Testicular Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology

Testicular cancer is relatively uncommon and accounts for <1% of all male tumors. However, it is the most common solid tumor in men between the ages of 20 and 34 years, and the global incidence has been steadily rising over the past several decades. Several risk factors for testicular cancer have been identified, including personal or family history of testicular cancer and cryptorchidism. Testicular germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes and are categorized into 2 main histologic subtypes: seminoma and nonseminoma. Although nonseminoma is the more clinically aggressive tumor subtype, 5-year survival rates exceed 70% with current treatment options, even in patients with advanced or metastatic disease. Radical inguinal orchiectomy is the primary treatment for most patients with testicular GCTs. Postorchiectomy management is dictated by stage, histology, and risk classification; treatment options for nonseminoma include surveillance, systemic therapy, and nerve-sparing retroperitoneal lymph node dissection. Although rarely occurring, prognosis for patients with brain metastases remains poor, with >50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.

Abstract

Testicular cancer is relatively uncommon and accounts for <1% of all male tumors. However, it is the most common solid tumor in men between the ages of 20 and 34 years, and the global incidence has been steadily rising over the past several decades. Several risk factors for testicular cancer have been identified, including personal or family history of testicular cancer and cryptorchidism. Testicular germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes and are categorized into 2 main histologic subtypes: seminoma and nonseminoma. Although nonseminoma is the more clinically aggressive tumor subtype, 5-year survival rates exceed 70% with current treatment options, even in patients with advanced or metastatic disease. Radical inguinal orchiectomy is the primary treatment for most patients with testicular GCTs. Postorchiectomy management is dictated by stage, histology, and risk classification; treatment options for nonseminoma include surveillance, systemic therapy, and nerve-sparing retroperitoneal lymph node dissection. Although rarely occurring, prognosis for patients with brain metastases remains poor, with >50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.

Overview

Testicular cancer is relatively uncommon and accounts for <1% of all male tumors.1 However, it is the most common solid tumor in men between the ages of 20 and 34 years, and the global incidence has been steadily rising over the past several decades.17 An estimated 9,560 new cases of testicular cancer will be diagnosed in the United States in 2019, resulting in approximately 410 deaths, which reflects the excellent 5-year survival rate for this disease (∼95%).1,8 Several risk factors for testicular cancer have been identified, including personal or family history of testicular cancer and cryptorchidism.2,9,10

Testicular germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes and are categorized into 2 main histologic subtypes: seminoma and nonseminoma.2,11,12 Nonseminomas are less common but are more aggressive and often include multiple cell types. When both seminoma and elements of nonseminoma are present, management follows that of a nonseminoma. The 4 types of nonseminomas are embryonal carcinoma, choriocarcinoma, yolk sac tumor, and teratoma.11 Most nonseminomas are mixed tumors of these 4 subtypes. Teratomas are sometimes classified as either mature or immature, but this distinction is of no known significance in adult men and does not affect management in these patients. Rarely, a teratoma may contain elements of a somatic cancer, such as a sarcoma or adenocarcinoma, and it is then referred to as a “teratoma with somatic type malignancy.”

Teratomas with somatic transformation are managed somewhat differently from other nonseminomatous GCTs. For example, stage I transformed teratoma is preferentially managed with retroperitoneal lymph node dissection (RPLND) whereas other stage I nonseminomas are typically managed using surveillance.

The serum tumor markers alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (beta-hCG) are critical in determining prognosis and assessing treatment outcomes in patients with testicular GCTs. These serum tumor markers should be determined before and after treatment and throughout the follow-up period. In addition, lactate dehydrogenase (LDH) is important for determining prognosis and is used to help risk-stratify patients starting first-line chemotherapy for disseminated nonseminomatous tumors.13 Although serum LDH concentrations are elevated in about half of men with advanced testicular cancer, LDH is a less specific marker for testicular cancer compared with AFP and beta-hCG. Therefore, decisions regarding treatment should not be made based on mildly elevated (<3 × upper limit of normal) LDH alone.

Beta-hCG is the most commonly elevated serum tumor marker in testicular cancer. Elevated serum concentrations of beta-hCG may be present with both seminomatous and nonseminomatous tumors. However, in patients with seminoma with beta-hCG levels >1,000 IU/L, consider the possibility of nonseminoma and re-review the surgical specimen with pathology. Discussion with a high-volume center experienced in the management of these patients should also be considered. Additionally, patients with postorchiectomy beta-hCG levels >5,000 IU/L should undergo brain MRI because they are at an increased risk of having brain metastases. Further workup should be considered before starting treatment of mildly elevated beta-hCG (generally <20 IU/L), because other factors such as hypogonadism, hyperthyroidism, and marijuana use can cause elevations of beta-hCG.1416 Intramuscular injection of 300 mg of testosterone cypionate may be administered in cases of mild beta-hCG elevations of unclear etiology to exclude hypogonadism as a cause. Elevated beta-hCG has also been reported in other tumors, such as lymphoma, bladder cancer, and adenocarcinomas, and is thus not specific for germ cell malignancies. Additionally, heterophile antibodies have been reported to result in substantially elevated false-positive beta-hCG results (>400 IU/L), so clinicians should consider repeating the test using a different assay if a false-positive result is suspected due to the absence of radiographic evidence of disease.17,18

Elevated serum AFP is not associated with pure seminoma. Among nonseminomas, it is particularly associated with yolk sac tumors but can also be produced by embryonal carcinomas and teratoma. When patients with a histologically “pure” seminoma have an elevated level of AFP, it is generally interpreted as meaning the tumor is a mixed GCT and that undetected nonseminomatous elements are present in addition to the seminoma.13,1921 However, a small number of people have a chronically elevated serum AFP level, and clinicians should be cautious about starting treatment for a mildly elevated but stable AFP level. In addition, other tumors such as hepatocellular carcinoma and gastric carcinomas can cause AFP elevation. If an elevation of serum AFP is due to a metastatic nonseminomatous GCT, then the AFP typically will be steadily rising. Generally, decisions to treat should not be based solely on AFP values <20 ng/mL.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Testicular Cancer focuses on the diagnosis and management of nonseminomatous GCTs (to view the complete and most recent version of these guidelines, visit NCCN.org).

Clinical Presentation, Workup, and Primary Treatment

Clinical Presentation

Testicular cancer most often presents as a painless or painful testicular nodule, mass, enlargement, or induration (hardening). Often, patients will present with testicular discomfort or swelling suggestive of epididymitis or orchitis. A trial of antibiotics is never warranted in a man with a mass suspicious for GCT but can be considered in men with pain without a mass on further workup. Other patients may present with enlarged lymph nodes of the lower neck or upper chest supraclavicular), a retroperitoneal mass, gynecomastia, venous thrombosis, or pulmonary embolism.

Workup

If testicular cancer is being considered as a possibility, then a transscrotal ultrasound with Doppler should be performed (see TEST-1, page 1530). Testicular ultrasound serves to confirm the presence of a testicular mass, determine whether a mass is intra- or extratesticular, and to explore the contralateral testis.22 Testicular GCTs are typically heterogeneous, hypoechoic, and vascular on ultrasound. If the ultrasound findings show a mass concerning for malignancy, then an inguinal orchiectomy is generally performed to make a diagnosis. Transscrotal biopsies of the testes should not be performed because violating the scrotum increases the risk of local or atypical regional recurrence and can complicate management. In addition, a thorough history and physical examination should be performed. Serum tumor markers, including LDH, AFP, and beta-hCG, need to be assessed as they are used for prognosis and staging.12 Marker levels should be assessed both before and after orchiectomy. Elevated levels of beta-hCG, LDH, or AFP should be followed up with repeated tests to allow precise staging. Given the higher rates of hypogonadism in the testicular cancer population, measuring baseline levels of gonadal function can also be considered.

Primary Treatment

Radical inguinal orchiectomy is the primary treatment for most patients who present with a testicular mass that is concerning for malignancy on ultrasound (see TEST-1, page 1530).23 Concurrent insertion of testicular prosthesis may be considered during radical inguinal orchiectomy if desired by the patient.2426 In cases in which ultrasound shows an ambiguous abnormality that might be malignant, an open inguinal biopsy (testis-sparing surgery or partial orchiectomy) with intraoperative frozen section analysis can be performed, but such cases are extremely rare. Reflex orchiectomy is recommended in most circumstances should malignancy be detected. Similarly, an open inguinal biopsy of the contralateral testis can be considered if an ambiguous suspicious mass is identified on ultrasound or if the testis is cryptorchid or shows marked atrophy.27 However, biopsies are not recommended for microcalcifications.

Sperm banking should be discussed with patients of reproductive age, if clinically indicated, before undergoing any therapeutic intervention that may compromise fertility.2831 If sperm banking is desired, it may be performed before orchiectomy in patients with risk factors for infertility (atrophic contralateral testicle, history of infertility), but certainly should be considered before subsequent therapy in patients who desire future fertility.

Further management is dictated by histology, stage, and whether the cancer is a pure seminoma or a nonseminoma (includes mixed GCTs that are partially comprised of seminoma and tumors that are histopathologically described as pure seminomas in patients with elevated serum AFP). Although it is rare, when a patient presents with: 1) markedly elevated beta-hCG or AFP levels; 2) a testicular mass and/or disease distribution typical for a testicular, retroperitoneal, or mediastinal GCT; or 3) a clinical scenario in which, due to the bulk, signs, or symptoms of disease, the risk of delaying systemic therapy outweighs the benefit of a tissue diagnosis, chemotherapy may be started immediately without waiting for a biopsy diagnosis or performing orchiectomy. Consolidative orchiectomy may be performed after completion of systemic therapy.

Staging

Staging of testicular GCTs is based on determination of the extent of disease and assessment of postorchiectomy levels of serum tumor markers.12 The tumor (T), node (N), and metastasis (M) staging system used by the AJCC is the internationally accepted standard for cancer staging and is a major factor influencing prognosis and treatment decisions. The AJCC TNM staging system incorporates serum tumor marker elevation as a distinct category (S), which is unique to this organ site. The extent of the primary tumor is classified after orchiectomy, and therefore pathologic (p) staging is assigned to the primary tumor (T).

The eighth edition of the AJCC Cancer Staging Manual12 introduced invasion of the epididymis and hilar soft tissue as new pathologic criteria used for T classification of stage I testicular GCTs.32 Due to the excellent clinical outcomes seen in testicular cancer, large-scale follow-up studies have historically used tumor relapse rather than tumor-specific survival to validate the relevance of pathologic parameters used for staging.12 However, the association of hilar soft tissue and epididymal invasion with relapse of stage I disease has not been validated. Current data only support their association with having advanced-stage disease at diagnosis.33,34 Therefore, the NCCN Panel believes that these factors should not be used for clinical decision-making in the management of these patients. Instead, the NCCN Guidelines recommend managing patients with stage I nonseminoma based on the presence or absence of lymphovascular invasion (LVI), invasion of the spermatic cord, or invasion of the scrotum, which are factors known to be associated with an increased risk of relapse.3543

Predominance of embryonal carcinoma has also been proposed as a prognostic indicator of relapse in stage I nonseminoma, with several studies showing that a high proportion of embryonal carcinoma in the primary tumor (>50%) is associated with an increased risk of relapse.37,4451 However, very few patients have a high volume of embryonal carcinoma without also having LVI, and the value of embryonal carcinoma predominance in predicting relapse in the absence of LVI is unclear.37,44,47,51 Therefore, predominance of embryonal carcinoma is not used by the NCCN Guidelines to risk-stratify patients with stage I nonseminoma. Patients with stage I nonseminoma with a high volume of embryonal carcinoma and no evidence of LVI are neither high-risk nor low-risk and could be considered for adjuvant therapy.

The eighth edition of the AJCC Cancer Staging Manual also introduced changes to pathologic staging based on the type of spermatic cord involvement. Currently, continuous involvement of the spermatic cord soft tissue by the primary tumor is staged as pT3, whereas discontinuous spermatic cord involvement by invasion of lymphovascular spaces is now considered as a metastatic deposit (pM1).12 This significant change results in patients with discontinuous spermatic cord involvement being upstaged from high risk stage I to stage III disease independent of radiologic or serologic assessment, which the panel is concerned may lead to overtreatment. The evidence used to support this change is unclear; presently, there are no data showing differences in clinical outcomes between men with discontinuous spermatic cord involvement compared with men with continuous involvement. A recent retrospective analysis assessing the impact of different patterns of spermatic cord involvement on clinical stage and patient outcomes found no significant differences in either clinical stage at presentation or risk of recurrence based on type of spermatic cord involvement (continuous versus discontinuous).52 Therefore, for management decisions, the panel recommends staging GCTs with discontinuous invasion of the spermatic cord as pT3 (high-risk stage I) and not as pM1 (stage III) as is recommended by the AJCC. If surveillance is elected as primary management, the pelvis should be included in the imaging due to a higher risk of pelvic relapses in these patients.

Nonseminoma

Nonseminomatous GCTs include nonseminoma tumors, mixed seminoma/nonseminoma tumors, and seminoma tumors in patients with elevated serum AFP levels. To assess for metastatic disease, CT scans of the chest, abdomen, and pelvis should be performed (see TEST-6, page 1531). Use of PET/CT scan is not clinically indicated for nonseminoma.53,54 In select patients, brain MRI should also be performed; these patients include those with neurologic symptoms, postorchiectomy serum beta-hCG >5,000 IU/L or AFP >10,000 ng/mL, nonpulmonary visceral metastasis or extensive lung metastases. Elevated levels of serum beta-hCG, LDH, or AFP should be followed up with repeated tests. Repeated measurement of serum tumor markers is important because TNM staging is based on postorchiectomy values. In patients who had elevated serum tumor markers before orchiectomy, it is important to obtain the half-life kinetics of the tumor markers after orchiectomy if the markers are declining, because a slower-than-expected decline often indicates the presence of metastatic disease. The NCCN Panel emphasizes that mildly elevated, nonrising AFP levels may not indicate the presence of a GCT. Therefore, decisions to treat should not be based on AFP levels <20 ng/mL. Similarly, further workup should be considered before initiating treatment of mildly elevated beta-hCG (generally <20 IU/L).

Treatment options for clinical stage I disease after inguinal orchiectomy include surveillance, systemic therapy, and RPLND. Patients with clinical stage I pure teratoma and normal markers should receive either surveillance or RPLND. Stage II disease may be treated with systemic therapy or RPLND. Systemic therapy is preferred if serum tumor markers are elevated and/or if the enlarged lymph nodes are >3 cm in greatest dimension. RPLND is preferred as primary treatment of stage I or II tumors with transformed teratoma and should be considered for stage II tumors with teratoma predominance if serum tumor markers are normal. The major morbidity associated with bilateral RPLND is retrograde ejaculation, resulting in infertility. Nerve-sparing dissection techniques preserve antegrade ejaculation in 90% of cases.55 Therefore, nerve-sparing RPLND is recommended. Limited data suggest increased frequency of aberrant recurrences with the use of minimally invasive laparoscopic or robotic approaches to RPLND. A recent study of recurrence patterns in patients after robotic RPLND found that recurrences were highly variable, were in unusual locations, and were associated with a high treatment burden.56 Therefore, minimally invasive RPLND is not recommended as standard management at this time. Stage II and stage III disease treated with systemic chemotherapy should be followed by surgical resection of any residual masses.

Patients with an extragonadal primary site, whether retroperitoneal or mediastinal, are managed similarly to patients with testicular GCTs regarding systemic therapies and management of residual masses.57 However, due to their rarity, the NCCN Panel recommends that patients with extragonadal GCTs be referred to high-volume centers with experience in managing these tumors.

Nonseminoma Stage I Without Risk Factors

Primary Treatment of Nonseminoma Stage I Without Risk Factors

The panel recommends treating patients with stage I nonseminoma based on the presence or absence of risk factors known to be associated with an increased risk of relapse (LVI, invasion of the spermatic cord, or invasion of the scrotum).3543 However, regardless of risk factors, patients with stage I nonseminoma with normal postorchiectomy serum AFP and beta-hCG levels have 3 management options after orchiectomy: surveillance,40,47,58,59 nerve-sparing RPLND,60 or chemotherapy (1 cycle of bleomycin, etoposide and cisplatin [BEP])61,62 as primary treatment (see TEST-7, page 1532, and TEST-E, page 1545). The major difference in the management of low-risk and high-risk patients is that surveillance is preferred for patients with stage I nonseminoma without risk factors, whereas all 3 management options should be carefully considered when risk factors are present. The survival rates for stage I nonseminoma managed with surveillance, nerve-sparing RPLND, or 1 cycle of BEP chemotherapy exceed 98%. However, the high survival rate associated with surveillance depends on adherence to periodic follow-up examinations and subsequent chemotherapy for the 20%–30% of patients who experience relapse. Therefore, patients who choose surveillance should adhere to the follow-up schedule. When nerve-sparing RPLND is performed, it should be done within 4 weeks of a CT scan and within 7 to 10 days of repeat serum marker testing to ensure accurate presurgical staging.63 Similarly, for patients electing 1 cycle of BEP, an abdominal/pelvic CT scan and chest X-ray or CT scan is recommended within 4 weeks before the initiation of chemotherapy to confirm staging, even if scans were done previously.

Management of Nonseminoma Stage I Without Risk Factors After RPLND

If the resected lymph nodes are negative for malignancy (pN0) after nerve-sparing RPLND, the patient should undergo surveillance (see TEST-10, page 1535). For positive lymph nodes (pN1 to pN3), the decision whether to use chemotherapy is based on the degree of nodal involvement. Surveillance is the preferred option for patients with pN1 disease, and chemotherapy is the preferred option for patients with pN2 disease. However, chemotherapy is the only option for patients with pN3 disease. Recommended chemotherapy regimens include 2 cycles of either etoposide and cisplatin (EP; preferred) or BEP for patients with pN1 or pN2 disease64,65 and 3 cycles of BEP or 4 cycles of EP (both preferred) for patients with pN3 disease.

Follow-up for Nonseminoma Stage I Without Risk Factors

Although no single follow-up plan is applicable to all patients, the NCCN Panel has provided guidance for the follow-up of patients with nonseminoma for the first 5 years after the completion of therapy. These recommendations may be individualized and extended beyond 5 years at the discretion of the physician. The long-term follow-up for patients with stage I nonseminoma without risk factors includes history and physical examination, serum tumor marker assessment, abdominal/pelvic CT scan, and chest X-ray. In select circumstances, an MRI can be considered to replace an abdominal/pelvic CT scan. The MRI protocol should include visualization of the retroperitoneal and pelvic nodes and should be performed in centers with experience in interpreting MRI results for testicular cancer. The same imaging modality (CT or MRI) should be used throughout surveillance. All imaging in this setting is performed with contrast. The frequency of these tests varies with the primary treatment modality received by the patient (see Tables 5 and 6 on TEST-B, page 1541). It should be noted that routine chest X-ray may have limited value for detecting relapse in stage I nonseminoma. In a recent retrospective study, a total of 76 relapses were detected among 561 patients with stage I nonseminoma managed using active surveillance after orchiectomy.66 All relapses were detected with either rising serum tumor markers or abnormal routine follow-up CT scans; not a single relapse was detected using chest X-ray alone. Similar results have been reported in other studies, calling into question the value of chest X-rays in surveillance settings for stage I nonseminomatous GCTs.47,67,68 The current schedule for routine chest X-ray in the follow-up of patients with stage I nonseminoma without risk factors is 2 chest X-rays in year 1 and 1 chest X-ray in years 2 through 5 in patients managed using surveillance. Chest X-ray is not indicated in years 3, 4, and 5 for patients with stage I nonseminoma without risk factors treated with adjuvant BEP or primary RPLND.

Nonseminoma Stage I With Risk Factors

Primary Treatment of Nonseminoma Stage I With Risk Factors

Surveillance, adjuvant chemotherapy (1 cycle of BEP), or nerve-sparing RPLND are the recommended primary treatment options for patients with stage I nonseminoma with LVI, invasion of the spermatic cord, or invasion of the scrotum (see TEST-7, page 1532). In a prospective trial by SWENOTECA, patients with stage I nonseminoma with or without LVI received 1 course of adjuvant BEP.62 The relapse rate at 5 years was 3.2% for patients with LVI and 1.6% for patients without LVI. Five-year overall survival (OS) was 100% in both groups.35 The results after a median follow-up of 7.9 years confirmed the low relapse rate with 1 course of adjuvant BEP, especially in patients with LVI.35 Several other studies using 2 cycles of BEP as primary treatment of stage I nonseminoma have similarly reported relapse-free survival rates >95%.59,65,6972 However, late consequences of cisplatin-based chemotherapy, such as hearing damage and loss, cardiovascular conditions, hypertension, and neuropathy, have been reported during long-term follow-up.7381 Therefore, 1 cycle of BEP is recommended due to its lower toxicity. Surveillance is also a recommended primary treatment option for patients with stage I nonseminoma with risk factors. However, it should be noted that LVI is a significant predictor of relapse when orchiectomy is followed by surveillance alone.23

Management of Nonseminoma Stage I With Risk Factors After RPLND

The management of patients with stage I nonseminoma with risk factors after primary RPLND is similar to that of patients with stage I nonseminoma without risk factors, as described previously.

Follow-up for Nonseminoma Stage I With Risk Factors

The long-term follow-up for patients with stage I nonseminoma with risk factors includes history and physical examination, serum tumor marker assessment, chest X-ray, and abdominal/pelvic CT scan. In select circumstances, an MRI can be considered to replace an abdominal/pelvic CT scan. All imaging in this setting is performed with contrast. The frequency of these tests varies with the primary treatment modality received by the patient (see Tables 6 and 7, pages 1541 and 1542, respectively). Chest X-ray may be used for routine follow-up, but chest CT with contrast is preferred in patients with thoracic symptoms.

Nonseminoma Stage IS

Patients with stage IS nonseminoma exhibit persistent elevation of serum tumor markers postorchiectomy but no radiographic evidence of disease. However, mildly elevated levels of AFP or beta-hCG after orchiectomy must be interpreted with caution. Mildly elevated, nonrising AFP levels (<20 ng/mL) may not indicate the presence of a GCT and should not be used to guide treatment decisions. In addition, hyperthyroidism, marijuana use, hypogonadism, and heterophile antibodies can result in significant elevations of beta-hCG.1418 Elevated beta-hCG due to metastatic disease typically rises steadily on serial measurements. In patients with mildly elevated but stable beta-hCG and no other evidence of metastatic disease, repeating the test using a different assay should be considered. Furthermore, many different conditions can result in an elevation of LDH, including many benign conditions. Therefore, patients should not be treated with chemotherapy for systemic disease if the only evidence of systemic disease is an elevation of LDH.

Primary Treatment of Nonseminoma Stage IS

The NCCN Panel recommends that patients with stage IS nonseminoma be treated with primary chemotherapy if the elevated marker is AFP or beta-hCG. For the purposes of this guideline, the panel assumes that patients with stage IS disease have markers in the S1 range. It would be extraordinarily rare for a patient to have an AFP >1,000 ng/mL or a beta-hCG >5,000 IU/L and yet have no evidence of metastatic disease on imaging studies. These guidelines cannot address every possible situation, and the management of those rare patients with T any, N0, M0, S2-3 disease should be individualized; consultation with a high-volume center is recommended. The vast majority of patients with stage IS have serum tumor markers in the S1 range, and they should receive primary chemotherapy for good-risk disease: either 3 cycles of BEP or 4 cycles of EP (both preferred; see TEST-11, page 1536, and TEST-E, page 1545). Both regimens are category 1 recommendations, and either is preferable to initial RPLND because these patients nearly always have disseminated disease.82,83

Management of Nonseminoma Stage IS After Primary Treatment

The management of patients with stage IS nonseminoma after primary treatment with chemotherapy is described subsequently (see “Management of Good, Intermediate, and Poor-Risk Nonseminoma After Chemotherapy,” page 1544).

Nonseminoma Stage IIA

Primary Treatment of Nonseminoma Stage IIA

Primary treatment of patients with stage IIA nonseminoma depends on postorchiectomy serum tumor marker levels (see TEST-8, page 1533). For patients with normal postorchiectomy levels of AFP and beta-hCG, the NCCN Panel recommends either nerve-sparing RPLND or chemotherapy with 3 cycles of BEP or 4 cycles of EP as primary treatment options (both BEP and EP are preferred regimens; see TEST-E, page 1545).84,85 Chemotherapy is considered particularly appropriate if the patient has multifocal disease. For patients with stage IIA disease with persistently elevated AFP and/or beta-hCG levels, the NCCN Panel recommends primary chemotherapy with 3 cycles of BEP or 4 cycles of EP (both category 1; both preferred).60,86 A bleomycin-free regimen should be considered in patients with reduced or borderline glomerular filtration rate (GFR), in patients over the age of 50, and in patients with chronic obstructive pulmonary disease or other lung disease resulting in reduced pulmonary function.

Management of Nonseminoma Stage IIA After Primary Treatment

Treatment options after primary nerve-sparing RPLND include either surveillance or chemotherapy, depending on the number of positive lymph nodes identified (see TEST-10, page 1535). Because RPLND is likely a curative procedure in patients with pN0 disease, surveillance is recommended for this group. Surveillance is also the preferred option for patients with pN1 disease, although chemotherapy with 2 cycles of either EP or BEP can also be considered.60,87 If chemotherapy is given, EP is the preferred regimen in this setting. The risk of relapse in patients with stage IIA nonseminoma with pN2 or pN3 disease after RPLND is >50%.60,88 This risk is reduced to <1% with 2 cycles of adjuvant cisplatin-based chemotherapy.60,89,90 Therefore, the NCCN Panel prefers 2 cycles of adjuvant chemotherapy with EP (preferred regimen) or BEP to surveillance for pN2 disease and recommends full-course chemotherapy (and not surveillance) for pN3 disease (either 3 cycles of BEP or 4 cycles of EP; both preferred).

Subsequent management after primary chemotherapy depends on the size of the residual mass on CT scan (see TEST-9, page 1534). Patients should thus undergo abdominal/pelvic CT scan with contrast within a month of completing chemotherapy; chest CT with contrast or chest X-ray may also be considered. If the residual mass is ≥1 cm after chemotherapy, nerve-sparing bilateral RPLND is recommended. A bilateral RPLND involves removal of lymphatic tissue between both ureters, spanning from the diaphragmatic crus to the bifurcation of the common iliac arteries. The rationale for this extended region of dissection is the greater likelihood of bilateral disease with greater tumor burden.91 Referral to high-volume centers should be considered for surgical resection of masses postchemotherapy. For patients with no residual mass or a residual mass <1 cm, surveillance is recommended. Nerve-sparing bilateral RPLND is a category 2B recommendation in this setting and may be performed in selected cases.

Follow-up for Nonseminoma Stage IIA

The long-term follow-up for patients with stage IIA nonseminoma includes history and physical examination, serum tumor marker assessment, chest X-ray, and abdominal/pelvic CT scan. In select circumstances, an MRI can be considered to replace an abdominal/pelvic CT. All imaging in this setting is performed with contrast. The frequency of these tests varies with the primary treatment modality and postsurgical management received by the patient (see Tables 8, 9, and 10 on TEST-B, pages 1542 and 1543). Chest X-ray may be used for routine follow-up, but chest CT with contrast is preferred in patients with thoracic symptoms.

Nonseminoma Stage IIB

Primary Treatment of Nonseminoma Stage IIB

Primary treatment of patients with stage IIB nonseminoma depends on postorchiectomy tumor marker levels and radiographic findings (see TEST-8, page 1533). When tumor marker levels are normal, the CT findings determine the proper course of treatment. If abnormal radiographic findings are limited to lymph node metastases within lymphatic drainage sites in the retroperitoneum (ie, the landing zone), patients may receive primary chemotherapy with either 3 cycles of BEP or 4 cycles of EP (both preferred; see TEST-E, page 1545) or primary nerve-sparing RPLND (reserved for highly selected cases). Both options of primary chemotherapy or primary nerve-sparing RPLND are comparable in terms of outcome, but side effects and toxicity are different.85 The reported relapse-free survival with either approach is close to 98%.8890,92,93 If metastatic disease (based on radiographic findings) is not confined to within the lymphatic drainage sites (ie, multifocal or symptomatic lymph node metastases with aberrant lymphatic drainage sites), primary chemotherapy (3 cycles of BEP or 4 cycles of EP; both preferred) is recommended. For patients with stage IIB nonseminoma with persistent marker elevation, the recommended treatment option is also primary chemotherapy with either 3 cycles of BEP or 4 cycles of EP (both category 1; both preferred). A bleomycin-free regimen should be considered in patients with reduced or borderline GFR and in patients over the age of 50.

Management of Nonseminoma Stage IIB After Primary Treatment

The management of patients with stage IIB nonseminoma after primary treatment with either nerve-sparing RPLND or chemotherapy is similar to the postprimary management scheme outlined previously for patients with stage IIA nonseminoma (see “Management of Nonseminoma Stage IIA After Primary Treatment,” page 1541).

Follow-up for Nonseminoma Stage IIB

The long-term follow-up schedule for stage IIB nonseminoma patients is similar to the follow-up schedule outlined previously for patients with stage IIA nonseminoma and is dependent on the primary treatment modality and postsurgical management received by the patient (see “Follow-up for Nonseminoma Stage IIA,” page 1541, and TEST-B, pages 1541–1543).

Advanced Metastatic Nonseminoma

The primary chemotherapy options for patients with advanced metastatic nonseminoma are based on the International Germ Cell Cancer Consensus Group (IGCCCG) risk classification, which categorizes patients as good, intermediate, or poor risk based on identification of clinically independent prognostic features such as extent of disease and postorchiectomy levels of serum tumor markers (see TEST-D, page 1544).94 When determining a patient’s risk classification, the relevant serum tumor marker value is the value on day 1 of cycle 1 of first-line chemotherapy.

Primary Treatment of Good-Risk Nonseminoma

The IGCCCG good-risk group includes patients with stages IS, IIA (S1), IIB (S1), IIC, and IIIA disease (see TEST-11, page 1536). Treatment of good-risk disease is designed to limit toxicity while maintaining maximal efficacy. Presently, 2 regimens are recommended by the NCCN Panel: 3 cycles of BEP9597 or 4 cycles of EP9698 (both category 1 preferred regimens; see TEST-E, page 1545). Although both regimens are well tolerated and cure approximately 90% of patients with good-risk disease,96,99 4 cycles of EP should be considered in patients with reduced or borderline GFR and in patients over the age of 50.

Primary Treatment of Intermediate-Risk (Stage IIIB) Nonseminoma

For patients with intermediate-risk disease, the cure rate is approximately 70% with the standard chemotherapy regimen of 4 cycles of BEP.100,101 Therefore, the NCCN Panel recommends 4 cycles of BEP (preferred), or 4 cycles of etoposide, ifosfamide, and cisplatin (VIP)100,102 for patients who may not tolerate bleomycin, for the treatment of intermediate-risk (stage IIIB) nonseminoma. Both regimens are category 1 recommendations. However, if intermediate-risk status is based solely on LDH levels 1.5 to 3 times the upper limit of normal, then 3 cycles of BEP can be considered.

Primary Treatment of Poor-Risk (Stage IIIC) Nonseminoma

The standard chemotherapy regimen for poor-risk disease is 4 cycles of BEP (preferred). Alternatively, 4 cycles of VIP can be used to treat patients who may not tolerate bleomycin (see TEST-E, above).102 Both regimens are category 1 recommendations. However, fewer than 50% of patients with poor-risk nonseminoma experience a durable complete response to 4 cycles of BEP, and at least 30% die of their disease.94,103 Therefore, consultation with a high-volume center should be considered for the management of these patients.99

Management of Good-, Intermediate-, and Poor-Risk Nonseminoma After Chemotherapy

At the conclusion of primary chemotherapy, chest/abdominal/pelvic CT scan with contrast and measurement of serum tumor marker levels are indicated to assess treatment response. If a complete response to chemotherapy is found using radiographic imaging and the tumor marker levels are normal, the NCCN Panel recommends surveillance (see TEST-11, page 1536). Nerve-sparing bilateral RPLND can be considered in select cases for patients who had retroperitoneal lymphadenopathy before chemotherapy (category 2B).104 RPLND is recommended within 4 weeks of the CT scan and 7 to 10 days of marker measurement. Referral to high-volume centers should be considered for surgical resection of residual masses after chemotherapy.

If there is a partial radiographic response to chemotherapy (as indicated by the presence of residual masses) and tumor marker levels are normal, then surgical resection of all residual masses is recommended (see TEST-12, page 1537).105108 As previously stated, referral to high-volume centers should be considered for surgical resection of masses postchemotherapy. If only necrotic debris or teratoma is present in the resected tissue, the patient should be put under surveillance. If embryonal, yolk sac, choriocarcinoma, or seminoma elements are found in the residual mass, then 2 cycles of chemotherapy with EP; paclitaxel, ifosfamide, and cisplatin (TIP); VIP; or vinblastine, ifosfamide, and cisplatin (VelP) should be administered. All regimens are preferred in this setting; however, EP should be reserved for patients with low-volume residual disease.

Further management for patients who experience a partial radiographic response to chemotherapy (residual masses) with abnormal tumor marker levels is guided by the kinetics of the tumor markers (see TEST-12, page 1537). If tumor marker levels are elevated and persistently rising, the NCCN Panel recommends a full course of second-line chemotherapy (see TEST-F, page 1546, and “Second-Line Therapy,” next column). Patients with elevated but stable marker levels should be closely surveilled. Patients with mildly elevated and normalizing markers should be considered for surgical resection of residual masses with subsequent postsurgical management as discussed previously. The panel recommends referral to a high-volume center for the management of patients with a partial response to primary chemotherapy and abnormal marker levels.

Follow-up for Good-, Intermediate-, and Poor-RiskNonseminoma

The long-term follow-up for patients with good-, intermediate-, and poor-risk nonseminoma after chemotherapy (with or without postchemotherapy RPLND) includes history and physical examination, serum tumor marker assessment, chest X-ray, and abdominal/pelvic CT scan. The frequency of these tests are outlined in Table 8 on TEST-B (page 1542). Patients who have an incomplete response to chemotherapy require more frequent imaging than is outlined in the table. Patients who undergo RPLND and are found to have pN0 disease or pN1 pure teratoma need only 1 CT scan at postoperative month 3 or 4 and then as clinically indicated. In select circumstances, an MRI can be considered to replace an abdominal/pelvic CT. All imaging in this setting is performed with contrast. Chest X-ray may be used for routine follow-up, but chest CT with contrast is preferred in patients with thoracic symptoms.

Second-Line and Subsequent Therapy for Metastatic Germ Cell Tumors

Second-Line Therapy

Patients with disease relapse after first-line therapy or those who do not experience a durable complete response to first-line therapy should receive second-line therapy. Patients with recurrent disease who have not been treated with prior chemotherapy should be managed per their risk status, as described in the preceding sections. The panel prefers that patients with recurrent nonseminoma be treated at centers with expertise in the management of this disease. Second-line therapy options for patients with early relapses (within 2 years of the completion of primary therapy) include enrollment in a clinical trial (preferred), conventional-dose chemotherapy, or high-dose chemotherapy (see TEST-13, page 1538). If chemotherapy is given, both conventional-dose and high-dose regimens are preferred in this setting. The conventional-dose regimens are TIP or VeIP.109112 The high-dose regimens include high-dose carboplatin plus etoposide followed by autologous stem cell transplant,113 or paclitaxel plus ifosfamide followed by high-dose carboplatin plus etoposide with stem cell support (see TEST-F, page 1546).114 Alternatively, surgical salvage may be considered if the recurrent mass is in a solitary resectable site.115 Late relapses (>2 years after completion of primary therapy) occur in 2%–3% of testicular cancer survivors.116,117 The NCCN Panel prefers surgical salvage for these patients if the recurrent mass is resectable.115 If it is unresectable, chemotherapy (conventional or high dose) is the preferred option. Clinical trial enrollment is also an option for patients with unresectable late relapse.

Because it is not currently known whether high-dose chemotherapy is better than conventional-dose chemotherapy in the second-line setting for patients with relapsed disease, the NCCN Panel recommends clinical trial enrollment for these patients. An ongoing, randomized, international phase III trial (TIGER) will compare second-line conventional-dose chemotherapy with high-dose chemotherapy in patients with relapsed GCTs.118 The foundation of the TIGER trial was formed based on the results of a large retrospective analysis by Lorch et al119 which showed the superiority of carboplatin-based high-dose chemotherapy compared with cisplatin-based conventional-dose chemotherapy with respect to 2-year progression-free survival (50% vs 28%; P<.001) and 5-year OS (53% vs 41%, P<.001).120 The TIGER trial will randomize patients with unequivocal disease progression after cisplatin-based primary chemotherapy to receive conventional-dose TIP or high-dose paclitaxel plus ifosfamide followed by high-dose carboplatin plus etoposide with stem cell support. OS is the primary endpoint. Secondary endpoints include progression-free survival, response rate, toxicity, quality of life, and biologic correlates.118,120 This trial is currently recruiting patients, and participation is highly encouraged (ClinicalTrials.gov identifier: NCT02375204).

Management of Metastatic Germ Cell Tumors After Second-Line Therapy

To assess response after second-line therapy, a CT scan with contrast of the chest, abdomen, pelvis, and any other sites of disease is recommended. Levels of serum tumor markers should also be measured. Patients with a complete response to second-line therapy with normal marker levels should be put under surveillance. Alternatively, select patients may receive nerve-sparing bilateral RPLND (category 2B), followed by surveillance. For patients with a partial response to second-line therapy (as indicated by residual masses on CT scan) and normal marker levels, surgical resection of all residual masses is recommended followed by surveillance. Patients with a partial response to second-line therapy (residual masses) and abnormal marker levels should be managed according to the kinetics of the tumor markers (see TEST-14, page 1539). If tumor marker levels are elevated and persistently rising, the panel recommends third-line therapy (see TEST-G, previous page and above, and “Third-Line Therapy,” subsequent section). Patients with elevated but stable tumor marker levels should be closely surveilled. Patients with mildly elevated and normalizing markers should be considered for surgical resection of residual masses followed by surveillance.

Third-Line Therapy

Participation in a clinical trial is the preferred treatment option for patients who experience relapse after first- and second-line therapy (see TEST-15, page 1540). Alternatively, patients previously treated with conventional-dose chemotherapy can receive high-dose regimens or be considered for surgical salvage if the recurrent mass is in a solitary resectable site. Alternative options for patients previously treated with high-dose regimens include conventional-dose salvage chemotherapy, surgical salvage (if solitary site), and microsatellite instability/mismatch repair (MSI/MMR) testing (if disease progresses after high-dose chemotherapy or third-line therapy). The preferred treatment option for patients who experience a late relapse (>2 years after completion of second-line therapy) is surgical salvage, if the recurrent mass is resectable. Conventional-dose or high-dose chemotherapy (if not previously received), are also options for patients with late relapse.

To maintain optimal efficacy and limit treatment-related toxicities, the chemotherapy regimens previously received by the patient should be considered when deciding on third-line therapy options. High-dose chemotherapy is the preferred third-line option if it has not been previously received (see TEST-G, page 1547). If high-dose chemotherapy was previously received by the patient, then palliative chemotherapy is the preferred third-line treatment option. Additionally, the panel considers pembrolizumab immunotherapy to be useful in certain circumstances (ie, in patients with MSI-high/deficient MMR [MSI-H/dMMR] tumors).

The recommended third-line palliative chemotherapy options for patients with intensively pretreated, cisplatin-resistant, or refractory GCTs are combinations of gemcitabine with paclitaxel and/or oxaliplatin,121127 or oral etoposide.128 The recommendation for gemcitabine and oxaliplatin (GEMOX) is based on data from phase II studies investigating the efficacy and toxicity of GEMOX in patients with relapsed or cisplatin-resistant GCTs.122,124,126 These studies showed that GEMOX is safe for patients with cisplatin-resistant testicular GCTs and may offer a chance of long-term survival.122,124,126 Gemcitabine and paclitaxel is another option that has shown promising results in a phase II study.123 Follow-up results showed long-term disease-free survival in patients who showed progression after high-dose chemotherapy and who had not received prior paclitaxel or gemcitabine.125 A phase II study of patients with treatment-resistant GCTs also found the combination of gemcitabine, oxaliplatin, and paclitaxel to be effective with acceptable toxicity.121 The overall response rate was 51% with 5% of patients experiencing a complete response. A second study reported similar results.127 Additionally, high-dose single-agent oral etoposide was shown to be effective in a phase II study involving patients who had previous treatment with cisplatin/etoposide combination regimens.128

Pembrolizumab, an anti-PD-1 antibody, was approved by the FDA for the treatment of patients with unresectable or metastatic MSI-H/dMMR solid tumors that have progressed after previous treatment and who have no satisfactory alternative treatment options.129 This first-ever tissue- and site-agnostic indication was based on data from phase II clinical trials that demonstrated the efficacy of pembrolizumab in MSI-H/dMMR solid tumors.130,131 In the only trial (phase II) investigating the efficacy of immunotherapy in testicular cancer, 12 patients with nonseminoma GCTs that progressed after first-line cisplatin-based chemotherapy and at least 1 salvage regimen (high-dose or conventional-dose chemotherapy) were treated with pembrolizumab.132 Two patients experienced stable disease for 28 and 19 weeks, respectively, but no partial or complete responses were seen. The study showed 6 grade-3 adverse events, but no immune-related adverse events were reported. Therefore, pembrolizumab was well tolerated but appears to have limited single-agent activity in refractory GCTs. However, larger phase II and phase III trials of pembrolizumab in patients with metastatic or refractory testicular cancers are needed to fully assess the value of this therapy, especially in treating MSI-H/dMMR testicular GCTs.

Treatment of Brain Metastases

Brain metastases from testicular GCTs are relatively rare and occur almost exclusively in patients with nonseminoma histology.133 The development of brain metastases may be more common in patients with a higher burden of systemic disease; lung, liver, and/or bone metastases; high levels of serum beta-hCG (>5,000 IU/L); and in those who experience relapse after cisplatin-based chemotherapy. The prognosis of patients with brain metastases from testicular GCTs is poor, with >50% of patients dying within 1 year of diagnosis.133,134 Patients with additional adverse prognostic factors, especially those with metachronous brain metastases, have even worse outcomes.133,135,136

In a recent retrospective analysis, Loriot et al137 reported on the pattern of relapse among patients with poor-risk nonseminomatous GCTs previously treated with chemotherapy. After a median follow-up of 4.1 years, 32% were found to have radiographic evidence of brain metastases. The brain was the only site of progression in 54% of these patients, and 19% experienced progression in the brain as the first progression event. Furthermore, involvement of the brain was more common among patients who were previously treated with high-dose chemotherapy (29%) compared with BEP (12%). These data suggest that brain metastases from testicular GCTs may occur more frequently than previously thought, often as the only site of progression, and may be more likely to occur in poor-risk patients previously treated with high-dose chemotherapy. However, it is unknown whether this effect was due to the lower cerebral drug penetrance of the high-dose regimen.

The optimal management of brain metastases from testicular GCTs is controversial, with a lack of evidence from prospective trials to guide treatment decisions.133,135 Therefore, management decisions are usually based on institutional preferences, which may in part explain the large variation in treatment modalities received by these patients. The NCCN Guidelines recommend primary treatment with cisplatin-based chemotherapy for patients with brain metastases. The addition of radiation therapy to chemotherapy regimens can also be considered.138 Surgical resection of metastatic brain lesions should be performed if clinically indicated and feasible.

Summary

The NCCN Guidelines for Testicular Cancer provide an evidence- and consensus-based treatment approach for the management of adult patients with seminomatous and nonseminomatous testicular GCTs. Testicular GCTs are sensitive to platinum-based chemotherapy, and patients have high cure rates even with metastatic disease. Although most metastatic GCTs are cured with chemotherapy, 20% to 30% of patients will experience relapse after first-line chemotherapy and require additional treatment strategies. The ongoing international phase III TIGER trial aims to determine whether high-dose or conventional-dose chemotherapy is more effective in the second-line setting for patients with relapsed disease. Patients with platinum-refractory or relapsing tumors after second-line therapy have very poor outcomes despite salvage treatments, with no effective alternative therapies. Targeted therapies appear to have limited activity in this setting, although more robust clinical trials are needed to assess their value in treating testicular GCTs. Prognosis for patients with brain metastases remains poor, with a lack of evidence from prospective trials to guide treatment decisions. Therefore, the NCCN panel encourages patients with metastatic, recurrent, or platinum-refractory testicular GCTs to participate in well-designed clinical trials investigating novel therapeutic strategies to enable further advances for the management of this disease.

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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult theNCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

© National Comprehensive Cancer Network, Inc. 2019. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

Disclosures for the NCCN Gestational Trophoblastic Neoplasia Panel

At the beginning of each NCCN Guidelines Panel meeting, panelmembers reviewall potential conflicts of interest.NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.

Individual disclosures for the NCCN Gestational Trophoblastic Neoplasia Panel members can be found on page 1391. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org.)

The complete and most recent version of these guidelines is available free of charge at NCCN.org.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Individual Disclosures for the NCCN Testicular Cancer Panel

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