submit to the journals

New Drugs in the Treatment of Germ Cell Tumours

European Oncology, 2008;4(1):86-91 DOI: http://doi.org/10.17925/EOH.2008.04.1.86

Abstract:

More than 80% of patients with metastatic germ cell tumours are cured by cisplatin-based chemotherapy (usually a bleomycin, etoposide and cisplatin [BEP] regimen) and surgery for residual disease.1 Nonetheless, only 25% of patients who relapse achieve long-term survival after second-line cisplatin-based chemotherapy (usually a vinblastine, ifosfamide and cisplatin [VeIP] regimen).2

Factors that predict outcome in relapsing patients include previous complete response (CR), non-mediastinal primary, low serum tumour markers and no visceral metastasis. High-dose chemotherapy (HDCT) plus peripheral blood stem cell transplantation (PBST) can help patients who relapse after conventional chemotherapy, but has not been shown to be effacious.3 A multi-institutional retrospective study of 310 patients treated with HDCT and PBST identified prognostic factors of response to HDCT and failure-free survival (FFS) in patients with relapsed or cisplatin-refractory germ cell tumours.4 This article reviews new or targeted agents in relapsed or cisplatin-refractory germ cell tumours. Cisplatin-refractory disease is defined as the partial response of the disease during cisplatin-based chemotherapy, with subsequent progression within four weeks of treatment. Absolute cisplatin-refractory disease is defined as tumour progression during cisplatin-based chemotherapy.

New Drugs Paclitaxel
Paclitaxel, a member of the taxoid family, is an antimicrotubule agent that promotes the assembly and stabilisation of microtubules from tubulin dimers. The drug has been investigated in three phase II trials.5–7 All patients were heavily pre-treated with standard chemotherapy regimens. Many had cisplatin-refractory disease and received a third or subsequent line of treatment. At a dose of 2256 to 250mg/m2,5 paclitaxel induced an objective response in 12 of 51 patients (23%). A response occurred in only two of 18 patients (11%) with doses of between 170 and 200mg/m2.7 These studies provided interesting results and sufficient background to include paclitaxel in both first-line8 and salvage treatments.9

Paclitaxel, Ifosfamide and Cisplatin First-line Salvage Therapy

Paclitaxel-based combinations have been tested for standard salvage chemotherapy using a paclitaxel plus ifosfamide and cisplatin (TIP) regimen9 and in combination with sequential HDCT.10 At the Memorial Sloan Kettering Cancer Center (MSKCC), paclitaxel was given at a dose of 200mg/m2 administered as a 24-hour continuous infusion on day one of the cycle. In the German group, paclitaxel was given on day one at a dose of 175mg/m2 and was administered as a three-hour infusion.11 The same dose and schedule were used in trials published by the Medical Research Council (MRC)12 and Mardiak et al.13 In the trial conducted by the French group, the dose of paclitaxel was 250mg/m2 administered as a three-hour infusion.14 At the MSKCC, the TIP regimen9 was administered as first-line salvage therapy in favourable-risk patients. Thirty patients were treated: the rates of CR, continuous CR and non-evolutive disease (NED) were 80, 73 and 80%, respectively. Similar TIP protocols induced a CR rate of 60% in 43 patients included in the MRC trial,12 and 65% in the study by Mardiak et al.13

Combination of Paclitaxel and High-dose Chemotherapy plus Peripheral Blood Stem Cell Transplantation in First-line Salvage Therapy

The German group developed a protocol with three cycles of TIP followed by one cycle of high-dose etoposide, carboplatin and thiotepa.11 Eighty patients were treated: 67% were treated in the first-line salvage setting, 76% were cisplatin-sensitive and only 35% had achieved previous CR. One patient experienced a toxic death and 18 patients did not receive HDCT. The CR, continuous CR and NED rates were 35, 26 and 33%, respectively.

The French group has developed a protocol with two cycles of epirubicin plus paclitaxel followed by one cycle of high-dose cyclophosphamide and thiotepa and two cycles of high-dose carboplatin plus etoposide (CE).14 Forty-five patients were studied. Of these, 15% were in the first-line salvage setting (refractory disease). Only 33 patients received HDCT, of whom 22 completed the programme. There were five treatment-related deaths. The CR, continuous CR and NED rates were 22, 19 and 23%, respectively.
References:
  1. Williams SD, Stablein DM, Einhorn LH, et al., Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer, N Engl J Med, 1987;317(23):1433–8.
  2. 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(7):2500–2504.
  3. Fléchon A, Biron P, Droz JP, High-dose chemotherapy with hematopoietic stem-cell support in germ-cell tumor patient treatment, Int J Cancer, 1999;83(6):844–7.
  4. Beyer J, Kramar A, Mandanas R, et al., High-dose chemotherapy as salvage treatment in germ cell tumors, J Clin Oncol, 1996;14(10):2638–45.
  5. Motzer RJ, Bajorin DF, Schwartz LH, et al., Phase II trial of paclitaxel shows antitumor activity in patients with previously treated germ cell tumors, J Clin Oncol, 1994;12(11):2277–83.
  6. Bokemeyer C, Beyer J, Metzner B, et al., Phase II study of paclitaxel in patients with relapsed or cisplatin-refractory testicular cancer, Ann Oncol, 1996;7(1):31–4.
  7. Sandler AB, Cristou A, Fox S, et al., A phase II trial of paclitaxel in refractory germ cell tumors, Cancer, 1998;82(7): 1381–6.
  8. de Wit R., Louwerens M, de Mulder PH, et al., Management of intermediate-prognosis germ-cell cancer: results of a phase I/II study of Taxol-BEP, Int J Cancer, 1999;83(6):831–3.
  9. 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.
  10. 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(1): 85–90.
  11. Rick O, Bokemeyer C, Beyer J, 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, 2001;19(1):81–8.
  12. Mead GM, Cullen MH, Huddart R, et al., A phase II trial of TIP given as second-line (post-BEP) salvage chemotherapy for patients with metastatic germ cell cancer, Br J Cancer, 2005;93(2):178–84.
  13. Mardiak J, Salek T, Sycova-Mila Z, et al., Paclitaxel plus ifosfamide and cisplatin in second-line treatment of germ cell tumors: a phase II study, Neoplasma, 2005;52(6):497–501.
  14. Lotz JP, Bui B, Gomez F, et al., Sequential high-dose chemotherapy protocol for relapsed poor prognosis germ cell tumors combining two mobilization and cytoreductive treatments followed by three high-dose chemotherapy regimens supported by autologous stem cell transplantation, Ann Oncol, 2005;16(3):411–18.
  15. McNeish IA, Kanfer EJ, Haynes R, et al., Paclitaxel-containing high-dose chemotherapy for relapsed or refractory testicular germ cell tumours, Br J Cancer, 2004;90(6):1169–75.
  16. Margolin KA, Doroshow JH, Frankel P, et al., Paclitaxel-based high-dose chemotherapy with autologous stem cell rescue for relapsed germ cell cancer, Biol Blood Marrow Transplant, 2005;11(11):903–11.
  17. Hartmann JT, Gauler T, Metzner B, et al., Phase I/II study of sequential dose-intensified ifosfamide, cisplatin, and etoposide plus paclitaxel as induction chemotherapy for poor prognosis germ cell tumors, J Clin Oncol, 2007;25(36):5742–7.
  18. Bokemeyer C, Gerl A, Schöffski P, et al., Gemcitabine in patients with relapsed or cisplatin-refractory testicular cancer, J Clin Oncol, 1999;17(2):512–16.
  19. Einhorn LH, Stender MJ, Williams SD, Phase II trial of gemcitabine in refractory germ cell tumors, J Clin Oncol, 1999;17(2):509–11.
  20. Chaney SG, Vaisman A, Specificity of platinum-DNA adduct repair, J Inorg Biochem, 1999;77(1–2):71–81.
  21. Kollmannsberger C, Rick O, Derigs HG, et al., Activity of oxaliplatin in patients with relapsed or cisplatin-refractory germ cell cancer, J Clin Oncol, 2002;20(8):2031–7.
  22. Soulié P, Garrino C, Bensmaïne MA, et al., Antitumoral activity of oxaliplatin/cisplatin-based combination therapy in cisplatin-refractory germ cell cancer patients, J Cancer Res Clin Oncol, 1999;125(12):707–11.
  23. Miki T, Sawada M, Nonomura N, et al., Antitumor effect of CPT-11, a camptothecin derivative, on human testicular tumor xenografts in nude mice, Eur Urol, 1997;31(1):92–6.
  24. Kollmannsberger C, Rick O, Klaproth H, et al., Irinotecan in patients with relapsed or cisplatin-refractory germ cell cancer, Br J Cancer, 2002;87(7):729–32.
  25. Miki T, Mizutani Y, Nonomura N, et al., Irinotecan plus cisplatin has substantial antitumor effect as salvage chemotherapy against germ cell tumors, Cancer, 2002;95(9):1879–85.
  26. 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(5):513–16.
  27. Einhorn L, Raghavan D, Kindler H, et al., A phase I trial of gemcitabine plus paclitaxel combination in patients with refractory solid tumors, Proc Am Soc Clin Oncol, 1998;17:207.
  28. Hinton S, Catalano P, Einhorn LH, et al., Phase II study of paclitaxel plus gemcitabine in refractory germ cell tumors (E9897), J Clin Oncol, 2002;20:1859–63.
  29. 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, 2004:493–7.
  30. Kollmannsberger C, Beyer J, Liersch R, et al., Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer, J Clin Oncol, 2004;22(1):108–14.
  31. De Giorgi U, Rosti G, Aieta M, et al., Phase II study of oxaliplatin and gemcitabine salvage chemotherapy in patients with cisplatin-refractory non-seminomatous germ cell tumor, Eur Urol, 2006;50(5):1032–8.
  32. Pectasides D, Pectasides M, Farmakis D, et al., Oxaliplatin and irinotecan plus granulocyte-colony stimulating factor as third-line treatment in relapsed or cisplatin-refractory germ-cell tumor patients: a phase II study, Eur Urol, 2004:216–21.
  33. Theodore C, Chevreau C, Yataqhene Y, et al., A phase II multicenter study of oxaliplatin in combination with paclitaxel in poor prognosis patients who failed cisplatin-based chemotherapy for germ-cell tumors, Ann Oncol, 2008; in press.
  34. Shamash J, Powles T, Mutsvangwa K, et al., A phase II study using a topoisomerase I-based approach in patients with multiply relapsed germ-cell tumours, Ann Oncol, 2007;18(5):925–30.
  35. De Giorgi U, Rosti G, Papiani G, et al., Weekly gemcitabine, paclitaxel, oxaliplatin combination chemotherapy in patient with Cisplatin-refractory germ cell tumor: preliminary experience, Am J Clin Oncol, 2004;27(5):457–60.
  36. Bokemeyer C, Oechsle K, Honecker F, et al., German Testicular Cancer Study Group. Combination chemotherapy with gemcitabine, oxaliplatin, and paclitaxel in patients with cisplatin-refractory or multiply relapsed germ-cell tumors, Ann Oncol, 2008;19(3):448–53.
  37. Reuter VE, Origins and molecular biology of testicular germ cell tumors, Mod Pathol, 2005;18(Suppl. 2):S51–60.
  38. Oosterhuis JW, Looijenga LH, Testicular germ-cell tumours in a broader perspective, Nat Rev Cancer, 2005;5(3):210–22.
  39. Looijenga LH, de Leeuw H, van Oorschot M, et al., Stem cell factor receptor (c-KIT) codon 816 mutations predict development of bilateral testicular germ-cell tumors, Cancer Res, 2003;63(22):7674–8.
  40. Looijenga LH, Zafarana G, Grygalewicz B, et al., Role of gain of 12p in germ cell tumour development, APMIS, 2003;111(1): 161–71.
  41. Zafarana G, Grygalewicz B, Gillis AJ, et al., 12p-amplicon structure analysis in testicular germ cell tumors of adolescents and adults by array CGH, Oncogene, 2003;22(48):7695–7701.
  42. Skotheim RI, Lothe RA, The testicular germ cell tumour genome, APMIS, 2003;111(1):136–50; discussion 50–51.
  43. Looijenga LH, Gillis AJ, Stoop HJ, et al., Chromosomes and expression in human testicular germ-cell tumors, Ann N Y Acad Sci, 2007;1120:187–214.
  44. de Jong J, Stoop H, Gillis AJ, et al., Differential expression of SOX17 and SOX2 in germ cells and stem cells has biological and clinical implications, J Pathol, 2008;215(1):21–30.
  45. Kersemaekers AM, Mayer F, Molier M, et al., Role of P53 and MDM2 in treatment response of human germ cell tumors, J Clin Oncol, 2002;20(6):1551–61.
  46. Olie RA, Looijenga LH, Boerrigter L, et al., N- and KRAS mutations in primary testicular germ cell tumors, Genes Chromosomes Cancer, 1995;12(2):110–16.
  47. McIntyre A, Summersgill B, Grygalewicz B, et al., Amplification and overexpression of the KIT gene is associated with progression in the seminoma subtype of testicular germ cell tumors of adolescents and adults, Cancer Res, 2005;65(18):8085–9.
  48. McIntyre A, Gilbert D, Goddard N, et al., Genes, chromosomes and the development of testicular germ cell tumors of adolescents and adults, Genes Chromosomes Cancer, 2008;47(7):547–57.
  49. Di Vizio D, Cito L, Boccia A, et al., Loss of the tumor suppressor gene PTEN marks the transition from R intratubulagerm cell neoplasias (ITGCN) to invasive germ cell tumors, Oncogene, 2005;24(11):1882–94.
  50. Sommerer F, Hengge UR, Markwarth A, et al., Mutations of BRAF and RAS are rare events in germ cell tumours, Int J Cancer, 2005;113(2):329–35.
  51. Kemmer K, Corless CL, Fletcher JA, et al., KIT mutations are common in testicular seminomas, Am J Pathol, 2004;164(1): 305–13.
  52. Goddard NC, McIntyre A, Summersgill B, et al., KIT and RAS signalling pathways in testicular germ cell tumours, Int J Androl, 2007;30(4):337–48.
  53. Skotheim RI, Abeler VM, Nesland JM, et al., Candidate genes for testicular cancer evaluated by in situ protein expression analyses on tissue microarrays, Neoplasia, 2003;5:397–404.
  54. Han DC, Shen TL, Guan JL, The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions, Oncogene, 2001;20:6315–21.
  55. McIntyre A, Summersgill B, Spendlove HE, et al., Activating mutations and/or expression levels of tyrosine kinase receptors GRB7, RAS, and BRAF in testicular germ cell tumors, Neoplasia, 2005;7(12):1047–52.
  56. Rönnstrand L, Signal transduction via the stem cell factor receptor/c-Kit, Cell Mol Life Sci, 2004;61(19-20):2535–48.
  57. Li J, Xia F, Li WX, Coactivation of STATand Ras is required for germ cell proliferation and invasive migration in Drosophila, Dev Cell, 2003;5:787–98.
  58. Motzer RJ, Dmitrovsky E, Miller WH Jr, et al., Suramin for germ cell tumors, Cancer, 1993;72(11):3313–17.
  59. Moasser MM, Motzer RJ, Khoo KS, et al., All-trans retinoic acid for treating germ cell tumors, Cancer, 1995;76(4):680–86.
  60. Gold EJ, Bosl GJ, Itri LM, Phase II trial of 13-cis-retinoic acid in patients with advanced non-seminomatous germ cell tumors, Cancer Treat Rep, 1984;68(10):1287–8.
  61. Rick O, Braun T, Siegert W, Beyer J, Activity of thalidomide in patients with platinum-refractory germ-cell tumours, Eur J Cancer, 2006;42(12):1775–9.
  62. Beer TM, Tangen CM, Nichols CR, et al., Southwest Oncology Group phase II study of arsenic trioxide in patients with refractory germ cell malignancies, Cancer, 2006;106(12): 2624–9.
  63. Bokemeyer C, Kuczyk MA, Dunn T, et al., Expression of stem-cell factor and its receptor c-kit protein in normal testicular tissue and malignant germ-cell tumours, J Cancer Res Clin Oncol, 1996;122(5):301–6.
  64. Sakuma Y, Matsukuma S, Yoshihara M, et al., Mutations of c-kit gene in bilateral testicular germ cell tumours in Japan, Cancer Lett, 2008;259(1):119–26.
  65. Biermann K, Göke F, Nettersheim D, et al., c-KIT is frequently mutated in bilateral germ cell tumours and down-regulated during progression from intratubular germ cell neoplasia to seminoma, J Pathol, 2007;213(3):311–18.
  66. Coffey J, Linger R, Pugh J, et al., Somatic KIT mutations occur predominantly in seminoma germ cell tumors and are not predictive of bilateral disease: report of 220 tumors and review of literature, Genes Chromosomes Cancer, 2008;47(1):34–42.
  67. Nikolaou M, Valavanis C, Aravantinos G, et al., Kit expression in male germ cell tumors, Anticancer Res, 2007;27(3B): 1685–8.
  68. Kollmannsberger C, Mayer F, Pressler H, et al., Absence of c-KIT and members of the epidermal growth factor receptor family in refractory germ cell cancer, Cancer, 2002;95(2):301–8.
  69. Madani A, Kemmer K, Sweeney C, et al., Expression of KIT and EGFR in chemotherapy refractory non-seminomatous germ-cell tumors, Ann Oncol, 2003;14(6):873–80.
  70. 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):12–13.
  71. Pedersini R, Vattemi E, Mazzoleni G, Graiff C, Complete response after treatment with imatinib in pre-treated disseminated testicular seminoma with overexpression of c-KIT, Lancet Oncol, 2007;8(11):1039–40.
  72. Hechelhammer L, Störkel S, Odermatt B, et al., Epidermal growth factor receptor is a marker for syncytiotrophoblastic cells in testicular germ cell tumors, Virchows Arch, 2003;443(1):28–31.
  73. Moroni M, Veronese S, Schiavo R, Carminati O, Sorensen BS, Gambacorta M, Siena S.Epidermal growth factor receptor expression and activation in nonseminomatous germ cell tumors, Clin Cancer Res, 2001;7(9):2770–75.
  74. Soule S, Baldridge L, Kirkpatrick K, et al., HER-2/neu expression in germ cell tumours, J Clin Pathol, 2002;55(9)656–8.
  75. Kollmannsberger C, Pressler H, Mayer F, et al., Cisplatin-refractory, HER2/neu-expressing germ-cell cancer, Ann Oncol, 1999;10(11):1393–4.
  76. Fukuda S, Shirahama T, Imazono Y, et al., Expression of vascular endothelial growth factor in patients with testicular germ cell tumors as an indicator of metastatic disease, Cancer, 1999;85(6):1323–30.
  77. Voigt W, Kegel T, Maher G, et al., Bevacizumab plus HD-ICE as third-line salvage chemotherapy induced an unexpected dramatic response in highly platinum refractory germ cell cancer, Ann Oncol, 2006;17(3):531–3.
  78. Mego M, Recková M, Sycova-Mila Z, et al., Bevacizumab in a growing teratoma syndrome, Ann Oncol, 2007;18(5):962–3.