Skip to main content

Advertisement

SpringerLink
Log in

Phase II study of cisplatin and oral VP16 in patients with refractory or relapsed Ewing sarcoma

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Background

Phase II trials demonstrate the activity of cisplatin in patients with refractory Ewing sarcoma family tumours (ESFT) and also the feasibility of giving cisplatin with oral VP16 in a variety of different cancers. This trial was conducted to evaluate the activity and toxicity profile of this combination delivered as outpatient therapy in patients with refractory/relapsed ESFT.

Methods

Cisplatin was administered on days 1, 8 and 15 and days 29, 36 and 43 (70 mg/m2/dose for patients <21 years of age and 50 mg/m2/dose ≥21 years). VP16 was administered at a dose of 50 mg/m2 on days 1–15 and days 29–43 inclusive. A three-stage Fleming statistical design was used for analysis.

Results

Between January 2003 and October 2006, 45 patients aged between 5 and 46 years (median 19) were enrolled. Thirty-eight were evaluable for response. Patients had previously received one to three lines of chemotherapy (median = one). Seventy-three per cent of the patients had grade 3/4 neutropenia, 20 % developed fever, 40 % had grade 3/4 anaemia, 68 % grade 3/4 thrombocytopenia and 16 % grade 2/3 ototoxicity. Measured response after 2 cycles: 0 CR, 7 PR (18 %), 13 SD (34 %), 18 PD (48 %). There was excellent concordance between unidimensional and bidimensional criteria in 31 of 33 responses (94 %). PFS at 1 year was 39 %, with a median PFS of 6 months. Overall survival at 1 year was 44 %; median survival was 11 months.

Conclusions

Cisplatin combined with oral VP16 is well tolerated and has acceptable side effects, but limited clinical activity in refractory/relapsed ESFT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Kolb EA, Kushner BH, Gorlick R et al (2003) Long-term event-free survival after intensive chemotherapy in Ewing’s family of tumors in children and young adults. J Clin Oncol 21(18):3423–3430

    Article  PubMed  CAS  Google Scholar 

  2. Paulussen M, Craft AW, Lewis I et al (2008) Results of the EICESS-92 Study: two randomized trials of Ewing’s sarcoma treatment—cyclophosphamide compared to ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol 26(27):4385–4393

    Article  PubMed  CAS  Google Scholar 

  3. Rodrigues-Galindo C, Spunt SL, Pappo AS (2003) Treatment of Ewing sarcoma family of tumours: current status and outlook for the future. Med Pediatr Oncol 40:276–287

    Article  Google Scholar 

  4. Cotterill SJ, Ahrens S, Paulussen M et al (2000) Prognostic factors in Ewing’s tumour of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. J Clin Oncol 18:3108–3114

    PubMed  CAS  Google Scholar 

  5. Bacci G, Ferrari S, Longhi A et al (2003) Therapy and survival after recurrence of Ewing’s tumors. The Rizzoli experience in 195 patients treated with adjuvant and neoadjuvant chemotherapy from 1979 to 1997. Ann Oncol 14:1654–1659

    Article  PubMed  CAS  Google Scholar 

  6. Barker LM, Pendergrass TW, Sanders JE, Hawkins DS (2005) Survival after recurrence of Ewing tumors. J Clin Oncol 23:4354–4362

    Article  PubMed  Google Scholar 

  7. Shankar AG, Ashley S, Craft AW, Pinkerton CR (2003) Outcome after relapse in an unselected cohort of children and adolescents with Ewing sarcoma. Med Pediatr Oncol 40:141–147

    Article  PubMed  CAS  Google Scholar 

  8. Baum ES, Gaynon P, Greenberg L et al (1981) Phase II trial cisplatin in refractory childhood cancer: Children’s Cancer Study Group Report. Cancer Treat Rep 65(9–10):815–822

    PubMed  CAS  Google Scholar 

  9. Balamuth NJ, Womer RB (2010) Ewing’s sarcoma. Lancet Oncol 11(2):184–192

    Article  PubMed  CAS  Google Scholar 

  10. Hofbauer S, Hamilton G, Theyer G et al (1993) Insulin-like growth factor-I-dependent growth and in vitro chemosensitivity of Ewing’s sarcoma and peripheral primitive neuroectodermal tumour cell lines. Eur J Cancer 29A(2):241–245

    Article  PubMed  CAS  Google Scholar 

  11. Planting AS, van der Burg ME, van den Bent MJ et al (1996) Phase II study of a short course of weekly high-dose cisplatin combined with long-term oral etoposide in metastatic colorectal cancers. Br J Cancer 73(12):1569–1575

    Article  PubMed  Google Scholar 

  12. Planting AS, de Mulder PH, de Graeff A, Verweij J (1997) Phase II study of weekly high-dose cisplatin for six cycles in patients with locally advanced squamous cell carcinoma of the head and neck. Eur J Cancer 33(1):61–65

    Article  PubMed  CAS  Google Scholar 

  13. Planting AS, van der Burg ME, Goey SH et al (1995) Phase II study of a short course of weekly high-dose cisplatin combined with long-term oral etoposide in pleural mesothelioma. Ann Oncol 6(6):613–615

    PubMed  CAS  Google Scholar 

  14. Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247

    Article  PubMed  CAS  Google Scholar 

  15. Miller AB, Hoogstraaten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47(1):207–214

    Article  PubMed  CAS  Google Scholar 

  16. Cancer Therapy Evaluation Program. Common Toxicity Criteria, Version 2.0. DCTD, NCI, NIH, DHHS March 1998

  17. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10

    Article  PubMed  CAS  Google Scholar 

  18. Fleming TR (1982) One-sample multiple testing procedure for phase II clinical trials. Biometrics 38(1):143–151

    Article  PubMed  CAS  Google Scholar 

  19. Combination Chemotherapy With or Without Peripheral Stem Cell Transplantation, Radiation Therapy, and/or Surgery in Treating Patients With Ewing’s Sarcoma (Euro-EWING 99) [NCT00020566]. Accessed 15 July 2012. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00020566

  20. Davidson A, Gowing R, Lowis S et al (1997) Phase II study of 21 day schedule oral etoposide in children. New agents group of the United Kingdom Children’s Cancer study group (UKCCSG). Eur J Cancer 33(11):1816–1822

    Article  PubMed  CAS  Google Scholar 

  21. Jazieh AR, Kyasa MJ, Muirhead MJ (2002) Prolonged administration of infusional cisplatin and oral etoposide in advanced non-small cell lung cancer. Anticancer Drugs 13(8):815–818

    Article  PubMed  CAS  Google Scholar 

  22. Loehrer PJ, Eihorn LH (1984) Drugs five years later. Cisplatin. Ann Intern Med 100(5):704–713

    PubMed  CAS  Google Scholar 

  23. Skinner R, Pearson AD, Coulthard MG et al (1991) Assessment of chemotherapy-associated nephrotoxicity in children with cancer. Cancer Chemother Pharmacol 28:81–92

    Article  PubMed  CAS  Google Scholar 

  24. McHaney VA, Thibadoux G, Hayes FA, Green AA (1983) Hearing loss in children receiving cisplatin chemotherapy. J Pediatr 102(2):314–317

    Article  PubMed  CAS  Google Scholar 

  25. Brock PR, Bellman SC, Yeomans EC et al (1991) Cisplatin ototoxicity in children: a practical grading system. Med Pediatr Oncol 19:295–300

    Article  PubMed  CAS  Google Scholar 

  26. Hunold A, Weddeling N, Paulussen M, Ranft A, Liebscher C, Jurgens H (2006) Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer 47(6):795–800

    Article  PubMed  Google Scholar 

  27. Wagner LM, McAllister N, Goldsby RE, Rausen AR, McNall-Knapp RY, McCarville MB et al (2007) Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer 48(2):132–139

    Article  PubMed  Google Scholar 

  28. Casey DA, Wexler LH, Merchant MS, Chou AJ, Merola PR, Price AP et al (2009) Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer 53(6):1029–1034

    Article  PubMed  Google Scholar 

  29. Fox E, Patel S, Wathen JK, Schuetze S, Chawla S, Harmon D et al (2012) Phase II Study of Sequential Gemcitabine Followed by Docetaxel for Recurrent Ewing Sarcoma, Osteosarcoma, or Unresectable or Locally Recurrent Chondrosarcoma: Results of Sarcoma Alliance for Research Through Collaboration Study 003. Oncologist 17(3):e321–e329

    Article  Google Scholar 

Download references

Acknowledgments

The authors would like to thank All centres and investigators: F. Doz, J. Michon, B. Bui, C. Delcambre, P. Boutard, M. Debled, X. Rialland, E. Plouvier, A. Thyss, O, Lejars, C. Schmitt, O. Bay, J. P. Vannier, T. Philip, F. Pichon, F. Mechinaud; Data Management: Guillaume Danton, Department of Biostatistics, Institut Gustave Roussy, Villejuif. This study was sponsored by Fédération Nationale des Centre de Lutte Contre le Cancer (FNCLCC), Paris, France and supported in part by Société Française des Cancers et leucémies de l’Enfant et de l’adolescent (France) and Association Enfants et Santé.

Conflict of interest

The authors declare no conflict of interest.

Ethical standards

The trial protocol was approved by the Ethics Committee of the Centre Hospitalier-Universitaire Kremlin Bicêtre, Paris.

Author information

Authors and Affiliations

  1. Department of Paediatric Oncology, Institut Gustave Roussy, Villejuif, France

    Cormac Owens & Odile Oberlin

  2. Department of Biostatistics, Institut Gustave Roussy, Villejuif, France

    Annie Rey

  3. Department of Radiology, Institut Gustave Roussy, Villejuif, France

    Dominique Couanet

  4. Department of Radiology, Institut Curie, Paris, France

    Hervé Brisse & Liliane Ollivier

  5. Department of Medical Oncology, Institut Curie, Paris, France

    Valerie Laurence

  6. Department of Medical Oncology, Centre hospitalo-universitaire Bretonneau, Tours, France

    Lofti Benboubker

  7. Department of General Oncology, Centre Oscar Lambret, Lille, France

    Anne-Sophie Defachelles

  8. Department of Medical Oncology, Centre Val d’Aurelle Paul Lamarque, Montpellier, France

    Didier Cupissol

  9. Department of Radiology, Centre hospitalo-universitaire Purpan, Toulouse, France

    Christiane Baunin

  10. Department of Paediatric Oncology, Centre hospitalo-universitaire Purpan, Toulouse, France

    Hervé Rubie

  11. Fédération Nationale des Centres Lutte Contre le Cancer, Paris, France

    Céline Mahier Aït-Oukhatar

Authors
  1. Cormac Owens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valerie Laurence
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lofti Benboubker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne-Sophie Defachelles
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Didier Cupissol
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hervé Rubie
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hervé Brisse
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Annie Rey
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Liliane Ollivier
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dominique Couanet
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christiane Baunin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Céline Mahier Aït-Oukhatar
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Odile Oberlin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cormac Owens.

Additional information

Cisplatin in combination with oral VP-16 is a relatively well tolerated regimen for use in patients with relapsed/refractory Ewing Sarcoma Family Tumours, but has limited effectiveness.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Owens, C., Laurence, V., Benboubker, L. et al. Phase II study of cisplatin and oral VP16 in patients with refractory or relapsed Ewing sarcoma. Cancer Chemother Pharmacol 71, 399–404 (2013). https://doi.org/10.1007/s00280-012-2015-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-012-2015-7

Keywords

Search

Navigation