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Bevacizumab in combination with sequential high-dose chemotherapy in solid cancer, a feasibility study

Bone Marrow Transplantation volume 45, pages 1704–1709 (2010)Cite this article

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Abstract

We evaluated the feasibility and toxicity of bevacizumab in combination with sequential high-dose (HD) ifosfamide, carboplatin and etoposide refractory to standard chemotherapy in patients with sarcoma and germ cell cancer (GCC). Sixteen patients (13 sarcomas, 3 GCC) received SD-ICE followed by 4 cycles of HD-ICE, qd22 with stem cell support in combination with bevacizumab. All 16 patients were evaluable for toxicity and efficacy, and received 51 cycles (median 3.3). There was no increase in toxicity except of a relatively high incidence of ifosfamide encephalopathy in 17 cycles when compared with previous HD-ICE protocols. One almost complete response in the patient with GCC, previously progressive with three preceding protocols, was observed. Six patients had a partial response (sarcoma 4/13 patients; GCC 2/3 patients), and five patients stable disease (sarcoma 5/13 patients). The median PFS/OS for sarcoma was 5 months (confidence interval (CI): 3.1–6.9) and 13 months (CI: 3.6–24.4), respectively. To our knowledge, this is the first report of the addition of bevacizumab to HD-ICE. This combination did not show new unexpected toxicities except for a relatively high rate of ifosfamide encephalopathy. The efficacy in these heavily pretreated patients including possible reversal of chemotherapy resistance by the addition of bevacizumab indicates a possible potential of bevacizumab in this combination.

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References

  1. Pedrazzoli P, Ledermann J, Lotz JP, Leyvraz S, Aglietta M, Rosti G et al. High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults. Ann Oncol 2006; 17: 1479–1488.

    Article  CAS  PubMed  Google Scholar 

  2. Maurel J, Lopez-Pousa A, de Las Penas R, Fra J, Martin J, Cruz J et al. Efficacy of sequential high-dose doxorubicin and ifosfamide compared with standard-dose doxorubicin in patients with advanced soft tissue sarcoma: an open-label randomized phase II study of the Spanish group for research on sarcomas. J Clin Oncol 2009; 27: 1893–1898.

    Article  CAS  PubMed  Google Scholar 

  3. Verma S, Younus J, Stys-Norman D, Haynes AE, Blackstein M . Dose-intensive chemotherapy with growth factor or autologous bone marrow/stem cell transplant support in first-line treatment of advanced or metastatic adult soft tissue sarcoma: a systematic review. Cancer 2008; 112: 1197–1205.

    Article  CAS  PubMed  Google Scholar 

  4. Kasper B, Lehnert T, Bernd L, Mechtersheimer G, Goldschmidt H, Ho AD et al. High-dose chemotherapy with autologous peripheral blood stem cell transplantation for bone and soft-tissue sarcomas. Bone Marrow Transplant 2004; 34: 37–41.

    Article  CAS  PubMed  Google Scholar 

  5. Krege S, Beyer J, Souchon R, Albers P, Albrecht W, Algaba F et al. European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): part II. Eur Urol 2008; 53: 497–513.

    Article  PubMed  Google Scholar 

  6. Schmoll HJ, Jordan K, Huddart R, Laguna MP, Horwich A, Fizazi K et al. Testicular non-seminoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 20: 89–96.

    PubMed  Google Scholar 

  7. Sharkey RM, Goldenberg DM . Targeted therapy of cancer: new prospects for antibodies and immunoconjugates. CA Cancer J Clin 2006; 56: 226–243.

    Article  PubMed  Google Scholar 

  8. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335–2342.

    Article  CAS  PubMed  Google Scholar 

  9. Chao C, Al-Saleem T, Brooks JJ, Rogatko A, Kraybill WG, Eisenberg B . Vascular endothelial growth factor and soft tissue sarcomas: tumor expression correlates with grade. Ann Surg Oncol 2001; 8: 260–267.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang L, Hannay JA, Liu J, Das P, Zhan M, Nguyen T et al. Vascular endothelial growth factor overexpression by soft tissue sarcoma cells: implications for tumor growth, metastasis, and chemoresistance. Cancer Res 2006; 66: 8770–8778.

    Article  CAS  PubMed  Google Scholar 

  11. D’Adamo DR, Anderson SE, Albritton K, Yamada J, Riedel E, Scheu K et al. Phase II study of doxorubicin and bevacizumab for patients with metastatic soft-tissue sarcomas. J Clin Oncol 2005; 23: 7135–7142.

    Article  PubMed  Google Scholar 

  12. Fukuda S, Shirahama T, Imazono Y, Tsushima T, Ohmori H, Kayajima T et al. Expression of vascular endothelial growth factor in patients with testicular germ cell tumors as an indicator of metastatic disease. Cancer 1999; 85: 1323–1330.

    Article  CAS  PubMed  Google Scholar 

  13. Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, Landuyt W et al. Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer 2003; 88: 1979–1986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Blay JY, Bouhour D, Ray-Coquard I, Dumontet C, Philip T, Biron P . High-dose chemotherapy with autologous hematopoietic stem-cell transplantation for advanced soft tissue sarcoma in adults. J Clin Oncol 2000; 18: 3643–3650.

    Article  CAS  PubMed  Google Scholar 

  15. Hildebrand J . Neurological complications of cancer chemotherapy. Curr Opin Oncol 2006; 18: 321–324.

    Article  CAS  PubMed  Google Scholar 

  16. Sweiss KI, Beri R, Shord SS . Encephalopathy after high-dose Ifosfamide: a retrospective cohort study and review of the literature. Drug Saf 2008; 31: 989–996.

    Article  CAS  PubMed  Google Scholar 

  17. David KA, Picus J . Evaluating risk factors for the development of ifosfamide encephalopathy. Am J Clin Oncol 2005; 28: 277–280.

    Article  CAS  PubMed  Google Scholar 

  18. Glusker P, Recht L, Lane B, Ozcan C, Wong SJ, Hari P et al. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 2006; 354: 980–982.

    Article  CAS  PubMed  Google Scholar 

  19. Schiff D, Wen PY, van den Bent MJ . Neurological adverse effects caused by cytotoxic and targeted therapies. Nat Rev Clin Oncol 2009; 6: 596–603.

    Article  PubMed  Google Scholar 

  20. Schiff D, Purow B . Bevacizumab in combination with irinotecan for patients with recurrent glioblastoma multiforme. Nat Clin Pract Oncol 2008; 5: 186–187.

    Article  PubMed  Google Scholar 

  21. Vredenburgh JJ, Desjardins A, Herndon II JE, Marcello J, Reardon DA, Quinn JA et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007; 25: 4722–4729.

    Article  CAS  PubMed  Google Scholar 

  22. Voigt W, Kegel T, Maher G, Jordan K, Muller L, Schmoll HJ . Bevacizumab plus high-dose ifosfamide, etoposide and carboplatin (HD-ICE) as third-line salvage chemotherapy induced an unexpected dramatic response in highly platinum refractory germ-cell cancer. Ann Oncol 2006; 17: 531–533.

    Article  CAS  PubMed  Google Scholar 

  23. Schlemmer M, Wendtner CM, Falk M, Abdel-Rahman S, Licht T, Baumert J et al. Efficacy of consolidation high-dose chemotherapy with ifosfamide, carboplatin and etoposide (HD-ICE) followed by autologous peripheral blood stem cell rescue in chemosensitive patients with metastatic soft tissue sarcomas. Oncology 2006; 71: 32–39.

    Article  CAS  PubMed  Google Scholar 

  24. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351: 337–345.

    Article  CAS  PubMed  Google Scholar 

  25. Baker LH, Rowinsky EK, Mendelson D, Humerickhouse RA, Knight RA, Qian J et al. Randomized, phase II study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 in patients with advanced soft tissue sarcoma. J Clin Oncol 2008; 26: 5583–5588.

    Article  CAS  PubMed  Google Scholar 

  26. Maki RG, D’Adamo DR, Keohan ML, Saulle M, Schuetze SM, Undevia SD et al. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol 2009; 27: 3133–3140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sleijfer S, Ray-Coquard I, Papai Z, Le Cesne A, Scurr M, Schoffski P et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol 2009; 27: 3126–3132.

    Article  CAS  PubMed  Google Scholar 

  28. Verweij J . Soft tissue sarcoma trials: one size no longer fits all. J Clin Oncol 2009; 27: 3085–3087.

    Article  PubMed  Google Scholar 

  29. Castillo-Avila W, Piulats JM, Garcia Del Muro X, Vidal A, Condom E, Casanovas O et al. Sunitinib inhibits tumor growth and synergizes with cisplatin in orthotopic models of cisplatin-sensitive and cisplatin-resistant human testicular germ cell tumors. Clin Cancer Res 2009; 15: 3384–3395.

    Article  CAS  PubMed  Google Scholar 

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  1. K Jordan and H H Wolf: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University of Halle, Halle/Wittenberg, Germany

    K Jordan, H H Wolf, W Voigt, T Kegel, L P Mueller, T Behlendorf, C Sippel, D Arnold & H J Schmoll

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  1. K Jordan
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Correspondence to K Jordan.

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Competing interests

Dirk Arnold, MD, has received compensation as a member of the scientific advisory board of Roche AG. Hans J Schmoll, MD, PhD, has received compensation as a member of the scientific advisory board of Roche AG. The remaining authors declare no conflict of interest.

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Jordan, K., Wolf, H., Voigt, W. et al. Bevacizumab in combination with sequential high-dose chemotherapy in solid cancer, a feasibility study. Bone Marrow Transplant 45, 1704–1709 (2010). https://doi.org/10.1038/bmt.2010.50

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