Efficacy of Reduced-Intensity Chemotherapy With Oxaliplatin and Capecitabine on Quality of Life and Cancer Control Among Older and Frail Patients With Advanced Gastroesophageal Cancer: The GO2 Phase 3 Randomized Clinical Trial | Esophageal Cancer | JAMA Oncology | JAMA Network
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    Original Investigation
    May 13, 2021

    Efficacy of Reduced-Intensity Chemotherapy With Oxaliplatin and Capecitabine on Quality of Life and Cancer Control Among Older and Frail Patients With Advanced Gastroesophageal Cancer: The GO2 Phase 3 Randomized Clinical Trial

    Author Affiliations
    • 1University of Leeds, Leeds, United Kingdom
    • 2University of Edinburgh, Edinburgh, United Kingdom
    • 3Leeds Teaching Hospitals National Health Service Trust, United Kingdom
    • 4Maidstone and Tunbridge Wells National Health Service Trust, Maidstone, United Kingdom
    • 5University of Dundee, Dundee, United Kingdom
    • 6Bristol Oncology Centre, Bristol, United Kingdom
    • 7Weston Park Cancer Centre, Sheffield, United Kingdom
    • 8Hull University Hospitals National Health Service Trust, Hull, United Kingdom
    • 9Royal United Hospitals Bath, Bath, United Kingdom
    • 10North Cumbria University Hospitals National Health Service Trust, Carlisle, United Kingdom
    • 11Royal Surrey County Hospital National Health Service Foundation Trust, Guildford, United Kingdom
    • 12The Royal Wolverhampton National Health Service Trust, Wolverhampton, United Kingdom
    • 13The Dudley Group National Health Service Foundation Trust, Dudley, United Kingdom
    • 14United Lincolnshire Hospitals National Health Service Trust, Lincoln, United Kingdom
    • 15Mid Yorkshire Hospitals National Health Service Trust, Wakefield, United Kingdom
    • 16The Shrewsbury and Telford Hospital National Health Service Trust, Shrewsbury, United Kingdom
    • 17Betsi Cadwaladr University Local Health Board, Bangor, United Kingdom
    • 18The Christie National Health Service Foundation Trust, Manchester, United Kingdom
    • 19Worcestershire Acute Hospitals National Health Service Trust, Worcester, United Kingdom
    • 20Guys and St Thomas’s National Health Service Foundation Trust, London, United Kingdom
    • 21York Teaching Hospital National Health Service Foundation Trust, Scarborough, United Kingdom
    • 22Calderdale and Huddersfield National Health Service Foundation Trust, Huddersfield, United Kingdom
    • 23University of Oxford, Oxford, United Kingdom
    • 24Maastricht University Medical Center, Maastricht, the Netherlands
    JAMA Oncol. 2021;7(6):869-877. doi:10.1001/jamaoncol.2021.0848
    Key Points

    Question  Do older and/or frail patients with advanced gastroesophageal cancer benefit from less intensive palliative chemotherapy, and can a formal geriatric assessment assist treatment decision-making?

    Findings  This phase 3 randomized clinical trial including 559 patients with advanced gastroesophageal cancer found that reducing the intensity of chemotherapy provided an improved patient experience with no significant detriment in cancer control. Baseline frailty, quality of life, and neutrophil/lymphocyte ratio (an inflammation marker) were predictive of outcome and may contribute to treatment decisions.

    Meaning  Decision-making for older and/or frail patients with advanced cancer can be enhanced using geriatric assessment; such patients generally benefit from reducing the intensity of chemotherapy.


    Importance  Older and/or frail patients are underrepresented in landmark cancer trials. Tailored research is needed to address this evidence gap.

    Objective  The GO2 randomized clinical trial sought to optimize chemotherapy dosing in older and/or frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making.

    Design, Setting, and Participants  This multicenter, noninferiority, open-label randomized trial took place at oncology clinics in the United Kingdom with nurse-led geriatric health assessment. Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable because of advanced age and/or frailty.

    Interventions  There were 2 randomizations that were performed: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (oxaliplatin 130 mg/m2 on day 1, capecitabine 625 mg/m2 twice daily on days 1-21, on a 21-day cycle), Level B (doses 0.8 times A), or Level C (doses 0.6 times A). Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, the patient could instead enter CHEMO-BSC, comparing Level C vs best supportive care.

    Main Outcomes and Measures  First, broad noninferiority of the lower doses vs reference (Level A) was assessed using a permissive boundary of 34 days reduction in progression-free survival (PFS) (hazard ratio, HR = 1.34), selected as acceptable by a forum of patients and clinicians. Then, the patient experience was compared using Overall Treatment Utility (OTU), which combines efficacy, toxic effects, quality of life, and patient value/acceptability. For CHEMO-BSC, the main outcome measure was overall survival.

    Results  A total of 514 patients entered CHEMO-INTENSITY, of whom 385 (75%) were men and 299 (58%) were severely frail, with median age 76 years. Noninferior PFS was confirmed for Levels B vs A (HR = 1.09 [95% CI, 0.89-1.32]) and C vs A (HR = 1.10 [95% CI, 0.90-1.33]). Level C produced less toxic effects and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in younger or less frail patients. A total of 45 patients entered the CHEMO-BSC randomization: overall survival was nonsignificantly longer with chemotherapy: median 6.1 vs 3.0 months (HR = 0.69 [95% CI, 0.32-1.48], P = .34). In multivariate analysis in 522 patients with all variables available, baseline frailty, quality of life, and neutrophil to lymphocyte ratio were independently associated with OTU, and can be combined in a model to estimate the probability of different outcomes.

    Conclusions and Relevance  This phase 3 randomized clinical trial found that reduced-intensity chemotherapy provided a better patient experience without significantly compromising cancer control and should be considered for older and/or frail patients. Baseline geriatric assessment can help predict the utility of chemotherapy but did not identify a group benefiting from higher-dose treatment.

    Trial Registration  isrctn.org Identifier: ISRCTN44687907