Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival. METHODS: New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0-2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m2 administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m2 administered intravenously over 2 h and oral capecitabine 1000 mg/m2 twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m2 followed by a weekly infusion of 250 mg/m2 with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367. FINDINGS: Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0-77·5). Median progression-free survival was 22·2 months (95% CI 18·3-26·8) in the chemotherapy alone group and 15·5 months (13·8-19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87-1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5-71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02-2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3-4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]). INTERPRETATION: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. FUNDING: Cancer Research UK.

Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial.

BACKGROUND: Surgery for colorectal liver metastases results in an overall survival of about 40% at 5 years. Progression-free survival is increased with the addition of oxaliplatin and fluorouracil chemotherapy. The addition of cetuximab to these chemotherapy regimens results in an overall survival advantage in patients with advanced disease who have the KRAS exon 2 wild-type tumour genotype. We aimed to assess the benefit of addition of cetuximab to standard chemotherapy in patients with resectable colorectal liver metastasis. METHODS: Patients with KRAS exon 2 wild-type resectable or suboptimally resectable colorectal liver metastases were randomised in a 1:1 ratio to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done using minimisation with factors of surgical centre, poor prognostic tumour (one or more of: ≥ 4 metastases, N2 disease, or poor differentiation of primary tumour), and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m(2) intravenously over 2 h and fluorouracil bolus 400 mg/m(2) intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m(2) repeated every 2 weeks (regimen one) or oxaliplatin 130 mg/m(2) intravenously over 2 h and oral capecitabine 1000 mg/m(2) twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m(2) intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given as an intravenous dose of 500 mg/m(2) every 2 weeks with regimen one and three or a loading dose of 400 mg/m(2) followed by a weekly infusion of 250 mg/m(2) with regimen two. The primary endpoint was progression-free survival. This is an interim analysis, up to Nov 1, 2012, when the trial was closed, having met protocol-defined futility criteria. This trial is registered, ISRCTN22944367. FINDINGS: 128 KRAS exon 2 wild-type patients were randomised to chemotherapy alone and 129 to chemotherapy with cetuximab between Feb 26, 2007, and Nov 1, 2012. 117 patients in the chemotherapy alone group and 119 in the chemotherapy plus cetuximab group were included in the primary analysis. The median follow-up was 21.1 months (95% CI 12.6-33.8) in the chemotherapy alone group and 19.8 months (12.2-28.7) in the chemotherapy plus cetuximab group. With an overall median follow-up of 20.7 months (95% CI 17.9-25.6) and 123 (58%) of 212 required events observed, progression-free survival was significantly shorter in the chemotherapy plus cetuximab group than in the chemotherapy alone group (14.1 months [95% CI 11.8-15.9] vs 20.5 months [95% CI 16.8-26.7], hazard ratio 1.48, 95% CI 1.04-2.12, p=0.030). The most common grade 3 or 4 adverse events were low neutrophil count (15 [11%] preoperatively in the chemotherapy alone group vs six [4%] in the chemotherapy plus cetuximab group; four [4%] vs eight [8%] postoperatively), embolic events (six [4%] vs eight [6%] preoperatively; two [2%] vs three [3%] postoperatively), peripheral neuropathy (six [4%] vs one [1%] preoperatively; two [2%] vs four [4%] postoperatively), nausea or vomiting (four [3%] vs six [4%] preoperatively; four [4%] vs two [2%] postoperatively), and skin rash (two [1%] vs 21 [15%] preoperatively; 0 vs eight [8%] postoperatively). There were three deaths in the chemotherapy plus cetuximab group (one interstitial lung disease and pulmonary embolism, one bronchopneumonia, and one pulmonary embolism) and one in the chemotherapy alone group (heart failure) that might have been treatment related. INTERPRETATION: Addition of cetuximab to chemotherapy and surgery for operable colorectal liver metastases in KRAS exon 2 wild-type patients results in shorter progression-free survival. Translational investigations to explore the molecular basis for this unexpected interaction are needed but at present the use of cetuximab in this setting cannot be recommended.

Randomized clinical trial of local infiltration plus patient-controlled opiate analgesia vs. epidural analgesia following liver resection surgery.

OBJECTIVES: Epidural analgesia is recommended for the provision of analgesia following major abdominal surgery. Continuous local anaesthetic wound infiltration may be an effective alternative. A prospective randomized trial was undertaken to compare these two methods following open liver resection. The primary outcome was length of time required to fulfil criteria for discharge from hospital. METHODS: Patients undergoing open liver resection were randomized to receive either epidural (EP group) or local anaesthetic wound infiltration plus patient-controlled opiate analgesia (WI group) for the first 2 days postoperatively. All other care followed a standardized enhanced recovery protocol. Time to fulfil discharge criteria, pain scores, physical activity measurements and complications were recorded. RESULTS: Between August 2009 and July 2010, 65 patients were randomized to EP (n = 32) or WI (n = 33). The mean time required to fulfil discharge criteria was 4.5 days (range: 2.5-63.5 days) in the WI group and 6.0 days (range: 3.0-42.5 days) in the EP group (P = 0.044). During the first 48 h following surgery, pain scores were significantly lower in the EP group both at rest and on movement. Resting pain scores within both groups were rated as mild (range: 0-3). There was no significant difference between the groups in time to first mobilization or overall complication rate (48.5% in the WI group vs. 58.1% in the EP group; P = 0.443). CONCLUSIONS: Local anaesthetic wound infiltration combined with patient-controlled opiate analgesia reduces the length of time required to fulfil criteria for discharge from hospital compared with epidural analgesia following open liver resection. Epidural analgesia provides superior analgesia, but does not confer benefits in terms of faster mobilization or recovery.

Adjuvant chemotherapy improves survival after resection of hepatic colorectal metastases: analysis of data from two continents.

BACKGROUND: In the US, systemic chemotherapy is often administered after liver resection for hepatic colorectal metastases, even though no clinical trials data directly support this practice. The bias in America for chemotherapeutic treatment has made studies difficult. Until recently, no well accepted staging systems existed to categorize these patients with liver metastases, who have greatly varied prognoses. STUDY DESIGN: All liver resections from an American and from a European tertiary care center performed between 1991 and 1998 were assembled from two prospective databases. Of 792 liver resections, the 518 patients treated with no chemotherapy (379 American, 139 European) were compared with 274 patients treated (240 American, 34 European) with 5-FU-based adjuvant chemotherapy. Patients treated by all other treatment regimens, including regional chemotherapy, were excluded, as were patients who died perioperatively. Patient survival analysis was performed by log-rank, with stratification by the clinical risk score (CRS, a staging system grading risk of recurrence by five clinical parameters: node-positive primary, short disease-free interval, large (> 5 cm) liver tumor, multiple liver tumors, and high carcinoembryonic antigen). RESULTS: Patients subjected to adjuvant chemotherapy had improved survival (p=0.007, log-rank test) even after stratification by clinical risk score (p=0.001, stratified log-rank test). In every clinical risk score category, patients subjected to adjuvant chemotherapy had a higher chance of survival (range 1.3 to 2.0 times). Adjuvant chemotherapy was an independent predictor of outcomes. CONCLUSIONS: This large study, with patients stratified by risk of recurrence, demonstrates that systemic adjuvant chemotherapy, such as a 5-FU-based regimen, prolongs survival after hepatic resection for colorectal metastases.

De-repression of heat shock transcription factor-1 in interleukin-6- treated hepatocytes is mediated by downregulation of glycogen synthase kinase 3beta and MAPK/ERK-1.

Expression of inducible heat shock protein (HSP70) requires activation of heat shock transcription factor-1 (HSF-1). Recent evidence suggests that interleukin-6 (IL-6) can modify the response of HSF-1 to heat. We hypothesized that IL-6 would prime the HSP response by causing de-repression of HSF-1 resulting in augmented HSP expression in stressed cells. In this study we show that IL-6 has no direct effect on HSP70 expression at 37 degrees C but does augment HSP70 expression in response to heat. IL-6 treatment decreased active MAPK/pERK and glycogen synthase kinase 3beta (GSK3beta) expression and GSK3beta kinase activity. In IL-6-treated cells, monomeric HSF-1 accumulated in the cytoplasm and nucleus, bound DNA but was transcriptionally inactive. On exposure to heat shock this modified monomer assumed the transcriptionally active phenotype with trimerization and hyperphosphorylation evident. The increased induction of HSP70 in IL-6 and heat-treated cells was inhibited using PI3-kinase inhibitors or Akt inhibition and was HSF-1 dependent. IL-6, via the PI3-kinase/Akt pathway leads to inhibition of the repressive kinases MAPK/pERK and GSK3beta, and this converts inactive HSF-1 to an intermediate DNA-binding form augmenting transcriptional activation in the presence of a second stressor.