Testicular Cancer Treatment Regimens
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Testicular Cancer Treatment Regimens |
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Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. |
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Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced health care team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. |
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Note: All recommendations are category 2A unless otherwise indicated. |
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▶Primary Chemotherapy for Germ Cell Tumors1 |
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REGIMEN |
DOSING |
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Preferred Regimens |
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BEP2-6,a-c |
Days 1,8,15 OR Days 2,9,16: Bleomycin 30units IV over 10 minutes daily Days 1-5: Etoposide 100mg/m2 IV over 1 hour daily Days 1-5: Cisplatin 20mg/m2 IV over 1 hour daily. Repeat cycle every 3 weeks for 3-4 cycles (seminoma) or 1-4 cycles (nonseminoma). |
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EP4,5,7,a,b |
Days 1-5: Etoposide 100mg/m2 IV over 1 hour daily Days 1-5: Cisplatin 20mg/m2 IV over 1 hour daily. Repeat cycle every 3 weeks for 4 cycles (seminoma) or 2-4 cycles (nonseminoma). |
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Other Recommended Regimens |
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Carboplatin (for patients with stage IA, IB seminoma)8-11 |
Day 1: Carboplatin AUC 7 IV over 30 minutes. Repeat cycle every 3 weeks for 1-2 cycles. |
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VIP (for intermediate risk patients with stage IIC, III seminoma or intermediate risk patients with stage IIIB nonseminoma or selected patients with poor-risk, stage IIIC nonseminoma)4,5,12-14,a,b,d,e |
Days 1-5: Etoposide 75mg/m2 IV over 1 hour daily Days 1-5: Mesna 240mg/m2 IV over 15 minutes three times daily (one dose before Ifosfamide, then at 4 and 8 hours from start of each Ifosfamide dose) Days 1-5: Ifosfamide 1200mg/m2 IV over 3 hours daily Days 1-5: Cisplatin 20mg/m2 IV over 1 hour daily. Repeat cycle every 3 weeks for 4 cycles. |
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▶Post-Surgical Chemotherapy for Patients with Germ Cell Tumors Treated With Primary Chemotherapy1 |
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Preferred Regimens |
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EP4,5,7,a,b |
Days 1-5: Etoposide 100mg/m2 IV over 1 hour daily Days 1-5: Cisplatin 20mg/m2 IV over 1 hour daily. Repeat cycle every 3 weeks for 2 cycles. |
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TIP5,13,15,16,a,b,d-f |
Day 1: Paclitaxel 250mg/m2 IV continuous infusion over 24 hours Days 2-5: Mesna 300mg/m2 IV over 15 minutes three times daily (one dose before Ifosfamide, then at 4 and 8 hours from start of each Ifosfamide dose) Days 2-5: Ifosfamide 1,500mg/m2 IV over 3 hours daily Days 2-5: Cisplatin 25mg/m2 IV over 1 hour daily. Repeat cycle every 3 weeks for 2 cycles. |
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VIP4,5,12-14,a,b,d,e |
Days 1-5: Etoposide 75mg/m2 IV over 1 hour daily Days 1-5: Mesna 240mg/m2 IV over 15 minutes three times daily (one dose before Ifosfamide, then at 4 and 8 hours from start of each Ifosfamide dose) Days 1-5: Ifosfamide 1200mg/m2 IV over 3 hours daily Days 1-5: Cisplatin 20mg/m2 IV over 1 hour daily. Repeat cycle every 3 weeks for 2 cycles. |
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VeIP5,13,14,17,18,a,b,d,e |
Days 1-2: Vinblastine 0.11mg/kg IV over 5-10 minutes daily Days 1-5: Mesna 240mg/m2 IV over 15 minutes three times daily (one dose before Ifosfamide, then at 4 and 8 hours from start of each Ifosfamide dose) Days 1-5: Ifosfamide 1,200mg/m2 IV over 3 hours daily Days 1-5: Cisplatin 20mg/m2 IV over 1 hour daily. Repeat cycle every 3 weeks for 2 cycles. |
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▶Post-Surgical Chemotherapy Following Primary Nerve-Sparing Retroperitoneal Lymph Node Dissection for Nonseminoma Tumors1 |
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Preferred Regimens for pN1, pN2 |
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EP4,5,7,a,b |
Days 1-5: Etoposide 100mg/m2 IV over 1 hour daily Days 1-5: Cisplatin 20mg/m2 IV over 1 hour daily. Repeat cycle every 3 weeks for 2 cycles. |
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Preferred Regimens for pN3 |
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BEP2-6,a-c |
Days 1,8,15 OR Days 2,9,16: Bleomycin 30units IV over 10 minutes daily Days 1-5: Etoposide 100mg/m2 IV over 1 hour daily Days 1-5: Cisplatin 20mg/m2 IV over 1 hour daily. Repeat cycle every 3 weeks for 3 cycles. |
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EP4,5,7,a,b |
Days 1-5: Etoposide 100mg/m2 IV over 1 hour daily Days 1-5: Cisplatin 20mg/m2 IV over 1 hour daily. Repeat cycle every 3 weeks for 4 cycles. |
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▶Second-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors1 |
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Conventional-Dose Chemotherapy Regimens |
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Preferred Regimens |
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TIP5,13,15,16,a,b,d-f |
Day 1: Paclitaxel 250mg/m2 IV continuous infusion over 24 hours Days 2-5: Mesna 300mg/m2 IV over 15 minutes three times daily (one dose before Ifosfamide, then at 4 and 8 hours from start of each Ifosfamide dose) Days 2-5: Ifosfamide 1,500mg/m2 IV over 3 hours daily Days 2-5: Cisplatin 25mg/m2 IV over 1 hour daily. Repeat cycle every 3 weeks for 4 cycles. |
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VeIP5,13,14,17,18,a,b,d,e |
Days 1-2: Vinblastine 0.11mg/kg IV over 5-10 minutes daily Days 1-5: Mesna 240mg/m2 IV over 15 minutes three times daily (one dose before Ifosfamide, then at 4 and 8 hours from start of each Ifosfamide dose) Days 1-5: Ifosfamide 1,200mg/m2 IV over 3 hours daily Days 1-5: Cisplatin 20mg/m2 IV over 1 hour daily. Repeat cycle every 3 weeks for 4 cycles. |
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High-Dose Chemotherapy Regimens |
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Preferred Regimens |
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Carboplatin/Etoposide4,11,19 |
Carboplatin 700mg/m2 IV Etoposide 750mg/m2 IV. Administer 5, 4 and 3 days before peripheral blood stem cell infusion for 2 cycles. |
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Paclitaxel/Ifosfamide/ |
Day 1: Paclitaxel 200mg/m2 IV over 24 hours Days 2-4: Ifosfamide 2000mg/m2 IV over 4 hours with mesna protection. Repeat every 2 weeks for 2 cycles, followed by: Days 1-3: Carboplatin AUC 7-8 IV over 1 hour Days 1-3: Etoposide 400mg/m2 IV. Administer with peripheral blood stem cell support at 2-3 week intervals for 3 cycles. |
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▶Third-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors1,g |
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High-Dose Chemotherapy NOT Previously Received |
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Preferred Regimens (High-Dose Chemotherapy) |
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Carboplatin/Etoposide4,11,19 |
Carboplatin 700mg/m2 IV Etoposide 750mg/m2 IV. Administer 5, 4 and 3 days before peripheral blood stem cell infusion for 2 cycles. |
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Paclitaxel/Ifosfamide/ |
Day 1: Paclitaxel 200mg/m2 IV over 24 hours Days 2-4: Ifosfamide 2000mg/m2 IV over 4 hours with mesna protection. Repeat every 2 weeks for 2 cycles, followed by: Days 1-3: Carboplatin AUC 7-8 IV over 1 hour Days 1-3: Etoposide 400mg/m2 IV. Administer with peripheral blood stem cell support at 2-3 week intervals for 3 cycles. |
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Other Recommended Regimens |
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Etoposide (oral)21,22 |
Days 1-21: Etoposide 50-100 mg orally daily. Repeat cycle every 4 weeks. |
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Gemcitabine/Paclitaxel16,23-25,f |
Days 1,8,15: Gemcitabine 1,000mg/m2 IV over 30 minutes Days 1,8,15: Paclitaxel 100mg/m2 IV over 1 hour. Repeat every 4 weeks for 6 cycles. |
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Gemcitabine/Paclitaxel/ |
Days 1,8: Gemcitabine 800mg/m2 IV over 30 minutes Day 1: Oxaliplatin 130mg/m2 IV over 2 hours Days 1,8: Paclitaxel 80mg/m2 IV over 1 hour. Repeat cycle every 3 weeks for 8 cycles. |
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Gemcitabine/Oxaliplatin24,26,28-30 |
Days 1,8: Gemcitabine 1,000-1,250mg/m2 IV over 30 minutes Day 1: Oxaliplatin 130mg/m2 IV over 2 hours. Repeat cycle every 3 weeks. |
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Useful in Certain Circumstances |
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Pembrolizumab (for MSI-H/dMMR or TMB-H tumors)31-35,a,h,i |
Day 1: Pembrolizumab 200mg IV over 30 minutes. Repeat cycle every 3 weeks up until 24 months of therapy has been completed. OR Day 1: Pembrolizumab 400mg IV over 30 minutes. Repeat cycle every 6 weeks up until 24 months of therapy has been completed. |
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▶Third-Line Chemotherapy Regimens for Metastatic Germ Cell Tumors1,g |
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High-Dose Chemotherapy Previously Received |
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Preferred Regimens |
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Etoposide (oral)21,22 |
Days 1-21: Etoposide 50-100 mg orally daily. Repeat cycle every 4 weeks. |
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Gemcitabine/Paclitaxel16,23-25,f Paclitaxel requires premedication. |
Days 1,8,15: Gemcitabine 1,000mg/m2 IV over 30 minutes Days 1,8,15: Paclitaxel 100mg/m2 IV over 1 hour. Repeat every 4 weeks for 6 cycles. |
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Gemcitabine/Paclitaxel/ |
Days 1,8: Gemcitabine 800mg/m2 IV over 30 minutes Day 1: Oxaliplatin 130mg/m2 IV over 2 hours Days 1,8: Paclitaxel 80mg/m2 IV over 1 hour. Repeat cycle every 3 weeks for 8 cycles. |
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Gemcitabine/Oxaliplatin23,26,28-30 |
Days 1,8: Gemicitabine 1000-1.250mg/m2 IV over 30 minutes Day 1: Oxaliplatin 130mg/m2 IV over 2 hours. Repeat cycle every 3 weeks. |
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Useful in Certain Circumstances |
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Pembrolizumab (for MSI-H/dMMR or TMB-H tumors)31-35,a,h,I |
Day 1: Pembrolizumab 200mg IV over 30 minutes. Repeat cycle every 3 weeks up until 24 months of therapy has been completed. OR Day 1: Pembrolizumab 400mg IV over 30 minutes. Repeat cycle every 6 weeks up until 24 months of therapy has been completed. |
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a BEP = Bleomycin/Etoposide/Cisplatin; dMMR = mismatch repair deficiency; EP = Etoposide/Cisplatin; MSI-H = microsatellite instability-high; TIP = Paclitaxel/Ifosfamide/Cisplatin; TMB-H = tumor mutational burden, high VeIP = Etoposide/Ifosfamide/Cisplatin; VIP = Etoposide/Ifosfamide/Mesna/Cisplatin b Hydration is required with supplemental electrolytes pre- and post-administration of Cisplatin. c For Bleomycin: Consider premedication for anaphylactoid reaction. Acetaminophen 650 mg orally 30 minutes – 60 minutes pre-Bleomycin AND/OR Diphenhydramine 12.5-50 mg IV or orally 30 minutes – 60 minutes pre-Bleomycin. d Hydration is required pre- and post-administration of Ifosfamide. e TIP, VeIP, VIP: These regimens are high risk for febrile neutropenia and granulocyte colony-stimulating factors (G-CSFs) should be used (See NCCN Guidelines for Hematopoietic Growth Factors). f For Paclitaxel: Premedication for hypersensitivity is required: famotidine 20 mg IV or orally (or equivalent H2 blocker) 30 minutes-60 minutes pre-paclitaxel AND diphephenhydramine 12.5-50 mg IV or orally 30 minutes-60 minutes pre-paclitaxel AND dexamethasone 20 mg PO approximately 12 and 6 hours pre-paclitaxel OR dexamethasone 20 mg IV 30 minutes pre-paclitaxel. g If VeIP or TIP received as second-line therapy, high-dose chemotherapy is the preferred third-line option. h Tumor mutation burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] tumors, as determined by a validated FDA-approved comprehensive genomic profiling (CGP) assay. i Early- and late-onset immune-related adverse events affecting multiple organ systems can occur in patients receiving immune checkpoint inhibitors. Patients with neurologic or life-threatening autoimmune disorders as well as receiving high levels of immunosuppression for their underlying disease should be approached with caution when considering immunotherapy. All patients will require extensive resources including ongoing intensive monitoring and supportive care. |
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References |
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1. Referenced with permission form the NCCN Clinical Practice Guidelines in Oncology™, Testicular Cancer, v2.2022. https://www.nccn.org/professionals/physician_gls/ pdf/testicular.pdf. Accessed August 26, 2022. 2. Saxman SB, Finch D, Gonin R, Einhorn LH. Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indian University experience. J Clin Oncol. 1998;16:702-706. 3. Bleomycin [package insert]. Lake Forest, IL: Hospira, Inc; April 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=905e0984-2ce3-481c-b1a0-0ef0a616479a&type=display. Accessed August 26, 2022. 4. Etoposide (Toposar) [package insert]. North Wales, PA. Teva Pharmaceuticals, Inc. April 2017. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=c9080cf5-4fc3-4cf9-a241-6e40a6fddc75&type=display. Accessed August 26, 2022. 5. Cisplatin [package insert]. North Wales, PA: Teva Pharmaceuticals, Inc.; August 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a440f077-46f6-4688-a209-65bce38d1c92&type=display. Accessed August 26, 2022. 6. 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(6):1629-1640. 7. Xiao H, Mazumdar M, Bajorin DF, et al. Long-term follow-up of patients with good-risk germ cell tumors treated with etoposide and cisplatin. J Clin Oncol. 1997;15:2553-2558. 8. 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. 9. Oliver RT, Mead GM, Rustin GJ, et al. Randomized trial of carboplatin versus radio- therapy 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. 10. 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. 11. Carboplatin [package insert]. Lake Forest, IL: Hospira, Inc. May 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=47677091-fd20-49af-933c-c9dd2be21de9&type=display. 12. Nichols CR, Catalano PJ, Crawford ED, et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. J Clin Oncol. 1998;16:1287-1293. 13. Ifosfamide [package insert]. Deerfield, IL: Baxter International, Inc; July 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=91e433a9-6800-43a6-ac13-a49a04a5aecd&type=display. Accessed August 26, 2022. 14. Mesna [package insert]. Deerfield, IL: Baxter International, Inc; December 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a880160b-fa82-453a-a971-29ab897876a7&type=display 15. 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. 16. Paclitaxel [package insert]. North Wales, PA: Teva Pharmaceuticals, Inc.; June 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=fbd32bd2-9685-41cb-bee2-730a45526b65&type=display. Accessed August 26, 2022. 17. Loehrer PJ Sr, Gonin R, Nichols CR, et al. Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol. 1998;16:2500-2504. 18. Loehrer PJ Sr, 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. 19. 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. 20. Feldman DR, Sheinfeld J, Bajorin DF, et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J Clin Oncol. 2010;28:1706-1713. 21. Etoposide (oral) [package insert]. Morgantown, WV: Mylan Pharmaceuticals, Inc.; April 2016. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=508a418e-985f-4208-9324-2230655bb5c2&type=display. Accessed August 26, 2022. 22. Miller JC, Einhorn LH. Phase II study of daily oral etoposide in refractory germ cell tumors. Semin Oncol. 1990;17(1 Suppl 2):36-9. 23. Gemcitabine [package insert]. Lake Forest, IL: Hospira, Inc.; May 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=dc02a23b- 3ff9-4441-aa91-8e9e629a7315&type=display. Accessed August 26, 2022 24. Einhorn LH, Brames MJ, Juliar B, Williams SD. Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol. 2007;25:513-516. 25. Mulherin BP, Brames MJ, Einhorn LH. Long-term survival with paclitaxel and gemcitabine for germ cell tumors after progression following high-dose chemo- therapy with tandem transplant. Am J Clin Oncol. 2015;38:373-376. 26. Oxaliplatin (Eloxatin) [package insert]. Deerfield, IL: Baxter International, Inc; August 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=21a2bb1d-d91d-4f99-97dd-cc67fe99a090. Accessed August 26, 2022. 27. Bokemeyer C, Oechsle K, Honecker F, et al. Combination chemotherapy with gemcitabine, oxaliplatin, and paclitaxel in patients with cisplatin-refractory or multiply relapsed germ-cell tumors: a study of the German Testicular Cancer Study Group. Ann Oncol. 2008;19:448-453. 28. Pectasides D, Pectasides M, Farmakis D, et al. Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: a phase II study. Ann Oncol. 2004;15:493-497. 29. Kollmannsberger C, Beyer J, Liersch R, et al. Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: a study of the German Testicular Cancer Study Group. J Clin Oncol. 2004;22:108-114. 30. De Giorgi U, Rosti G, Aieta M, et al. Phase II study of oxaliplatin and gemcitabine salvage chemotherapy in patients with cisplatin-refractory nonseminomatous germ cell tumor. Eur Urol. 2006;50:1032-1038. 31. Pembrolizumab (Keytruda) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; August 2022. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Accessed August 26,2022. 32. 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. 33. 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. 34. Lala M, Li TR, de Alwis DP, et al. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation [published correction appears in Eur J Cancer. 2021 Feb;144:400]. Eur J Cancer. 2020;131:68-75. 35. Marabelle A, Fekih 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(10):1353-1365. |
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(Revised 9/2022; NCCN Testicular Cancer Guidelines v2.2022) © 2022 by Haymarket Media, Inc.) |
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