1413O - Zoledronate does not reduce the risk of treatment failure in osteosarcoma: results of the French multicentre OS2006 randomised trial

Date 29 September 2014
Event ESMO 2014
Session Sarcoma
Topics Bone Sarcomas
Supportive measures
Presenter Sophie Piperno-Neumann
Citation Annals of Oncology (2014) 25 (suppl_4): iv494-iv510. 10.1093/annonc/mdu354
Authors S. Piperno-Neumann1, M. Le Deley2, F. Rédini3, P. Marec-Bérard4, H. Pacquement5, C. Lervat6, J. Gentet7, N. Entz-Werlé8, A. Italiano9, N. Corradini10, E. Bompas11, N. Penel12, M. Tabone13, G. De Pinieux14, P. Petit15, K. Buffard16, J. Blay17, L. Brugières18
  • 1Medical Oncology, Institut Curie, 75248 - Paris/FR
  • 2Biostatistics, Gustave Roussy, Villejuif/FR
  • 3Inserm, Umr957, Faculté de Médecine, EA 3822, Nantes/FR
  • 4Pediatric Oncology, Institut d’Hémato-Oncologie Pédiatrique, Lyon/FR
  • 5Pediatric Oncology, Institut Curie, 75248 - Paris/FR
  • 6Pediatric Oncology, Centre Oscar-Lambret, Lille/FR
  • 7Pediatric Oncology, Hôpital de la Timone, Marseille/FR
  • 8Pediatric Oncology, CHRU, Strasbourg/FR
  • 9Medical Oncology, Institut Bergonié, Bordeaux/FR
  • 10Pediatric Oncology, CHU, Nantes/FR
  • 11Oncology, ICO Institut de Cancerologie de l'Ouest René Gauducheau, Nantes/FR
  • 12Medical Oncology, Centre Oscar Lambret, 59000 - Lille/FR
  • 13Pediatric Oncology, Hôpital Trousseau, Paris/FR
  • 14Pathology, Hôpital Trousseau, Tours/FR
  • 15Radiology, Hopital de la Timone, Marseille/FR
  • 16Sarcoma Group, Unicancer, Paris/FR
  • 17Medical Oncology, Centre Léon-Berard, Lyon/FR
  • 18Pediatric Oncology, Gustave Roussy, Villejuif/FR

Abstract

Aim

Based on anti-tumour effect of zoledronate in vitro and in experimental models of rat osteosarcoma, we assessed whether zoledronate (Z) in combination with chemotherapy and surgery improved Event-Free Survival (EFS) in children and adult patients (pts) with osteosarcoma.

Methods

Experimental treatment consisted of 10 Z-injections (4 pre and 6 postoperative), 4 mg/injection in adults, 0.05 mg/kg/injection in younger pts. Chemotherapy included methotrexate-etoposide-ifosfamide +/-adriamycine-cisplatin in children/adolescents, and doxorubicin-ifosfamide/doxorubicin-ifosfamide-cisplatinum in adults. Balanced randomisation between Z+arm and Z-arm was stratified by center, age, chemotherapy type and risk group (localised resectable disease versus unresectable primary and/or metastases). The study was planned as an open-label superiority trial, with 3 interim analyses (early stopping for efficacy or harm) disclosed to an independent safety monitoring board (DSMB). 470 pts (170 events) were required to achieve an 80%-power to detect a 13%-improvement of 3-year EFS (H1: 55% versus 68%, HR(event)=0.65) with zoledronate (2-sided alpha=0.05).

Results

A second interim analysis was performed after 318 pts (82% with a localised and resectable tumour) have been recruited between April 2007 and February 2014: 158 Z- and 160 Z+. No significant increase in toxicity was found in Z+, except expected hypocalcemia grade 2-4 (p<0.0001). With a median follow-up of 3.1 years, 106 events and 58 deaths were reported, including one treatment-related death. The risk of treatment failure was not reduced in Z+ compared to Z-: HR(event)=1.31 [0.79–2.18], p=0.17; HR(death)=1.42 [0.70–2.88], p=0.21. Results were similar after exclusion of eight Z+patients who had received 0 or1 zoledronate injection, and were homogeneous across the randomisation strata. Futility analysis, performed on DSMB request, showed that the probability of demonstrating a benefit for Z+ was <0.0001. Following DSMB recommendation, the trial steering committee decided to stop accrual in the trial.

Conclusions

With current follow-up, the addition of zoledronate to chemotherapy did not reduce the risk of failure in osteosarcoma patients.

Disclosure

All authors have declared no conflicts of interest.