Susan J Dutton1, David R Ferry2, Jane M Blazeby3, Haider Abbas4, Asa Dahle-Smith5, Wasat Mansoor6, Joyce Thompson7, Mark Harrison8, Anirban Chatterjee9, Stephen Falk10, Angel Garcia-Alonso11, David W Fyfe12, Richard A Hubner6, Tina Gamble7, Lynnda Peachey13, Mina Davoudianfar13, Sarah R Pearson13, Patrick Julier13, Janusz Jankowski14, Rachel Kerr13, Russell D Petty5. 1. Oxford Clinical Trials Research Unit and Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Oxford, UK. Electronic address: susan.dutton@csm.ox.ac.uk. 2. Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, UK; Lilly UK, Erl Wood Manor, Windlesham, UK. 3. University Hospitals Bristol NHS Foundation Trust, Bristol, UK; School of Social and Community Medicine, University of Bristol Senate House, Bristol, UK. 4. Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, UK. 5. University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK. 6. Christie Hospital NHS Foundation Trust, Manchester, UK. 7. Birmingham Heartlands Hospital, Birmingham, UK. 8. Mount Vernon Cancer Centre, Northwood, UK. 9. Royal Shrewsbury Hospital, Shrewsbury, UK. 10. University Hospitals Bristol NHS Foundation Trust, Bristol, UK. 11. North Wales Cancer Centre, Glan Clwyd Hospital, Rhyl, UK. 12. University Hospitals of Morecombe Bay, Furness General Hospital, Barrow-in-Furness, UK. 13. Oncology Clinical Trials Office, University of Oxford, Department of Oncology, Old Road Campus Research Building, University of Oxford, Old Road Campus, Oxford, UK. 14. Health and Life Sciences, Coventry University, Coventry, UK.
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.
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.
Authors: Yongjing Liu; Zhaohui Xiong; Andrea Beasley; Thomas D'Amico; Xiaoxin Luke Chen Journal: Ann N Y Acad Sci Date: 2016-07-11 Impact factor: 5.691
Authors: Simon A Carter; Talia Gutman; Charlotte Logeman; Dan Cattran; Liz Lightstone; Arvind Bagga; Sean J Barbour; Jonathan Barratt; John Boletis; Dawn Caster; Rosanna Coppo; Fernando C Fervenza; Jürgen Floege; Michelle Hladunewich; Jonathan J Hogan; A Richard Kitching; Richard A Lafayette; Ana Malvar; Jai Radhakrishnan; Brad H Rovin; Nicole Scholes-Robertson; Hérnan Trimarchi; Hong Zhang; Karolis Azukaitis; Yeoungjee Cho; Andrea K Viecelli; Louese Dunn; David Harris; David W Johnson; Peter G Kerr; Paul Laboi; Jessica Ryan; Jenny I Shen; Lorena Ruiz; Angela Yee-Moon Wang; Achilles Hoi Kan Lee; Samuel Fung; Matthew Ka-Hang Tong; Armando Teixeira-Pinto; Martin Wilkie; Stephen I Alexander; Jonathan C Craig; Allison Tong Journal: Clin J Am Soc Nephrol Date: 2020-04-30 Impact factor: 8.237
Authors: Asunción Díaz-Serrano; Barbara Angulo; Carolina Dominguez; Roberto Pazo-Cid; Antonieta Salud; Paula Jiménez-Fonseca; Ana Leon; Maria Carmen Galan; Maria Alsina; Fernando Rivera; J Carlos Plaza; Luis Paz-Ares; Fernando Lopez-Rios; Carlos Gómez-Martín Journal: Oncologist Date: 2018-04-26
Authors: Vincent T Janmaat; Ewout W Steyerberg; Ate van der Gaast; Ron Hj Mathijssen; Marco J Bruno; Maikel P Peppelenbosch; Ernst J Kuipers; Manon Cw Spaander Journal: Cochrane Database Syst Rev Date: 2017-11-28