five-year PFS and OS rates for these patients were 89 and 92 percent, respectively. Among the approximately 28 percent of males 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 males 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 [41,42]. 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 [41]. A separate analysis of 1889 males 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 [43].

●Another study evaluated 321 males with metastatic seminomas and 803 with metastatic nonseminomas treated between 2004 and 2015 in the United States [40]. In this study, for males with nonseminomas, five-year OS was 89, 75, and 60 percent for good-, intermediate-, and poor-risk groups, respectively.

Long-term prognosis — Males with metastatic GCTs are generally followed on a surveillance schedule for at least five years after treatment. Most relapses occur within two years of treatment completion. Not surprisingly, males 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 males 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 [42]. Within the study population, 26 percent of patients had seminoma, and 74 percent had 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 topic (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), is one of the most curable cancers. Although most patients with testicular cancer present with early-stage disease, many patients with advanced-stage disease can also be successfully treated with chemotherapy. (See 'Introduction' above and 'Prognosis' above.)

●Risk stratification – All patients with advanced testicular GCTs are stratified into good-, intermediate-, or poor-risk categories prior to treatment based upon their histology, primary tumor site, anatomic staging, and levels of serum markers following orchiectomy (table 2 and algorithm 1). (See 'Risk stratification' above.)

●Good-risk disease

•For patients with good-risk disease who are not at increased risk for bleomycin pulmonary toxicity, we suggest either three cycles of bleomycin, etoposide, and cisplatin (BEP) (table 3) or four cycles of etoposide plus cisplatin (EP) rather than other platinum-based regimens (Grade 2B). (See 'Good-risk disease' above.)

•For patients with good-risk GCTs who are at increased risk of bleomycin pulmonary toxicity we suggest four cycles of EP (table 4) rather than three cycles of BEP (Grade 2B). Patients at increased risk of bleomycin toxicity include those who are 50 years of age or older, those with compromised kidney or pulmonary function, those who actively smoke, and/or those who have previously had chest radiation therapy (RT). (See 'Good-risk disease' above.)

•For patients 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). (See 'Good-risk disease' above.)

•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 patients with intermediate- or poor-risk GCTs who are not at increased risk for bleomycin lung toxicity, we suggest four cycles of BEP (table 3) rather than other cisplatin-based combinations (Grade 2B). For those who are not candidates for bleomycin, four cycles of etoposide, ifosfamide, and cisplatin (VIP) (table 5) is an appropriate alternative. (See 'Intermediate- or poor-risk disease' above.)

•The management of primary mediastinal GCTs is discussed separately. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum".)

ACKNOWLEDGMENT — 

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