Overview of the treatment of testicular germ cell tumors

INTRODUCTION — 

Testicular cancers are among the most curable solid tumors. Germ cell tumors (GCTs) account for 95 percent of testicular cancers. Testicular GCTs can consist of one predominant histologic pattern or represent a mix of multiple histologic subtypes (table 1). For treatment purposes, testicular GCTs are divided into two groups: pure seminoma and nonseminomatous germ cell tumors (NSGCTs). (See "Anatomy and pathology of testicular tumors".)

The management of testicular GCT is based on tumor histology and disease stage, among other clinical factors. An overview of the treatment of testicular GCTs (seminoma or NSGCT) is presented here. The epidemiology and risk factors of testicular cancer; the clinical presentation, diagnosis, and staging of testicular GCTs; and testicular sex cord stromal tumors are discussed separately.

●(See "Epidemiology and risk factors for testicular cancer".)

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

●(See "Testicular sex cord stromal tumors".)

DIAGNOSTIC EVALUATION

Initial evaluation — The initial diagnostic evaluation of the patient with suspected testicular cancer should include a physical examination, testicular (scrotal) ultrasound, serum tumor markers (beta subunit of human chorionic gonadotropin [beta-hCG], alpha-fetoprotein [AFP], and lactate dehydrogenase [LDH]), and imaging studies to assess disease extent. Further details are discussed separately. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Diagnostic evaluation' and "Serum tumor markers in testicular germ cell tumors".)

Radical inguinal orchiectomy (diagnosis/initial treatment) — The diagnosis of testicular cancer is generally established at radical inguinal orchiectomy, which simultaneously serves as the initial treatment for the primary tumor. (See "Radical inguinal orchiectomy for testicular germ cell tumors".)

The surgical specimen obtained from radical inguinal orchiectomy is evaluated so that the GCT can be classified on histopathology as either a seminoma, nonseminomatous germ cell tumor (NSGCT), or other histology (table 1). Further details on the anatomy and pathology of testicular tumors are discussed separately. (See "Anatomy and pathology of testicular tumors".)

Postorchiectomy tumor markers — Tumor markers (AFP, beta-hCG, and LDH) must be re-evaluated following orchiectomy to determine the final disease stage and to monitor treatment response. (See "Serum tumor markers in testicular germ cell tumors", section on 'Monitoring response to therapy'.)

Fertility preservation — Fertility is a concern for patients with testicular cancer, which is most common in early adulthood. For patients with testicular cancer, clinicians should discuss sperm cryopreservation (ie, sperm banking) prior to initiating any treatment that may reduce fertility, such as chemotherapy, radiation therapy (RT), and retroperitoneal lymph node dissection (RPLND). For patients with a normal contralateral testicle, sperm cryopreservation can be performed after unilateral orchiectomy. However, for patients undergoing bilateral orchiectomy and those who do not have a normal contralateral testicle, sperm cryopreservation should be offered prior to orchiectomy. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Sperm cryopreservation'.)

STAGING — 

Testicular cancer is staged using the eighth edition tumor, node, metastasis (TNM) staging system developed jointly by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) (table 2 and table 3), which applies to both seminoma and nonseminomatous germ cell tumor (NSGCT). The staging of testicular cancer is discussed separately. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Staging'.)

TREATMENT OF SEMINOMA — 

For patients with testicular seminoma who have completed radical inguinal orchiectomy, subsequent management is based on disease stage, postorchiectomy tumor markers, and other clinical risk factors. This section provides a brief overview of treatment strategies for seminoma, with further details discussed in the relevant UpToDate topics.

Clinical characteristics of seminoma — Seminomas have the following clinical and biologic characteristics, which influence management [1].

●Patients with seminomas are likely to present with localized disease. Among all patients with seminoma, the frequency of clinical stage I disease (limited to the testicle) is 80 percent [2], the frequency of stage II disease (limited to retroperitoneal nodes) is 15 to 20 percent [3], and the frequency of advanced or metastatic disease (involving the retroperitoneal lymph nodes and distant organs) is approximately 5 percent or less [1].

●Seminomas display relatively indolent growth and have a more predictable pattern of spread. Seminomas almost always spread to the retroperitoneal lymph nodes prior to spreading to other areas such as liver, lung, bones, or brain.

●Seminomas do not produce alpha-fetoprotein (AFP). Patients with seminoma and elevated levels of serum AFP (typically >30 ng/mL) are classified and treated as a nonseminomatous germ cell tumor (NSGCT). Some patients with pure seminomas may have elevated levels of beta subunit of human chorionic gonadotropin (beta-hCG; 15 to 20 percent) but these elevations are typically modest (<200 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 4)) would generally be interpreted as diagnostic for NSGCT. (See "Anatomy and pathology of testicular tumors", section on 'Seminoma' and "Serum tumor markers in testicular germ cell tumors" and "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Seminomas'.)

●Seminomas are exquisitely sensitive to radiation therapy (RT), which is an option for treatment following radical orchiectomy.

Stage I seminoma — Most patients with stage I seminoma (table 2 and table 3) who have been treated with radical orchiectomy are offered surveillance, given the low-relapse rates, excellent long-term overall survival (>95 percent), and avoidance of treatment-related toxicity. For patients unwilling or unable to adhere to surveillance or those who desire treatment, alternative options include either adjuvant chemotherapy with one to two cycles of carboplatin or RT (algorithm 1). (See "Treatment of stage I seminoma".)

Patients with stage IS seminoma are those with disease limited to testicle but with persistently elevated tumor markers following orchiectomy (table 2 and table 3). Treatment of stage IS seminoma is discussed separately. (See "Treatment of stage I seminoma", section on 'Diagnosis and initial treatment'.)

Stage II seminoma — For patients with stage II seminoma (table 2 and table 3) who have been treated with radical orchiectomy, management options include observation of small (≤1 cm) retroperitoneal lymph nodes; chemotherapy with either four cycles of etoposide plus cisplatin (EP) (table 5) or three cycles of bleomycin, etoposide, and cisplatin (BEP) (table 6); RT; or retroperitoneal lymph node dissection (RPLND) (algorithm 2). Treatment of stage II seminoma is discussed separately. (See "Treatment of stage II seminoma".)

Advanced and metastatic seminoma — Patients with advanced or metastatic seminoma typically have disease involving the retroperitoneal lymph nodes and beyond (ie, stage III disease) (table 2 and table 3). Such patients are treated with systemic chemotherapy. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'General approach to advanced disease'.)

Patients with advanced or metastatic seminoma are designated as having either good- or intermediate-risk disease based on the International Germ Cell Cancer Collaborative Group (IGCCCG) risk stratification system (table 4). There is no poor-risk disease classification for pure seminomas. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Seminomas'.)

For patients who have completed orchiectomy, disease risk-stratification and the patient's risk for bleomycin-induced lung toxicity influences the selection of chemotherapy regimen (algorithm 3). For patients with good-risk disease, options include four cycles of EP (table 5) or three cycles of BEP (table 6). For patients with intermediate-risk disease, options include four cycles of BEP or four cycles of etoposide, ifosfamide, and cisplatin (VIP) (table 7). Further details on selection of therapy are discussed separately. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Good-risk disease' and "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'BEP'.)

Management of residual masses following chemotherapy (seminoma) — Some patients with advanced or metastatic seminoma who are treated with chemotherapy may have persistent residual retroperitoneal masses on initial posttreatment imaging. The management of these patients is discussed separately. (See "Management of residual masses in advanced testicular germ cell tumors following initial systemic therapy", section on 'Seminoma'.)

TREATMENT OF NSGCT — 

For patients with testicular nonseminomatous germ cell tumor (NSGCT) who have completed radical inguinal orchiectomy, subsequent management is based on disease stage, postorchiectomy tumor markers, and other clinical risk factors. For patients with NSGCT whose treatment includes primary retroperitoneal lymph node dissection (RPLND), pathologic staging supersedes clinical staging and may result in further changes in treatment. This section provides a brief overview of treatment strategies for NSGCT, with further details discussed in the relevant UpToDate topics.

Clinical characteristics of NSGCT — Nonseminomatous germ cell tumors (NSGCTs) have the following clinical behavior, which influences management [1,4].

●Among patients with NSGCT, the frequency of stage I disease (limited to the testicle) is approximately 70 percent while the frequency of more advanced or metastatic disease is 30 percent [4].

●Most patients with advanced and metastatic NSGCT present with elevated levels of serum beta subunit of human chorionic gonadotropin (beta-hCG) and alpha-fetoprotein (AFP). (See "Serum tumor markers in testicular germ cell tumors".)

●NSGCTs are relatively resistant to radiation therapy (RT), which is not used to treat these tumors.

Stage I NSGCT — Patients with stage I nonseminomatous germ cell tumor (NSGCT) (table 2 and table 3) who are treated with orchiectomy are stratified into low-risk versus high-risk disease based on the presence of lymphovascular invasion (LVI), the predominance of embryonal carcinoma (EC), and tumor stage above T2 within the testicular cancer specimen. Patients with low-risk disease have none of these factors, while patients with high-risk disease have any of these factors. (See "Treatment of stage I nonseminomatous germ cell tumors", section on 'Risk stratification'.)

Selection of therapy is based on risk-stratification (algorithm 4). Most patients with low-risk disease are offered surveillance, given excellent long-term overall survival and the avoidance of treatment-related toxicity. For patients who are unwilling or unable to adhere to surveillance or those who desire treatment, alternative options include either adjuvant chemotherapy with one cycle of bleomycin, etoposide, and cisplatin (BEP) or RPLND (if appropriate surgical expertise with urology is available). For patients with high-risk disease, management options include adjuvant chemotherapy with one cycle of BEP, RPLND, or surveillance. The treatment of stage I NSGCT is discussed separately. (See "Treatment of stage I nonseminomatous germ cell tumors", section on 'Treatment approach'.)

Patients with stage IS NSGCT are those with disease limited to the testicle but with persistently elevated tumor markers following orchiectomy (table 2 and table 3). Treatment of stage IS NSGCT is discussed separately. (See "Treatment of stage I nonseminomatous germ cell tumors", section on 'General principles'.)

Stage II NSGCT — Stage II nonseminomatous germ cell tumor (NSGCT) refers to tumors that have spread to the regional (ie, retroperitoneal) lymph nodes without distant metastases and with normal (S0) or mild elevation of serum tumor markers (S1) following orchiectomy (table 2 and table 3). Stage II NSGCT can be classified as either clinical (based on imaging studies and/or clinician judgment of nodal involvement) or pathologic stage II (following primary RPLND that histopathologically confirms nodal disease). For patients with NSGCT whose treatment includes primary RPLND, pathologic staging supersedes clinical staging and may impact subsequent management (algorithm 4). (See "Treatment of stage II nonseminomatous germ cell tumors", section on 'Definition of Stage II NSGCT'.)

For patients with clinical stage II NSGCT, treatment options include primary RPLND (with subsequent treatment according to the final pathologic stage), chemotherapy with either four cycles of etoposide plus cisplatin (EP) (table 5) or three cycles of BEP (table 6), or surveillance. Further details are discussed separately. (See "Treatment of stage II nonseminomatous germ cell tumors", section on 'Clinical stage II NSGCT'.)

For patients with pathologic stage II NSGCT who have completed primary RPLND, treatment options include surveillance or adjuvant chemotherapy, depending upon the pathologic disease stage and the presence or absence of teratoma in the retroperitoneal lymph nodes. Further details are discussed separately. (See "Treatment of stage II nonseminomatous germ cell tumors", section on 'Pathologic stage II NSGCT'.)

Advanced and metastatic NSGCT — Patients with advanced or metastatic nonseminomatous germ cell tumor (NSGCT) typically have disease involving the retroperitoneal lymph nodes and beyond (ie, stage III disease) (table 2 and table 3). (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'General approach to advanced disease'.)

Patients with advanced or metastatic NSGCT are designated as having either good-risk, intermediate-risk, or poor-risk disease based on the International Germ Cell Cancer Collaborative Group (IGCCCG) risk stratification system (table 4). (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Nonseminomatous germ cell tumors'.)

For patients who have completed orchiectomy, the disease risk-stratification and the patient's risk for bleomycin-induced lung toxicity influence the selection of chemotherapy regimen (algorithm 3). For patients with good-risk disease, options include four cycles of EP (table 5) or three cycles of BEP (table 6). For patients with intermediate- or poor-risk disease, options include four cycles of BEP or four cycles of etoposide, ifosfamide, and cisplatin (VIP) (table 7). Further details on selection of therapy are discussed separately (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Treatment options'.)

Management of residual masses following chemotherapy (NSGCT) — Some patients with advanced or metastatic nonseminomatous germ cell tumor (NSGCT) who are treated with chemotherapy may have persistent residual masses in the retroperitoneum or elsewhere on initial posttreatment imaging. The management of these patients is discussed separately. (See "Management of residual masses in advanced testicular germ cell tumors following initial systemic therapy", section on 'Nonseminomatous germ cell tumor'.)

POSTTREATMENT SURVEILLANCE — 

Most patients with testicular GCT who will relapse do so in the first two years after initial treatment. Late relapses (after five years) can occur but are rare. For patients with testicular GCT who have completed primary treatment, surveillance guidelines are influenced by the tumor histology (seminoma versus nonseminomatous germ cell tumor [NSGCT]), the stage and risk of recurrence at presentation, and the treatment received. Posttreatment follow-up for testicular GCTs is discussed separately. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Guidelines for follow-up'.)

TREATMENT OF RELAPSED OR REFRACTORY DISEASE — 

For patients with relapsed testicular GCTs, management depends upon prior therapy, the location and timing of the relapse, and the tumor histology. Further details are discussed separately. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors".)

SPECIAL POPULATIONS

Brain metastases — For patients with either testicular seminoma or nonseminomatous germ cell tumor (NSGCT), brain metastases may present as an isolated manifestation of metastatic disease or in conjunction with other systematic metastases. Systemic chemotherapy is used for initial treatment, which can penetrate the blood-brain barrier. However, in selected cases, chemotherapy may be used in combination with radiation therapy (RT) and/or surgical resection. The management of patients with testicular GCTs and brain metastases is discussed separately. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors", section on 'Brain metastases'.)

Testicular germ cell neoplasia in situ — Germ cell neoplasia in situ (GCNIS) is typically a precursor of testicular GCTs in adults (except for spermatocytic tumors [ie, spermatocytic seminomas]) and yolk sac tumors and mature teratomas in prepubertal children. GCNIS is found in the testicular tissue adjacent to a testicular GCT in more than 90 percent of adults with testicular cancer. The clinical presentation, diagnosis, and management of testicular GCNIS is discussed separately. (See "Testicular germ cell neoplasia in situ".)

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 topic (see "Patient education: Testicular cancer (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

●General principles – Testicular cancers are among the most curable solid tumors. Germ cell tumors (GCTs) account for 95 percent of testicular cancers (table 1) and are generally divided into pure seminoma and nonseminomatous germ cell tumors (NSGCTs). (See "Anatomy and pathology of testicular tumors".)

●Diagnosis and staging – Diagnosis is generally established by radical inguinal orchiectomy, which simultaneously serves as the initial treatment for the primary tumor. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors".)

•Postorchiectomy tumor markers – Tumor markers (alpha-fetoprotein [AFP], beta subunit of human chorionic gonadotropin [beta-hCG], and lactate dehydrogenase [LDH]) must be re-evaluated following orchiectomy for staging and monitoring treatment response. (See "Serum tumor markers in testicular germ cell tumors", section on 'Monitoring response to therapy'.)

•Staging – Testicular cancer is staged using the eighth edition American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system (table 2 and table 3). (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Staging'.)

●Treatment of seminoma after orchiectomy

•Stage I seminoma – Most patients with stage I seminoma are offered surveillance, given the low-relapse rates, excellent long-term overall survival, and avoidance of treatment-related toxicity. For patients unwilling or unable to adhere to surveillance or those who desire treatment, alternative options include either adjuvant chemotherapy with one to two cycles of carboplatin or radiation therapy (RT) (algorithm 1). (See "Treatment of stage I seminoma".)

•Stage II seminoma – For patients with stage II seminoma (table 2 and table 3), management options include observation of small (≤1 cm) retroperitoneal lymph nodes; chemotherapy with either four cycles of etoposide plus cisplatin (EP) (table 5) or three cycles bleomycin, etoposide, and cisplatin (BEP) (table 6); RT; or retroperitoneal lymph node dissection (RPLND) (algorithm 2). (See "Treatment of stage II seminoma".)

●Treatment of NSGCT after orchiectomy

•Stage I NSGCT – Patients with stage I NSGCT are stratified into low-risk versus high-risk disease based on the presence of lymphovascular invasion (LVI), the predominance of embryonal carcinoma (EC), and tumor stage above T2 (algorithm 4). (See "Treatment of stage I nonseminomatous germ cell tumors", section on 'Risk stratification'.)

-Low-risk disease – Patients with low-risk disease (no factors) are offered surveillance, given excellent long-term overall survival and the avoidance of treatment-related toxicity. For patients who are unwilling or unable to adhere to surveillance or those who desire treatment, alternative options include one cycle of BEP or RPLND. (See "Treatment of stage I nonseminomatous germ cell tumors", section on 'Low-risk disease'.)

-High-risk disease – For patients with high-risk disease (one or more factors), management options include one cycle of BEP, RPLND, or surveillance. (See "Treatment of stage I nonseminomatous germ cell tumors", section on 'High-risk disease'.)

•Stage II NSGCT – Stage II NSGCT is classified either as clinical (based on imaging studies and/or clinician judgment of nodal involvement) or pathologic stage II (following primary RPLND that confirms nodal disease) (algorithm 4). (See "Treatment of stage II nonseminomatous germ cell tumors".)

-Clinical stage II NSGCT – Options include primary RPLND (with subsequent treatment according to the final pathologic stage), chemotherapy with either four cycles of EP (table 5) or three cycles of BEP (table 6), or surveillance. (See "Treatment of stage II nonseminomatous germ cell tumors", section on 'Clinical stage II NSGCT'.)

-Pathologic stage II NSGCT – After RPLND, treatment options include surveillance or adjuvant chemotherapy, depending upon the pathologic disease stage and presence or absence of teratoma in the retroperitoneal lymph nodes. (See "Treatment of stage II nonseminomatous germ cell tumors", section on 'Pathologic stage II NSGCT'.)

●Advanced and metastatic disease (seminoma or NSGCT) – Chemotherapy is administered based on risk stratification (table 4) and risk for bleomycin-induced lung toxicity (algorithm 3). (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

•Good-risk disease – Options include four cycles of EP (table 5) or three cycles of BEP (table 6). (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Good-risk disease'.)

•Intermediate- or poor-risk disease – Options include four cycles of BEP or four cycles of etoposide, ifosfamide, and cisplatin (VIP) (table 7).

●Management following treatment completion – Management of residual masses following chemotherapy, posttreatment surveillance, and management of relapsed and refractory disease are discussed separately.

•(See "Management of residual masses in advanced testicular germ cell tumors following initial systemic therapy".)

•(See "Posttreatment follow-up for testicular germ cell tumors", section on 'Guidelines for follow-up'.)

•(See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors".)