ArticlesEpirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial
Introduction
Gastric and oesophageal cancers are among the most common causes of cancer-related mortality, and were responsible for more than 1·1 million deaths worldwide in 2008.1 Combination chemotherapy is beneficial in perioperative and advanced disease settings, although overall survival is poor. In patients with metastatic disease, median overall survival with best supportive care is about 3 months, which can be extended to about 10 months with chemotherapy.2, 3 No internationally accepted standard of care regimen exists for advanced oesophagogastric adenocarcinoma, although most centres use doublet or triplet chemotherapy combinations with a platinum-fluoropyrimidine backbone. The REAL2 non-inferiority study established epirubicin, oxaliplatin, and capecitabine (EOC) as a standard first-line regimen, and noted a median overall survival of 11·2 months.3 This result compared favourably with the alternative regimens assessed in REAL2, including a combination of epirubicin, cisplatin, and fluorouracil that had a median overall survival of 9·9 months.
In the past decade, the EGFR pathway has been recognised as one of the key proliferative pathways that is dysregulated during tumorigenesis. Preclinical data confirm that transfection of EGFR into human cancer cells is associated with an aggressive phenotype,4 and several molecular aberrations within this pathway can function as potent oncogenes. In oesophagogastric adenocarcinoma, EGFR overexpression is reported in 27–55% of cases in published literature,5, 6 and has been associated with reduced overall survival in some series.5, 7 Amplification of EGFR, measured by fluorescence in-situ hybridisation, is also reported in a smaller subset of oesophagogastric adenocarcinoma.5, 8 This pathway therefore represents a potential therapeutic target in this disease setting, and single-drug phase 2 trials have reported a small number of responses with monoclonal antibodies9 or tyrosine-kinase inhibitors10 targeting EGFR in advanced oesophagogastric adenocarcinoma.
Panitumumab is a fully human immunoglobulin G2 monoclonal antibody directed against EGFR that has confirmed survival benefits in advanced colorectal cancer.11 We designed the REAL3 trial to assess the addition of panitumumab to EOC in molecularly unselected patients with advanced oesophagogastric adenocarcinoma.
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Study design and participants
REAL3 was an open-label, multicentre, phase 3, randomised controlled trial, undertaken at 63 parti-cipating centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Safety, response, and survival outcomes were compared between standard EOC and modified EOC plus panitumumab (mEOC+P). The mEOC+P schedule was established in an unplanned dose-finding study,12 which was done because excessive toxicity (primarily diarrhoea) was noted when the drugs were
Results
Between June 2, 2008, and Oct 17, 2011, we enrolled 575 patients, three of whom were withdrawn because they did not fulfil eligibility criteria. Additionally, 19 patients randomly allocated during the phase 1 dose-finding study were excluded from the intention-to-treat analysis.12 We included 553 eligible patients in the phase 3 intention-to-treat population, representing 76% of the planned accrual at the time of trial closure (figure 1; table 1). 494 (89%) patients had metastatic disease.
Discussion
The REAL3 trial is one of two concurrent randomised phase 3 trials (the other being the EXPAND trial15) assessing the addition of anti-EGFR monoclonal antibodies to chemotherapy in first-line oesophagogastric cancer. Based on the findings of REAL3, use of panitumumab in combination with EOC cannot be recommended in an unselected population with advanced oesophagogastric adenocarcinoma, and was associated with inferior overall survival and PFS. Notably, this detrimental outcome in the
References (30)
- et al.
Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells
Cell
(1987) - et al.
A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma
Ann Oncol
(2011) - et al.
Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial
Lancet
(2011) - et al.
Cetuximab with irinotecan, folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-center biomarker-oriented phase II study
Ann Oncol
(2011) - et al.
Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008
Int J Cancer
(2010) - et al.
Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer
Cancer
(1993) - et al.
Capecitabine and oxaliplatin for advanced esophagogastric cancer
N Engl J Med
(2008) - et al.
EGFR in gastric carcinomas: prognostic significance of protein overexpression and high gene copy number
Histopathology
(2008) - et al.
Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study
J Clin Pathol
(2006) - et al.
Expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) is an independent prognostic indicator of worse outcome in gastric cancer patients
Ann Surg Oncol
(2008)
Gene amplification in esophageal adenocarcinomas and Barrett's with high-grade dysplasia
Clin Cancer Res
A phase II study of gefitinib monotherapy in advanced esophageal adenocarcinoma: evidence of gene expression, cellular, and clinical response
Clin Cancer Res
Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study
J Clin Oncol
Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for advanced esophagogastric cancer: dose-finding study for the prospective multicenter, randomized, phase II/III REAL-3 trial
J Clin Oncol
New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada
J Natl Cancer Inst
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