Optimising Chemotherapy for Frail and Older Patients With Advanced Gastroesophageal Cancer: The GO2 Phase III Trial

Background: GO2 sought to optimise chemotherapy dosing in older/frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making.  Methods: Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable. Two randomisation options were available: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (doses as used in the standard epirubicin/oxaliplatin/capecitabine regimen), B (0·8x A) or C (0·6x A). Non-inferiority of PFS was assessed using boundary HR=1·34, selected by a forum of patients and clinicians. Overall Treatment Utility (OTU), which combines efficacy, toxicity, QL and patient value/acceptability, was scored at nine weeks. Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, they could enter the CHEMO-BSC randomisation, comparing Level C versus best supportive care. Findings: 514 patients entered the CHEMO-INTENSITY randomisation: non-inferior PFS was confirmed for B vs A (HR=1·09 [CI=0·89-1·32]) and C vs A (HR=1·10 [0·90-1·33]). Level C produced less toxicity and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in the younger, fitter patients. 45 patients entered the CHEMO-BSC randomisation: overall survival was non-significantly longer with chemotherapy: median 6·1 vs 3·0 months, HR=0·69 [0·32-1·48], p=0·34. In multivariate analysis, baseline frailty, QL and neutrophil:lymphocyte ratio were independently associated with OTU, so can be combined in a model to estimate the probability of better or worse outcome.  Interpretation: Reduced-intensity chemotherapy provided non-inferior efficacy with an improved patient experience. Baseline geriatric assessment can help predict the utility of chemotherapy. Trial Registration: [Trial registration: ISRCTN44687907]  Funding Statement: Cancer Research UK [CRUK/12/022] Declaration of Interests: Dr. Grabsch reports personal fees from Merck Sharpe Dome, outside the submitted work; all other authors have nothing to declare. Ethics Approval Statement: This study was approved by the UK National Research Ethics Service and overseen by independent Trial Steering and Data Monitoring & Ethics Committees (TSC; IDMC).