Summary Background EGFR overexpression occurs in 27–55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to ...epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. Methods In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 and capecitabine 1250 mg/m2 per day on days 1–21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m2 and oxaliplatin 100 mg/m2 on day 1, capecitabine 1000 mg/m2 per day on days 1–21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov , number NCT00824785. Findings Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11·3 months (95% CI 9·6–13·0) compared with 8·8 months (7·7–9·8) in 278 patients allocated mEOC+P (hazard ratio HR 1·37, 95% CI 1·07–1·76; p=0·013). mEOC+P was associated with increased incidence of grade 3–4 diarrhoea (48 17% of 276 patients allocated mEOC+P vs 29 11% of 266 patients allocated EOC), rash (29 11% vs two 1%), mucositis (14 5% vs none), and hypomagnesaemia (13 5% vs none) but reduced incidence of haematological toxicity (grade ≥3 neutropenia 35 13% vs 74 28%). Interpretation Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. Funding Amgen, UK National Institute for Health Research Biomedical Research Centre.
Summary Background Patients with poor-risk rectal cancer defined by MRI can be at high risk of disease recurrence despite standard chemoradiotherapy and optimum surgery. We aimed to assess the safety ...and long-term efficacy of neoadjuvant chemotherapy with capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision, a treatment strategy developed to enhance the outcome of this population. Methods Between November, 2001, and August, 2005, we enrolled eligible patients with poor-risk rectal cancer defined by high-resolution MRI and without metastatic disease. The protocol was amended in January, 2004, following clinically significant cardiotoxic events (nine events in eight of 77 patients), to exclude patients with a recent history of clinically significant cardiac problems. Patients received 12 weeks of neoadjuvant capecitabine and oxaliplatin (oxaliplatin 130 mg/m2 on day 1 with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks) followed by chemoradiotherapy (54 Gy over 6 weeks) with capecitabine (825 mg/m2 twice daily), total mesorectal excision, and 12 weeks of postoperative adjuvant capecitabine (1250 mg/m2 twice daily for 14 days every 3 weeks). The primary endpoint was pathological complete response rate. We followed up patients for a median of 55 months (IQR 47–67). Efficacy analyses were undertaken for the intention-to-treat population, unless otherwise specified. This study is registered with ClinicalTrials.gov , number NCT00220051. Findings 105 eligible patients were enrolled. Radiological response rates after neoadjuvant chemotherapy and chemoradiotherapy were 74% (78/105) and 89% (93/105), respectively. 97 patients underwent surgery, of whom 95 underwent total mesorectal excision, of whom 93 had microscopically clear resection margins and 21 had pathological complete response (21/105 20%). 3-year progression-free and overall survival were 68% (95% CI 59–77) and 83% (76–91), respectively. 3-year relapse-free survival for patients who had complete resection was 74% (65–83). Following the protocol amendment for cardiovascular safety, only one further thromboembolic event was reported (fatal pulmonary embolism). Interpretation Intensification of systemic therapy with neoadjuvant combination chemotherapy before standard treatment is feasible in poor-risk potentially operable rectal cancer, with acceptable safety and promising long-term outcomes. Future development of this multidisciplinary treatment strategy in randomised trials is warranted. Funding UK National Health Service, Sanofi-Aventis.
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