EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment†

J. S. Whelan 0 S. S. Bielack 0 N. Marina 0 S. Smeland 0 G. Jovic 0 J. M. Hook 0 M. Krailo 0 J. Anninga 0 T. Butterfass-Bahloul 0 T. Bhling 0 G. Calaminus 0 M. Capra 0 C. Deffenbaugh 0 C. Dhooge 0 M. Eriksson 0 A. M. Flanagan 0 H. Gelderblom 0 A. Goorin 0 R. Gorlick 0 G. Gosheger 0 R. J. Grimer 0 K. S. Hall 0 K. Helmke 0 P. C. W. Hogendoorn 0 G. Jundt 0 L. Kager 0 T. Kuehne 0 C. C. Lau 0 G. D. Letson 0 J. Meyer 0 P. A. Meyers 0 C. Morris 0 H. Mottl 0 H. Nadel 0 R. Nagarajan 0 R. L. Randall 0 P. Schomberg 0 R. Schwarz 0 L. A. Teot 0 M. R. Sydes 0 M. Bernstein 0 on behalf of the EURAMOS collaborators 0 0 125 Kingsway , London WC2B 6NH , UK. Tel: Background: Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response. Patients and methods: Patients with resectable osteosarcoma aged 40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m2, doxorubicin 75 mg/m2, methotrexate 12 g/m2 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with 10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality of life was undertaken. Results: Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. About 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3-4 neutropenia affected 83% - introduction methods | Whelan et al. Diagnostic biopsies were to be examined by local institutional pathologists and reviewed by each study groups reference pathologists. study design treatment Chemotherapy for the control arm (Figure 2) was based on the standard described in the previous largest RCT for osteosarcoma [8]. Pre-operative treatment comprised methotrexate 12 g/m2 (M), doxorubicin 75 mg/m2 (Adriamycin, A) and cisplatin 120 mg/m2 (P). Preferred schedules were 48-h infusion for doxorubicin and either 72-h infusion or two 4-h infusions on separate days for cisplatin. Methotrexate was given over 4 h and folinic acid rescue commenced at 24 h. Surgery was scheduled after two cycles of MAP, i.e., 10 weeks after starting chemotherapy. Biopsy-proven diagnosis of resectable osteosarcoma REGISTER MAP (induction) Histological response assessment Good RANDOMIZE RANDOMIZE A Doxorubicin 75 mg/m2/course P Cisplatin 120 mg/m2/course M Methotrexate 12 g/m2/course E Etoposide 500 mg/m2/course I Ifosfamide 14 g/m2/course i Ifosfamide 9 g/m2/course Ifn Interferon-a 0.51.0 mg/kg weekly A A P M M P M M Week 1 2 3 4 5 6 7 8 9 10 Evaluation of histological response S Eligible, consenting patients with good histological response were randomised to complete six cycles of MAP or MAP followed by maintenance pegylated interferon -2b (Ifn; Merck) at 0.51.0 g/kg/week to 24 months after starting chemotherapy. Eligible, consenting patients with poor histological response were randomised to continue standard chemotherapy with MAP or to MAP/IE over 28 weeks, a schedule designed to deliver the same total doses as post-operative MAP with additional ifosfamide and etoposide (IE), agents previously demonstrating activity in osteosarcoma [9]. Ifosfamide 3000 mg/m2 3 days, total dose 9 g/m2, was given with doxorubicin in cycles designated as Ai, and at 2800 mg/m2 5 days, total dose 14 g/m2, with etoposide 100 mg/m2 5 days, designated IE cycles. The protocol detailed dose modifications to account for toxicity for all treatments. Granulocyte growth factors were recommended but not mandated. Dexrazoxane could be used at investigators discretion for reduced cardiac function remaining in the normal range; this applied throughout in North America but was withdrawn by the European Medicines Agency in 2011. Response assessment was required to determine suitability for surgery and to exclude progression (see supplementary Material, available at Annals of Oncology online). quality-of-life evaluation outcome measures metastases, progression of metastatic disease, detection of secondary malignancy or death from any cause. EFS was chosen because prevention of first recurrence is the principal goal of adjuvant treatment of osteosarcoma, given the low rate of survival after first recurrence. Furthermore, treatment of recurrence is heterogeneous; treatment guidance for relapse accompanied the protocol, but sites existing standard practice was accepted. Secondary outcome measures were overall survival (OS), toxicity and QL. Toxicity was assessed using CTCAE version 3.0 [13]. sample size calculations We assumed 70% 3-year EFS on MAP for good response and 45% for poor response, timed from randomisation. Each sample size was based on 5% two-sided significance level and 80% power. The Good Response randomisation needed 147 EFS events to detect improved 3-year EFS from 70% to 80%, i.e., hazard ratio (HR) = 063 [14]. Five-year survival was estimated as 70% so long-term analyses for survival were planned for when 147 deaths are reported, for the same relative and absolute improvements. For poor response, 378 events were targeted to detect improved 3-year EFS and 5-year OS from 45% to 55% (HR = 075). We anticipated 45% (567) randomised patients would have good response and 55% (693) poor response [8]. We planned to register 1400 patients over 3.5 years to randomise 1260, assuming 10% non-randomisation for ineligibility or non-consent. The observed non-randomisation rate was higher and the registration target was increased to 2000 patients. statistical analysis This paper describes the full, registered patient population, including all patients who signed the informed consent documents, up to the point of surgery. Standard descriptive statistics are used. results study participants randomisation histology | Whelan et al. assessment of both diagnostic biopsy and resected specimen, the classification was different for 75 (4%) patients. Of these, 36/75 were re-classified as different subtypes of osteosarcoma, 15/75 as conventional, 13/75 as telangiectatic, 6/75 as high-grade surface osteosarcoma and 5/75 were ineligible. Pathological assessment of histological response to pre-operative chemotherapy was available for 1975/2012 patients; 979 reported a good response and 996 a poor response. The response rate of good histological response to MAP was 50% overall, ranging from 46% (433/949) COG, to 53% COSS (265/ 499), 53% SSG (58/110) and 54% EOI (223/417). chemotherapy Ninety-four percent registered patients (2123/2248) completed two cycles of MAP pre-operatively. Median receive (...truncated)