Meg Finch-Jones

Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial

Summary Background Surgical resection alone is regarded as the standard of care for patients with liver metastases from colorectal cancer, but relapse is common. We assessed the combination of perioperative chemotherapy and surgery compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Methods This parallel-group study reports the trials final data for progression-free survival for a protocol unspecified interim time-point, while overall survival is still being monitored. 364 patients with histologically proven colorectal cancer and up to four liver metastases were randomly assigned to either six cycles of FOLFOX4 before and six cycles after surgery or to surgery alone (182 in perioperative chemotherapy group vs 182 in surgery group). Patients were centrally randomised by minimisation, adjusting for centre and risk score. The primary objective was to detect a hazard ratio (HR) of 0·71 or less for progression-free survival. Primary analysis was by intention to treat. Analyses were repeated for all eligible (171 vs 171) and resected patients (151 vs 152). This trial is registered with ClinicalTrials.gov, number NCT00006479. Findings In the perioperative chemotherapy group, 151 (83%) patients were resected after a median of six (range 1–6) preoperative cycles and 115 (63%) patients received a median six (1–8) postoperative cycles. 152 (84%) patients were resected in the surgery group. The absolute increase in rate of progression-free survival at 3 years was 7·3% (from 28·1% [95·66% CI 21·3–35·5] to 35·4% [28·1–42·7]; HR 0·79 [0·62–1·02]; p=0·058) in randomised patients; 8·1% (from 28·1% [21·2–36·6] to 36·2% [28·7–43·8]; HR 0·77 [0·60–1·00]; p=0·041) in eligible patients; and 9·2% (from 33·2% [25·3–41·2] to 42·4% [34·0–50·5]; HR 0·73 [0·55–0·97]; p=0·025) in patients undergoing resection. 139 patients died (64 in perioperative chemotherapy group vs 75 in surgery group). Reversible postoperative complications occurred more often after chemotherapy than after surgery (40/159 [25%] vs 27/170 [16%]; p=0·04). After surgery we recorded two deaths in the surgery alone group and one in the perioperative chemotherapy group. Interpretation Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients. Funding Swedish Cancer Society, Cancer Research UK, Ligue Nationale Contre le Cancer, US National Cancer Institute, Sanofi-Aventis.

Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial

BACKGROUND Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up. METHODS This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18-80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m(2), folinic acid 200 mg/m(2) (DL form) or 100 mg/m(2) (L form) on days 1-2 plus bolus, and fluorouracil 400 mg/m(2) (bolus) and 600 mg/m(2) (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. FINDINGS Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8·5 years (IQR 7·6-9·5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0·88, 95% CI 0·68-1·14; p=0·34). In all randomly assigned patients, median overall survival was 61·3 months (95% CI 51·0-83·4) in the perioperative chemotherapy group and 54·3 months (41·9-79·4) in the surgery alone group. 5-year overall survival was 51·2% (95% CI 43·6-58·3) in the perioperative chemotherapy group versus 47·8% (40·3-55·0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment. INTERPRETATION We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients. FUNDING Norwegian and Swedish Cancer Societies, Cancer Research UK, Ligue Nationale Contre Cancer, US National Cancer Institute, Sanofi-Aventis.

Predictive factors for the benefit of perioperative FOLFOX for resectable liver metastasis in colorectal cancer patients (EORTC Intergroup Trial 40983)

Objective:In EORTC study 40983, perioperative FOLFOX increased progression-free survival (PFS) compared with surgery alone for patients with initially 1 to 4 resectable liver metastases from colorectal cancer (CRC). We conducted an exploratory retrospective analysis to identify baseline factors possibly predictive for a benefit of perioperative FOLFOX on PFS. Methods:The analysis was based on 237 events from 342 eligible patients. Cox proportional hazards regression models with a significance level of 0.1 were used to build up univariate and multivariate models. Results:After adjustment for identified prognostic factors, moderately (5.1–30 ng/mL) and highly (>30 ng/mL) elevated carcinoembryonic antigen (CEA) serum levels were both predictive for the benefit of perioperative chemotherapy (interaction P = 0.07; hazard ratio [HR] = 0.58 and HR = 0.52 for treatment benefit). For patients with moderately or highly elevated CEA (>5 ng/mL), the 3-year PFS was 35% with perioperative chemotherapy compared to 20% with surgery alone. Performance status (PS) 0 and BMI lower than 30 were also predictive for the benefit of perioperative chemotherapy (interaction P = 0.04 and P = 0.02). However, the number of patients with PS 1 and BMI 30 or higher were limited. The benefit of perioperative therapy was not influenced by the number of metastatic lesions (1 vs 2–4, interaction HR = 0.98). Conclusions:Perioperative FOLFOX seems to benefit in particular patients with resectable liver metastases from CRC when CEA is elevated and when PS is unaffected, regardless of the number of metastatic lesions.ClinicalTrials.gov number NCT00006479.

Contrast-enhanced intraoperative ultrasound improves detection of liver metastases during surgery for primary colorectal cancer

BACKGROUND Computed tomography (CT) is the most common staging investigation in colorectal cancer (CRC). Up to 25% of patients are found to have previously undetected hepatic lesions when intraoperative ultrasound (IOUS) of the liver is used during CRC resection. We aimed to assess the ability of IOUS to detect additional liver lesions/metastases at primary colorectal resection, and to evaluate whether contrast-enhanced IOUS (CE-IOUS) improves the detection and characterization of hepatic lesions. METHODS We performed a single-centre, prospective pilot study. At CRC resection, patients underwent IOUS of the liver. Contrast-enhanced IOUS of the liver was undertaken using i.v. sulphur hexafluoride micro-bubbles (SonoVue, 4.8 ml). Findings of CT, non-enhanced IOUS and CE-IOUS were compared. Changes in staging or management were noted. Additional lesions were corroborated with iron oxide magnetic resonance imaging (MRI). RESULTS Among 21 patients, IOUS demonstrated additional lesions in seven (33%). Contrast altered the diagnosis of non-enhanced IOUS in four (20%) and changed the management strategy in three (14%) patients. Thus, IOUS in combination with the contrast agent altered the intraoperative or postoperative management plan in four patients. CONCLUSIONS In the first study of its kind, early results suggest that the ability of IOUS to detect additional metastases is improved by CE-IOUS, and that this may impact on surgical staging and management.

542PANALYSIS OF PROGRESSION FREE SURVIVAL IN THE NEW EPOC STUDY IN AN ALL RAS WILD-TYPE POPULATION

ABSTRACT Aim: The New EPOC study randomised KRAS exon 2 wild-type (WT) patients with resectable or suboptimally resectable colorectal liver metastases (CRLM) to receive chemotherapy with or without cetuximab before and after liver resection. KRAS status was determined using pyrosequencing in codons 12, 13 and 61. The trial demonstrated a detriment in progression free survival (PFS) from 20·5 to 14·1 months with the addition of cetuximab to chemotherapy (HR 1·48 95%CI 1·04-2·12 p = 0·03). Subsequently, benefit from epidermal growth factor inhibition in advanced disease was shown to be improved by further defining the population as all RAS WT (Douillard NEJM 2013). Methods: Samples of tumour from the primary colorectal and liver resections were obtained. Patients were further analysed using MiSeq for KRAS (codon 12, 13, 61, 117 and 146), BRAF (V600E), NRAS (12, 13, 61, 117 and 146), PIK3CA (547 and 1047) and EGFR S492R. Survival analyses were completed using the Kaplan-Meier method and the log-rank test. Results: To date 140 samples of primary tumour and 103 samples of CRLM have been analysed. Paired samples of primary tumour and CRLM were analysed for 61 patients. Further mutations were found in samples from 12 patients in the initial “KRAS WT” group, 8 KRAS (4 in codons previously analysed by pyrosequencing) and 4 NRAS. 3 mutations identified in CRLM were not in the matching primary. Analysis of the all RAS WT primary tumour population (chemo alone arm n = 53, chemo plus cetuximab arm n = 72) demonstrated a detriment in median PFS of 20 months to 15 months respectively (HR 1·4 95%CI 0·82-2·4 p = 0·22). 7 tumours were found to be BRAF mutated in all patients sequenced. Conclusions: In this study the addition of cetuximab to chemotherapy and surgery for operable CRLM in KRAS wild-type patients resulted in an inferior PFS. More stringent selection of an all RAS WT cohort did not alter the detriment observed. BRAF mutation is uncommon and likely reflects the selection of a relatively good prognosis cohort. Differences in mutational status between primary and metastasis were infrequent and could reflect either a treatment effect or clonal outgrowth. Initial pyrosequencing failed to detect Disclosure: J.A. Bridgewater: reports personal fees from Merck advisory board, Bayer advisory board, Sanofi-aventis advisory board, and Roche advisory board; R. Thiebaut: Employee of IntegraGen SA, Evry, France; F. Liebaert: Employee of IntegraGen SA, Evry, France; S. Falk: reports an Advisory board for Merck pharmaceuticals; J.W. Valle: reports personal fees and non-financial support from Merck J. Hornbuckle: reports non-financial support from Merck UK; T. Iveson: reports personal fees from Advisory Board for Merck Serono; T. Hickish: reports personal fees from Roche, Amgen, Sanofi Aventis, Novartis, Merck Serono advisory boards; D. Cunningham: reports grants from Roche, Amgen, Celgene, Sanofi, Merck Serono, Novartis, Astra Zeneca; T.S. Maughan: reports income from advisory board for Merck;J.N. Primrose: reports personal fees from Merck advisory board, Bayer advisory board, Sanofi-aventis advisory board, and Roche advisory board. All other authors have declared no conflicts of interest.

The clinical impact of magnetic resonance imaging in diagnosing focal hepatic lesions and suspected cancer

AIMS To compare the clinical utility of contrast enhanced magnetic resonance imaging (MRI) to ultrasound (USS) and computed tomography (CT) in focal hepatic lesions (FHLs) METHODS This retrospective study analysed 125 consecutive iron oxide enhanced (SPIO) MRI. RESULTS MRI made a difference in 74% of patients who had USS and in 42% of patients who had a CT scan. In suspected cancer, MRI changed diagnosis in 58% and 37% (13/35), respectively. CONCLUSIONS MRI is superior to other noninvasive imaging modalities for lesion identification and characterisation.