Annals of Hematology

, Volume 72, Issue 1, pp 1–9

Hematopoietic growth factors and treatment of testicular cancer: Biological interactions, routine use and dose-intensive chemotherapy

  • C. Bokemeyer
  • M. A. Kuczyk
  • H. Köhne
  • H. Einsele
  • B. Kynast
  • H. -J. Schmoll
Review Article


With the use of aggressivecis-platinum-based combination chemotherapy the majority of patients with metastatic testicular cancer will be cured. Hematopoietic growth factors (HGFs), particularly G-and GM-CSF, have been investigated for the treatment of testicular cancer in order to (a) ameliorate chemotherapy-induced myelosuppression, (b) increase the dose intensity of treatment, or (c) generate peripheral blood stem cells (PBSC) as hematopoietic support for mega-dose chemotherapy. Results from in vitro and animal models have excluded a significant influence of both factors, G-CSF and GM-CSF, on tumor growth and response to cytotoxic treatment. For the group of ‘good-risk’ patients with metastatic testicular cancer, 85–90% of whom will reach long-term survival, the incidence of granulocytopenic infections after standard chemotherapy regimens appears to be lower than 20%. The prophylactic use of HGFs for these patients is not routinely recommended but may be considered in case of an increased risk for infections. For ‘risk’ patients, who will achieve a 50% survival following standard chemotherapy, different attempts of treatment intensification have been investigated. The use of aggressive multidrug regimens is associated with granulocytopenic infections in 20–70% of patients. A randomized trial has demonstrated that the prophylactic use of G-CSF significantly reduces granulocytopenia, the number of septic infections, and the infection-related death rate. For “poor-risk” patients the prophylactic use of HGFs, particularly G-CSF due to its favorable side effect profile, is recommended. The availability of G- and GM-CSF has made it possible to develop dose-intensified chemotherapy regimens. Demonstrated particularly for GM-CSF, a 1.5-fold dose increase can be achieved by the use of a myeloid growth factor alone, and thrombocytopenia and other organ toxicity will become dose limiting. Mobilization of PBSC, either after stimulation with HGFs alone or with HGFs, following chemotherapy has been successfully used in patients with testicular cancer. For the treatment of patients with relapsed disease PBSC support followed by HGFs has allowed the use of mega-dose therapy in multiple phase-II studies. This has prompted the investigation of high-dose therapy as first-line treatment for 'poor-risk' patients. In these patients sequential high-dose treatment withcis-platinum, etoposide, and ifosfamide for four consecutive cycles, each supported by G- or GM-CSF and PBSC, is currently being investigated by the German Testicular Cancer Study Group. HGFs have substantially reduced treatment-associated morbidity and mortality in patients receiving chemotherapy for testicular cancer. They make it possible for the first time to clinically explore the true value of dose-intensified chemotherapy regimens in testis cancer, serving as a model of a highly chemotherapy sensitive disease. Enrollment of patients in prospective clinical trials evaluating the role of high-dose therapy is strongly recommended.

Key words

Testicular cancer Germ cell tumors Hematopoietic growth factors G-CSF GM-CSF Stem cell factor (SCF) Peripheral blood stem cells (PBSC) Dose-intensive chemotherapy Neutropenia Infection Human testicular cancer cell lines 


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  1. 1.
    Amman KS, Griffin JD, Elias A, Socinski MA, Ryan L, Cannistra SA, Oette D, Whitley M, Frei E, Schnipper LE (1988) Effect of recombinant human granulocyte-macrophage colony-stimulating factor on chemotherapy-induced myelosuppression. N Engl J Med 319:593–598Google Scholar
  2. 2.
    Bajorin DF, Nichols CR, Schmoll HJ, Kantoff PW, Bokemeyer C, Demetri GD, Einhorn LH, Bosl GJ (1995) Recombinant human granulocyte-macrophage colony-stimulating factor as an adjunct to conventional-dose ifosfamide-based chemotherapy for patients with advanced or relapsed germ cell tumors: a randomized trial. J Clin Oncol 13:79–86Google Scholar
  3. 3.
    Beyer J, Schwella N, Strohscheer I, Schwander I, Zingsem J, Serke S, Huhn D, Siegert W (1994) Randomized comparison of hematopoietic rescue with stem/progenitor cells from bone marrow or peripheral blood after high-dose chemotherapy in germ cell tumors. Bone Marrow Transplant 14 [Suppl 1]: 45Google Scholar
  4. 4.
    Birch R, Williams S, Cone A, Einhorn LH, Roark P, Turner S, Greco FA (1986) Prognostic factors for favourable outcome in disseminated germ cell tumours. J Clin Oncol 4:400–407Google Scholar
  5. 5.
    Blanke C, Loehrer PJ, Einhorn LH, Nichols C (1994) A phase-II study of VP-16 plus ifosfamide plus cisplatin plus vinblastine plus bleomycin (VIP/VB) with filgrastim for advanced stage testicular cancer. Proc Am Soc Clin Oncol 13:234Google Scholar
  6. 6.
    Bokemeyer C, Schmoll HJ, Casper J, Kuczyk M, Poliwoda H (1993) No growth stimulation of heterotransplanted human testicular cancer cell lines by recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). Int J Oncol 3:77–80Google Scholar
  7. 7.
    Bokemeyer C, Schmoll HJ, Harstrick A (1993) Side effects of GM-CSF in advanced testicular cancer. Eur J Cancer 29A:924 (letter)Google Scholar
  8. 8.
    Bokemeyer C, Schmoll HJ, Harstrick A, Illiger HJ, Metzner B, Räth U, Hohnloser J, Clemm C, Berdel W, Siegert W, Ruther U, Ostermann H, Kneba M, Hartlapp JH, Schröder M, Poliwoda H (1993) A phase-1/11 study of a stepwise doseescalated regimen of cisplatin, etoposide and ifosfamide plus granulocyte-macrophage colony-stimulating factor (GMCSF) in patients with advanced germ cell tumours. Eur J Cancer 29A:2225–2231Google Scholar
  9. 9.
    Bokemeyer C, Beyer J, Schmoll HJ (1994) The role of doseintensified chemotherapy for the treatment of metastatic germ cell tumours. Forum 4:671–680Google Scholar
  10. 10.
    Bokemeyer C, Schmoll HJ, Arseniev L, Metzner B, Ruther U, Illiger HJ, Link H, Poliwoda H (1994) Treatment of advanced testicular cancer with dose intensified chemotherapy plus GM-CSF alone or G-CSF and sequential harvesting and reinfusion of peripheral blood stem cells (PBSC). Proc Am Soc Clin Oncol 13:236Google Scholar
  11. 11.
    Bokemeyer C, Harstrick A, Ruther U, Metzner B, Arseniev L, Kadar J, Illiger HJ, Link H, Raichele A, Beyer J, Hossfeld DK, Schmoll HJ (1995) Sequential treatment with high-dose VIP-chemotherapy plus peripheral blood stem cell (PBSC) support in advanced germ cell cancer. Proc Am Soc Clin Oncol 14:596Google Scholar
  12. 12.
    Boogaerts MA (1994) Growth factors in hematology: prophylactic versus interventional use. Eur J Cancer 30A: 238–243Google Scholar
  13. 13.
    Bosl GJ, Geller N, Cirrincone C, Vogelzang NJ, Kennedy BJ, Whitmore WF, Vugrin D, Scher H, Nisselbaum J, Golbey RB (1983) Multivariate analysis of prognostic variables in patients with metastatic testicular cancer. Cancer Res 43:3403–3407Google Scholar
  14. 14.
    Brugger W, Bross K, Frisch J, Lindemann A, Kanz L, Mertelsmann R (1992) Mobilization of peripheral blood progenitor cells by sequential administration of interleukin-3 and granulocyte-macrophage colony stimulating factor following polychemotherapy with etoposide, ifosfamide and cisplatin. Blood 79:1193–1200Google Scholar
  15. 15.
    Buzello H (1995) Effect of granulocyte colony stimulating factor (G-CSF) on growth of testicular cancer cells in vitro. In: Schnorr D, Loenig SA, Wei\bach L (eds) Hodentumoren — testis cancer, Blackwell Wissenschaftsverlag, Berlin, pp 197–198Google Scholar
  16. 16.
    Cimoli G, Russo P, Billi G, Nariani GL, Rovini E, Venturini M (1991) Human granulocyte-macrophage colony-stimulating factor, a growth factor active on human ovarian cancer cells. Jpn J Cancer Res 82:1196–1198Google Scholar
  17. 17.
    Daugaard G, Roerth M (1992) Treatment of poor-risk germcell tumors with high-dose cisplatin and etoposide combined with bleomycin. Ann Oncol 3:277–282Google Scholar
  18. 18.
    Diaz-Rubio E, Adrover E (1994) Use of granulocyte growth factors in solid tumours. Eur J Cancer 30A: 120–122Google Scholar
  19. 19.
    Dunn T, Bokemeyer C, Hartmann K, Rie C, Schmoll HJ (1994) Effect of hematopoietic growth factors (HGFs) on the growth of human embryonic carcinoma cell lines in reduced or serum free culture. Ann Oncol 5 [Suppl 8]: 38Google Scholar
  20. 20.
    Einborn LH (1990) Treatment of testicular cancer: a new improved model. J Clin Oncol 11:1777–1781Google Scholar
  21. 21.
    Einhorn LH, Williams SD, Loehrer PJ, Birch R, Drasga R, Omura G, Greco FA (1989) Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group Protocol. J Clin Oncol 7:387–391Google Scholar
  22. 22.
    Elias AD, Eder JP, Shea T, Begg CB, Frei E, Antman KH (1990) High-dose ifosfamide with mesna uroprotection. J Clin Oncol 8:170–178Google Scholar
  23. 23.
    Fossa S, Kaye SB, Cullen M, De Wit R, Bodrogi I, van Groeningen C, Sylvester R, Stenning S, Kaye SB, Cullen M, De Wit R, Lallemand E, Mead GM (1995) An MRC/EORTC randomized trial in poor-prognosis metastatic teratoma, comparing treatment with/without filgrastim. Proc Am Soc Clin Oncol 14:656Google Scholar
  24. 24.
    Harstrick A, Schmoll HJ, Kohne-Wompner CH, Bergamnn L, Lammers U, Hohnloser J, Dölken G, Reichhardt P, Siegert W, Natt F, Räth U, Wilke H, Poliwoda H (1991) Cisplatin, etoposide, ifosfamide, vincristine and bleomycin combination chemotherapy for far advanced testicular carcinoma. Ann Oncol 2:197–202Google Scholar
  25. 25.
    Harstrick A, Schmoll HJ, Wilke H, Kohne-Wompner CH, Stahl M, Schöber C, Casper J, Bruderek L, Schmoll E, Bokemeyer C, Bergmann L, Lammers U, Freund M, Poliwoda H (1991) Cisplatin, etoposide and ifosfamide salvage therapy for refractory or relapsed germ cell carcinoma. J Clin Oncol 9:1549–1555Google Scholar
  26. 26.
    Husband DJ, Green JA (1992) POMB/ACE chemotherapy in non-seminomatous germ cell tumours: outcome and importance of dose intensity. Eur J Cancer 28A: 86–91Google Scholar
  27. 27.
    Jost LM, Pichert G, Stahel RA (1990) Placebo controlled phase-I/II study of subcutaneous GM-CSF in patients with germ cell tumors undergoing chemotherapy. Ann Oncol 1:439–442Google Scholar
  28. 28.
    Kanz L, Lindemann A, Oster W, Herrmann F, Mertelsmann R (1991) Hemopoietins in clinical oncology. J Clin Oncol 14 [Suppl I]: 27–33Google Scholar
  29. 29.
    Levi JA, Toner G (1993) Dose intensive chemotherapy for poor prognosis germ cell malignancies. International Germ Cell Tumour Conference, Leeds, EnglandGoogle Scholar
  30. 30.
    Lewis CR, Fossa SD, Mead G, Ten Bokkel Huinik W, Harding MJ, Mill L, Paul J, Jones WG, Rodenburg CJ, Cantwell B (1991) BOP/VIP — a new platinum-intensive chemotherapy regimen for poor prognosis germ cell tumours. Ann Oncol 2:203–211Google Scholar
  31. 31.
    Lieschke GJ, Burgess AW (1992) Granulocyte-colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. N Engl J Med 327:28–35Google Scholar
  32. 32.
    Linkesch W, Krainer M, Wagner A (1992) Phase I/I1 trial of ultrahigh carboplatin, etoposide, cyclophosphamide with ABMT in refractory or relapsed non-seminomatous germ cell tumors (NSGCT). Proc Am Soc Clin Oncol 11:196Google Scholar
  33. 33.
    Loehrer PJ, Einhorn LH, Williams SD (1986) VP-16 plus ifosfamide plus cisplatin as salvage therapy in refractory germ cell cancer. J Clin Oncol 4:528–536Google Scholar
  34. 34.
    Loehrer PJ, Einhorn LH, Elson P, Williams SD, Havlin K, Vogelzang NJ, Crawford ED, Trump DL (1993) Phase-III study of cisplatin plus etoposide (VP16) with either bleomycin (B) or ifosfamide (1) in advanced-stage germ cell tumours (GCT): an Intergroup trial. Proc Am Soc Clin Oncol 12:831Google Scholar
  35. 35.
    Logothetis CJ, Samuels ML, Selig D, Swanson D, Johnson DE (1985) Improved survival with cyclic chemotherapy for nonseminomatous germ cell tumors of the testis. J Clin Oncol 3:326–335Google Scholar
  36. 36.
    Lynch J, Lee R, Gross M, Vellis K, Hutchenson C, Ayash L, Weiner R, Moreb J (1994) Time to myeloid recovery is related to number of peripheral blood (PB) progenitors infused after high-dose chemotherapy. Proc Am Sac Clin Oncol 13:97Google Scholar
  37. 37.
    Mandanas RA, Broun ER, Nichols CR, Salzman D, Turns M, Einhorn LH (1993) Phase-I/II dose-escalation study of carboplatin (CBDCA) and etoposide (VP-16) with autologous marrow support done in tandem for refractory germ cell tumors (GCT). Proc Am Soc Clin Oncol 12:240Google Scholar
  38. 38.
    Medical Research Council Working Party on Testicular Tumours (1985) Prognostic factors in advanced non-seminomatous germ-cell testicular tumours: results of a multicenter study. Lancet 1:8–11Google Scholar
  39. 39.
    Miyagawa K, Chiba S, Shibuya K, Piao YF, Matsuki S, Yokota J, Terada M, Miyazono K, Takaku F (1990) Frequent expression of receptors for granulocyte-macrophage colony stimulating factor on nonhematopoietic tumour cell lines. J Cell Physiol 143:483–487Google Scholar
  40. 40.
    Motzer RJ, Bosl GJ (1992) High-dose chemotherapy for resistant germ cell tumors: recent advances and future directions. J Natl Cancer Inst 84:1703–1709Google Scholar
  41. 41.
    Motzer RJ, Geller NL, Bosl GJ (1990) The effect of a 7-day delay in chemotherapy cycles on complete response and event-free survival in good-risk disseminated germ cell tumor patients. Cancer 66:857–861Google Scholar
  42. 42.
    Motzer RJ, Bajorin DF, Bost GJ (1992) “Poor risk” germ cell tumours: current progress and future directions. Semin Oncol 19:206–214Google Scholar
  43. 43.
    Motzer RJ, Gulati SC, Crown JP, Weisen S, Doherty M, Herr H, Fair W, Sheinfeld J, Sogani P, Russo P, Bosl GJ (1992) High-dose chemotherapy and autologous bone marrow rescue for patients with refractory germ cell tumors. Cancer 69:550–556Google Scholar
  44. 44.
    Motzer RJ, Gulati SC, Mazumdar M, Bajorin DF, Vlamis V, Lyn P, Bost GJ (1993) Phase-II trial of VAB-6+ high-dose carboplatin + etoposide (HD C+E) with autologous bone marrow transplantation (AUBMT) for poor-risk germ cell tumor (GCT) patients (PTS). Proc Am Soc Clin Oncol 12:233Google Scholar
  45. 45.
    Motzer RJ, Mazumdar M, Subhash CG, Bajorin DF, Lyn P, Vlamis V, Bost GJ (1993) Phase-II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors. J Natl Cancer Inst 85:1828–1835Google Scholar
  46. 46.
    Murphy BA, Motzer RJ, Mazumdar M, Vlamis V, Bajorin DF, Currie V, Bosl GJ (1993) An analysis of the effect of dose intensity on response, event-free survival and overall survival in patients with germ cell tumours (GCT) receiving ifosfamide-based salvage therapy. Proc Am Soc Clin Oncol 12:721Google Scholar
  47. 47.
    Nakagawa S, Sugimoto K, Mikamie K, Watanabe H, Sonoda Y, Kuzuyama Y, Abe T, Fuji H (1994) Successful collection of peripheral blood stem cells mobilized by high-dose etoposide for patients with chemotherapy-resistant and/or poor prognostic testicular cancer. Nippon Hinyokika Gakkai Zasshi 85:571–578Google Scholar
  48. 48.
    Nichols CR, Roth BJ, Heerema N, Griep J, Tricot G (1990) Hematologic neoplasia associated with primary mediastinal germ cell tumours. N Engl J Med 322:1425–1429Google Scholar
  49. 49.
    Nichols CR, Williams SD, Loehrer PJ, Greco FA, Crawford ED, Weetlaufer J, Miller ME, Bartolucci A, Schacter L, Einhorn LH (1991) Randomized study of cisplatin dose intensity in poor risk germ cell tumours: a Southeastern Cancer Study Group and Southwest Oncology Group protocol. J Clin Oncol 9:1163–1172Google Scholar
  50. 50.
    Roach S, Cooper S, Bennet W, Pera MF (1993) Cultured cell lines from human teratomas: windows into tumor growth and differentiation and early human development. Eur Urol 23:82–88Google Scholar
  51. 51.
    Rodenhuis S, Baars JW, Schornagel JH, Vlasveld LT, Mandjes I, Pinedo HM, Richel DJ (1992) Feasibility and toxicity study of a high-dose chemotherapy regimen for autotransplantation incorporating carboplatin, cyclophosphamide and thiotepa. Ann Oncol 3:855–860Google Scholar
  52. 52.
    Rodenhuis S, van der Wall E, Schornagel JH, Holtkamp M, Nooijen WJ, Baars JW (1994) Development of a multiple high-dose chemotherapy regimen incorporating cyclophosphamide, thiotepa and carboplatin with peripheral stem cell transplantation (PSCT). Proc Am Soc Clin Oncol 13:248Google Scholar
  53. 53.
    Schmoll HJ, Schubert I, Arnold H, Dölken G, Hecht T, Bergmann L, Illiger J, Fink U, Preiss J, Pfreundschuh M, Kaulen H, Bonfert B, Ho AD, Manegold C, Mayr A, Hoffmann L, Weiss J, Hecker H (1987) Disseminated testicular cancer with bulky disease: results of a phase-11 study with cisplatin ultra high dose/VP-16/bleomycin. Int J Androl 10:311–317Google Scholar
  54. 54.
    Sehrt J, Pietsch T, Schöffski P, Bokemeyer C, Kuczyk MA, Schmoll HJ, Jonas U (1994)A possible role for stem cell factor (SCF) and its receptor C-kit in malignant germ cell tumors. Proc Am Assoc Cancer Res 35:255Google Scholar
  55. 55.
    Siegert W, Beyer J, Strohscheer I, Baurmann H, Oettle H, Zingsem J, Zimmermann R, Bokemeyer C, Schmoll HJ, Huhn D (1994) 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. J Clin Oncol 12:1223–1231Google Scholar
  56. 56.
    Sobrevilla-Calvo P, Zinser JW, Lara FU, Acosta-Barreda A, Guarner-Lans J, Miranda-Lopez E, Reynoso-Gomez E (1994) High-dose ICE (ifosfamide (I), carboplatin (C) and etoposide (E)) regimen supported with autologous transplantation of refrigerated peripheral blood stem cells (PAPBSC), mobilized with G-CSF: description of a standard method to give high-dose chemotherapy (CT). Proc Am Soc Clin Oncol 13:465Google Scholar
  57. 57.
    Spitzer G, Adkins DR, Spencer V, Dunphy FR, Petruska PJ, Velasquez WS, Bowers CE, Kronmueller N, Niemeyer R, McIntyre W (1994) Randomized study of growth factors postperipheral-blood stem-cell transplant: neutrophil recovery is improved with modest clinical benefit. J Clin Oncol 12:661–670Google Scholar
  58. 58.
    Stoter G, Sleijfer DT, Schornagel JH, ten Bokkel-Huinink WW, Vermeijlen K, Sylvester R on behalf of the EORTC Genito-Urinary Group (1993) BEP versus VIP in interme diate risk patients with disseminated non-seminomatous testicular caner (NSTC). Proc Am Soc Clin Oncol 12:232Google Scholar
  59. 59.
    Tjulandin S, Garin A, Stenina M, Mesherjakov N, Sidorova A, Sokolov N, Ljubimova N, Gutierrez F, Kupchan D, Graubner M (1993) Carboplatin (CBDA), etoposide (VP-16), bleomycin (B) and GM-CSF in patients (pts) with poor risk nonseminomatous germ cell tumours (NSGCT). Proc Am Soc Clin Oncol 12:245Google Scholar
  60. 60.
    Williams SD, Birch R, Einhorn LH, Irwin L, Greco FA, Loehrer PJ (1987) Treatment of disseminated germ-cell tumors with cisplatin, bleomycin and either vinblastine or etoposide. N Engl J Med 316:1435–1440Google Scholar
  61. 61.
    Wolff SN, Johnson DH, Hainsworth JD, Greco FA (1984) High-dose VP-16-213 monotherapy for refractory germinal malignancies. A phase-II study. J Clin Oncol 4:271–274Google Scholar
  62. 62.
    Wozniak AJ, Samson MK, Shah NT, Crawford ED, Ford CD, Altman SJ, Stephens RL, Natale RB, Bouroncle BA, Blumenstein BA, Cummings GD (1991) A randomized trial of cisplatin, vinblastine and bleomycin versus vinblastine, cisplatin and etoposide in the treatment of advanced germ cell tumors of the testis: a Southwest Oncology Group Study. J Clin Oncol 9:70–76Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • C. Bokemeyer
    • 1
  • M. A. Kuczyk
    • 2
  • H. Köhne
    • 4
  • H. Einsele
    • 1
  • B. Kynast
    • 3
  • H. -J. Schmoll
    • 3
  1. 1.Department of Internal Medicine IIUniversity of TübingenTübingenGermany
  2. 2.Department of UrologyHannover University Medical SchoolHannoverGermany
  3. 3.Department of Hematology/OncologyHannover University Medical SchoolHannoverGermany
  4. 4.Department of Hematology/OncologyRobert-Rössle-KlinikBerlinGermany

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