Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial

Susan J Dutton, David R Ferry, Jane M Blazeby, Haider Abbas, Asa Dahle-Smith, Wasat Mansoor, Joyce Thompson, Mark Harrison, Anirban Chatterjee, Stephen Falk, Angel Garcia-Alonso, David W Fyfe, Richard A Hubner, Tina Gamble, Lynnda Peachey, Mina Davoudianfar, Sarah R Pearson, Patrick Julier, Janusz Jankowski, Rachel KerrRussell David Petty

Research output: Contribution to journalArticlepeer-review

249 Citations (Scopus)


BACKGROUND: Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare gefitinib with placebo in previously treated advanced oesophageal cancer.

METHODS: For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0-2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179.

FINDINGS: Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 3·73 months, 95% CI 3·23-4·50, for gefitinib vs 3·67 months, 95% CI 2·97-4·37, for placebo; hazard ratio [HR] 0·90, 95% CI 0·74-1·09, p=0·29). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference -8·61, 95% CI -14·49 to -2·73; n=227; p=0·004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (2·69, 95% CI -2·33 to 7·72, n=231, p=0·293), dysphagia (-3·18, 95% CI -8·36 to 2·00, n=231, p=0·228), and eating (-4·11, 95% CI -9·96 to 1·75, n=229, p=0·168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (1·57 months, 95% CI 1·23-1·90 in the gefitinib group vs 1·17 months, 95% CI 1·07-1·37 in the placebo group; HR 0·80, 95% CI 0·66-0·96, p=0·020). The most common toxicities were diarrhoea (36 [16%] of 224 patients on gefitinib vs six [3%] of 225 on placebo) and skin toxicity (46 [21%] vs two [1%]), both mostly grade 2. The commonest grade 3-4 toxicities were fatigue (24 [11%] vs 13 [6%] patients) and diarrhoea (13 [6%] vs two [1%]). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0·023).

INTERPRETATION: The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients.

FUNDING: Cancer Research UK.

Original languageEnglish
Pages (from-to)894-904
Number of pages11
JournalThe Lancet Oncology
Issue number8
Early online date17 Jun 2014
Publication statusPublished - Jul 2014

Bibliographical note

Cancer Research UK.

The study was funded by Cancer Research UK and jointly sponsored by the University of Oxford and the Royal Wolverhampton Hospitals NHS Trust. Gefitinib and matching placebo were supplied free of charge by AstraZeneca as 250 mg tablets. We thank the patients who participated in the COG trial; the investigators, the research nurses, clinical staff from the individual trial centres and staff members from the Oncology Clinical Trials Office (OCTO) at the University of Oxford who provided ongoing support. We thank the members of the trial steering committee (Tom Crosby [Velindre Cancer Centre], Christopher Poole [University of Warwick], and Helen Marshall [University of Leeds]), and the independent data and safety monitoring committee (Matthew Sydes [MRC Clinical Trials Unit], Mark Saunders [Christie Hospital NHS Foundation Trust], and Nicola Levitt [John Radcliffe Hospital]).


  • Adenocarcinoma
  • Aged
  • Antineoplastic Agents
  • Carcinoma, Squamous Cell
  • Deglutition Disorders
  • Diarrhea
  • Disease Progression
  • Disease-Free Survival
  • Double-Blind Method
  • Drug Eruptions
  • Eating
  • Esophageal Neoplasms
  • Fatigue
  • Female
  • Humans
  • Male
  • Middle Aged
  • Pain
  • Proportional Hazards Models
  • Quality of Life
  • Quinazolines
  • Retreatment


Dive into the research topics of 'Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial'. Together they form a unique fingerprint.

Cite this