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Rationale of the study

Results of a randomised phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced , soft tissue sarcoma: a survival study by the EORTC Soft Tissue and Bone Sarcoma Group.

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Rationale of the study

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  1. Results of a randomised phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced, soft tissue sarcoma: a survival study by the EORTC Soft Tissue and Bone Sarcoma Group. Ian Judson, Jaap Verweij, Hans Gelderblom, Jorg- Thomas Hartmann, Patrick Schöffski, Jean-Yves Blay, Angelo Paolo dei Tos, Sandrine Marreaud, Saskia Litiere, Winette van der Graaf

  2. Rationale of the study • The outcome of patients with soft tissue sarcomas with locally advanced unresectable primary tumors and/or metastatic disease is poor. • Systemic treatment is usually given in this situation with a palliative intent, but has toxicity. • There is (transatlantic) debate about the best first-line treatment in this situation: single agent doxorubicin or a combination of doxorubicin and ifosfamide

  3. Rationale of the study (II) Which situation justifies which treatment, especially the more toxic combination treatment? And in designing studies with new drugs/treatments: what will be the standard treatment arm to compare with?

  4. Previous studies EORTC study: randomized phase III trial (all grades) 663 pts (Santoro, et al 1995) A: doxorubicin 75 mg/m2 B: cyclophosphamide, vincristine, doxorubicin, and dacarbazine (CYVADIC) C: doxorubicin 50 mg/m2 plus ifosfamide 5 g/m2 Results: Overall Response rate: 24% median overall survival: Arm A: Doxorubicine : 23.3% 52 weeks Arm B: CYVADIC: 28.4% 51 weeks Arm C: Dox-IFOS: 28.1% 55 weeks

  5. Several phase 2 studies: • Doxorubine 75 mg/m2 plus ifosfamide 10 g/m2 plus G-CSF. RR 66% in 33 pts, febrile neutropenia 31% of cycles (Patel, Am J Clin Oncol,1998) • High grade: Epirubicin 90 mg/m2 plus ifosfamide 12.5 g/m2 .RR 52% (Reichardt, J Clin Oncol, 1998). • Doxorubicin 90 mg/m2 plus ifosfamide 10 g/m2. RR 55%, grade 4 BM toxicity and sepsis (Leyvraz, Ann Oncol 1998)

  6. The design • Stratification: • Age (<50 vs ≥50) • PS (0 vs 1) • Liver metastases (0 vs +) • Histological grade (2 vs 3) Doxorubicin 75 mg/m2 d 1 or as a 72 hour continousi.v. infusion R New Treatment: B Doxorubicin 25 mg/m2 d 1-3 + Ifosfamide2.5 g/m2 d 1-4 + Neulasta 6mg s.c. d5

  7. End-points of the study The primary end point: overall-survival The secondary end points: response (RECIST) toxicity (CTC 2.0) treatment related mortality Early stopping rule: as PFS was used as surrogate for OS a failure to produce a significant improvement in PFS (at least 50% increase) would predict a likely failure

  8. Statistical assumption • Improvement of survival is clinically significant if 1yr survival is at least 10% higher in the combination arm (60 versus 50%), corresponding with a HR of 0.737 or less. Two-sided logrank test (alpha=0.05, beta 0.2).

  9. Inclusion criteria • Histological STS: advanced unresectable or metastatic disease. Surgery (for primary or metastatic disease) after chemotherapy following response allowed. • Histological grade 2 and 3 • Following tumor types: - leiomyosarcoma - malignant fibrous histiocytoma - liposarcoma (Myxoid/round cell, pleomorphic or dediferentiated) - synovial sarcoma - myxofibrosarcoma - fibrosarcoma - angiosarcoma - malignant peripheral nerve sheath tumor - epithelioid sarcoma

  10. Inclusion criteria (continued) • Tumor material available for central review • Measurable disease according to RECIST 1.0 • No prior chemotherapy for advanced disease • Prior adjuvant chemotherapy allowed unless disease progression within 6 months following end of treatment • Age 18-60 years • WHO PS 0 or 1 • ANC higher than 2.0 and Platelets above 100 • Serum creatinine lower than 120 or clearance higher than 65, two functioning kidneys • Bilirubin less than 30 umol/l, albumin above 25 • No other serious illness • Normal LVEF • No symptomatic or known brain metastases • No prior or second primary malignancies (except CIS cervix or BCC)

  11. Study status Accrual: • 455 patients entered the study • 38 centers in 9 countries • Start: 4-2003 (start EORTC), 5-2008 (NCIC- 13 patients) • Study Closure: 5-2010 Clinical cut-off • 5-7-2012 • Median follow-up: 56 months

  12. The patient population Total randomized, N=455 Doxorubicin, N=228 Doxorubicin + Ifosfamide, N=227 3 did not start treatment 2 started other arm Ineligible, n = 7 Ineligible, n = 8 5 did not start treatment 1 started other arm 215 eligible patients started allocated treatment 217 eligible patients started allocated treatment

  13. Patient characteristics

  14. Disease characteristics

  15. Disease characteristics

  16. Exposure to treatment

  17. Reason for discontinuation of treatment

  18. Adverse events (grade ≥ 3)

  19. Overall survival HR = 0.83 (95.5% CI 0.67 – 1.03) Stratified logrank test, p = 0.076

  20. Median overall survival: Doxorubicin: 12.8 months (95.5 CI 10.5-14.3) Doxorubicin-ifosfamide: 14.3 months (95.5% CI 12.5-16.5). Survival at 1-year: Doxorubicin: 51% (95.5% CI 44-58) Doxorubicin-ifosfamide: 60% (95.5% CI 53-66)

  21. Overall survival

  22. Progression free survival HR = 0.74 (95% CI 0.60 – 0.90) Stratified logrank test, p = 0.003

  23. Median PFS Median PFS in the doxorubicin arm: 4.6 months (95% CI 2.9 – 5.6), in the combination arm 7.4 months (95% CI 6.6 – 8.3).

  24. Progression free survival

  25. Best overall response Significant difference between the two arms: p < 0.001

  26. Post protocol treatment

  27. Conclusions In this group of patients all below 60, median age 48 years The combination of doxorubicin and ifosfamide: • doubled the response rate • improved PFS significantly • it did not significantly improve survival • It was considerably more toxic than doxorubicin alone.

  28. This study supports personalised medicine in daily practice... • The standard treatment in the palliative setting remains single agent doxorubicin • If surgery for unresectable tumors or curative metastasectomy is considered, combination therapy gives the highest chance of response • In highly symptomatic disease in patients without co-morbidity combination treatment is optional and pro’s and cons should – as always- be discussed with the patient. • ….and since we have the results of this study, these discussions can be more balanced than before.

  29. Acknowledgements • Patients and their families • Investigators of all participating hospitals of EORTC, NCIC • The membership of the EORTC STBSG • EORTC Headquarters

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