Zoledronate does not reduce the risk of treatment failure in osteosarcoma: results of the French multicentre OS2006 randomised trial L Brugières, MC Le Deley, F Rédini, P Marec-Bérard, H Pacquement, C Lervat, JC Gentet, N Entz-Werlé, B Bui, N Corradini, G de Pinieux, P Petit, K Buffard, JY Blay, S Piperno-Neumann 15-18 October 2014, Berlin
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Zoledronate does not reduce the risk of treatment failure in osteosarcoma: results of the French multicentre OS2006 randomised trial L Brugières, MC Le.
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Zoledronate does not reduce the risk of treatment failure in osteosarcoma:
results of the French multicentre OS2006 randomised trial
L Brugières, MC Le Deley, F Rédini, P Marec-Bérard, H Pacquement, C Lervat, JC Gentet, N Entz-Werlé, B Bui, N Corradini, G de Pinieux, P Petit, K Buffard, JY Blay, S Piperno-Neumann
15-18 October 2014, Berlin
Disclosures
Novartis Chugaï
15-18 October 2014, Berlin
Zoledronate in osteosarcoma Preclinical models
Rat -transplantable model of osteosarcoma- Z prevents the formation of bone osteolytic lesions and reduces local tumor growth- IFO+Z enhances tumor regression and tissue repair
Lung metastases model in mice (IV injection of POS-1 murine osteosarcoma cells)- Z suppresses lung mets in vivo and prolongs overall survival of osteosarcoma-bearing mice- Z has a direct antitumoral effect on POS-1 cells in vitro
Ory et al, Cancer (2005)
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implantation Z OL (100 µg/kg) sacrifice
J0 J7 J14 J21 J28 J35
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I I+Z
15-18 October 2014, Berlin
OS2006 trial
Randomised phase III trial involving all French paediatric oncology and most adult sarcoma centres (overall 48 centres)
Objective: To evaluate the impact of the addition of a 10-month Zoledronate treatment to chemotherapy and surgery on the event-free survival of osteosarcoma patients
Primary endpoint : EFS
15-18 October 2014, Berlin
OS2006 - Inclusion criteria All newly diagnosed high grade osteosarcoma
except :• Small cell osteosarcoma• Maxillary osteosarcoma• Extra-osseous osteosarcoma • Patients with
• primary resection• multiple metastases for whom complete removal was not
expected to be feasible even after shrinkage with chemotherapy
Age > 5 years and < 50 years 15-18 October 2014, Berlin
OS2006 - Chemotherapy
MTX-ETO-IFO
according to OS94 protocol
API-AI
according to FSG protocol
<18 years 18-25 years > 25 years
left to the choice of each center
(Assi et al Curr Oncol 2010,
Piperno-Neumann et al ASCO 2006)(Le Deley et al Eur J Cancer 2007)
* : GR = Good histological response (<10% viable cells) **: PR = Poor histological response (≥10% viable cells)
and patients with non resectable primary tumor or metastatic disease
Lenograstim 263 µg D6-D12
Zoledronate Randomisation at diagnosis between 2 arms with or
without zoledronate Dose of Zoledronate
• 10 monthly IV infusions: 4 before/ 6 after surgery• Dose
• >25 years: 4 mg• <18 years : 0.05 mg/kg (max 4 mg/ dose)• 18-25 y: 0.05 mg/kg for the first 2 courses, then 4 mg
• Dose reduction if gr 3-4 hypocalcemia Vitamin D3 and calcium supplementation in both arms
15-18 October 2014, Berlin
Statistical considerations Randomisation stratified on:
age and type of chemotherapy => 4 strata risk group : non metastatic and resectable versus
metastatic or not resectable centre
Sample size : 470 patients required to achieve a 80%-power to detect a 13% improvement of 3 y-EFS (from
55% to 68%) in the Zoledronate arm (HR=0.65), with a two-sided log-rank test (alpha=5%) and 3 interim analyses
This is the results of the second interim analysis performed after the inclusion of 318 pts
15-18 October 2014, Berlin
Participant flow (Apr 2007-Feb 2014)
Did not meet eligibility criteria N=70
No zoledronate (Z-)N=158
zoledronate (Z+)N=160
Suspension of randomisation N=17
Not included in the randomised trialN = 116 including 69 refusal
Assessed for eligibilityN=521
Included in the randomised trialN=318 (73%)
Potentially eligibleN=434
15-18 October 2014, Berlin
15-18 October 2014, Berlin
Z- Z+ TotalN=158 N=160 N=318 %
Age and planned chemotherapy
109 110 219 69 Less than 18y – MTX-Eto-Ifo 18-25 years – MTX-Eto-Ifo 18 19 37 12 18-25 years – API-AI 12 11 23 7 > 25 years – API-AI 19 20 39 12Risk group
132 129 261 82 Non metastatic and primary resectable Non metastatic and primary non resectable 1 3 4 1 Metastatic disease 25 28 53 17Site of the primary (MD=33) Limb 130 132 262 92 Axial 13 10 23 8Size of the primary (MD=44) <10 cm 76 58 134 49 >10 cm 62 78 140 51Alkaline phosphatases (MD=41) Normal level 80 73 153 55 Above the upper limit (> 1xULN) 59 65 124 45LDH (MD=58) Normal level 78 79 157 60 Above the upper limit (> 1xULN) 54 49 103 40
Baseline characteristics
Zoledronate - Total administration
In Zoledronate arm: 55 patients had an omission of >1 injection, including
• 4 patients with no Zoledronate injection • 4 patients who stopped Zoledronate after 1st injection
Zoledronate dose = protocol dose (+/-10%) for 851/1013 injections (84%)
No patient allocated to Z- arm received Zoledronate
15-18 October 2014, Berlin
Toxicity during treatment
15-18 October 2014, Berlin
No significant increase of toxicity regarding the most frequent expected toxicities (i.e. hematotoxicity, infection, transfusion, ASAT/ALAT elevation, mucositis…)
Hypocalcemia grade 2-4 significantly more frequent in Z+ arm• per course: OR = 7.2, 95%CI, 4.9 – 10.6, p<0.001• decreasing risk over time
Surgery and histological analysis of the primary tumour