Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

High-dose chemotherapy for relapsed testicular germ cell tumours

Abstract

Relapsed testicular germ cell tumours (GCTs) might be cured with salvage chemotherapy. Accepted salvage treatment is conventional-dose chemotherapy (CDCT) or high-dose chemotherapy (HDCT). HDCT with peripheral blood stem cell transplant might produce a higher number of durable responses than CDCT. We discuss studies reporting on outcomes of salvage HDCT in relapsed GCTs. The most reproducible results were achieved with HDCT with two cycles of etoposide and carboplatin or three cycles of the paclitaxel, ifosfamide, carboplatin and etoposide regime. Using these two regimens, sustained cure rates of 50–66% were reported in phase I, phase II and retrospective studies published in the past two decades. Cure rates in patients with cisplatin-resistant disease are between 30% and 45%. Two phase III randomized studies were conducted with certain limitations and were unsuccessful in showing a survival benefit of HDCT. Thus, salvage treatment remains a controversial topic. Salvage HDCT with peripheral blood stem cell transplant and CDCT are two recommended treatment options for relapsed GCTs. Consistently reported cure rates from phase I, phase II and large retrospective studies support the use of HDCT in the hands of an experienced team of oncologists.

Key points

  • Established salvage treatment for relapsed testicular germ cell tumours is conventional-dose chemotherapy or high-dose chemotherapy (HDCT), which might cure 20–60% of patients.

  • Consistently reported cure rates from phase I and II studies and large retrospective cohorts suggest that HDCT with two cycles of etoposide and carboplatin or three cycles of paclitaxel, ifosfamide, carboplatin and etoposide might be superior to conventional-dose chemotherapy.

  • HDCT with peripheral blood stem cell transplant is a standard approach in several high-volume institutions.

  • HDCT with peripheral blood stem cell transplant should be performed by teams of experienced oncologists.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Milestones in HDCT for relapsed GCTs.

Similar content being viewed by others

References

  1. Einhorn, L. H. Treatment of testicular cancer: a new and improved model. J. Clin. Oncol. 8, 1777–1781 (1990).

    Article  CAS  PubMed  Google Scholar 

  2. Hanna, N. H. & Einhorn, L. H. Testicular cancer — discoveries and updates. N. Engl. J. Med. 371, 2005–2016 (2014).

    Article  PubMed  Google Scholar 

  3. Chovanec, M., Hanna, N., Cary, K. C., Einhorn, L. & Albany, C. Management of stage I testicular germ cell tumours. Nat. Rev. Urol. 13, 663–673 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. Beyer, J. et al. Survival and new prognosticators in metastatic seminoma: results from the IGCCCG-update consortium. J. Clin. Oncol. 39, 1553–1562 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gillessen, S. et al. Predicting outcomes in men with metastatic nonseminomatous germ cell tumors (NSGCT): results from the IGCCCG update consortium. J. Clin. Oncol. 39, 1563–1574 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Motzer, R. J. et al. Salvage chemotherapy for patients with germ cell tumors. The Memorial Sloan-Kettering Cancer Center experience (1979–1989). Cancer 67, 1305–1310 (1991).

    Article  CAS  PubMed  Google Scholar 

  7. Mardiak, J. et al. Paclitaxel plus ifosfamide and cisplatin in second-line treatment of germ cell tumors: a phase II study. Neoplasma 52, 497–501 (2005).

    CAS  PubMed  Google Scholar 

  8. Motzer, R. J. Paclitaxel (Taxol) combination therapy for resistant germ cell tumors. Semin. Oncol. 27, 33–35 (2000).

    CAS  PubMed  Google Scholar 

  9. Adra, N. et al. High-dose chemotherapy and autologous peripheral-blood stem-cell transplantation for relapsed metastatic germ cell tumors: the Indiana University experience. J. Clin. Oncol. 35, 1096–1102 (2017).

    Article  PubMed  Google Scholar 

  10. Feldman, D. R. et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J. Clin. Oncol. 28, 1706–1713 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lorch, A. et al. Conventional-dose versus high-dose chemotherapy as first salvage treatment in male patients with metastatic germ cell tumors: evidence from a large international database. J. Clin. Oncol. 29, 2178–2184 (2011).

    Article  PubMed  Google Scholar 

  12. Li, M. C., Whitmore, W. F. Jr., Golbey, R. & Grabstald, H. Effects of combined drug therapy on metastatic cancer of the testis. JAMA 174, 1291–1299 (1960).

    Article  CAS  PubMed  Google Scholar 

  13. Hanna, N. & Einhorn, L. H. Testicular cancer — discoveries and updates. N. Engl. J. Med. 371, 2342 (2014).

    Article  Google Scholar 

  14. Rosenberg, B., Vancamp, L. & Krigas, T. Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature 205, 698–699 (1965).

    Article  CAS  PubMed  Google Scholar 

  15. Higby, D. J., Wallace, H. J. Jr, Albert, D. J. & Holland, J. F. Diaminodichloroplatinum: a phase I study showing responses in testicular and other tumors. Cancer 33, 1219–1215 (1974).

    Article  CAS  PubMed  Google Scholar 

  16. Einhorn, L. H. & Donohue, J. Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann. Intern. Med. 87, 293–298 (1977).

    Article  CAS  PubMed  Google Scholar 

  17. Einhorn, L. H. & Williams, S. D. Chemotherapy of disseminated testicular cancer. A random prospective study. Cancer 46, 1339–1344 (1980).

    Article  CAS  PubMed  Google Scholar 

  18. Einhorn, L. H., Williams, S. D., Troner, M., Birch, R. & Greco, F. A. The role of maintenance therapy in disseminated testicular cancer. N. Engl. J. Med. 305, 727–731 (1981).

    Article  CAS  PubMed  Google Scholar 

  19. Stoter, G. et al. High-dose versus low-dose vinblastine in cisplatin-vinblastine-bleomycin combination chemotherapy of non-seminomatous testicular cancer: a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group. J. Clin. Oncol. 4, 1199–1206 (1986).

    Article  CAS  PubMed  Google Scholar 

  20. Williams, S. D. et al. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N. Engl. J. Med. 316, 1435–1440 (1987).

    Article  CAS  PubMed  Google Scholar 

  21. Powis, G. Dose-dependent metabolism, therapeutic effect, and toxicity of anticancer drugs in man. Drug. Metab. Rev. 14, 1145–1163 (1983).

    Article  CAS  PubMed  Google Scholar 

  22. Bleyer, W. A. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 41, 36–51 (1978).

    Article  CAS  PubMed  Google Scholar 

  23. Creasey, W. A. et al. Clinical effects and pharmacokinetics of different dosage schedules of adriamycin. Cancer Res. 36, 216–221 (1976).

    CAS  PubMed  Google Scholar 

  24. Hillcoat, B. L., McCulloch, P. B., Figueredo, A. T., Ehsan, M. H. & Rosenfeld, J. M. Clinical response and plasma levels of 5-fluorouracil in patients with colonic cancer treated by drug infusion. Br. J. Cancer 38, 719–724 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ozols, R. F. et al. A randomized trial of standard chemotherapy v a high-dose chemotherapy regimen in the treatment of poor prognosis nonseminomatous germ-cell tumors. J. Clin. Oncol. 6, 1031–1040 (1988).

    Article  CAS  PubMed  Google Scholar 

  26. Miller, R. P., Tadagavadi, R. K., Ramesh, G. & Reeves, W. B. Mechanisms of cisplatin nephrotoxicity. Toxins 2, 2490–2518 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Blijham, G. et al. The treatment of advanced testicular carcinoma with high dose chemotherapy and autologous marrow support. Eur. J. Cancer 17, 433–441 (1981).

    Article  CAS  Google Scholar 

  28. Mulder, P. O. et al. Chemotherapy with maximally tolerable doses of VP 16-213 and cyclophosphamide followed by autologous bone marrow transplantation for the treatment of relapsed or refractory germ cell tumors. Eur. J. Cancer Clin. Oncol. 24, 675–679 (1988).

    Article  CAS  PubMed  Google Scholar 

  29. Nichols, C. R. et al. Dose-intensive chemotherapy in refractory germ cell cancer — a phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation. J. Clin. Oncol. 7, 932–939 (1989).

    Article  CAS  PubMed  Google Scholar 

  30. Broun, E. R. et al. Long-term outcome of patients with relapsed and refractory germ cell tumors treated with high-dose chemotherapy and autologous bone marrow rescue. Ann. Intern. Med. 117, 124–128 (1992).

    Article  CAS  PubMed  Google Scholar 

  31. Einhorn, L. H. VP 16 plus ifosfamide plus cisplatin as salvage therapy in refractory testicular cancer. Cancer Chemother. Pharmacol. 18, S45–S50 (1986).

    Article  PubMed  Google Scholar 

  32. Harstrick, A. et al. Cisplatin, etoposide, and ifosfamide salvage therapy for refractory or relapsing germ cell carcinoma. J. Clin. Oncol. 9, 1549–1555 (1991).

    Article  CAS  PubMed  Google Scholar 

  33. Nichols, C. R. et al. High-dose carboplatin and etoposide with autologous bone marrow transplantation in refractory germ cell cancer: an Eastern Cooperative Oncology Group protocol. J. Clin. Oncol. 10, 558–563 (1992).

    Article  CAS  PubMed  Google Scholar 

  34. Ayash, L. J. et al. Double dose-intensive chemotherapy with autologous stem cell support for relapsed and refractory testicular cancer: the University of Michigan experience and literature review. Bone Marrow Transplant. 27, 939–947 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Einhorn, L. H. et al. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N. Engl. J. Med. 357, 340–348 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Motzer, R. J. et al. High-dose chemotherapy and autologous bone marrow rescue for patients with refractory germ cell tumors. Early intervention is better tolerated. Cancer 69, 550–556 (1992).

    Article  CAS  PubMed  Google Scholar 

  37. Pizzocaro, G. et al. Modified cisplatin, etoposide (or vinblastine) and ifosfamide salvage therapy for male germ-cell tumors. Long-term results. Ann. Oncol. 3, 211–216 (1992).

    Article  CAS  PubMed  Google Scholar 

  38. Vaena, D. A., Abonour, R. & Einhorn, L. H. Long-term survival after high-dose salvage chemotherapy for germ cell malignancies with adverse prognostic variables. J. Clin. Oncol. 21, 4100–4104 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Lorch, A. et al. High-dose chemotherapy (HDCT) as second-salvage treatment in patients with multiple relapsed or refractory germ-cell tumors. Ann. Oncol. 21, 820–825 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Siegert, W. et al. High-dose treatment with carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in relapsed or refractory germ cell cancer: a phase I/II study. The German Testicular Cancer Cooperative Study Group. J. Clin. Oncol. 12, 1223–1231 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. Beyer, J. et al. Long-term survival of patients with recurrent or refractory germ cell tumors after high dose chemotherapy. Cancer 79, 161–168 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Beyer, J., Stenning, S., Gerl, A., Fossa, S. & Siegert, W. High-dose versus conventional-dose chemotherapy as first-salvage treatment in patients with non-seminomatous germ-cell tumors: a matched-pair analysis. Ann. Oncol. 13, 599–605 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Motzer, R. J. et al. High-dose carboplatin, etoposide, and cyclophosphamide for patients with refractory germ cell tumors: treatment results and prognostic factors for survival and toxicity. J. Clin. Oncol. 14, 1098–1105 (1996).

    Article  CAS  PubMed  Google Scholar 

  44. Rick, O. et al. Salvage treatment with paclitaxel, ifosfamide, and cisplatin plus high-dose carboplatin, etoposide, and thiotepa followed by autologous stem-cell rescue in patients with relapsed or refractory germ cell cancer. J. Clin. Oncol. 19, 81–88 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Motzer, R. J. et al. Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. J. Clin. Oncol. 18, 1173–1180 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Kondagunta, G. V. et al. Paclitaxel plus ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors. J. Clin. Oncol. 25, 85–90 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Feldman, D. R. et al. Phase I/II trial of paclitaxel with ifosfamide followed by high-dose paclitaxel, ifosfamide, and carboplatin (TI-TIC) with autologous stem cell reinfusion for salvage treatment of germ cell tumors. Clin. Genitourin. Cancer 13, 453–460 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Pico, J. L. et al. A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours. Ann. Oncol. 16, 1152–1159 (2005).

    Article  PubMed  Google Scholar 

  49. Lorch, A. et al. Single versus sequential high-dose chemotherapy in patients with relapsed or refractory germ cell tumors: a prospective randomized multicenter trial of the German Testicular Cancer Study Group. J. Clin. Oncol. 25, 2778–2784 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Lorch, A. et al. High dose chemotherapy as salvage treatment for unresectable late relapse germ cell tumors. J. Urol. 184, 168–173 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Richardson, R. et al. Late relapse of germ cell tumors: detection and treatment outcomes. J. Clin. Oncol. 39, abstr 5007 (2021).

  52. Feldman, D. R., Huddart, R., Hall, E., Beyer, J. & Powles, T. Is high dose therapy superior to conventional dose therapy as initial treatment for relapsed germ cell tumors? The TIGER Trial. J. Cancer 2, 374–377 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Spiess, P. E. et al. Viable germ cell tumor at postchemotherapy retroperitoneal lymph node dissection: can we predict patients at risk of disease progression? Cancer 110, 2700–2708 (2007).

    Article  PubMed  Google Scholar 

  54. Oldenburg, J. et al. Testicular seminoma and non-seminoma: ESMO-EURACAN Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 33, 362–375 (2022).

    Article  CAS  PubMed  Google Scholar 

  55. Gilligan, T. et al. Testicular cancer, version 2.2020, NCCN clinical practice guidelines in oncology. J. Natl Compr. Canc. Netw. 17, 1529–1554 (2019).

    Article  CAS  PubMed  Google Scholar 

  56. Cary, C. et al. Outcomes of postchemotherapy retroperitoneal lymph node dissection following high-dose chemotherapy with stem cell transplantation. Cancer 121, 4369–4375 (2015).

    Article  PubMed  Google Scholar 

  57. Miller, M. I. et al. Surgical management of patients with advanced germ cell tumors following salvage chemotherapy: Memorial Sloan Kettering Cancer Center (MSKCC) experience. Urology 124, 174–178 (2019).

    Article  PubMed  Google Scholar 

  58. Anouti, B. et al. Maintenance oral etoposide (VP-16) after high-dose chemotherapy (HDCT) for patients with relapsed metastatic germ-cell tumors (mGCT). J. Clin. Oncol. 38, 5051–5051 (2020).

    Article  Google Scholar 

  59. Ashkar, R. et al. Randomized phase 2 trial of maintenance oral etoposide or observation following high-dose chemotherapy for relapsed metastatic germ cell tumor. J. Clin. Oncol. 40, TPS429–TPS429 (2022).

    Article  Google Scholar 

  60. Haugnes, H. S. et al. High-dose chemotherapy with autologous stem cell support in patients with metastatic non-seminomatous testicular cancer - a report from the Swedish Norwegian Testicular Cancer Group (SWENOTECA). Acta Oncol. 51, 168–176 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Kawai, K. et al. Neutropenic colitis as a complication of high-dose chemotherapy for refractory testicular cancer. Jpn. J. Clin. Oncol. 28, 571–573 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. Fergadis, E. et al. Myeloablative chemotherapy and autologous stem cell transplantation can lead to successful postengraftment mobilization of hematopoietic progenitors to support planned subsequent cycle(s) of high-dose chemotherapy and autografting in a patient with relapsed germ-cell tumor. Anticancer Drugs 30, 205–208 (2019).

    Article  CAS  PubMed  Google Scholar 

  63. Boccadoro, M. et al. Oral melphalan at diagnosis hampers adequate collection of peripheral blood progenitor cells in multiple myeloma. Haematologica 87, 846–850 (2002).

    CAS  PubMed  Google Scholar 

  64. Kroger, N. et al. Successful mobilization of peripheral blood stem cells in heavily pretreated myeloma patients with G-CSF alone. Ann. Hematol. 76, 257–262 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Kobold, S. et al. Plerixafor is effective and safe for stem cell mobilization in heavily pretreated germ cell tumor patients. Bone Marrow Transplant. 46, 1053–1056 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. Tomblyn, M. et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol. Blood Marrow Transpl. 15, 1143–1238 (2009).

    Article  CAS  Google Scholar 

  67. Jathavedam, A. et al. Infectious complications from high-dose chemotherapy and autologous stem cell transplantation for metastatic germ cell tumors. Biol. Blood Marrow Transpl. 14, 595–600 (2008).

    Article  Google Scholar 

  68. Beyer, J. et al. High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables. J. Clin. Oncol. 14, 2638–2645 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. Chovanec, M. et al. Long-term toxicity of cisplatin in germ-cell tumor survivors. Ann. Oncol. 28, 2670–2679 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chovanec, M. et al. Late adverse effects and quality of life in survivors of testicular germ cell tumour. Nat. Rev. Urol. 18, 227–245 (2021).

    Article  PubMed  Google Scholar 

  71. Laguna, M. P. et al. EAU guidelines on testicular cancer. Edition presented at the EAU Annual Congress Amsterdam 2022 (EAU, 2022).

  72. Loehrer, P. J. Sr et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann. Intern. Med. 109, 540–546 (1988).

    Article  PubMed  Google Scholar 

  73. Mead, G. M. et al. A phase II trial of TIP (paclitaxel, ifosfamide and cisplatin) given as second-line (post-BEP) salvage chemotherapy for patients with metastatic germ cell cancer: a medical research council trial. Br. J. Cancer 93, 178–184 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kondagunta, G. V. 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. 23, 6549–6555 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

M.C. acknowledges funding from the Slovak Research and Development Agency under contract nos. APVV-15-0086, APVV-19-0411 and VEGA 1/0327/19.

Author information

Authors and Affiliations

Authors

Contributions

M.C. and N.A. researched data for the article, made a substantial contribution to discussion of the content, wrote and reviewed/edited the manuscript before submission. M.A.Z., R.A. and L.E. made a substantial contribution to discussion of the content, wrote and reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Michal Chovanec.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Urology thanks Anja Lorch, Christoph Oing and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chovanec, M., Adra, N., Abu Zaid, M. et al. High-dose chemotherapy for relapsed testicular germ cell tumours. Nat Rev Urol 20, 217–225 (2023). https://doi.org/10.1038/s41585-022-00683-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41585-022-00683-1

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer