TY - JOUR
T1 - 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
T2 - The GO2 Phase 3 Randomized Clinical Trial
AU - GO2 Trial Investigators
AU - Hall, Peter S.
AU - Swinson, Daniel
AU - Cairns, David A.
AU - Waters, Justin S.
AU - Petty, Russell
AU - Allmark, Christine
AU - Ruddock, Sharon
AU - Falk, Stephen
AU - Wadsley, Jonathan
AU - Roy, Rajarshi
AU - Tillett, Tania
AU - Nicoll, Jonathan
AU - Cummins, Sebastian
AU - Mano, Joseph
AU - Grumett, Simon
AU - Stokes, Zuzana
AU - Konstantinos-Velios, Kamposioras
AU - Chatterjee, Anirban
AU - Garcia, Angel
AU - Waddell, Tom
AU - Guptal, Kamalnayan
AU - Maisey, Nick
AU - Khan, Mohammed
AU - Dent, Jo
AU - Lord, Simon
AU - Crossley, Ann
AU - Katona, Eszter
AU - Marshall, Helen
AU - Grabsch, Heike I.
AU - Velikova, Galina
AU - Ow, Pei Loo
AU - Handforth, Catherine
AU - Howard, Helen
AU - Seymour, Matthew T.
N1 - Funding Information:
grants from Cancer Research UK during the conduct of the study and institutional research funding from Novartis, Pfizer, Eli Lilly, Daiichi-Sanchyo, and Eisai outside the submitted work. Dr Waters reported nonfinancial support from Ipsen and Mylan outside the submitted work. Dr Petty reported personal fees from Eli Lilly, Bristol Myers Squib, and Servier, and grants from AstraZeneca, Roche, Sanofi, Merck Sharp & Dohme, Five Prime Therapeutics, and Jansen outside the submitted work. Dr Wadsley reported grants, personal fees, and nonfinancial support from AstraZeneca, personal fees and nonfinancial support from Sanofi-Genzyme, and personal fees from Novartis (AAA), Lilly, Roche, Eisai, Ipsen, and Celgene outside the submitted work. Dr Chatterjee reported personal fees from Pfizer and AstraZeneca and travel grant and accommodation for attending educational meeting from Roche and Leo Pharma. Dr Waddell reported research funding, travel expenses, honoraria and advisory board fees from Bristol Myers Squibb, research funding, honoraria and advisory board fees from Pfizer, honoraria and travel expenses from EUSA pharma, travel expenses, honoraria and advisory board fees from Ipsen, funding and advisory board fees from Eisai Research, Research grant and advisory board fees from Merck Sharpe & Dohme, and research funding and advisory board fees from Roche Research outside the submitted work. Dr Lord reported funding of clinical trial activities from the National Institute for Health Research during the conduct of the study; personal fees from Eisai, Prosigna, Roche, and Shionogi; grants from Pathios Therapeutics; travel, accommodation, expenses from Pfizer; travel, accommodation, expenses from
Funding Information:
Roche; travel, accommodation, expenses, and other from Sython; and travel, accommodation, and other expenses from Piqur Therapeutics outside the submitted work; in addition, Dr Lord had a patent for Mitox Therapeutics issued related to role as co-founder of biotech company. Dr Marshall reported grants from Cancer Research UK during the conduct of the study. Dr Grabsch reported personal fees from Merck Sharpe & Dohme outside the submitted work. Dr Velikova reported personal fees from Roche, Eisai, Novartis, and Seattle Genetics, and grants from Breast Cancer Now, European Organisation for Research and Treatment of Cancer, Yorkshire Cancer Research, and Pfizer outside the submitted work. Dr Howard reported grants from Cancer Research UK during the conduct of the study; grants from Bristol Myers Squibb, Servier, and Roche; and nonfinancial support from AstraZeneca and Sanofi outside the submitted work. Dr Seymour reported grants from Cancer Research UK during the conduct of the study. No other disclosures were reported.
Funding Information:
National Health Service and was supported by the National Institute for Health Research (NIHR) Clinical Research Network.
Publisher Copyright:
© 2021 American Medical Association. All rights reserved.
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
U2 - 10.1001/jamaoncol.2021.0848
DO - 10.1001/jamaoncol.2021.0848
M3 - Article
C2 - 33983395
SN - 2374-2437
VL - 7
SP - 869
EP - 877
JO - JAMA Oncology
JF - JAMA Oncology
IS - 6
ER -
