Articles
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, Russell D Petty
Summary Lancet Oncol 2014; 15: 894–904 Published Online June 18, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70024-5 See Comment page 790 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 (S J Dutton MSc); Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, UK (Prof D R Ferry PhD, H Abbas MRCP); Lilly UK, Erl Wood Manor, Windlesham, UK (Prof D R Ferry); University Hospitals Bristol NHS Foundation Trust, Bristol, UK (Prof J M Blazeby MD, S Falk MD); School of Social and Community Medicine, University of Bristol Senate House, Bristol, UK (Prof J M Blazeby); University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK (A Dahle-Smith MBChB, R D Petty MRCP); Christie Hospital NHS Foundation Trust, Manchester, UK (W Mansoor PhD, R A Hubner PhD); Birmingham Heartlands Hospital, Birmingham, UK (J Thompson FRCP, T Gamble); Mount Vernon Cancer Centre, Northwood, UK (M Harrison PhD); Royal Shrewsbury Hospital, Shrewsbury, UK (A Chatterjee FRCR); North Wales Cancer Centre, Glan Clwyd Hospital, Rhyl, UK (A Garcia-Alonso MD); University Hospitals of Morecombe Bay, Furness General Hospital, Barrow-inFurness, UK (D W Fyfe MD); Oncology Clinical Trials Office, University of Oxford,
894
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 patientreported 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.
Introduction Oesophageal cancer is the sixth most common cause of cancer death in the world.1 Clinical outcomes are poor, with 5-year survival only 10–15%, and most patients presenting with advanced disease.2 In the western hemisphere the incidence of adenocarcinoma has risen steeply in the past 25 years, associated with increasing body-mass index.3 In the other parts of the world, squamous-cell cancers dominate and are increasing
rapidly in incidence in Japan, India, China, and Africa associated with increased smoking.4 Accordingly, treatment of oesophageal cancer is largely palliative in intent.5 In advanced oesophagogastric cancer, first-line treatment with cisplatin or oxaliplatin combined with fluorouracil or capecitabine can improve survival.6 Addition of epirubicin and taxanes can offer some additional benefit, and in gastric and gastrooesophageal junction adenocarcinomas, the addition of www.thelancet.com/oncology Vol 15 July 2014
Articles
766 patients assessed for eligibility 316 excluded 185 did not meet inclusion criteria 131 declined to participate 450 randomised 1 withdrew consent
225 allocated placebo 219 received allocated intervention 6 did not start treatment 214 completed baseline PRO questionnaire 11 did not complete baseline PRO questionnaire
41 discontinued intervention early 12 toxicity 11 clinical decision 13 patient decision 5 other 0 lost to follow-up
224 allocated gefitinib 213 received allocated intervention 11 did not start treatment 209 completed baseline PRO questionnaire 15 did not complete baseline PRO questionnaire
55 discontinued intervention early 21 toxicity 16 clinical decision 16 patient decision 2 other 0 lost to follow-up
154 alive and progression free at 4 weeks 127 completed follow-up PRO questionnaire 82 alive and progression free at 8 weeks 60 completed follow-up PRO questionnaire 55 alive and progression free at 12 weeks 33 completed follow-up PRO questionnaire
158 alive and progression free at 4 weeks 118 completed follow-up PRO questionnaire 98 alive and progression free at 8 weeks 73 completed follow-up PRO questionnaire 72 alive and progression free at 12 weeks 51 completed follow-up PRO questionnaire
225 analysed for survival 121 completed baseline and 4 week questionnaires and were analysed for PROs
224 analysed for survival 110 completed baseline and 4 week questionnaires and were analysed for PROs
Department of Oncology, Old Road Campus Research Building, University of Oxford, Old Road Campus, Oxford, UK (L Peachey BSc, M Davoudianfar BA, S R Pearson BSc, P Julier MSc, R Kerr MD); and Health and Life Sciences, Coventry University, Coventry, UK (Prof J Jankowski PhD) Correspondence to: Mrs Susan J Dutton, Oxford Clinical Trials Research Unit and Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK [email protected]
Figure 1: Trial profile PRO=patient-reported outcome.
trastuzumab in HER2-positive patients improves survival.7 For squamous-cell cancer, mitomycin combined with ifosfamide and cisplatin is active.8 When progression occurs, the role of second-line chemotherapy in oesophageal cancer in particular is controversial with only scarce data for clinical effectiveness.9 No randomised phase 3 trials have been done of second-line chemotherapy in either adenocarcinoma or squamouscell carcinomas of the oesophagus specifically, and well designed and undertaken studies in second-line chemotherapy with patient-reported outcomes, which are important in decision making when life expectancy is poor, are lacking. In gastric cancer, randomised second-line therapy trials have shown benefits for survival and patient-reported outcomes with docetaxel, paclitaxel, ramucirumab, ramucirumab plus paclitaxel, and irinotecan.10 Clinicians have tended to extrapolate this evidence from gastric cancer to the second-line treatment of oesophageal cancer. However, in view of the clinical and biological differences between gastric and oesophageal cancer, this approach is likely to result in suboptimum treatment for patients with oesophageal cancer. www.thelancet.com/oncology Vol 15 July 2014
EGFR is expressed in most oesophageal cancers and is associated with poor survival.11 Gene copy number changes are common in oesophageal adenocarcinomas relative to other gastrointestinal tract adenocarcinomas.12 Increased copy number of EGFR is found in 5–10% of patients, and is associated with poor survival.12 Additionally, activating mutations in exons 18–21 of EGFR have been found in patients with oesophageal cancer.13 This finding provided the rationale for investigation of anti-EGFR therapies in oesophageal cancer and five phase 2 trials have been reported of the EGFR tyrosine kinase inhibitors (TKIs) gefitinib14 or erlotinib involving 147 patients, with objective responses being noted in 8·8% of patients and responses seen in squamous-cell carcinoma and adenocarcinomas.9 These results contrast with the inactivity of EGFR TKIs in gastric cancer, for which no responses have been seen in 80 patients in phase 2 trials.15,16 On the basis of this activity of gefitinib in oesophageal cancer after chemotherapy failure, and the data implicating EGFR and its signalling transduction pathway in pathogenesis and prognosis, we designed a phase 3 trial of sufficient statistical power to reliably detect possible benefits in both survival and patient895
Articles
Placebo (N=225)
Gefitinib (N=224)
Clinical characteristics Age at randomisation (years)
64·9 (58·2–70·7)
Time since diagnosis (years)
0·92 (0·60–1·47), n=216
0·96 (0·62–1·45), n=220
Men
189 (84%)
183 (82%)
36 (16%)
41 (18%)
168 (75%)
173 (77%)
56 (25%)
50 (22%)
Women
64·7 (58·0–70·1)
Original diagnosis Adenocarcinoma Squamous-cell carcinoma Undifferentiated
1 (
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, Russell D Petty
Summary Lancet Oncol 2014; 15: 894–904 Published Online June 18, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70024-5 See Comment page 790 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 (S J Dutton MSc); Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, UK (Prof D R Ferry PhD, H Abbas MRCP); Lilly UK, Erl Wood Manor, Windlesham, UK (Prof D R Ferry); University Hospitals Bristol NHS Foundation Trust, Bristol, UK (Prof J M Blazeby MD, S Falk MD); School of Social and Community Medicine, University of Bristol Senate House, Bristol, UK (Prof J M Blazeby); University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK (A Dahle-Smith MBChB, R D Petty MRCP); Christie Hospital NHS Foundation Trust, Manchester, UK (W Mansoor PhD, R A Hubner PhD); Birmingham Heartlands Hospital, Birmingham, UK (J Thompson FRCP, T Gamble); Mount Vernon Cancer Centre, Northwood, UK (M Harrison PhD); Royal Shrewsbury Hospital, Shrewsbury, UK (A Chatterjee FRCR); North Wales Cancer Centre, Glan Clwyd Hospital, Rhyl, UK (A Garcia-Alonso MD); University Hospitals of Morecombe Bay, Furness General Hospital, Barrow-inFurness, UK (D W Fyfe MD); Oncology Clinical Trials Office, University of Oxford,
894
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 patientreported 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.
Introduction Oesophageal cancer is the sixth most common cause of cancer death in the world.1 Clinical outcomes are poor, with 5-year survival only 10–15%, and most patients presenting with advanced disease.2 In the western hemisphere the incidence of adenocarcinoma has risen steeply in the past 25 years, associated with increasing body-mass index.3 In the other parts of the world, squamous-cell cancers dominate and are increasing
rapidly in incidence in Japan, India, China, and Africa associated with increased smoking.4 Accordingly, treatment of oesophageal cancer is largely palliative in intent.5 In advanced oesophagogastric cancer, first-line treatment with cisplatin or oxaliplatin combined with fluorouracil or capecitabine can improve survival.6 Addition of epirubicin and taxanes can offer some additional benefit, and in gastric and gastrooesophageal junction adenocarcinomas, the addition of www.thelancet.com/oncology Vol 15 July 2014
Articles
766 patients assessed for eligibility 316 excluded 185 did not meet inclusion criteria 131 declined to participate 450 randomised 1 withdrew consent
225 allocated placebo 219 received allocated intervention 6 did not start treatment 214 completed baseline PRO questionnaire 11 did not complete baseline PRO questionnaire
41 discontinued intervention early 12 toxicity 11 clinical decision 13 patient decision 5 other 0 lost to follow-up
224 allocated gefitinib 213 received allocated intervention 11 did not start treatment 209 completed baseline PRO questionnaire 15 did not complete baseline PRO questionnaire
55 discontinued intervention early 21 toxicity 16 clinical decision 16 patient decision 2 other 0 lost to follow-up
154 alive and progression free at 4 weeks 127 completed follow-up PRO questionnaire 82 alive and progression free at 8 weeks 60 completed follow-up PRO questionnaire 55 alive and progression free at 12 weeks 33 completed follow-up PRO questionnaire
158 alive and progression free at 4 weeks 118 completed follow-up PRO questionnaire 98 alive and progression free at 8 weeks 73 completed follow-up PRO questionnaire 72 alive and progression free at 12 weeks 51 completed follow-up PRO questionnaire
225 analysed for survival 121 completed baseline and 4 week questionnaires and were analysed for PROs
224 analysed for survival 110 completed baseline and 4 week questionnaires and were analysed for PROs
Department of Oncology, Old Road Campus Research Building, University of Oxford, Old Road Campus, Oxford, UK (L Peachey BSc, M Davoudianfar BA, S R Pearson BSc, P Julier MSc, R Kerr MD); and Health and Life Sciences, Coventry University, Coventry, UK (Prof J Jankowski PhD) Correspondence to: Mrs Susan J Dutton, Oxford Clinical Trials Research Unit and Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK [email protected]
Figure 1: Trial profile PRO=patient-reported outcome.
trastuzumab in HER2-positive patients improves survival.7 For squamous-cell cancer, mitomycin combined with ifosfamide and cisplatin is active.8 When progression occurs, the role of second-line chemotherapy in oesophageal cancer in particular is controversial with only scarce data for clinical effectiveness.9 No randomised phase 3 trials have been done of second-line chemotherapy in either adenocarcinoma or squamouscell carcinomas of the oesophagus specifically, and well designed and undertaken studies in second-line chemotherapy with patient-reported outcomes, which are important in decision making when life expectancy is poor, are lacking. In gastric cancer, randomised second-line therapy trials have shown benefits for survival and patient-reported outcomes with docetaxel, paclitaxel, ramucirumab, ramucirumab plus paclitaxel, and irinotecan.10 Clinicians have tended to extrapolate this evidence from gastric cancer to the second-line treatment of oesophageal cancer. However, in view of the clinical and biological differences between gastric and oesophageal cancer, this approach is likely to result in suboptimum treatment for patients with oesophageal cancer. www.thelancet.com/oncology Vol 15 July 2014
EGFR is expressed in most oesophageal cancers and is associated with poor survival.11 Gene copy number changes are common in oesophageal adenocarcinomas relative to other gastrointestinal tract adenocarcinomas.12 Increased copy number of EGFR is found in 5–10% of patients, and is associated with poor survival.12 Additionally, activating mutations in exons 18–21 of EGFR have been found in patients with oesophageal cancer.13 This finding provided the rationale for investigation of anti-EGFR therapies in oesophageal cancer and five phase 2 trials have been reported of the EGFR tyrosine kinase inhibitors (TKIs) gefitinib14 or erlotinib involving 147 patients, with objective responses being noted in 8·8% of patients and responses seen in squamous-cell carcinoma and adenocarcinomas.9 These results contrast with the inactivity of EGFR TKIs in gastric cancer, for which no responses have been seen in 80 patients in phase 2 trials.15,16 On the basis of this activity of gefitinib in oesophageal cancer after chemotherapy failure, and the data implicating EGFR and its signalling transduction pathway in pathogenesis and prognosis, we designed a phase 3 trial of sufficient statistical power to reliably detect possible benefits in both survival and patient895
Articles
Placebo (N=225)
Gefitinib (N=224)
Clinical characteristics Age at randomisation (years)
64·9 (58·2–70·7)
Time since diagnosis (years)
0·92 (0·60–1·47), n=216
0·96 (0·62–1·45), n=220
Men
189 (84%)
183 (82%)
36 (16%)
41 (18%)
168 (75%)
173 (77%)
56 (25%)
50 (22%)
Women
64·7 (58·0–70·1)
Original diagnosis Adenocarcinoma Squamous-cell carcinoma Undifferentiated
1 (
