Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial

Hugo E R Ford,Andrea Marshall,John A Bridgewater,Tobias Janowitz,Fareeda Y Coxon,Jonathan Wadsley,Wasat Mansoor,David Fyfe,Srinivasan Madhusudan,Gary W Middleton,Daniel Swinson,Stephen Falk,Ian Chau,David Cunningham,Paula Kareclas,Natalie Cook,Jane M Blazeby,Janet A Dunn

doi:10.1016/s1470-2045(13)70549-7

Abstract

Second-line chemotherapy for patients with oesophagogastric adenocarcinoma refractory to platinum and fluoropyrimidines has not shown benefits in health-related quality of life (HRQoL). We assessed whether the addition of docetaxel to active symptom control alone can improve survival and HRQoL for patients. For this open-labelled, multicentre trial, we recruited patients aged 18 years or older from 30 UK centres. Patients were eligible if they had an advanced, histologically confirmed adenocarcinoma of the oesophagus, oesophagogastric junction, or stomach that had progressed on or within 6 months of treatment with a platinum-fluoropyrimidine combination. Patients could have an Eastern Cooperative Oncology Group performance status of 0-2. We randomly assigned patients using a central, computerised minimisation procedure to receive docetaxel plus active symptom control, or active symptom control alone (1:1; stratified by disease status, disease site, duration of response to previous chemotherapy, and performance status). Docetaxel was given at a dose of 75 mg/m(2) by intravenous infusion every 3 weeks for up to six cycles. The primary endpoint was overall survival, analysed by intention to treat. This is the report of the planned final analysis. This study is an International Standardised Randomised Controlled Trial, number ISRCTN13366390. Between April 21, 2008, and April 26, 2012, we recruited 168 patients, allocating 84 to each treatment group. After a median follow-up of 12 months [IQR 10-21]) and 161 (96%) deaths (80 in the docetaxel group, 81 in the active symptom control group), median overall survival in the docetaxel group was 5.2 months (95% CI 4.1-5.9) versus 3.6 months (3.3-4.4) in the active symptom control group (hazard ratio 0.67, 95% CI 0.49-0.92; p=0.01). Docetaxel was associated with higher incidence of grade 3-4 neutropenia (12 [15%] patients vs no patients), infection (15 [19%] patients vs two [3%] patients), and febrile neutropenia (six [7%] patients vs no patients). Patients receiving docetaxel reported less pain (p=0.0008) and less nausea and vomiting (p=0.02) and constipation (p=0.02). Global HRQoL was similar between the groups (p=0.53). Disease specific HRQoL measures also showed benefits for docetaxel in reducing dysphagia (p=0.02) and abdominal pain (p=0.01). Our findings suggest that docetaxel can be recommended as an appropriate second-line treatment for patients with oesophagogastric adenocarcinoma that is refractory to treatment with platinum and fluoropyrimidine. Cancer Research UK.

Highlights

Securing improvements in healthcare quality is challenging (Powell et al, 2009)
Recognition has grown of the need to approach improvement interventions from a broader cultural and institutional perspective, accounting for the role of organisational structures and social processes (Aveling et al, 2013) and developing approaches to implementation that can adapt to contextual modifiers in more dynamic ways
We present our findings in terms of whether and how the case studies met three key challenges for community-based approaches: mobilising a diverse community; establishing a strong sense of community and reciprocal ties between members; and ensuring plans are implemented and momentum sustained

Summary

Introduction

Securing improvements in healthcare quality is challenging (Powell et al, 2009). Even where interventions prove successful in one context, attempts to replicate positive impacts elsewhere are variable in their results (Dixon-Woods et al, 2013), and often disappointing (Lomas, 2005). Recognition has grown of the need to approach improvement interventions from a broader cultural and institutional perspective, accounting for the role of organisational structures and social processes (Aveling et al, 2013) and developing approaches to implementation that can adapt to contextual modifiers in more dynamic ways. In this context, the potential of community-based approaches is receiving increasing attention (Greenhalgh et al, 2010). That community-based approaches to healthcare improvement have yet to be optimised (Gabbay et al, 2003; Li et al, 2009; Nadeem et al, 2013)

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Discussion

Conclusion