Generic placeholder image

Current Cancer Therapy Reviews


ISSN (Print): 1573-3947
ISSN (Online): 1875-6301

Review Article

Systemic Therapies for Metastatic Testicular Germ Cell Tumors: Past, Present and Future

Author(s): Sunil Parimi*, Jennifer M. Rauw and Jenny J. Ko

Volume 15, Issue 2, 2019

Page: [86 - 99] Pages: 14

DOI: 10.2174/1573394714666180706150427

Price: $65


Testicular germ cell tumors (TGCTs) are unique to that of most other solid tumors because they are highly curable in the metastatic setting. While the use of cisplatin-based chemotherapy continues to drive cure in this patient population, important improvements in the delivery of therapy, creation of risk-adjusted treatment paradigms, and salvage-therapy options have further enhanced survival as well. The future holds promise for a more multidisciplinary approach to care, through advancements in biochemical markers and a better understanding of how surgical and radiotherapy approaches can integrate into our existing management strategies.

Keywords: Metastatic, testicular germ cell tumor (TGCTs), systemic therapies, risk stratification, solid tumors, chemotherapy.

« Previous
Graphical Abstract
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66(1): 7-30.
Huyghe E. Matsuda Tomohiro, Thonneau P. Increasing incidence of testicular cancer worldwide: A review. J Urol 2003; 170(1): 5-11.
Horner MJ, Ries LAG, Krapcho M. SEER Cancer Stat Rev 2008; 2008: 1975-2006.
MacKenzie AR. Chemotherapy of metastatic testis cancer: Results in 154 patients. Cancer 1966; 19: 1369-76.
Samuels ML, Lanzotti VJ, Holoye PY, et al. Combination chemotherapy in germinal cell tumors. Cancer Treat Rev 1976; 3: 185-204.
Einhorn LH. Treatment of testicular cancer: A new and improved model. J Clin Oncol 1990; 8(11): 1777-81.
Rosenberg B, Vancamp L, Krigas T. Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature 1965; 205: 698-9.
Higby DJ, Wallace HJ, Albert DJ, Holland JF. Diaminodichloro-platinum: A phase I study showing responses in testicular and other tumors. Cancer 1974; 33(5): 1219-5.
Einhorn LH, Donohue J. Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med 1977; 87(3): 293-8.
Mead GM. International germ cell consensus classification: A prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997; 15(2): 594-603.
Fitzharris BM, Kaye SB, Saverymuttu S, et al. VP16-213 as a single agent in advanced testicular tumors. Eur J Cancer Clin Oncol 1980; 16(9): 1193-7.
Williams SD, Birch R, Einhorn LH, Irwin L, Greco FA, Loehrer PJ. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 1987; 316(23): 1435-40.
Ko JJ, Bernard B, Tran B, et al. Conditional survival of patients with metastatic testicular germ cell tumors treated with first-line curative therapy. J Clin Oncol 2016; 34(7): 714-20.
Einhorn LH, Williams SD, Loehrer PJ, et al. Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: A Southeastern Cancer Study Group Protocol. J Clin Oncol 1989; 7(3): 387-91.
Bajorin DF, Sarosdy MF, Pfister DG, et al. Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: A multiinstitutional study. J Clin Oncol 1993; 11(4): 598-606.
Loehrer PJ, Johnson D, Elson P, Einhorn LH, Trump D. Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: An Eastern Cooperative Oncology Group trial. J Clin Oncol 1995; 13(2): 470-6.
Culine C, Theodore C, Terrier-Lacombe MJ, Droz JP. Are 3 cycles of bleomycin, etoposide and cisplatin or 4 cycles of etoposide and cisplatin equivalent optimal regimens for patients with good risk metastatic germ cell tumors of the testis? The need for a randomized trial. J Urol 1997; 157(3): 855-8.
Horwich A, Sleijfer DT, Fossa SD, et al. Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: A Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol 1997; 15: 1844-52.
de Wit R, Stoter G, Kaye SB, et al. Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: A randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. J Clin Oncol 1997; 15(5): 1837-43.
Saxman SB, Finch D, Gonin R, Einhorn LH. Long-term follow-up of a phaseIII study of three versus four cycles of bleomycin, etoposide and cisplatin in favorable-prognosis germ-cell tumors: The Indiana University Experience. J Clin Oncol 1998; 16(2): 702-6.
de Wit R, Roberts JT, Wilkinson PM, et al. Equivalence of three of four cycles of bleomycin, etoposide, adn 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: 1629-40.
O’Sullivan JM, Huddart RA, Norman AR, Nicholls J, Dearnaley DP, Horwich A. Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours. Ann Oncol 2003; 14(1): 91-6.
Travis LB, Fossa SD, Schonfeld SJ, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 2005; 97(18): 1354-65.
Bahl G, Pathak RS, Sia M, et al. The use of chemotherapy instead of radiation therapy does not reduce the incidence of second cancers in survivors of early-stage seminoma: A population-based study from British Columbia. Int J Radiat Oncol Biol Phys 2017; 99(2): S209.
Warszawski N, Schmucking M. Relapses in early-stage testicular seminoma: Radiation therapy versus retroperitoneal lymphadenectomy. Scand J Urol Nephrol 1997; 31(4): 355-9.
Nichols CR, Williams SD, Loehrer PJ, et al. Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: A southeastern cancer study group and southwest oncology group protocol. J Clin Oncol 1991; 9(7): 1163-72.
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: 1287-93.
Kaye SB, Mead GM, Fossa A, et al. Intensive induction-sequential chemotherapy with BOP/VIP-B compared with treatment with BEP/EP for poor-prognosis metastatic nonseminomatous germ cell tumor: A randomized Medical Research Council/European Organization for Research and Treatment of Cancer. J Clin Oncol 1998; 16: 692-701.
Motzer RJ, Nichols CJ, Margolin KA, et al. Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol 2007; 25(3): 247-56.
Culine S, Kramar A, Théodore C, et al. Randomized trial comparing bleomycin/etoposide/cisplatin with alternating cisplatin/cyclophosphamide/doxorubicin and vinblastine/bleomycin regimens of chemotherapy for patients with intermediate- and poor-risk metastatic nonseminomatous germ cell tumors. J Clin Oncol 2008; 26(3): 421-7.
Daugaard G, Skoneczna I, Aass N, et al. A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974). Ann Oncol 2011; 22(5): 1054-61.
Fizazi K, Prow DM, Do K-A, et al. Alternating dose-dense chemotherapy in patients with high-volume disseminated nonseminomatous germ-cell tumors. Br J Cancer 2002; 86(10): 1555-60.
Fizazi K, Pagliaro L, Laplanche A, et al. Personalised chemotherapy based on tumor marker decline in poor prognosis germ-cell tumors (GETUG 13): A phase 3, multicentre, randomized trial. Lancet Oncol 2014; 15(13): 1442-50.
Gerl A, Clemm C, Schmeller N, et al. Late relapse of germ cell tumors after cisplatin-based chemotherapy. Ann Oncol 1997; 8(1): 41-7.
Sim HG, Lange PH, Lin DW. Role of post-chemotherapy surgery in germ cell tumors. Urol Clin North Am 2007; 34(2): 199-217.
Flechon A, Bompas E, Biron P, Droz J-P. Management of post-chemotherapy residual masses in advanced seminoma. J Urol 2002; 168(5): 1975-9.
De Santis M, Becherer A, Bokemeyer C, et al. 2-18fluoro-deoxy-D-glucose positron emission tomography is a reliable predictor for viable tumor in postchemotherapy seminoma: An update of the prospective multicentric SEMPET trial. J Clin Oncol 2004; 22(6): 1034-9.
Oechsle K, Hartmann M, Brenner W, et al. [18F]Fluorode-oxyglucose positron emission tomography in nonseminomatous germ cell tumors after chemotherapy: The German multicenter positron emission tomography study group. J Clin Oncol 2008; 26(36): 5930-5.
Kesler KA, Kruter LE, Perkins SM, et al. Survival after resection for metastatic testicular nonseminomatous germ cell cancer to the lung or mediastinum. Ann Thorac Surg 2011; 91: 1085-93.
Feldman DR, Bosl GJ, Sheinfeld J, Motzer RJ. Medical treatment of advanced testicular cancer. JAMA 2008; 299(6): 672-84.
International Prognostic Factors Study Group, Lorch A, Beyer J, et al. Prognostic factors in patients with metastatic germ cell tumor who experienced treatment failure with cisplatin based first-line chemotherapy. J Clin Oncol 2010; 28(33): 4906-11.
Segal R, Lukka H, Klotz LH, et al. Cancer care ontario practice guidelines initiative genitourinary cancer disease site group surveillance programs for early stage nonseminomatous testicular cancer: A practice guideline. Can J Urol 2001; 8(1): 1184-92.
Loehrer PJ, Lauer R, Roth BJ, Williams SD, Kalasinski LA, Einhorn LH. Salvage therapy in recurrent germ cell cancer: Ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 1988; 109(7): 540-6.
McCaffrey JA, Mazumdar M, Bajorin DF, Bosl GJ, Vlamis V, Motzer RJ. Ifosfamide- and cisplatin-containing chemotherapy as first-line salvage therapy in germ cell tumors: Response and survival. J Clin Oncol 1997; 15(7): 2559-63.
Loehrer PJ, 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(7): 2500-4.
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(27): 6549-55.
Mead GM, Cullen MH, Huddart R, 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 2005; 93: 178-84.
Nichols CR, Guido T, Williams SD. 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 1989; 7: 932-9.
Beyer J, Schwella N, Zingsem J, et al. Hematopoietic rescue after high-dose chemotherapy using autologous peripheral-blood progenitor cells or bone marrow: A randomized comparison. J Clin Oncol 1995; 13(6): 1328-35.
Einhorn LH, Williams SD, Chamness A, Brames MJ, Perkins SM, Abonour R. High-Dose Chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 2007; 357(4): 340-8.
Le Cornet C, Lortet-Tieulent J, Forman D, et al. Testicular cancer incidence to rise by 25% by 2025 in Europe? Model-based predictionsin 40 countries using population-based registry data. Eur J Cancer 2014; 50(4): 831-9.
Di Pietro A, Vries EG, Gietema JA, Spierings DC, de Jong S. Testicular germ cell tumours: The paradigm of chemo-sensitive solid tumours. Int J Biochem Cell Biol 2005; 37: 2437-56.
Welsh C, Day R, McGurk C, Masters JR, Wood RD, Köberle B. Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. Int J Cancer 2004; 110: 352-61.
Peng HQ, Hogg D, Malkin D, et al. Mutations of the p53 gene do not occur in testis cancer. Cancer Res 1993; 53: 3574-8.
Chen X, Ko LJ, Jayaraman L, Prives C. p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells. Genes Dev 1996; 10: 2438-51.
Facchini G, Rossetti S, Cavaliere C, et al. Exploring the molecular aspects associated with testicular germ cell tumors: A review. Oncotarget 2018; 9(1): 1365-79.
Fung MK, Cheung HW, Ling MT, et al. Role of MEK/ERK pathway in the MAD2-mediated cisplatin sensitivity in testicular germ cell tumour cells. Br J Cancer 2006; 95: 475-84.
De Bono J. OUdard S, Ozguroglu M, et al Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet 2010; 376(9747): 1147-54.
Oechsle K, Honecker F, Cheng T, et al. Preclinical and clinical activity of sunitnib in patients with cisplatin-refractory or multiply relaspsed germ cell tumors: A Canadian Urologic Oncology Group/German Testicular Cancer Study Group cooperative study. Ann Oncol 2011; 22(12): 2654-60.
Giannatempo P, Nicolai N, Fare E, et al. Activity of pazopanib in chemo-resistant patients with germ cell tumors (GCT): First results of the open-label, single-group, phase II PAZOTEST-01 trial. J Clin Oncol 2014. 32(suppl 4): abstr367.
Skoneczna IA, Natorska U, Tacikowska M, et al. Sorafenib monotherapy in patients with inoperable/recurrent germ cell tumors (GCT) refractory to chemotherapy: Phase II study. J Clin Oncol 2014. 32(suppl 4): abstr367.
Einhorn LH, Brames MJ, Heinrich MC, et al. Phase II study of imatinib mesylate in chemotherapy refractory germ cell tumors expressing KIT. Am J Clin Oncol 2006; 29(1): 12-3.
Oechsle K, Bokemeyer C, Honecker F. Lenalidomide in patients with cisplatin-refractory and multiply relapsed germ cell tumors. J Cancer Res Clin Oncol 2010; 136(1): 165-7.
Rick O, Braun T, Seigert W, et al. Activity of thalidomide in patients with platinum-refractory germ-cell tumours. Eur J Cancer 2006; 42(12): 1775-9.
Zschabitz S, Lasitschka F, Jager D, et al. Activity of immune check-point inhibition in platinum refractory germ cell tumors. Ann Oncol 2016; 27(7): 1356-60.
Robert C, Ribas A, Hamid O, et al. Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. J Clin Oncol 2019; 30(4): 582-8.
Adra N, Einhorn LH, Althouse SK, et al. Phase II trial of pembrolizumab in patients with platinum refracotry germ-cell tumors: A Hoosier Cancer Research Network Study GU14-206. Ann Oncol 2018; 29(1): 209-14.
Fankhauser CD, Curioni-Fontecedro A, Allmann V, et al. Frequent PD-L1 expression in testicular germ cell tumors. Br J Cancer 2015; 113(3): 411-3.
Cierna Z, Mego M, Miskovska V, et al. Prognostic value of programmed-death-1 receptor (PD-1) and its ligand (PD-L10 in testicular germ cell tumors. Ann Oncol 2016; 27(2): 300-5.
Chovanec M, Cierna Z, Miskovska V, et al. Prognostic role of programmed-death ligand 1 (PD-L1) expressing tumor infiltrating lymphocytes in testicular germ cell tumors. 2017; 8(13): 21794-805.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy