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 Kerr & 1 others Russell David Petty

Research output: Contribution to journalArticle

136 Citations (Scopus)

Abstract

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
Volume15
Issue number8
Early online date17 Jun 2014
DOIs
Publication statusPublished - Jul 2014

Fingerprint

Esophageal Neoplasms
Randomized Controlled Trials
Placebos
Drug Therapy
gefitinib
Survival
Diarrhea
Therapeutics
Deglutition Disorders
Random Allocation
Life Expectancy
Disease-Free Survival
Fatigue
Disease Progression
Squamous Cell Carcinoma
Neoplasms
Adenocarcinoma

Keywords

  • 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

Cite this

Gefitinib for oesophageal cancer progressing after chemotherapy (COG) : a phase 3, multicentre, double-blind, placebo-controlled randomised trial. / Dutton, Susan J; Ferry, David R; Blazeby, Jane M; Abbas, Haider; Dahle-Smith, Asa; Mansoor, Wasat; Thompson, Joyce; Harrison, Mark; Chatterjee, Anirban; Falk, Stephen; Garcia-Alonso, Angel; Fyfe, David W; Hubner, Richard A; Gamble, Tina; Peachey, Lynnda; Davoudianfar, Mina; Pearson, Sarah R; Julier, Patrick; Jankowski, Janusz; Kerr, Rachel; Petty, Russell David.

In: The Lancet Oncology, Vol. 15, No. 8, 07.2014, p. 894-904.

Research output: Contribution to journalArticle

Dutton, SJ, Ferry, DR, Blazeby, JM, Abbas, H, Dahle-Smith, A, Mansoor, W, Thompson, J, Harrison, M, Chatterjee, A, Falk, S, Garcia-Alonso, A, Fyfe, DW, Hubner, RA, Gamble, T, Peachey, L, Davoudianfar, M, Pearson, SR, Julier, P, Jankowski, J, Kerr, R & Petty, RD 2014, 'Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial', The Lancet Oncology, vol. 15, no. 8, pp. 894-904. https://doi.org/10.1016/S1470-2045(14)70024-5
Dutton, Susan J ; Ferry, David R ; Blazeby, Jane M ; Abbas, Haider ; Dahle-Smith, Asa ; Mansoor, Wasat ; Thompson, Joyce ; Harrison, Mark ; Chatterjee, Anirban ; Falk, Stephen ; Garcia-Alonso, Angel ; Fyfe, David W ; Hubner, Richard A ; Gamble, Tina ; Peachey, Lynnda ; Davoudianfar, Mina ; Pearson, Sarah R ; Julier, Patrick ; Jankowski, Janusz ; Kerr, Rachel ; Petty, Russell David. / Gefitinib for oesophageal cancer progressing after chemotherapy (COG) : a phase 3, multicentre, double-blind, placebo-controlled randomised trial. In: The Lancet Oncology. 2014 ; Vol. 15, No. 8. pp. 894-904.
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title = "Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial",
abstract = "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.",
keywords = "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",
author = "Dutton, {Susan J} and Ferry, {David R} and Blazeby, {Jane M} and Haider Abbas and Asa Dahle-Smith and Wasat Mansoor and Joyce Thompson and Mark Harrison and Anirban Chatterjee and Stephen Falk and Angel Garcia-Alonso and Fyfe, {David W} and Hubner, {Richard A} and Tina Gamble and Lynnda Peachey and Mina Davoudianfar and Pearson, {Sarah R} and Patrick Julier and Janusz Jankowski and Rachel Kerr and Petty, {Russell David}",
note = "Funding Cancer Research UK. Acknowledgments 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]).",
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month = "7",
doi = "10.1016/S1470-2045(14)70024-5",
language = "English",
volume = "15",
pages = "894--904",
journal = "The Lancet Oncology",
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TY - JOUR

T1 - Gefitinib for oesophageal cancer progressing after chemotherapy (COG)

T2 - a phase 3, multicentre, double-blind, placebo-controlled randomised trial

AU - Dutton, Susan J

AU - Ferry, David R

AU - Blazeby, Jane M

AU - Abbas, Haider

AU - Dahle-Smith, Asa

AU - Mansoor, Wasat

AU - Thompson, Joyce

AU - Harrison, Mark

AU - Chatterjee, Anirban

AU - Falk, Stephen

AU - Garcia-Alonso, Angel

AU - Fyfe, David W

AU - Hubner, Richard A

AU - Gamble, Tina

AU - Peachey, Lynnda

AU - Davoudianfar, Mina

AU - Pearson, Sarah R

AU - Julier, Patrick

AU - Jankowski, Janusz

AU - Kerr, Rachel

AU - Petty, Russell David

N1 - Funding Cancer Research UK. Acknowledgments 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]).

PY - 2014/7

Y1 - 2014/7

N2 - 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.

AB - 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.

KW - Adenocarcinoma

KW - Aged

KW - Antineoplastic Agents

KW - Carcinoma, Squamous Cell

KW - Deglutition Disorders

KW - Diarrhea

KW - Disease Progression

KW - Disease-Free Survival

KW - Double-Blind Method

KW - Drug Eruptions

KW - Eating

KW - Esophageal Neoplasms

KW - Fatigue

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Pain

KW - Proportional Hazards Models

KW - Quality of Life

KW - Quinazolines

KW - Retreatment

U2 - 10.1016/S1470-2045(14)70024-5

DO - 10.1016/S1470-2045(14)70024-5

M3 - Article

VL - 15

SP - 894

EP - 904

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 8

ER -