BACKGROUNDPrognosis of unresectable glioblastoma (GB) remains poor, despite temozolomide (TMZ)-based chemoradiation. Activity of bevacizumab (BEV) and irinotecan (IRI) has been reported in recurrent disease. We evaluated BEV and IRI as neo-adjuvant and adjuvant treatment combined with TMZ-based chemoradiation for unresectable GB.PATIENTS AND METHODSPatients with unresectable GB, age 18-70, IK ≥50 were eligible. The experimental arm (BEV/IRI) consisted of neo-adjuvant intravenous BEV, 10 mg/kg, and IRI, 125 mg/m(2), every 2 weeks for four cycles before radiotherapy (RT) (60 Gy), concomitant oral TMZ, 75 mg/m(2)/day, and BEV, 10 mg/kg every 2 weeks. Adjuvant BEV and IRI were given every 2 weeks for 6 months. The control arm consisted of concomitant oral TMZ, 75 mg/m(2)/day during RT, and 150-200 mg/m(2) for 5 days every 28 days for 6 months. The use of BEV was allowed at progression in the control arm.RESULTSPatients (120) were included from April 2009 to January 2011. The working hypothesis was that treatment would increase the progression-free survival at 6 month (PFS-6) from 50% to 66%. The primary objective was not achieved, and only 30 out of 60 patients were alive without progression at 6 months (50.0% [IC95% (36.8; 63.1)] in the BEV/IRI arm when 37 out of 60 patients were required according to the Fleming decision rules. PFS-6 was 7.1 months in BEV/IRI versus 5.2 months in the control arm. The median overall survival was not different between the two arms (11.1 months). Main toxicities were three fatal intracranial bleedings, three bile duct or digestive perforations/infections (1 fatal), and six thrombotic episodes in the BEV/IRI arm, whereas there was one intracranial bleeding, two bile duct or digestive perforations/infections (1 fatal), and one thrombotic episode in the control arm.CONCLUSIONSNeo-adjuvant and adjuvant BEV/IRI, combined with TMZ-radiation, is not recommended for further evaluation in the first-line treatment of unresectable GB.CLINICAL TRIAL REGISTRATIONClinical trial registered under EUDRACT number 2008-002775-28 (NCT01022918).

2029^ Background: The prognosis of unresectable glioblastoma (GBM) remains poor despite temozolomide- based chemoradiation with a median of 6 month progression-free survival (PFS). Activity of bevacizumab/irinotecan has been reported in patients with relapsed GBM (Vredenburgh, 2007). The objective of this randomized phase II trial was to evaluate the efficacy and safety of irinotecan (IRI) and bevacizumab (BVZ) as neo-adjuvant and adjuvant treatment to chemoradiation with temozolomide (TMZ) and BVZ for naive unresectable glioblastoma. Control arm was TMZ as concomitant and adjuvant treatment to radiation. Methods: Pts with de novo unresectable GBM, aged 18-70, and KPS > 50, and EORTC RPA class 5 were eligible. Experimental arm (A) consisted of neo-adjuvant BVZ 10 mg/kg and IRI 125 mg/m2, every 2 wk for 4 cycles before radiotherapy 60 Gy in 30 fractions with concurrent TMZ 75 mg/m2/day and BVZ every 2 wk. Adjuvant BVZ and IRI were given every 2 wk for 6 month. The control arm (B) consisted of concomitant TMZ 75 mg/m2/d during radiotherapy and 150-200 mg/m2 for 5 d every 28 d for 6 month. Cross over were allowed for progression. The inclusion of 67 pts/arm was planned, using Fleming’s 2 steps design aiming at an increase of PFS at 6 month (PFS6) from 50 % to 66 %, with unilateral alpha 5% and 80% power. Results: Patients (134) were included from April 2009 to January 2011. Clinical factors were well balanced between arms. At interim analysis 6 month after inclusion of the first 30 pts in arm A, 17 were alive and free of progression (57%). In arm B, 13 patients were alive and free of progression (43%). Four deaths were related to treatment in arm A (3 cerebral haemorrhages, 1 peritonitis) and 0 in arm B. According to Fleming’s rules it was required to include 30 pts more in arm A for final analysis. Conclusions: Interim results suggest that experimental arm could reach efficacy hypotheses based on the favourable trend in PFS. The risk of severe cerebral haemorrhage due to BVZ appears as unusually high in this patient population. Updated results will be presented at the meeting.

ICON3 trial results have suggested that CAP and carboplatin–taxol regimens as first-line treatment of advanced ovarian cancer (AOC) yield similar survival. We explored the impact of increased dose of cyclophosphamide in a modified CAP regimen on the disease-free survival (DFS) and overall survival (OS) of AOC patients. From February 1994 to June 1997, 164 patients were randomised to receive six cycles every 3 weeks of either standard CEP (S) combining cyclophosphamide (C), 500 mg m −2 , epirubicin (E) 50 mg m −2 , and cisplatin (P) 75 mg m −2 or intensive CEP (I) with E and P at the same doses, but with (C) 1800 mg m −2 and filgrastim 5 μ g kg −1 per day × 10 days. Response was evaluated at second-look surgery. Patient characteristics were well balanced. Except for grade 3–4 neutropaenia (S: 54%, I: 38% of cycles), Arm1 presented a significantly more important toxicity: infection requiring antibiotics, grade 3–4 thrombocytopaenia, anaemia, nausea-vomiting, diarrhoea, mucositis. Median follow-up was 84 months. DFS (15.9 vs 14.8 months) and OS (33 vs 30 months) were not significantly different between S and I ( P >0.05). Increasing cyclophosphamide dose by more than 3 times with filgrastim support in the modified CAP regimen CEP induces more toxicity but not better efficacy in AOC.

Purpose: To compare concomitant and sequential adjuvant chemoradiotherapy regimens in node-positive, operable breast cancer patients.Methods and Materials: This was a randomized, French, multicenter, phase III trial enrolling 638 eligible women with prior breast surgery and positive axillary dissection. Patients in Arm A received 500 mg/m(2) 5-fluorouracil, 12 mg/m(2) mitoxantrone, and 500 mg/m(2) cyclophosphamide, with concomitant radiotherapy (50 Gy +/- 10-20-Gy boost). Patients in Arm B received 500 mg/m(2) 5-fluorouracil, 60 mg/m(2) epirubicin, and 500 mg/m(2) cyclophosphamide, with subsequent radiotherapy. Chemotherapy was administered on Day 1 every 21 days for 4 cycles.Results: Median treatment durations were 64 and 126 days (Arms A and B, respectively), with no significant difference in overall or disease-free survival. Five-year locoregional relapse-free survival favored patients with conservative surgery (two thirds of the population), with less local and/or regional recurrence in Arm A than in Arm B (3% vs. 9%; p = 0.01). Multivariate analysis in this subgroup showed a 2.8-fold increased risk of locoregional recurrence with sequential chemoradiotherapy, independent of other prognostic factors (p = 0.027). Febrile neutropenia and Grade 3-4 leukopenia were significantly more frequent in Arm A. Subclinical left ventricular ejection fraction events at 1 year were more frequent with concomitant radiotherapy (p = 0.02).Conclusions: Concomitant radiotherapy with adjuvant fluorouracil, mitoxantrone, and cyclophosphamide has significantly better locoregional control in node-positive breast cancer after conservative surgery and 50% shorter treatment, albeit with slightly more acute toxicity. With mitoxantrone no longer available for adjuvant breast cancer treatment, alternative concomitant chemoradiotherapy studies are needed. (C) 2006 Elsevier Inc.

BACKGROUND:This multicenter, randomized, phase III study compared the efficacy, including progression-free survival (PFS), and safety of gemcitabine-docetaxel (GD) combination versus cisplatin-vinorelbine (CV) in the treatment of advanced non-small-cell lung cancer (NSCLC).PATIENTS AND METHODS:Chemonaive patients with stage IIIB or IV NSCLC were treated with GD (gemcitabine 1000 mg/m(2) days 1 and 8 plus docetaxel 85 mg/m(2) day 8, every 3 weeks for eight cycles) or CV (cisplatin 100 mg/m(2) day 1 plus vinorelbine 30 mg/m(2), days 1, 8, 15 and 22, every 4 weeks for six cycles).RESULTS:A total of 311 patients were enrolled (155 GD and 156 CV). Neither PFS nor overall survival differed significantly between the two arms (median PFS 4.2 and 4 months; median survival 11.1 and 9.6 months; 1-year survival 46% and 42%, for GD and CV, respectively). For the GD arm compared with the CV arm, the hazard ratio for PFS was 1.04 [95% confidence interval (CI) 0.83-1.32], and for overall survival, it was 0.90 (95% CI 0.70-1.16). Objective response rates did not differ significantly (31% for GD, 35.9% for CV). Myelosupression, emesis and frequency of febrile neutropenia were less pronounced on the GD arm, whereas fluid retention and pulmonary events were more pronounced. The CV arm experienced a higher number of serious adverse events and a lower compliance with the protocol. There was no quality of life (QoL) difference between arms. Median time to definite impairment of health-related QoL was 153 and 168 days in GD and CV arms, respectively.CONCLUSIONS:There was no advantage in PFS with GD compared with CV; however, the CV regimen had higher rate of toxic events, mainly myelosuppression. The herein, non-platinum-containing regimen could be considered as a rational alternative to the cisplatin-based doublet.

Purpose: A phase II-III randomised study to compare safety and efficacy of an oxaliplatin/cyclophosphamide (OXAC) combination, vs. the reference combination of cisplatin/cyclophosphamide (CPC), in untreated advanced ovarian cancer patients.Patients and methods: 182 patients were enrolled, of whom 177 were treated; 86 with OXAC (130 mg/m(2) oxaliplatin two-hour intravenous (i.v.) infusion, 1000 mg/m(2) cyclophosphamide two-hour i.v. infusion), and 91 with CPC (100 mg/m(2) cisplatin one-hour i.v. infusion, 1000 mg/m(2) cyclophosphamide two-hour i.v. infusion). Treatment cycles were repeated every three weeks (maximum of six cycles).Results: The main toxicities, which were significantly less severe in the OXAC arm, were myelosuppression and vomiting, including (OXAC vs CPC, % patients): grade 3-4 leukopenia (37% vs. 56%), and anaemia (7% vs. 32%), with blood transfusions in 8% vs. 21%. In the OXAC arm, 64% of surgically assessable patients and 33% of clinically assessable patients achieved an objective response. In the CPC arm, 67% patients achieved a surgical response and 42% achieved an objective clinical response. In the OXAC and CPC arms, median progression free-survival was 13.0 and 13.3 months, and overall survival was 36.0 and 25.1 months respectively, without statistically significant difference.Conclusion: The activity and time-related parameters of the OXAC and CPC combinations in advanced ovarian cancer patients, are comparable. Combined with the better safety profile of the oxaliplatin-containing regimen, this confirms the interest of oxaliplatin combined with active new agents in this indication.