NCCN Continuing Education
Target Audience: This journal article is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-25-011-H01-P
PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until April 10, 2026. PAs should only claim credit commensurate with the extent of their participation.
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/Apr2025; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.
Release date: April 10, 2025; Expiration date: April 10, 2026
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Integrate into professional practice the updates to the NCCN Guidelines for Testicular Cancer
• Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Testicular Cancer
Disclosure of Relevant Financial Relationships
None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.
Individuals Who Provided Content Development and/or Authorship Assistance:
The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.
Timothy Gilligan, MD, MS, Panel Chair
Daniel W. Lin, MD, Vice Chair
Kosj Yamoah, MD, PhD, Panel Member
Sarah Montgomery, BA, Guidelines Layout Specialist, NCCN
Bailee Sliker, PhD, Oncology Scientist/Medical Writer, NCCN
The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.
Nabil Adra, MD, MSc, Panel Member, has disclosed receiving grant/research support from Amgen Inc., Bristol Myers Squibb, Exelixis, Inc., Genentech, Inc., Gilead Sciences, Inc., Merck & Co., Inc., and Novartis Pharmaceuticals Corporation; and serving as a scientific advisor for Astellas Pharma US, Inc., AVEO Pharmaceuticals, Inc., Bristol Myers Squibb, EMD Serono, Exelixis, Inc., and Sanofi-Aventis U.S.
Aditya Bagrodia, MD, Panel Member, has disclosed receiving consulting fees from Ferring Pharmaceuticals and Veracyte.
Darren R. Feldman, MD, Panel Member, has disclosed receiving grant/research support from Bristol Myers Squibb, Exelixis, Inc., and Telix Pharmaceuticals; and receiving consulting fees from BioNTech, Debiopharm Group, Exelixis, Inc., Renibus Therapeutics, Telix Pharmaceuticals, and Xencor.
To view disclosures of external relationships for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels
This activity is supported by educational grants from AstraZeneca, Coherus BioSciences, Geron, Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC, Novartis, SpringWorks Therapeutics, Inc., and Taiho Oncology, Inc. This activity is supported by an independent educational grant from Rigel Pharmaceuticals, Inc.
Overview
Testicular cancer accounts for <1% of new cancer cases, with a majority of patients being diagnosed between the ages of 20 and 34 years.1 The global incidence of this disease has been steadily rising over the past several decades, with an estimated 9,720 new cases of testicular cancer projected to be diagnosed in the United States in 2025.1–8 An estimated 600 deaths will occur from testicular cancer in the United States during this same period, reflecting the excellent 5-year relative survival rate for this disease (∼94%).1 The vast majority (95%) of testicular cancers are germ cell tumors (GCTs) and in this article, the term testicular cancer refers to testicular GCTs and not the other rarer types of testicular cancer.2,9,10 Several risk factors for testicular cancer have been identified, including personal or family history of testicular cancer and cryptorchidism.2,11,12
Testicular cancer most often presents as a painless or painful testicular nodule, mass, enlargement, or induration (hardening), which should be further evaluated with a transscrotal ultrasound with Doppler. If ultrasound findings indicate a mass suspicious for malignancy, a radical inguinal orchiectomy is performed to make a diagnosis. In certain cases of advanced disease, systemic therapy may be initiated if there is an unequivocal diagnosis of GCT with marker elevation or after percutaneous biopsy of a metastasis. GCTs are broadly categorized into 2 main histologic subtypes: seminoma and nonseminoma.2,9,10 Seminomas and nonseminomas typically occur at about the same rate, but nonseminomas tend to be more aggressive and often include multiple cell types. Further management strategies are dictated by histology and stage. If both seminoma and any elements of nonseminoma are present, the tumor should be treated as a nonseminoma.
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Testicular Cancer provide an evidence- and consensus-based approach for the treatment of adult patients with either seminomatous or nonseminomatous testicular GCTs. These NCCN Guidelines Insights specifically focus on the currently recommended treatment landscape for patients with pure seminoma.
Serum Tumor Markers in Seminoma
The AJCC TNM staging system for testis cancer incorporates serum tumor marker elevation as a distinct category (S), which is unique to this organ site. The serum tumor markers lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), and beta-human chorionic gonadotropin (beta-hCG) are currently used to determine prognosis and stage, and thus should be assessed both before and after orchiectomy.10 A diagnosis of pure seminoma is restricted to pure seminoma histology, which would not include germ cell elements that are associated with AFP production. Accordingly, patients with pure seminoma should have normal serum AFP levels. Elevated AFP levels with pure seminoma histology should be treated as a nonseminoma; however, mild elevations in AFP that are stable do not connote nonseminoma and can be treated as seminoma.13,14 Additionally, mildly elevated, nonrising levels of AFP do not always indicate the presence of a GCT, given that a small number of people have a chronically elevated serum AFP level, and therefore clinicians should be cautious in the interpretation of mildly elevated but stable AFP levels.13 Beta-hCG and LDH may be elevated in patients with seminoma, but these levels alone should not be used to stage or risk-stratify patients with pure seminoma. Mild to moderate elevations of beta-hCG (S1) are not used to risk-stratify pure seminomas; however, a level of 5,000 IU/L, which is the cutoff for S2, is not generally thought to be compatible with a pure seminoma. Whether an elevated LDH should be used to stage or risk-stratify patients with pure seminoma is controversial, and practice patterns among the panel members vary. For patients with otherwise good-risk disseminated seminoma (stage II–III), an LDH level >2.5 times the upper limit of normal (ULN) is associated with a worse prognosis, but there is no consensus as to whether treatment for such patients should therefore be intensified.15 Some panel members advocate treating these patients as having good risk, whereas others advocate for a more aggressive approach.
Primary Treatment of Seminoma
The primary initial treatment for most patients with a suspicious testicular mass is orchiectomy. For patients diagnosed with a pure seminoma, further treatment postorchiectomy can involve surveillance, chemotherapy, radiation therapy (RT), or surgery, depending on stage of disease.
Primary Treatment for Pure Seminoma
Stages IA and IB
Given that 80% to 85% of patients with stage I pure seminoma are cured by orchiectomy alone, the NCCN panel continues to strongly prefer surveillance for pT1–pT3 tumors as the standard postorchiectomy treatment option for these patients because the risk of relapse is low when considered in relation to the potential harms of adjuvant therapy. For patients who decline surveillance or for whom surveillance is not a good option, the panel recommends chemotherapy with 1 or 2 cycles of single-agent carboplatin (area under the curve [AUC] × 7), or RT as alternatives to reduce the risk of relapse (see Figure 1). If RT is delivered, the panel recommends a total dose of 20 Gy be administered in 10 fractions of 2.0 Gy each.16 Alternatively, a total dose of 25.5 Gy can be given in 17 fractions of 1.5 Gy each.17 Disease-specific survival for stage I disease approaches 100% irrespective of the initial management strategy used, including surveillance.18 Each approach has distinct advantages and disadvantages that should be discussed with patients and their families to select the best individual treatment plan.
SEM-2. NCCN Clinical Practice Guidelines in Oncology for Testicular Cancer, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 4; 10.6004/jnccn.2025.0018
Several studies evaluating surveillance for the management of stage I seminoma have been conducted.19–24 The relapse rates seen in these studies have ranged from 15% to 20%, with most disease relapse detected in the infradiaphragmatic lymph nodes. The best established risk factor for relapse of pure seminoma is larger size of the primary tumor.25 As the tumor size increases, the risk of relapse also increases, but any particular size cutoff is arbitrary.19,21,26–29 Although the 8th edition of the AJCC Cancer Staging Manual uses a cutoff point of 3 cm to subclassify stage IA pure seminoma into pT1a and pT1b, this small cutoff size was chosen in an effort to be conservative due to the large variability in size cutoffs reported in the literature.10 Additionally, lymphovascular invasion is a risk factor for relapse,30,31 and some studies have reported that rete testis invasion is an independent risk factor for relapse in stage I pure seminoma, whereas others have reported that it is not.19,21,25–27,32 The NCCN panel discourages risk-adapted management in stage I pure seminoma, and instead strongly recommends surveillance for all patients who are able to adhere to the surveillance schedule.
As noted, chemotherapy or RT are potential therapeutic options for those patients with stage I seminoma for whom surveillance is not a suitable option. A study reporting the results of a trial that randomized 1,477 patients with stage I seminoma to receive either RT (n=885) or 1 cycle of intravenous carboplatin (n=560) at the dose AUC × 7 (ie, based on the formula 7 × [glomerular filtration rate (GFR, mL/min) + 25 mg]) showed that at a follow-up of 3 years, the relapse-free survival (RFS) rates for both groups were similar (95.9% for the RT group and 94.8% for the carboplatin group), which established the noninferiority of carboplatin compared with RT.33 The mature results of this trial confirmed the noninferiority of single-dose carboplatin versus RT in terms of RFS.34 In an intent-to-treat analysis, the RFS rates at 5 years were 96% in the RT arm and 94.7% in the carboplatin arm (hazard ratio [HR], 1.25; P=.37). One seminoma-related death occurred after RT and none occurred after carboplatin. Additionally, patients who received carboplatin were less lethargic and less likely to take time off work than those who received RT. Therefore, the authors concluded that a single dose of carboplatin is less toxic and equally effective as adjuvant RT in preventing disease relapse in males with stage I pure seminoma after orchiectomy.34 However, it should be noted that there are limited long-term follow-up data regarding the toxicity and efficacy of carboplatin.19,35 A nonrandomized, population-based study of 897 patients with stage I seminoma suggested that those with tumor size >4 cm, rete testis invasion, or both derive a smaller reduction in relapse rate with 1 cycle of carboplatin than previously reported.19,21,35 After a median follow-up of 5.6 years, the relapse rate was 15.5% in patients with one or both risk factors who underwent surveillance, compared with 9.3% in those who received 1 cycle of carboplatin.19 Given the toxicity, an absolute reduction in the risk of relapse by only 6.2% may not be sufficient to justify the use of single-cycle adjuvant carboplatin.35 Platinum-based chemotherapy for testis cancer has also been associated with cardiac toxicity and an increased risk for secondary cancers, as well as a 23% higher risk of death from causes other than testis cancer.36–39 However, most of the data on late effects of platinum-based chemotherapy in testis cancer survivors are derived from men receiving multiagent cisplatin-based chemotherapy; whether such long-term risks ensue from 1 or 2 cycles of single-agent carboplatin as dosed for stage I seminoma remains unknown. Therefore, more data are needed to assess the value of 1 cycle of carboplatin in treating patients with stage I seminoma.
Use of 2 cycles of adjuvant carboplatin in this setting has also been studied. The Spanish Germ Cell Cancer Cooperative Group reported that among 412 males treated with 2 cycles of adjuvant carboplatin for high-risk stage I seminoma, the 10-year RFS rate was 97% and 10-year overall survival (OS) rate was 100%.40–42 The efficacy of 2 cycles of adjuvant carboplatin was confirmed in a study by the Hellenic Cooperative Oncology Group, which reported a 5-year RFS rate of 96.8% among 138 patients with stage I seminoma treated with this regimen.43 A prospective study reported treatment outcomes for 725 patients with stage I seminoma who underwent with surveillance, 1 cycle of carboplatin, or 2 cycles of carboplatin.44 Although disease-specific survival was 100% for all 3 strategies, crude relapse rates were significantly higher with the 1-cycle regimen (5%) compared with the 2-cycle regimen (1.5%) after a median follow-up of 30 months. Furthermore, 1 cycle of carboplatin demonstrated low efficacy to control large tumors. In the absence of randomized data comparing 1 versus 2 doses of carboplatin, as well as the lack of long-term data, the panel does not currently recommend one dose over the other for the minority of patients for whom chemotherapy would be appropriate.
Numerous studies have also found an increased risk for late toxicities in patients with seminoma treated with RT, including development of secondary malignancies and an increased risk of death from causes other than testis cancer.39,45,46 A population-based study of >5,700 testis cancer survivors, including 1,500 treated with RT, reported that RT was associated with a 28% increase in the risk of death from non–testis cancer–related causes.39 The increased risk of death was seen specifically for secondary malignancies and diseases of the digestive system. However, most of these patients were treated with larger treatment fields and higher radiation doses than are currently recommended for stage I seminoma. Another population-based study reported that RT for stage I seminoma was associated with an 80% increase in the risk of death from secondary cancers.47 Similarly, it has been reported that moderate-dose infradiaphragmatic RT for stage I seminoma was associated with an increased risk for secondary cancers in organs within the radiation field.48 Another multicenter cohort study also reached similar conclusions.38 Additionally, nodal mapping studies suggest that treatment fields should target the retroperitoneal lymph nodes but not necessarily the ipsilateral renal hilar nodes.49,50 Special circumstances, such as ipsilateral pelvis surgery, may alter the lymphatic drainage of the testis. Therefore, irradiation of the ipsilateral iliac and inguinal lymph nodes has been advocated in such patients.49,51,52 It should be noted that patients treated with para-aortic RT have a slightly higher rate of pelvic relapse compared with those treated with “dog-leg” RT.52–55 Prophylaxis to the mediastinum is not provided, because relapse rarely occurs at this site and mediastinal RT introduces additional toxicities and late effects. Because of the potential for toxicities and late effects, the panel continues to only recommend RT at this stage for a minority of patients.
Stage IS
Stage IS pure seminoma is very uncommon and requires persistent elevation of serum tumor markers following orchiectomy in the absence of radiologic evidence of metastatic disease. Elevated tumor markers increase the risk of disease outside the retroperitoneum; therefore, systemic therapy is encouraged by members of the panel. However, the panel cautions against treating a patient based solely on an elevated LDH or a mildly elevated beta-hCG level, because other causes may be responsible for elevation of these markers. Persistent and progressive increases in elevated beta-hCG levels is usually evidence of metastatic disease, which will show up radiographically if doubt exists in the diagnosis.
Stages IIA and IIB
The most significant recent changes made by the panel have occurred for stage IIA/B seminoma. Stage IIA pure seminoma is defined as metastatic disease to lymph nodes, with a lymph node mass measuring ≤2 cm in greatest diameter.10 A lymph node mass measuring 2 to 5 cm in greatest diameter is classified as stage IIB disease.10 Clinically, patients are often categorized as having “nonbulky” clinical stage II disease (largest node <3 cm on long axis) or “bulky” clinical stage II disease (largest node>3 cm on long axis). Options for the primary treatment of nonbulky clinical stage II seminomas are RT, first-line chemotherapy with 3 cycles of BEP (bleomycin, etoposide, cisplatin) or 4 cycles of EP (etoposide and cisplatin), carboplatin + RT, or nerve-sparing retroperitoneal lymph node dissection (RPLND). If disease is between 3 and 5 cm, then first-line chemotherapy is given, with both EP and BEP being preferred regimens in this setting (see Figure 2). However, the panel suggests considering the use of a bleomycin-free regimen in patients at risk for bleomycin-related toxicity, such as those with a reduced GFR or older age (age >50 years). The presence of chronic obstructive pulmonary disease (COPD) or other lung disease resulting in reduced pulmonary function are also risk factors for bleomycin-related toxicity. Different studies have reported different outcomes with regard to whether chemotherapy or RT is more effective in this setting. A study that used data from the National Cancer Database to assess survival outcomes according to treatment strategy in patients with stage IIA/B seminoma showed that when RT was compared with multiagent chemotherapy, 5-year OS was significantly higher with RT compared with chemotherapy in patients with stage IIA seminoma, whereas no significant difference in 5-year OS was seen in patients with stage IIB seminoma treated with postorchiectomy RT or chemotherapy.56 A second study that also used data from the National Cancer Database demonstrated similar results.57 However, these studies were not randomized trials and treatment decisions were based on the treating physician’s clinical judgment, which presumably was influenced by the specific characteristics of each patient. Therefore, it is possible that patients with more extensive disease were selected for chemotherapy. Nevertheless, these studies provide some support for the use of RT over chemotherapy to treat stage IIA seminoma. In contrast, a study by Mortensen et al29 evaluating 363 patients with stage II–III seminoma reported that the relapse rate was 6% among those treated with chemotherapy compared with 12.6% among those treated with RT. It should be noted that patients who received chemotherapy had more advanced-stage disease than those who received RT in this study. This has led some physicians to prefer chemotherapy for patients with stage II seminoma; however, these results must be interpreted with caution because this study was not a randomized trial and did not specifically compare the 2 treatment modalities for stage IIA disease. Therefore, the panel recommends first-line chemotherapy as primary treatment for both stage IIA and IIB seminoma but suggests RT should be reserved for patients with nonbulky seminomas (ie, all enlarged lymph nodes should be <3 cm in the long axis).58
SEM-3. NCCN Clinical Practice Guidelines in Oncology for Testicular Cancer, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 4; 10.6004/jnccn.2025.0018
Although primary treatment with RT or first-line chemotherapy results in favorable survival outcomes, they bear the risks of acute and late toxic effects. Therefore, evaluation and development of alternative strategies is of interest to the broader field in order to mitigate toxicity while maintaining efficacy. Prospective and retrospective studies have reported the use of primary RPLND in clinical stage II seminoma with curative intent and demonstrated that it can cure many clinical stage II seminomas, with a 2-year recurrence free survival of 72% to 90%, allowing patients to avoid chemotherapy and RT.59–62 Due to these promising results, the panel decided to include RPLND as an option for stage IIA and stage IIB nonbulky (<3 cm) disease. However, for stage IIB nonbulky disease (2–3 cm) this is a category 2B recommendation, because some panel members expressed concern regarding the potential for higher disease recurrence rates compared with chemotherapy as well as the limited number of patients with this extent of disease included in these trials. Moreover, the panel chose not to recommend RPLND for bulky (>3 cm) stage IIB disease due to very limited data for those patients and higher relapse rates with increasing node size.
Furthermore, the recent single-arm phase II SAKK (01/10) trial investigated whether 1 cycle of single-agent carboplatin followed by involved-node RT was effective in treating patients with stage IIA or IIB seminoma (n=116) with minimal toxicity.63 After a median follow-up of 4.5 years, the 3-year progression-free survival (PFS) was 93.7%, which was short of the target 3-year PFS of 95%. Although the study failed to meet its primary endpoint, survival was favorable and toxic effects were minimal with this treatment strategy. Grade 3–4 treatment-related adverse events included neutropenia, thrombocytopenia, and vomiting, which occurred in 4%, 3%, and 1% of patients, respectively. No treatment-related deaths and no late toxic effects were reported. Serious adverse events were reported in only 4% of patients. Based on the promising efficacy of this regimen in the SAKK (01/10) trial, the panel added it as an option for patients with involved lymph nodes measuring <3 cm; however, due to the lack of evaluation of late toxicities beyond 3 years, voted to include it as a category 2B option for this patient population.
Stages IIC and III
Patients with stage IIC or stage III seminomas are classified as either good or intermediate risk. All stage IIC and III seminomas are considered good risk except for stage IIIC disease, which involves nonpulmonary visceral metastases (eg, bone, liver, brain) and is considered intermediate risk. Standard first-line chemotherapy is unanimously recommended by the panel for both groups of patients (see Figure 3).
SEM-4. NCCN Clinical Practice Guidelines in Oncology for Testicular Cancer, Version 2.2025.
Citation: Journal of the National Comprehensive Cancer Network 23, 4; 10.6004/jnccn.2025.0018
For patients with good risk, 3 cycles of BEP or 4 cycles of EP are recommended (both preferred).64–66 These 2 regimens have not been compared head-to-head in patients with seminoma, and therefore the panel recommends that a number of factors be considered when choosing between them. The specific schedule of the regimens is different (9 weeks for 3 cycles of BEP compared with 12 weeks for 4 cycles of EP), which may make one more convenient for certain patients. Although EP is associated with a dose-dependent increased risk of secondary cancers, there are no data addressing whether the risk is significantly higher with 4 cycles versus 3. Bleomycin, which is cleared by the kidneys, is associated with a risk of pneumonitis and diminished pulmonary function. Therefore, 4 cycles of EP is preferred by the panel for patients with a reduced GFR (who would be expected to clear bleomycin more slowly), those aged >50 years (because renal function decreases with age), and those with COPD or other lung disease resulting in significantly diminished pulmonary function. Some oncologists prefer 4 cycles of EP for heavy smokers regardless of lung function. The panel does recommend considering therapy intensification in good-risk patients with an LDH >2.5 times the ULN, because they tend to have worse outcomes, but no consensus was reached on an exact regimen.
For patients with intermediate-risk disease, more intensive chemotherapy with 4 cycles of BEP (preferred) or 4 cycles of etoposide, mesna, ifosfamide, and cisplatin (VIP) is recommended.67–72 VIP should be reserved for patients with a contraindication to bleomycin (ie, a reduced or borderline GFR, age >50 years, COPD, or other lung disease), but it should be kept in mind that this regimen confers a high risk for febrile neutropenia and therefore granulocyte colony-stimulating factors (G-CSFs) should be used. All of these chemotherapy options are category 1 recommendations except for VIP, which is category 2A.
Management of Pure Seminoma Stages IIA, IIB, IIC, and III After Chemotherapy
After primary treatment with first-line chemotherapy, patients with stage IIA, IIB, IIC, or III seminoma should be evaluated by CT scan with contrast or MRI with and without contrast of the chest, abdomen, and pelvis as well as measurement of serum tumor markers. Patients with normal serum AFP and beta-hCG levels and either no residual mass or a residual mass ≤3 cm should undergo surveillance.
For patients with a residual mass >3 cm and normal serum AFP and beta-hCG levels, continued surveillance or obtaining an FDG-PET/CT scan from skull base to mid-thigh ≥6 weeks after completing chemotherapy should be considered. If FDG-PET/CT is obtained and is negative or indeterminate, then surveillance can be continued. If the FDG-PET/CT is positive, the residual mass should be resected or biopsied. If the residual disease is completely resected and histopathology shows viable seminoma, 2 cycles of adjuvant chemotherapy can be considered with the following regimens: EP, TIP (paclitaxel, ifosfamide, cisplatin),73 VIP, or VeIP (vinblastine, mesna, ifosfamide, cisplatin).74,75 The panel could not reach a consensus on which of these 4 treatments would be best at this stage, due to the rarity of such occurrences. If the resection is incomplete and the pathology shows viable seminoma, or if there is progressive disease (growing mass or rising markers), a full course of second-line chemotherapy (4 cycles of TIP or 4 cycles of VeIP or treatment with high-dose chemotherapy with carboplatin and etoposide) is recommended.73–77
If a patient experiences progressive disease after second-line therapy, third-line therapy is recommended and would be based on whether a patient had prior conventional-dose chemotherapy or prior high-dose chemotherapy. High-dose chemotherapy is preferred by the panel for patients who have not previously received it, whereas conventional-dose third-line chemotherapy or a clinical trial (preferred) is recommended for those who have previously received high-dose chemotherapy. Molecular testing, including microsatellite instability/mismatch repair (MSI/MMR) and tumor mutational burden (TMB) testing, for patients who experience disease progression after second-line therapy was also added by the panel in light of the recent influx of pan-cancer approvals for many biomarker-directed regimens. The panel decided to specifically add pembrolizumab, which has been approved by the FDA for the treatment of patients with unresectable or metastatic MSI-high (MSI-H)/deficient MMR (dMMR) or TMB-high (TMB-H) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.78–80 Additionally, the panel recommends that other pan-cancer, tumor-agnostic treatments can be considered for third-line treatment in patients with actionable mutations observed upon molecular testing, but decided not to specifically list them at this time because many lack specific data in cases of advanced testicular cancer.
Conclusions
Despite the high cure rates for testicular cancer, treatments for testicular GCTs, especially seminomas, are still evolving and seek to reduce toxicities and late effects. These NCCN Guidelines Insights discuss the latest clinical data and panel discussions regarding alterations to the treatment landscape of pure seminomas included in Version 2.2025 of the NCCN Guidelines for Testicular Cancer. For a complete list of the recent updates, see the full version of these guidelines at NCCN.org.
References
- 1.↑
Siegel RL, Kratzer TB, Giaquinto AN, et al. Cancer statistics, 2025. CA Cancer J Clin 2025;75:10–45.
- 3.↑
Huyghe E, Matsuda T, Thonneau P. Increasing incidence of testicular cancer worldwide: a review. J Urol 2003;170:5–11.
- 4.↑
Shanmugalingam T, Soultati A, Chowdhury S, et al. Global incidence and outcome of testicular cancer. Clin Epidemiol 2013;5:417–427.
- 5.↑
Verhoeven RHA, Gondos A, Janssen-Heijnen MLG, et al. Testicular cancer in Europe and the USA: survival still rising among older patients. Ann Oncol 2013;24:508–513.
- 6.↑
Chia VM, Quraishi SM, Devesa SS, et al. International trends in the incidence of testicular cancer, 1973-2002. Cancer Epidemiol Biomarkers Prev 2010;19:1151–1159.
- 7.↑
Pishgar F, Haj-Mirzaian A, Ebrahimi H, et al. Global, regional and national burden of testicular cancer, 1990–2016: results from the Global Burden of Disease Study 2016. BJU Int 2019;124:386–394.
- 8.↑
Ghazarian AA, McGlynn KA. Increasing incidence of testicular germ cell tumors among racial/ethnic minorities in the United States. Cancer Epidemiol Biomarkers Prev 2020;29:1237–1245.
- 9.↑
Vasdev N, Moon A, Thorpe AC. Classification, epidemiology and therapies for testicular germ cell tumours. Int J Dev Biol 2013;57:133–139.
- 10.↑
Amin MB, Edge SB, Greene F, et al. AJCC Cancer Staging Manual, 8th ed. Springer International Publishing; 2017.
- 11.↑
Turnbull C, Rahman N. Genome-wide association studies provide new insights into the genetic basis of testicular germ-cell tumour. Int J Androl 2011;34:e86–96.
- 12.↑
Greene MH, Kratz CP, Mai PL, et al. Familial testicular germ cell tumors in adults: 2010 summary of genetic risk factors and clinical phenotype. Endocr Relat Cancer 2010;17:R109–121.
- 13.↑
Albany C, Einhorn L. Pitfalls in management of patients with germ cell tumors and slight elevation of serum alpha-fetoprotein. J Clin Oncol 2014;32:2114–2115.
- 14.↑
Wymer KM, Daneshmand S, Pierorazio PM, et al. Mildly elevated serum alpha-fetoprotein (AFP) among patients with testicular cancer may not be associated with residual cancer or need for treatment. Ann Oncol 2017;28:899–902.
- 15.↑
Beyer J, Collette L, Sauve N, et al. Survival and new prognosticators in metastatic seminoma: results from the IGCCCG-Update Consortium. J Clin Oncol 2021;39:1553–1562.
- 16.↑
Garmezy B, Pagliaro LC. Choosing treatment for stage I seminoma: who should get what? Oncology (Williston Park) 2009;23:753–759.
- 17.↑
Choo R, Sandler H, Warde P, et al. Survey of radiation oncologists: practice patterns of the management of stage I seminoma of testis in Canada and a selected group in the United States. Can J Urol 2002;9:1479–1485.
- 18.↑
Mead GM, Fossa SD, Oliver RT, et al. Randomized trials in 2466 patients with stage I seminoma: patterns of relapse and follow-up. J Natl Cancer Inst 2011;103:241–249.
- 19.↑
Tandstad T, Stahl O, Dahl O, et al. Treatment of stage I seminoma, with one course of adjuvant carboplatin or surveillance, risk-adapted recommendations implementing patient autonomy: a report from the Swedish and Norwegian Testicular Cancer Group (SWENOTECA). Ann Oncol 2016;27:1299–1304.
- 20.↑
Aparicio J, García del Muro X, Maroto P, et al. Multicenter study evaluating a dual policy of postorchiectomy surveillance and selective adjuvant single-agent carboplatin for patients with clinical stage I seminoma. Ann Oncol 2003;14:867–872.
- 21.↑
Warde P, Specht L, Horwich A, et al. Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. J Clin Oncol 2002;20:4448–4452.
- 22.↑
Chung P, Parker C, Panzarella T, et al. Surveillance in stage I testicular seminoma - risk of late relapse. Can J Urol 2002;9:1637–1640.
- 23.↑
Groll RJ, Warde P, Jewett MA. A comprehensive systematic review of testicular germ cell tumor surveillance. Crit Rev Oncol Hematol 2007;64:182–197.
- 24.↑
Escudero-Ávila R, Rodríguez-Castaño JD, Osman I, et al. Active surveillance as a successful management strategy for patients with clinical stage I germ cell testicular cancer. Clin Transl Oncol 2019;21:796–804.
- 25.↑
Zengerling F, Kunath F, Jensen K, et al. Prognostic factors for tumor recurrence in patients with clinical stage I seminoma undergoing surveillance-a systematic review. Urol Oncol 2018;36:448–458.
- 26.↑
Aparicio J, Maroto P, García Del Muro X, et al. Prognostic factors for relapse in stage I seminoma: a new nomogram derived from three consecutive, risk-adapted studies from the Spanish Germ Cell Cancer Group (SGCCG). Ann Oncol 2014;25:2173–2178.
- 27.↑
Chung P, Daugaard G, Tyldesley S, et al. Evaluation of a prognostic model for risk of relapse in stage I seminoma surveillance. Cancer Med 2015;4:155–160.
- 28.↑
Chung P, Warde P. Stage I seminoma: adjuvant treatment is effective but is it necessary? J Natl Cancer Inst 2011;103:194–196.
- 29.↑
Mortensen MS, Lauritsen J, Gundgaard MG, et al. A nationwide cohort study of stage I seminoma patients followed on a surveillance program. Eur Urol 2014;66:1172–1178.
- 30.↑
Boormans JL, Sylvester R, Anson-Cartwright L, et al. Prognostic factor risk groups for clinical stage I seminoma: an individual patient data analysis by the European Association of Urology Testicular Cancer Guidelines Panel and Guidelines Office. Eur Urol Oncol 2024;7:537–543.
- 31.↑
Wagner T, Toft BG, Lauritsen J, et al. Prognostic factors for relapse in patients with clinical stage I testicular non-seminoma: a nationwide, population-based cohort study. Eur J Cancer 2024;202:114025.
- 32.↑
Boormans JL, Mayor de Castro J, Marconi L, et al. Testicular tumour size and rete testis invasion as prognostic factors for the risk of relapse of clinical stage I seminoma testis patients under surveillance: a systematic review by the Testicular Cancer Guidelines Panel. Eur Urol 2018;73:394–405.
- 33.↑
Oliver RT, Mason MD, Mead GM, et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet 2005;366:293–300.
- 34.↑
Oliver RT, Mead GM, Rustin GJ, et al. Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214). J Clin Oncol 2011;29:957–962.
- 35.↑
van de Wetering RAW, Sleijfer S, Feldman DR, et al. Controversies in the management of clinical stage I seminoma: carboplatin a decade in-time to start backing out. J Clin Oncol 2018;36:837–840.
- 36.↑
Huddart RA, Norman A, Shahidi M, et al. Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 2003;21:1513–1523.
- 37.↑
van den Belt-Dusebout AW, de Wit R, Gietema JA, et al. Treatment- specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 2007;25:4370–4378.
- 38.↑
Groot HJ, Lubberts S, de Wit R, et al. Risk of solid cancer after treatment of testicular germ cell cancer in the platinum era. J Clin Oncol 2018;36:2504–2513.
- 39.↑
Hellesnes R, Myklebust TA, Fossa SD, et al. Testicular cancer in the cisplatin era: causes of death and mortality rates in a population-based cohort. J Clin Oncol 2021;39:3561–3573.
- 40.↑
Aparicio J, García Del Muro X, Maroto P, et al. Patterns of relapse and treatment outcome after active surveillance or adjuvant carboplatin for stage I seminoma: a retrospective study of the Spanish Germ Cell Cancer Group. Clin Transl Oncol 2021;23:58–64.
- 41.↑
Aparicio J, Germà JR, García del Muro X, et al. Risk-adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study. J Clin Oncol 2005;23:8717–8723.
- 42.↑
Aparicio J, Maroto P, García del Muro X, et al. Risk-adapted treatment in clinical stage I testicular seminoma: the third Spanish Germ Cell Cancer Group study. J Clin Oncol 2011;29:4677–4681.
- 43.↑
Koutsoukos K, Tzannis K, Christodoulou C, et al. Two cycles of adjuvant carboplatin in stage I seminoma: 8-year experience by the Hellenic Cooperative Oncology Group (HECOG). World J Urol 2016;34:853–857.
- 44.↑
Dieckmann KP, Dralle-Filiz I, Matthies C, et al. Testicular seminoma clinical stage 1: treatment outcome on a routine care level. J Cancer Res Clin Oncol 2016;142:1599–1607.
- 45.↑
Travis LB, Curtis RE, Storm H, et al. Risk of second malignant neoplasms among long-term survivors of testicular cancer. J Natl Cancer Inst 1997;89:1429–1439.
- 46.↑
Travis LB, Fosså SD, Schonfeld SJ, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 2005;97:1354–1365.
- 47.↑
Beard CJ, Travis LB, Chen MH, et al. Outcomes in stage I testicular seminoma: a population-based study of 9193 patients. Cancer 2013;119:2771–2777.
- 48.↑
Horwich A, Fossa SD, Huddart R, et al. Second cancer risk and mortality in men treated with radiotherapy for stage I seminoma. Br J Cancer 2014;110:256–263.
- 49.↑
McMahon CJ, Rofsky NM, Pedrosa I. Lymphatic metastases from pelvic tumors: anatomic classification, characterization, and staging. Radiology 2010;254:31–46.
- 50.↑
Dinniwell R, Chan P, Czarnota G, et al. Pelvic lymph node topography for radiotherapy treatment planning from ferumoxtran-10 contrast-enhanced magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2009;74:844–851.
- 51.↑
Jones WG, Fossa SD, Mead GM, et al. Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I testicular seminoma: a report on Medical Research Council trial TE18, European Organisation for the Research and Treatment of Cancer trial 30942 (ISRCTN18525328). J Clin Oncol 2005;23:1200–1208.
- 52.↑
Fossa SD, Horwich A, Russell JM, et al. Optimal planning target volume for stage I testicular seminoma: a Medical Research Council randomized trial. J Clin Oncol 1999;17:1146.
- 53.↑
Livsey JE, Taylor B, Mobarek N, et al. Patterns of relapse following radiotherapy for stage I seminoma of the testis: implications for follow-up. Clin Oncol (R Coll Radiol) 2001;13:296–300.
- 54.↑
Martin JM, Panzarella T, Zwahlen DR, et al. Evidence-based guidelines for following stage 1 seminoma. Cancer 2007;109:2248–2256.
- 55.↑
van As NJ, Gilbert DC, Money-Kyrle J, et al. Evidence-based pragmatic guidelines for the follow-up of testicular cancer: optimising the detection of relapse. Br J Cancer 2008;98:1894–1902.
- 56.↑
Glaser SM, Vargo JA, Balasubramani GK, Beriwal S. Stage II testicular seminoma: patterns of care and survival by treatment strategy. Clin Oncol (R Coll Radiol) 2016;28:513–521.
- 57.↑
Paly JJ, Lin CC, Gray PJ, et al. Management and outcomes of clinical stage IIA/B seminoma: results from the National Cancer Data Base 1998–2012. Pract Radiat Oncol 2016;6:e249–258.
- 58.↑
Classen J, Schmidberger H, Meisner C, et al. Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial. J Clin Oncol 2003;21:1101–1106.
- 59.↑
Tachibana I, Alabd A, Tong Y, et al. Primary retroperitoneal lymph node dissection for stage II seminoma: is surgery the new path forward? J Clin Oncol 2023;41:3930–3938.
- 60.↑
Daneshmand S, Cary C, Masterson T, et al. Surgery in early metastatic seminoma: a phase II trial of retroperitoneal lymph node dissection for testicular seminoma with limited retroperitoneal lymphadenopathy. J Clin Oncol 2023;41:3009–3018.
- 61.↑
Heidenreich A, Paffenholz P, Hartmann F, et al. Retroperitoneal lymph node dissection in clinical stage IIA/B metastatic seminoma: results of the COlogne Trial of Retroperitoneal Lymphadenectomy In Metastatic Seminoma (COTRIMS). Eur Urol Oncol 2024;7:122–127.
- 62.↑
Hiester A, Che Y, Lusch A, et al. Phase 2 single-arm trial of primary retroperitoneal lymph node dissection in patients with seminomatous testicular germ cell tumors with clinical stage IIA/B (PRIMETEST). Eur Urol 2023;84:25–31.
- 63.↑
Papachristofilou A, Bedke J, Hayoz S, et al. Single-dose carboplatin followed by involved-node radiotherapy for stage IIA and stage IIB seminoma (SAKK 01/10): a single-arm, multicentre, phase 2 trial. Lancet Oncol 2022;23:1441–1450.
- 64.↑
de Wit R, Roberts JT, Wilkinson PM, et al. Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 2001;19:1629–1640.
- 65.↑
Kondagunta GV, Bacik J, Bajorin D, et al. Etoposide and cisplatin chemotherapy for metastatic good-risk germ cell tumors. J Clin Oncol 2005;23:9290–9294.
- 66.↑
Cary C, Jacob JM, Albany C, et al. Long-term survival of good-risk germ cell tumor patients after postchemotherapy retroperitoneal lymph node dissection: a comparison of BEP x 3 vs. EP x 4 and treating institution. Clin Genitourin Cancer 2018;16:e307–313.
- 67.↑
Kawai K, Akaza H. Current status of chemotherapy in risk-adapted management for metastatic testicular germ cell cancer. Cancer Sci 2010;101:22–28.
- 68.↑
Calabrò F, Albers P, Bokemeyer C, et al. The contemporary role of chemotherapy for advanced testis cancer: a systematic review of the literature. Eur Urol 2012;61:1212–1221.
- 69.↑
Feldman DR, Bosl GJ, Sheinfeld J, Motzer RJ. Medical treatment of advanced testicular cancer. JAMA 2008;299:672–684.
- 70.↑
Fizazi K, Delva R, Caty A, et al. A risk-adapted study of cisplatin and etoposide, with or without ifosfamide, in patients with metastatic seminoma: results of the GETUG S99 multicenter prospective study. Eur Urol 2014;65:381–386.
- 71.↑
Yoshida T, Yonese J, Kitsukawa S, et al. [Treatment results of VIP (etoposide, ifosfamide and cisplatin) chemotherapy as a first-line therapy in metastatic germ cell tumors]. Nihon Hinyokika Gakkai Zasshi 2000;91:55–61.
- 72.↑
Ishioka J, Kageyama Y, Inoue M, et al. [Result of treatment for advanced germ cell tumor in the last decade]. Nihon Hinyokika Gakkai Zasshi 2010;101:539–546.
- 73.↑
Kondagunta GV, Bacik J, Donadio A, et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol 2005;23:6549–6555.
- 74.↑
Loehrer PJ, Lauer R, Roth BJ, et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 1988;109:540–546.
- 75.↑
Miller KD, Loehrer PJ, Gonin R, Einhorn LH. Salvage chemotherapy with vinblastine, ifosfamide, and cisplatin in recurrent seminoma. J Clin Oncol 1997;15:1427–1431.
- 76.↑
Kondagunta GV, Bacik J, Sheinfeld J, et al. Paclitaxel plus ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors. J Clin Oncol 2007;25:85–90.
- 77.↑
Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 2007;357:340–348.
- 78.↑
Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409–413.
- 79.↑
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509–2520.
- 80.↑
Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 2020;21:1353–1365.
