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Palliative radiotherapy after oesophageal cancer stenting (ROCS): a multicentre, open-label, phase 3 randomised controlled trial

Palliative radiotherapy after oesophageal cancer stenting (ROCS): a multicentre, open-label, phase 3 randomised controlled trial
Palliative radiotherapy after oesophageal cancer stenting (ROCS): a multicentre, open-label, phase 3 randomised controlled trial

Background: patients with advanced oesophageal cancer have a median survival of 3–6 months, and most require intervention for dysphagia. Self-expanding metal stent (SEMS) insertion is the most typical form of palliation in these patients, but dysphagia deterioration and re-intervention are common. This study examined the efficacy of adjuvant external beam radiotherapy (EBRT) compared with usual care alone in preventing dysphagia deterioration and reducing service use after SEMS insertion.

Methods: this was a multicentre, open-label, phase 3 randomised controlled trial based at cancer centres and acute care hospitals in England, Scotland, and Wales. Patients (aged ≥16 years) with incurable oesophageal carcinoma receiving stent insertion for primary management of dysphagia were randomly assigned (1:1) to receive usual care alone or EBRT (20 Gy in five fractions or 30 Gy in ten fractions) plus usual care after stent insertion. Usual care was implemented according to need as identified by the local multidisciplinary team (MDT). Randomisation was via the method of minimisation stratified by treating centre, stage at diagnosis (I–III vs IV), histology (squamous or non-squamous), and MDT intent to give chemotherapy (yes vs no). The primary outcome was difference in proportions of participants with dysphagia deterioration (>11 point decrease on patient-reported European Organisation for Research and Treatment of Cancer quality of life questionnaire-oesophagogastric module [QLQ-OG25], or a dysphagia-related event consistent with such a deterioration) or death by 12 weeks in a modified intention-to-treat (ITT) population, which excluded patients who did not have a stent inserted and those without a baseline QLQ-OG25 assessment. Secondary outcomes included survival, quality of life (QoL), morbidities (including time to first bleeding event or hospital admission for bleeding event and first dysphagia-related stent complications or re-intervention), and cost-effectiveness. Safety analysis was undertaken in the modified ITT population. The study is registered with the International Standard Randomised Controlled Trial registry, ISRCTN12376468, and ClinicalTrials.gov, NCT01915693, and is completed.

Findings: 220 patients were randomly assigned between Dec 16, 2013, and Aug 24, 2018, from 23 UK centres. The modified ITT population (n=199) comprised 102 patients in the usual care group and 97 patients in the EBRT group. Radiotherapy did not reduce dysphagia deterioration, which was reported in 36 (49%) of 74 patients receiving usual care versus 34 (45%) of 75 receiving EBRT (adjusted odds ratio 0·82 [95% CI 0·40–1·68], p=0·59) in those with complete data for the primary endpoint. No significant difference was observed in overall survival: median overall survival was 19·7 weeks (95% CI 14·4–27·7) with usual care and 18·9 weeks (14·7–25·6) with EBRT (adjusted hazard ratio 1·06 [95% CI 0·78–1·45], p=0·70; n=199). Median time to first bleeding event or hospital admission for a bleeding event was 49·0 weeks (95% CI 33·3–not reached) with usual care versus 65·9 weeks (52·7–not reached) with EBRT (adjusted subhazard ratio 0·52 [95% CI 0·28–0·97], p=0·038; n=199). No time versus treatment interaction was observed for prespecified QoL outcomes. We found no evidence of differences between trial group in time to first stent complication or re-intervention event. The most common (grade 3–4) adverse event was fatigue, reported in 19 (19%) of 102 patients receiving usual care alone and 22 (23%) of 97 receiving EBRT. On cost-utility analysis, EBRT was more expensive and less efficacious than usual care.

Interpretation: patients with advanced oesophageal cancer having SEMS insertion for the primary management of their dysphagia did not gain additional benefit from concurrent palliative radiotherapy and it should not be routinely offered. For a minority of patients clinically considered to be at high risk of tumour bleeding, concurrent palliative radiotherapy might reduce bleeding risk and the need for associated interventions. Funding: National Institute for Health Research Health Technology Assessment Programme.

2468-1253
292-303
Adamson, Douglas
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Byrne, Anthony
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Porter, Catharine
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Blazeby, Jane
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Griffiths, Gareth
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Nelson, Annmarie
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Sewell, Bernadette
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Jones, Mari
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Svobodova, Martina
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Fitzsimmons, Deborah
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Nixon, Lisette
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Fitzgibbon, Jim
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Thomas, Stephen
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Millin, Anthony
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Crosby, Tom
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Staffurth, John
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Hurt, Christopher
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et al.
Adamson, Douglas
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Byrne, Anthony
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Porter, Catharine
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Blazeby, Jane
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Griffiths, Gareth
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Nelson, Annmarie
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Sewell, Bernadette
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Jones, Mari
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Svobodova, Martina
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Fitzsimmons, Deborah
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Nixon, Lisette
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Fitzgibbon, Jim
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Thomas, Stephen
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Millin, Anthony
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Crosby, Tom
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Staffurth, John
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Hurt, Christopher
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Adamson, Douglas, Byrne, Anthony and Porter, Catharine , et al. (2021) Palliative radiotherapy after oesophageal cancer stenting (ROCS): a multicentre, open-label, phase 3 randomised controlled trial. The Lancet Gastroenterology & Hepatology, 6 (4), 292-303. (doi:10.1016/S2468-1253(21)00004-2).

Record type: Article

Abstract

Background: patients with advanced oesophageal cancer have a median survival of 3–6 months, and most require intervention for dysphagia. Self-expanding metal stent (SEMS) insertion is the most typical form of palliation in these patients, but dysphagia deterioration and re-intervention are common. This study examined the efficacy of adjuvant external beam radiotherapy (EBRT) compared with usual care alone in preventing dysphagia deterioration and reducing service use after SEMS insertion.

Methods: this was a multicentre, open-label, phase 3 randomised controlled trial based at cancer centres and acute care hospitals in England, Scotland, and Wales. Patients (aged ≥16 years) with incurable oesophageal carcinoma receiving stent insertion for primary management of dysphagia were randomly assigned (1:1) to receive usual care alone or EBRT (20 Gy in five fractions or 30 Gy in ten fractions) plus usual care after stent insertion. Usual care was implemented according to need as identified by the local multidisciplinary team (MDT). Randomisation was via the method of minimisation stratified by treating centre, stage at diagnosis (I–III vs IV), histology (squamous or non-squamous), and MDT intent to give chemotherapy (yes vs no). The primary outcome was difference in proportions of participants with dysphagia deterioration (>11 point decrease on patient-reported European Organisation for Research and Treatment of Cancer quality of life questionnaire-oesophagogastric module [QLQ-OG25], or a dysphagia-related event consistent with such a deterioration) or death by 12 weeks in a modified intention-to-treat (ITT) population, which excluded patients who did not have a stent inserted and those without a baseline QLQ-OG25 assessment. Secondary outcomes included survival, quality of life (QoL), morbidities (including time to first bleeding event or hospital admission for bleeding event and first dysphagia-related stent complications or re-intervention), and cost-effectiveness. Safety analysis was undertaken in the modified ITT population. The study is registered with the International Standard Randomised Controlled Trial registry, ISRCTN12376468, and ClinicalTrials.gov, NCT01915693, and is completed.

Findings: 220 patients were randomly assigned between Dec 16, 2013, and Aug 24, 2018, from 23 UK centres. The modified ITT population (n=199) comprised 102 patients in the usual care group and 97 patients in the EBRT group. Radiotherapy did not reduce dysphagia deterioration, which was reported in 36 (49%) of 74 patients receiving usual care versus 34 (45%) of 75 receiving EBRT (adjusted odds ratio 0·82 [95% CI 0·40–1·68], p=0·59) in those with complete data for the primary endpoint. No significant difference was observed in overall survival: median overall survival was 19·7 weeks (95% CI 14·4–27·7) with usual care and 18·9 weeks (14·7–25·6) with EBRT (adjusted hazard ratio 1·06 [95% CI 0·78–1·45], p=0·70; n=199). Median time to first bleeding event or hospital admission for a bleeding event was 49·0 weeks (95% CI 33·3–not reached) with usual care versus 65·9 weeks (52·7–not reached) with EBRT (adjusted subhazard ratio 0·52 [95% CI 0·28–0·97], p=0·038; n=199). No time versus treatment interaction was observed for prespecified QoL outcomes. We found no evidence of differences between trial group in time to first stent complication or re-intervention event. The most common (grade 3–4) adverse event was fatigue, reported in 19 (19%) of 102 patients receiving usual care alone and 22 (23%) of 97 receiving EBRT. On cost-utility analysis, EBRT was more expensive and less efficacious than usual care.

Interpretation: patients with advanced oesophageal cancer having SEMS insertion for the primary management of their dysphagia did not gain additional benefit from concurrent palliative radiotherapy and it should not be routinely offered. For a minority of patients clinically considered to be at high risk of tumour bleeding, concurrent palliative radiotherapy might reduce bleeding risk and the need for associated interventions. Funding: National Institute for Health Research Health Technology Assessment Programme.

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e-pub ahead of print date: 19 February 2021
Published date: 11 March 2021
Additional Information: Funding Information: Declaration of interests DA reports grants from the UK National Institute for Health Research (NIHR), during the conduct of the study; grants from Roche and Boehringer Ingelheim, outside the submitted work; and has given advice to Roche on the development of multidisciplinary team software but has received no financial recompense for this. AB reports grants from the NIHR and Marie Curie, during the conduct of the study. DF reports being an active member of the European Organisation for Research and Treatment of Cancer Quality of Life Group. GG reports grants from Janssen-Cilag, Novartis, Astex, Roche, Heartflow, Bristol Myers Squibb, and BioNtech, grants and personal fees from AstraZeneca, and personal fees from Celldex, outside the submitted work. JS reports personal fees and non-financial support from Janssen Oncology, non-financial support from Bayer, and personal fees from Astellas, Novartis, and AstraZeneca, outside the submitted work. ST reports personal fees from the NIHR Evaluation, Trials and Studies Coordinating Centre Prioritisation Panel of the NIHR Health Technology Assessment Programme, outside the submitted work. All other authors declare no competing interests. Funding Information: this project was funded by the NIHR Health Technology Assessment Programme, project number 10/50/49, and will be published in full in a Health Technology Assessment monograph. AB and AN are supported by a Marie Curie core programme grant (MCCC_FCO_17_C). The Centre for Trials Research at Cardiff University is funded by Cancer Research UK and Health and Care Research Wales. JB is supported by funding from the UK Medical Research Council (MRC) as director of the Collaboration and Innovation in Difficult and Complex Randomised Controlled Trials MRC Methodology Hub, and funding from the NIHR Bristol and Weston Biomedical Research Centre, and is an NIHR senior investigator. We thank all the patients who participated in this trial, and their families and carers. We are indebted to the principal investigators at each site for their dedication to identifying and recruiting patients: Carys Morgan, Andrew Bateman, Olivia Chan, Mathilda Cominos, Serena Hilman, Eleanor James, Danielle Power, Ashraf Rasheed, Angus Robinson, Martin Scott-Brown, Elizabeth Selvaduri, Paul Shaw, David Tsang, Ravi Vohra, Nick Wadd, Jonathan Wadsley, and Julie Walther. We thank current and former staff of Cardiff University for supporting the development and running of this trial, and members of the trial steering and independent monitoring committees.

Identifiers

Local EPrints ID: 447241
URI: http://eprints.soton.ac.uk/id/eprint/447241
ISSN: 2468-1253
PURE UUID: 7ca1823b-9eb9-4e47-a8e9-99188687186f
ORCID for Gareth Griffiths: ORCID iD orcid.org/0000-0002-9579-8021
ORCID for Christopher Hurt: ORCID iD orcid.org/0000-0003-1206-8355

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Date deposited: 05 Mar 2021 17:31
Last modified: 21 Mar 2024 03:14

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Contributors

Author: Douglas Adamson
Author: Anthony Byrne
Author: Catharine Porter
Author: Jane Blazeby
Author: Annmarie Nelson
Author: Bernadette Sewell
Author: Mari Jones
Author: Martina Svobodova
Author: Deborah Fitzsimmons
Author: Lisette Nixon
Author: Jim Fitzgibbon
Author: Stephen Thomas
Author: Anthony Millin
Author: Tom Crosby
Author: John Staffurth
Author: Christopher Hurt ORCID iD
Corporate Author: et al.

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