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, Jankusz Jankowski, Rachel Kerr & 1 others Russell D. Petty

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    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
    Original languageEnglish
    Pages (from-to)894-904
    JournalThe Lancet Oncology
    Volume15
    Issue number8
    Early online date17 Jun 2014
    DOIs
    Publication statusPublished - Jul 2014

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    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
    Adenocarcinoma

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    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, Jankusz; Kerr, Rachel; Petty, Russell D.

    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, Jankusz ; Kerr, Rachel ; Petty, Russell D. / 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.
    @article{2b1557fbbd54497f9f850fb70e070986,
    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",
    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 Jankusz Jankowski and Rachel Kerr and Petty, {Russell D.}",
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    T1 - Gefitinib for oesophageal cancer progressing after chemotherapy (COG): 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, Jankusz

    AU - Kerr, Rachel

    AU - Petty, Russell D.

    N1 - This article is not yet available in the repository

    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

    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

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

    M3 - Article

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    SP - 894

    EP - 904

    JO - The Lancet Oncology

    JF - The Lancet Oncology

    SN - 1470-2045

    IS - 8

    ER -