Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial.
BACKGROUND
Based on preclinical data for the antitumour effect of zoledronate in osteosarcoma, we assessed whether zoledronate combined with chemotherapy and surgery improved event-free survival in children and adults with osteosarcoma.


METHODS
In this randomised, multicentre, open-label, phase 3 trial (OS2006), patients aged between 5 years and 50 years with newly diagnosed high-grade osteosarcoma were randomly assigned to receive standard chemotherapy with or without ten zoledronate intravenous infusions (four preoperative and six postoperative). Adults older than 25 years received 4 mg zoledronate per infusion, patients aged 18-25 years received 0·05 mg/kg for the first two infusions and 4 mg for the remaining eight infusions, and younger patients received 0·05 mg/kg per infusion. Chemotherapy comprised high-dose methotrexate based chemotherapy in patients younger than 18 years, and doxorubicin, ifosfamide, and cisplatin in adults older than 25 years; patients aged 18-25 years were treated with either regime at the discretion of the treating centre. Balanced randomisation between the two groups was done centrally with online randomisation software, based on a minimisation algorithm taking into account centre, age, combined with chemotherapy regimen, and risk group (resectable primary and no metastasis vs other). Patients and investigators were not masked to treatment assignment, but the endpoint adjudication committee members who reviewed suspected early progressions were masked to group allocation. The primary endpoint was event-free survival, estimated from the randomisation to the time of first failure (local or distant relapse, progression, death) or to the last follow-up visit for the patients in first complete remission, analysed on a modified intention-to-treat population, which excluded patients found not to have a malignant tumour after central review. Three interim analyses were planned. This trial is registered with ClinicalTrials.gov, number NCT00470223.


RESULTS
Between April 23, 2007, and March 11, 2014, 318 patients, median age 15·5 years (range 5·8-50·9), were enrolled from 40 French centres; of whom 158 were assigned to the control group (chemotherapy alone) and 160 to the zoledronate group, including 55 (17%) patients with definite metastases. The trial was stopped for futility after the second interim analysis. With a median follow-up of 3·9 years (IQR 2·7-5·1), 125 events occurred (55 in the control group and 70 in the with zoledronate group). Event-free survival at 3 years for all 315 randomly assigned patients was 60·3% (95% CI 64·5-65·9); 3-year event-free survival was 63·4% (55·2-70·9) for the control group and 57·1% (48·8-65·0) for the zoledronate group. The risk of failure was not reduced and was even marginally higher in the zoledronate group than in the control group (hazard ratio [HR] 1·36 [95% CI 0·95-1·96]; p=0·094). No major increase in severe toxic effects of grade 3 or higher associated with zoledronate, barring expected hypocalcaemia (45 [29%] of 153 participants in the zoledronate group vs ten [6%] of 155 participants in the control group; p<0·0001) and hypophosphataemia (61 [40%] of 151 in the zoledronate group vs 26 [17%] of 156 in the control group; p<0·0001). No significant difference in orthopaedic complications was noted between the two groups (27 in the control group and 29 in the zoledronate group). Two treatment-related deaths were reported (one from cardiomyopathy in the control group and one from multiorgan failure in the zoledronate group before the first zoledronate infusion).


CONCLUSIONS
From the results observed in this study, we do not recommend zoledronate in osteosarcoma patients. Further biological studies are required to understand the discordance between the results of OS2006 trial and preclinical data.


BACKGROUND
French National Cancer Institute (INCa), Novartis, Chugai, Ligue Nationale contre le Cancer, Fédération Enfants et Santé, Société Française des Cancers et Leucémies de l'Enfant.
Medical Oncology Department, Institut Curie, Paris, France. Electronic address: sophie.piperno-neumann@curie.fr.
Sophie
S
Piperno-Neumann
Paris-Saclay University, Paris-Sud University, CESP, INSERM, Villejuif, France; Biostatistics Unit, Gustave Roussy, Villejuif, France.
Marie-Cécile
MC
Le Deley
UMR 957, INSERM, Université de Nantes, France.
Françoise
F
Rédini
Pediatric Oncology Department, Institut Curie, Paris, France.
Hélène
H
Pacquement
Pediatric Oncology Department, Centre Léon Bérard, Lyon, France.
Perrine
P
Marec-Bérard
Department of Radiology, CHU La Timone, Marseille, France.
Philippe
P
Petit
Department of Radiology, Institut Curie, Paris, France.
Hervé
H
Brisse
Pediatric Oncology Department, Centre Oscar Lambret, Lille, France.
Cyril
C
Lervat
Pediatric Oncology Department, CHU La Timone, Marseille, France.
Jean-Claude
JC
Gentet
Pediatric Oncology Department, CHU Hautepierre, Strasbourg, France.
Natacha
N
Entz-Werlé
Medical Oncology Department, Institut Bergonié, Bordeaux, France.
Antoine
A
Italiano
Pediatric Oncology Department, Hôpital Mère-enfant, Nantes, France.
Nadège
N
Corradini
Medical Oncology Department, Institut de Cancérologie de l'Ouest, Saint Herblain, France.
Emmanuelle
E
Bompas
Medical Oncology Department, Centre Oscar Lambret, Lille, France.
Nicolas
N
Penel
Pediatric Oncology Department, Hôpital Trousseau, Paris, France.
Marie-Dominique
MD
Tabone
Pathology Department, CHU Toulouse, France.
Anne
A
Gomez-Brouchet
Pathology Department, Institut Curie, Saint-Cloud, France.
Jean-Marc
JM
Guinebretière
Pediatric Orthopedic Surgery Department, Hôpital Necker Enfants Malades, Paris, France.
Eric
E
Mascard
CHU Hôtel-Dieu, and INSERM UI957, Nantes, France.
François
F
Gouin
Biostatistics Unit, Gustave Roussy, Villejuif, France.
Aurélie
A
Chevance
Unicancer, Paris, France.
Naïma
N
Bonnet
Medical Oncology Department Centre Léon Bérard, and Claude Bernard University, Lyon, France.
Jean-Yves
JY
Blay
Department of Children and Adolescents Oncology, Gustave Roussy, Villejuif, France.
Laurence
L
Brugières
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004164:Diphosphonates / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007093:Imidazoles / Q000008:administration & dosage; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012516:Osteosarcoma / Q000188:drug therapy* / Q000556:secondary / Q000601:surgery*; D011379:Prognosis; D015996:Survival Rate; D055815:Young Adult; D000077211:Zoledronic Acid
D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D004317:Doxorubicin; D002945:Cisplatin; D007069:Ifosfamide