Showing papers by "Laurence Collette published in 2014"

Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study

Abstract: Summary Background EORTC trial 22921 examined the addition of preoperative or postoperative chemotherapy to preoperative radiotherapy in patients with rectal cancer. After a median follow-up of 5 years, chemotherapy—irrespective of timing—significantly improved local control. Adjuvant chemotherapy did not improve survival, but the Kaplan-Meier curves diverged, suggesting possible delayed benefit. Here, we report the updated long-term results. Methods We randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy with or without concomitant chemotherapy before surgery followed by either adjuvant chemotherapy or surveillance. Randomisation was done using minimisation with factors of institution, sex, T stage, and distance from the tumour to the anal verge. Study coordinators, clinicians, and patients were aware of assignment. Radiotherapy consisted of 45 Gy to the posterior pelvis in 25 fractions of 1·8 Gy over 5 weeks. Each course of chemotherapy consisted of fluorouracil (350 mg/m 2 per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m 2 per day intravenous bolus). For preoperative chemotherapy, two courses were given (during weeks 1 and 5 of radiotherapy). Adjuvant chemotherapy was given in four cycles, every 3 weeks. The primary endpoint was overall survival. This analysis was done by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00002523. Findings 1011 patients were randomly assigned to treatment between April, 1993, and March, 2003 (252 to preoperative radiotherapy and 253 to each of the other three groups). After a median follow-up of 10·4 years (IQR 7·8–13·1), 10-year overall survival was 49·4% (95% CI 44·6–54·1) for the preoperative radiotherapy group and 50·7% (45·9–55·2) for the preoperative radiotherapy and chemotherapy group (HR 0·99, 95% CI 0·83–1·18; p=0·91). 10-year overall survival was 51·8% (95% CI 47·0–56·4) for the adjuvant chemotherapy group and 48·4% (43·6–53·0) for the surveillance group (HR 0·91, 95% CI 0·77–1·09, p=0·32). 10-year disease-free survival was 44·2% (95% CI 39·5–48·8) for the preoperative radiotherapy group and 46·4% (41·7–50·9) for the preoperative radiotherapy and chemotherapy group (HR 0·93, 95% CI 0·79–1·10; p=0·38). 10-year disease-free survival was 47·0% (95% CI 42·2–51·6) for the adjuvant chemotherapy group and 43·7% (39·1–48·2) for the surveillance group (HR 0·91, 95% CI 0·77–1·08, p=0·29). At 10 years, cumulative incidence of local relapse was 22·4% (95% CI 17·1–27·6) with radiotherapy alone, 11·8% (7·8–15·8) with neoadjuvant radiotherapy and chemotherapy, 14·5% (10·1–18·9) with radiotherapy and adjuvant chemotherapy and 11·7% (7·7–15·6) with both adjuvant and neoadjuvant chemotherapy (p=0·0017). There was no difference in cumulative incidence of distant metastases (p=0·52). The frequency of long-term side-effects did not differ between the four groups (p=0·22). Interpretation Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival. Our trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy. New treatment strategies incorporating neoadjuvant chemotherapy are required. Funding EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, Ligue contre le Cancer Comite du Doubs.

Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial

Abstract: Summary Background Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stage III colon cancer improved disease-free survival (DFS). Methods For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patients with resected (R0) stage III disease (1:1) to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene ( KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23. Findings Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2–3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85–1·29; p=0·66), and in patients with KRAS exon 2/ BRAF wild-type (n=984, HR 0·99; 95% CI 0·76–1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82–1·37). We noted heterogeneous responses to the addition of cetuximab in preplanned subgroup analyses. Grade 3 or 4 acne-like rash (in 209 of 785 patients [27%] vs four of 805 [ vs 70 [9%]), mucositis (63 [8%] vs 10 [1%]), and infusion-related reactions (55 [7%] vs 30 [4%]) were more frequent in patients treated with FOLFOX4 plus cetuximab than in those patients who received FOLFOX4 alone. Interpretation The addition of cetuximab to FOLFOX4 did not improve DFS compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted. Funding Federation Francophone de Cancerologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.

One-step TNM staging of high-risk prostate cancer using magnetic resonance imaging (MRI): toward an upfront simplified "all-in-one" imaging approach?

Abstract: BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) is the standard for local prostate cancer (PCa) staging. Whole-body MRI (wbMRI) has shown capabilities for metastatic screening. This study assesses the feasibility and value of an all-in-one AJCC TNM staging of PCa during a unique MRI session combining mpMRI and wbMRI. METHODS: Thirty consecutive patients with "high-risk" PCa prospectively underwent mpMRI of the prostate and wbMRI, in addition to (99m) Tc bone scan (BS), completed with standard X-rays (±TXR) and contrast enhanced CT for distant staging. For the statistical analysis, a "best valuable comparator" (BVC) combining a panel review of all available baseline and follow-up imaging, biological, and clinical data was used to adjudicate lymph node and bone metastatic status. RESULTS: Prostate mpMRI was analyzed using ESUR guidelines. Sensitivity of BS ± TXR combined with CT and of wbMRI for detecting metastases (bones or nodes) was 85% and 100%, respectively, and specificity was 88% and 100%, respectively. For the overall staging of the patients as being either N0M0 or having disease extension beyond the prostate, wbMRI was superior to the combination of BS and CT (improvement in all ROC characteristics and of AUC by 13.6% (95% CI: +0.7% to +26.5%, P = 0.039)). The main limitation is the limited number of patients. CONCLUSIONS: AJCC M and N staging using wbMRI is feasible during the same imaging session as mpMRI performed for T staging, in less then one hour. wbMRI outperforms BS ± TXR and abdomino-pelvic CT work up for discriminating subsets of patients with or without distant spread of the cancer.