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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

Efficacy of Reduced-Intensity Chemotherapy With Oxaliplatin and Capecitabine on Quality of Life... Research JAMA Oncology | Original Investigation 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 Peter S. Hall, PhD; Daniel Swinson, MD; David A. Cairns, PhD; Justin S. Waters, PhD; Russell Petty, PhD; Christine Allmark; Sharon Ruddock, BSc; Stephen Falk, MD; Jonathan Wadsley, MA; Rajarshi Roy, MSc; Tania Tillett, MSc; Jonathan Nicoll, MA; Sebastian Cummins, MBBS; Joseph Mano, MD; Simon Grumett, PhD; Zuzana Stokes, MUDr; Kamposioras Konstantinos-Velios, PhD; Anirban Chatterjee, MBBS; Angel Garcia, MD; Tom Waddell, MD; Kamalnayan Guptal, MD; Nick Maisey, MD; Mohammed Khan, MD; Jo Dent, MSc; Simon Lord, PhD; Ann Crossley, DipHE; Eszter Katona, MA; Helen Marshall, MSc; Heike I. Grabsch, PhD; Galina Velikova, PhD; Pei Loo Ow, MSc; Catherine Handforth, PhD; Helen Howard, PhD; Matthew T. Seymour, MD; for the GO2 Trial Investigators Supplemental content 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/m on day 1, capecitabine 625 mg/m 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 Author Affiliations: Author reduced-intensity chemotherapy provided a better patient experience without significantly affiliations are listed at the end of this compromising cancer control and should be considered for older and/or frail patients. article. Baseline geriatric assessment can help predict the utility of chemotherapy but did not Corresponding Author: Matthew T. identify a group benefiting from higher-dose treatment. Seymour MD, Institute of Oncology, St James’s University Hospital, TRIAL REGISTRATION isrctn.org Identifier: ISRCTN44687907 University of Leeds, Leeds LS9 7TF, JAMA Oncol. 2021;7(6):869-877. doi:10.1001/jamaoncol.2021.0848 United Kingdom (matt.seymour@ Published online May 13, 2021. nihr.ac.uk). (Reprinted) 869 Research Original Investigation Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer ancerismostcommoninolderpeople.InNorthAmerica and Europe, gastroesophageal cancer is the third most Key Points C common cause of cancer death, with more than half Question Do older and/or frail patients with advanced these deaths in people over 75 years, many of whom are frail gastroesophageal cancer benefit from less intensive palliative and with comorbidities. But evidence guiding treatment for chemotherapy, and can a formal geriatric assessment assist vulnerable older patients is poor: standard chemotherapy regi- treatment decision-making? mens were developed in trials involving predominantly non- Findings This phase 3 randomized clinical trial including 2-5 frail, noncomorbid patients of median age less than 65, and 559 patients with advanced gastroesophageal cancer found that although selected older people participated they cannot be reducing the intensity of chemotherapy provided an improved assumed to fully represent the older population. patient experience with no significant detriment in cancer control. Baseline frailty, quality of life, and neutrophil/lymphocyte ratio In 2011, MRC FOCUS2, a national randomized trial de- (an inflammation marker) were predictive of outcome and may signed for frail and older patients with colorectal cancer, was contribute to treatment decisions. reported. It used reduced doses of chemotherapy and intro- duced a novel composite end point, Overall Treatment Utility Meaning Decision-making for older and/or frail patients with advanced cancer can be enhanced using geriatric assessment; (OTU), combining clinical efficacy, tolerability, and the pa- such patients generally benefit from reducing the intensity of tient’s own assessment of treatment value and acceptability. chemotherapy. In the same year we surveyed 50 gastrointestinal oncologists in the UK : 49 reported routinely treating older patients with gastroesophageal cancer with standard schedules at reduced inselectingpatients.Thekeyeligibilitycriterionwasthattheon- doses, or omitting agents. There was wide variation in practice cologist considered full-dose standard combination chemo- and no use of objective geriatric assessment (GA) to guide de- therapy (at that time epirubicin/oxaliplatin/capecitabine or cisions.Thisledto321GO,arandomizedfeasibilitytrialinwhich cisplatin/fluorouracil/trastuzumab ) unsuitable because of the older and/or frail patients with gastroesophageal cancer re- patient’sadvancedageand/orfrailty.Itwasmadecleartopatients ceived 80% doses of the standard 3-drug schedule epirubicin/ and clinicians that GO2 was a trial for older patients, but there oxaliplatin/capecitabine (EOCap), the same treatment omit- were no chronological age limits. Furthermore, since scoring ting epirubicin (OCap), or the same treatment omitting both of performance status (PS) by oncologists in older patients is epirubicin and oxaliplatin (Cap). The best balance of benefits inconsistent, afixedPSthresholdwasnotspecified,butpatients and tolerability was achieved with the OCap doublet. This trial hadtobeconsideredfitforanyofthetreatmentsintheirselected 7,8 allowed further development of the OTU end point. randomization. Patients with moderate renal/hepatic dysfunc- The GO2 randomized clinical trial takes the OCap sched- tion could be entered with dose adjustment to compensate for ule from 321GO and compares 3 dose levels, seeking the best reduced clearance. Medical comorbidity was allowed provided balance of efficacy and patient experience. For patients with the oncologist did not consider this to preclude chemotherapy. uncertainty regarding whether to use chemotherapy at all, ResponseEvaluationCriteriainSolidTumors–assessabledisease an alternative randomization compares the lowest dose level was not mandatory. vs supportive care alone. We ask whether a baseline GA may aid personalized dose selection and perhaps identify patients Randomization unlikelytobenefitfromchemotherapy.Morebroadly,GO2aims If the clinician and/or patient considered chemotherapy defi- to stimulate researchers across all cancer types to evaluate nitely indicated, patients entered the CHEMO-INTENSITY ran- patient-centered assessment, dosing, and outcome measure- domization and were allocated (1:1:1) to OCap dose Level A, B, ment for vulnerable patients. or C. Level A treatment was oxaliplatin 130 mg/m on day 1 and capecitabine 625 mg/m twice daily on days 1-21, on a 21-day cycle; Level B treatment was 80% of Level A doses; and Level C treatment was 60% of Level A doses. If the patient and cli- Methods nician agreed that best supportive care alone (BSC) would be Study Design and Participants an acceptable alternative, patients could instead enter the TheGO2trial(ISRCTN44687907)wasanacademic,multicenter, CHEMO-BSC randomization, with allocation (1:1) to OCap Level open-label randomized trial, approved by the UK National C or BSC. Randomization used an automated telephone/web ResearchEthicsService,overseenbyindependentTrialSteering system and validated minimization algorithm, with age, PS, and Data Monitoring & Ethics Committees. All participants gave metastases, histology, renal function, planned trastuzumab fully informed written consent. The study is closed and use, and center as stratification factors. The treatment alloca- follow-up is complete. The authors assume responsibility for tion was not masked from study investigators or patients. accuracy, completeness, and fidelity to the trial protocol (Supplement 1) and statistical analysis plan (Supplement 2). Procedures Eligibility criteria are detailed in the Trial Protocol. Patients The GA, aligned with the European Organization for Re- had locally advanced and/or metastatic gastroesophageal can- search and Treatment of Cancer (EORTC) Elderly Minimum cer that was not pretreated. In the absence of established objec- Data set, was administered after consent but before random- tive frailty thresholds, and given the complex interrelations of ization; results were not communicated to the clinician. It in- 13 14 frailtyandadvancedage,weusedoncologists’clinicaljudgment cluded G8, Instrumental Activities of Daily Living (IADL), 870 JAMA Oncology June 2021 Volume 7, Number 6 (Reprinted) jamaoncology.com Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer Original Investigation Research 15 16,17 Timed Up and Go test, EORTC QLQ-C30/OG25, and EQ-5D andquality-adjustedsurvival.FatiguewasscoredusingQLQ-C30 and visual analogue scale (EQ-VAS). Frailty was scored by with time-to-deterioration from randomization to a deteriora- assessing impairment (yes/no) in nine domains (weight loss, tionof16percentagepointsormore.IntheCHEMO-BSCrandom- mobility, falls, neuropsychiatric, physical functioning, social ization,theprimaryendpointwasOS;secondaryendpointswere functioning, mood, fatigue, and polypharmacy) and partici- patient-reported fatigue and QL. pants were categorized as not frail (0-1/9 domain impaired), mildly frail (2/9 domains), or severely frail (≥3/9 domains). Statistical Analysis Patients with estimated glomerular filtration rate (eGFR) In the CHEMO-INTENSITY randomization, reducing the dose of 30 to 50 mL/min or bilirubin 1.5 to 2 times the upper limit of of chemotherapy was hypothesized to provide a better patient normal received 75% of their allocated dose of capecitabine. experience without major detriment in PFS. The trial there- Patients with ERBB2 (formerly HER2)-positive cancers could fore used a PFS noninferiority design but with a relatively non- additionally receive trastuzumab. Imaging was repeated every stringent boundary, set following careful discussion at a fo- 9 weeks, and chemotherapy stopped in the event of radiologi- rumofpatientsandclinicians,whereacceptableabsolutePFS/OS cal or clinical progression, unacceptable toxic effects, or pa- losses were considered as a trade-off against toxicity. Patients tient choice. Patients allocated to BSC had access to specialist were prepared to sacrifice 6 weeks or more of PFS in return palliative care, pain and psychosocial services, blood transfu- for reduced treatment toxic effects, but clinicians were more sions,nutritionalsupport,radiotherapy,stenting,orsurgicalpro- conservative and the trial was eventually powered to exclude ceduresasindicated;chemotherapy,althoughnotplanned,was 34 days or greater reduction in median PFS from a predicted 134 allowable if it later became indicated. days,equivalenttohazardratio(HR)atorover1.34.With1-sided Overall Treatment Utility was scored once, 9 weeks after 5% significance and 80% power, this required 284 events or starting chemotherapy. It comprised computed tomography more per pairwise comparison, requiring recruitment of 501 pa- (CT) and clinical assessment of cancer progression status; toxic tients or more. In the CHEMO-BSC randomization, chemo- effects (Common Terminology Criteria for Adverse Events, therapy was hypothesized to improve OS; however, given that CTCAE) and serious adverse events (SAEs); quality of life (QL, the uptake of this randomization was not predicable at the time as scored with QLQ-C30 Global Health Status subscale), and of designing the trial, the sample size could not be predeter- patient value/acceptability, scored from 2 questions posed in mined and only exploratory analysis was planned. a questionnaire before patients received their scan results: Efficacy analyses were by intention to treat (ITT); safety “Since you started chemotherapy, how worthwhile do you and toxic effect analyses in patients who received 1 or more think your treatment has been?” and “How much has your che- dose of protocol therapy. Kaplan-Meier methods were used to motherapy interfered with your normal daily activities?” both estimate survivor functions for time-to-event end points. Cox scored “not at all/a little/quite a bit/very much.” Overall Treat- proportional hazards regression adjusted for minimization fac- ment Utility was not measurable in patients allocated BSC. tors were used to estimate HRs and CIs, using 1-sided 95% CIs Treatment beyond 9 weeks continued until CT progres- for the noninferiority comparison. Proportional hazards were sion or clinical/patient decision. Longitudinal QL comprised assessed using a permutation test of martingale residuals. No weekly EQ-VAS and every 3 weeks EQ-5D and QLQ-C30 violations were observed. Overall Treatment Utility compari- Fatigue Subscale during chemotherapy, then then once every sons used ordinal logistic regression adjusting for minimiza- 9 weeks until a year from randomization. tion factors to estimate odds ratios (ORs) and 95% CIs. ForQLsubscales,wefoundnoevidenceagainstthemissing- at-random assumption using descriptive and logistic regres- Outcomes Endpoints,conformingtothejointEORTC/Alliance/International sion analysis, so we applied multiple imputation by chained 20 26 SocietyofGeriatricOncology(SIOG)Statement, aredefinedin equations (MICE). We compared allocated groups for QL and the trial protocol (Supplement 1) and statistical analysis plan symptom subscales using multiple linear regression adjusted (Supplement 2). In the CHEMO-INTENSITY randomization the for the baseline subscale and minimization factors (excluding primaryendpointwasinvestigator-determinedprogression-free center). For fatigue we compared groups using multilevel re- survival (PFS). The key secondary end point was OTU. A score peated mixed-model analyses allowing for time effects, treat- of “Good OTU” requires no radiological or clinical evidence of ment-time interactions, baseline fatigue (fixed effects), and pa- cancer progression, no major toxic effects (a serious adverse re- tient and patient-time interaction (random effects). These action[SAR],oranygrade≥3non-hematologicaltoxicity),nosig- models were also used to estimate treatment effects and 95% nificantdeteriorationinQL(≥16percentage-pointsdropinEORTC CI. We performed sensitivity analyses for complete cases. GlobalQLsubscale )andnoadverseresponsestopatientvalue/ Subgroupanalysisusedthesamemodelmethodsasprimary acceptability questions (“not at all” worthwhile or “very much” and secondary end point comparisons, prespecified for poten- interference).PoorOTUdenotesevidenceofcancerprogression tiallyprognosticvariables:patientcharacteristics/minimization and at least 1 other negative factor (toxic effects, SAE, QL dete- factors, frailty, QL/symptoms, and laboratory tests. Tests for rioration, or poor value/acceptability), or the patient has died. heterogeneity correspond to 1 degree of freedom for 2-category IntermediateOTUmeanseithercancerprogressionwithoutany subgroups (or continuous scales), 2 degrees of freedom for othernegativefactorornegativefactorswithoutcancerprogres- 3-category subgroups, and so on. Following univariate analyses sion. Other secondary end points were toxic effects; symptoms with ordinal logistic regression, we performed multivariable (QLQ-C30/OG250);QL;RECISTresponse ;overallsurvival(OS); analysis using backward elimination including all variables, jamaoncology.com (Reprinted) JAMA Oncology June 2021 Volume 7, Number 6 871 Research Original Investigation Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer Figure 1. CONSORT Diagrams CONSORT diagram for the CHEMO-INTENSITY pathway 514 Patients were randomized in the CHEMO-INTENSITY pathway 170 Randomized to Level A 171 Randomized to Level B 173 Randomized to Level C 161 Received Level A 163 Received Level B 168 Received Level C 9 Received no treatment 8 Received no treatment 5 Received no treatment 170 Included in ITT analysis 171 Included in ITT analysis 173 Included in ITT analysis 142 Progressed or died 147 Progressed or died 149 Progressed or died 28 Alive and progression-free 24 Alive and progression-free 24 Alive and progression-free CONSORT diagram for the CHEMO-BSC pathway 45 Patients were randomized in the CHEMO-BSC pathway 23 Randomized to Level C 22 Randomized to BSC 18 Received Level C 5 Received no treatment A, CONSORT diagram for the CHEMO-INTENSITY pathway. 23 Included in ITT analysis 22 Included in ITT analysis B, CONSORT diagram for the CHEMO-BSC pathway. Treatment pathways are detailed in the 17 Died 20 Progressed or died Randomization section of Methods. 6 Alive 2 Alive BSC indicates best supportive care alone; ITT, intention to treat. irrespectiveofunivariateresult.Finally,weconstructedanomo- CHEMO-INTENSITY Randomization gram using a transformation of the linear predictor to a scale In the ITT analysis, both lower doses satisfied the prespecified estimating the probability of each OTU outcome. trial definition of noninferior PFS compared with Level A; nei- P values for superiority comparisons are 2-sided and con- ther CI crosses the HR boundary of 1.34 (Figure 2). A total of 438 sidered significant at an overall significance level of 5%. All (85%) patients experienced PFS events, with HR = 1.09 (95% CI, other analyses are described in the statistical analysis plan 0.89-1.32) for B vs A and HR = 1.10 (95% CI, 0.90-1.33) for C vs A. (Supplement 2). For analysis, SAS version 9.4 (SAS Institute) After 373 (73%) deaths, there is no evidence that higher-dose and R version 3.2.3 (R Project) were used. treatment improved OS: B vs A HR = 1.09 (95% CI, 0.88-1.36); C vs A HR = 1.14 (95% CI, 0.92-1.41) (Figure 2). No subgroup was identifieddemonstratingclearbenefitwithLevelAforeitherPFS or OS (eFigures 1-4 in Supplement 3). Among the 349 (68%) Results RECIST-assessable patients there was a lower response rate A total of 514 patients entered the CHEMO-INTENSITY and 45 (CR/PR) in Level B, but not Level C (B vs A OR = 0.53 [90% CI, entered the CHEMO-BSC randomization, between January 0.33-0.85]; C vs A HR = 0.63 [90% CI, 0.36-1.11]), with little dif- 2014 and November 2017, at 61 UK medical centers (Figure 1; ferenceindiseasecontrol(CR/PR/SD)(eTable11inSupplement3). eTable 1 in Supplement 3); cutoff date was February 2019. Slow ResultsforPFSweresimilarintheper-protocolanalysis(n = 492), recruitment in some centers was attributed to patients opting withHR = 1.09(95%CI,0.89-1.34)forBvsAandHR = 1.10(95% for the lower dose levels off-trial. Populations were well- CI, 0.90-1.34) for C vs A (eFigure 13 in Supplement 3). balanced within each randomization but differed between the Overall Treatment Utility, assessed in all 514 patients by two, with CHEMO-BSC patients having higher rates of poor PS ITT, was good in 196 patients (38%), intermediate in 149 (29%), andseverefrailty,drivenespeciallybyimpairedADL,lowmood and poor in 169 (33%). Level C produced more good (43%) and and social care requirements (Table 1;eTable2in Supple- fewer poor (29%) OTU outcomes than A or B, but these differ- ment 3). Of the total 559 patients, 44 (8%) were neither frail ences were not statistically significant (eFigure 1 in Supple- nor aged over 75 years, reflecting the flexibility of the selec- ment 3). Other patient experience end points also trended tion criteria (eTable 3 in Supplement 3). toward better outcomes with lower doses (eTables 4-9 in 872 JAMA Oncology June 2021 Volume 7, Number 6 (Reprinted) jamaoncology.com Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer Original Investigation Research Table 1. Baseline Patient Characteristics No. (%) a a CHEMO-INTENSITY pathway CHEMO-BSC pathway Level A Level B Level C Level C BSC Treatment allocation (n = 170) (n = 171) (n = 173) (n = 23) (n = 22) Age, median (range), y 76 (57-96) 76 (51-91) 77 (56-88) 79 (66-89) 78.5 (58-88) Male gender 131 (77) 129 (75) 125 (72) 14 (61) 13 (59) WHO performance status 0 27 (16) 23 (13) 22 (13) 0 0 1 90 (53) 94 (55) 95 (55) 9 (39) 6 (27) 2 49 (29) 47 (27) 52 (30) 11 (48) 14 (64) >2 3 (1.8) 7 (4.1) 3 (1.7) 3 (13) 2 (9.1) Frailty Not frail (0-1 domains) 23 (14) 30 (18) 41 (24) 2 (8.7) 1 (4.5) Slightly frail (2 domains) 44 (26) 45 (26) 32 (18) 5 (22) 6 (27) Severely frail (≥3 domains) 103 (61) 96 (56) 100 (58) 16 (70) 15 (69) Frailty/age Age ≥75 y and frail 74 (44) 81 (47) 71 (41) 15 (65) 16 (73) Age ≥75 y and nonfrail 16 (9) 15 (9) 20 (12) 1 (4) 1 (4) Age <75 y and frail 73 (43) 60 (35) 61 (35) 6 (26) 5 (23) Age <75 y and nonfrail 7 (4) 15 (9) 21 (12) 1 (4) 0 Squamous histology 20 (12) 18 (11) 20 (12) 4 (17) 5 (23) Site of primary tumor Esophagus 55 (32) 73 (43) 69 (40) 13 (57) 9 (49) GO junction 50 (29) 34 (20) 39 (23) 4 (17) 4 (18) Gastric 64 (38) 64 (37) 64 (37) 6 (26) 9 (41) Distant metastases 115 (68) 118 (69) 121 (70) 11 (48) 10 (46) Trastuzumab use 7 (4.1) 10 (5.8) 10 (5.8) 0 0 Individual domains contributing to the Frailty Score BMI<18.5 7 (4.1) 13 (7.6) 11 (6.4) 2 (8.7) 6 (27) Abbreviations: ADL, activities of daily Weight loss 92 (54) 94 (55) 85 (49) 11 (48) 10 (45) living; BMI, body mass index; Mobility (TUGT) 103 (61) 91 (53) 95 (55) 19 (83) 14 (64) WHO, World Health Organization; Falls 8 (4.7) 9 (5.3) 7 (4.0) 2 (8.7) 0 TUGT, Timed Up and Go Test. BMI is Cognition 22 (13) 25 (15) 26 (15) 4 (17) 3 (14) calculated as weight in kilograms divided by height in meters squared. Function (ADL) 97 (57) 97 (57) 100 (58) 16 (70) 19 (86) Treatment pathways are detailed in Social care 0 2 (1.2) 1 (0.6) 23 (100) 21 (95) the Randomization section of Mood 2 (1.2) 4 (2.3) 3 (1.7) 21 (91) 22 (100) Methods. Fatigue 42 (25) 42 (25) 42 (24) 5 (22) 7 (32) For frailty definitions, see the trial Polypharmacy 127 (75) 129 (75) 116 (67) 19 (83) 14 (64) protocol (Supplement 2). Supplement 3). Time-to-deterioration of fatigue favored Level respectively, and 30 (18%), 36 (21%), and 47 (27%) went on to C (C vs A HR = 0.88 [95% CI, 0.65-1.19]). Global QL (EORTC receive 6 or more cycles. Second-line therapy was recorded Core Quality of Life questionnaire, QLQ-C30, and EuroQoL-5 in 23 (14%), 18 (11%), and 24 (14%) patients. Dimension, EQ-5D) improved between baseline and 9 weeks with Levels B and C, but not A (eFigures 4-7 in Supple- CHEMO-BSC Randomization ment 3). Longitudinal fatigue and QL showed no major differ- A total of 45 patients entered the CHEMO-BSC randomization. ences. Cancer symptoms improved between baseline and Inthoseallocatedchemotherapy,toxicitywashigherthaninpa- 9 weeks in all arms similarly (eFigures 8-12 in Supplement 3). tients allocated the same dose level in the CHEMO-INTENSITY The rate of toxic effects fell markedly with reducing dose randomization (Table 2). Longer OS was observed with chemo- levels (Table 2). Consequently, treatment delivery was more therapy than with BSC, but the difference was not statistically reliable: during the first three 3-week cycles, comparing Lev- significant (HR = 0.69 [95% CI, 0.35-1.48]). Both QL and els A, B, and C, a dose reduction was required in 63 (39%), fatigue were nonsignificantly better with chemotherapy than 39 (24%), and 21 (13%) patients, respectively; 53 (33%), 47 BSC (eFigure 8 and eFigure 9 in Supplement 3). (29%), and 34 (20%) patients stopped treatment wholly or partly owing to toxicity, and 51 (32%), 72 (44%), and 97 (58%) Baseline Predictors of OTU patients respectively completed their first 3 cycles without Univariate analysis in all 537 patients allocated chemo- reduction or stoppage (eTable 15 in Supplement 3). Mean (SD) therapy identified the following baseline factors associated treatment duration was 4.4 (3.3), 4.6 (4.0), and 5.4 (4.1) cycles, with worse OTU (P ≤ .05): distant metastases, raised B-type jamaoncology.com (Reprinted) JAMA Oncology June 2021 Volume 7, Number 6 873 Research Original Investigation Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer Figure 2. Survival Curves A CHEMO-INTENSITY progression-free survival 1.0 Level A 0.8 Level B Level C 0.6 0.4 0.2 0 1 23 4 561 7 8 90 11 12 13 Time since randomization, mo No. at risk Level A 170 153 137 110 100 76 64 38 32 26 23 20 12 0 Level B 171 157 126 97 85 66 58 40 34 27 23 20 8 0 Level B 173 156 125 107 100 79 64 42 31 24 22 17 7 0 B CHEMO-INTENSITY overall survival 1.0 Level A 0.8 Level B Level C 0.6 0.4 0.2 0 1 23 4 561 7 8 90 11 12 13 Time since randomization, mo No. at risk Level A 170 159 145 136 125 115 98 83 66 61 53 48 32 0 Level B 171 163 145 127 113 95 87 78 72 62 50 39 25 0 Level B 173 167 148 131 123 112 97 90 77 64 56 43 31 0 C CHEMO-BSC overall survival 1.0 BSC 0.8 BSC/Level C 0.6 0.4 0.2 A, CHEMO-INTENSITY progression-free survival. B, CHEMO-INTENSITY overall 0 1 23 4 561 7 8 90 11 12 13 survival. C, CHEMO-BSC overall Time since randomization, mo survival. Treatment pathways are No. at risk detailed in the Randomization BSC 22 20 15 10 8 7 5 3 2 2 210 BSC/Level C 23 17 15 14 13 13 12 10 9 7 666 0 section of Methods. BSC indicates best supportive care alone. natriuretic peptide (BNP) or N-terminal prohormone of brain can be used to calculate a predictive score: (0.27 if not se- natriuretic peptide (NT-proBNP), leukocytosis, raised neutro- verely frail) + (0.39 if EQ-VAS ≥ 50) + (0.34 if NLR ≤ 4.0). This phil to lymphocyte ratio (NLR), hypoalbuminaemia, raised score (range 0-1) translates into the probability of good, inter- urea, severe frailty (dementia, activities of daily living [ADL], mediate, or poor OTU at 9 weeks (eTable 10 and eTable 11 and polypharmacy domains), poor global QL, and impaired in Supplement 3). Thus, a slightly frail patient with baseline taste (eFigure 1 in Supplement 3). EQ-VAS = 55 and NLR = 3.0 (predictive score = 1) has a 44% In multivariable analysis, baseline frailty, EQ5D-VAS, and probability of good and 27% probability of poor OTU. Con- NLR were independently associated with OTU. These factors versely, a severely frail patient with baseline EQ-VAS = 45 and 874 JAMA Oncology June 2021 Volume 7, Number 6 (Reprinted) jamaoncology.com Proportion alive Proportion alive Proportion alive and progression free Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer Original Investigation Research Table 2. Toxic Effects Reported Within 9 Weeks of Starting Chemotherapy Randomization, No. (%) a a CHEMO-INTENSITY CHEMO-BSC Allocation Level A (n = 162) Level B (n = 162) Level C (n = 168) Level C (n = 18) Max CTCAE grade (week 1-9) ≥2 ≥3 ≥2 ≥3 ≥2 ≥3 ≥2 ≥3 Nausea or vomiting 47 (29) 14 (8.6) 33 (20) 8 (4.9) 29 (17) 12 (7.1) 2 (11) 0 Anorexia 45 (28) 11 (6.7) 46 (28) 14 (8.6) 32 (19) 3 (1.8) 13 (17) 0 Diarrhea 34 (21) 10 (6.2) 19 (12) 10 (6.2) 7 (4.2) 3 (1.8) 1 (5.6) 1 (5.6) Peripheral neuropathy 24 (15) 4 (2.5) 11 (6.7) 1 (0.6) 6 (3.6) 1 (0.6) 2 (11) 0 Fatigue 86 (53) 24 (15) 72 (44) 20 (12) 67 (40) 18 (11) 6 (33) 4 (22) Infection 7 (4.3) 4 (2.5) 15 (9.3) 9 (5.6) 5 (3.0) 1 (0.6) 0 0 Thrombosis 5 (3.1) 5 (3.1) 4 (2.5) 3 (1.9) 3 (1.8) 2 (1.2) 2 (11) 2 (11) Any nonhematological 125 (77) 62 (38) 116 (72) 58 (36) 101 (60) 38 (23) 10 (56) 7 (39) WBC/neutrophils (×10 /l) 10 (6.2) 1 (0.6) 3 (1.9) 0 5 (3.0) 1 (0.6) 0 0 Anaemia 26 (16) 1 (0.6) 33 (20) 6 (3.7) 22 (13) 3 (1.8) 2 (11) 0 Any hematological 33 (20) 3 (1.9) 36 (22) 6 (3.7) 27 (16) 4 (2.4) 2 (11) 0 Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; “Any nonhematological” is defined as any of the following: nausea, vomiting, WBC, white blood cell count. anorexia, stomatitis, diarrhea, hand-foot syndrome, peripheral neuropathy, a fatigue, infection, thrombosis, or dehydration. Treatment pathways are detailed in the Randomization section of Methods. b “Any hematological” is defined as any of the following: low white blood cell Maximum CTCAE grade experienced weeks 1-9 in patients receiving1 cycle count, low neutrophils/granulocytes, low platelets, or anemia. of their allocated chemotherapy. Individual listings are shown for more common toxic effects. NLR = 5.0 (score = 0) has only 18% probability of good OTU but In designing GO2, decisions were necessary for patient se- 57% probability of poor OTU. lection, treatment, and statistical design, all of which may be In the CHEMO-INTENSITY randomization (n = 514), inter- debated. For example, previous trials could not characterize action was seen between the multivariable predictive score and patients who were not included, but it was precisely those pa- doselevel(P = .01)withgreaterincrementalbenefitoflower-dose tients who were to be selected for GO2. It was therefore nec- treatment in patients with better baseline scores: thus a patient essary to use clinicians’ experience, rather than an objective with score = 1 allocated to Level C has 68% probability of good, tool, to offer trial entry to patients they assessed as unsuited 20% intermediate, and 12% poor OTU, but if the same patient to full-dose combination chemotherapy but able to receive is allocated Level A these probabilities are 41%, 30%, and 29%. reduced-intensity treatment. No baseline score was identified as predicting better OTU with EventhehighestdoseinGO2,LevelA,wasless-than-standard higher-dose treatment (eTables 12-14 in Supplement 3). treatment, comprising just 2 drugs from the standard EOCap triplet. Althoughthisincludesfull-doseoxaliplatin,itiscombined withlow-dosecontinuouscapecitabineratherthantheintensive intermittent schedule typically used in doublet therapy. Level C Discussion thereforerepresentsjust60%of2outof3drugs,around40% The GO2 randomized clinical trial is the first large trial testing of full standard dose intensity. It is also important to recognize the relationship between treatment intensity and patient- that Level A, although a reference schedule for this trial, is not focused outcomes in frail and/or older patients with cancer. standard therapy; indeed, the stimulus for the trial was a survey Previous reports have studied older patients who were fit showing that there is no standard for this population. For this enough to enter all-comer trials, or relied on traditional ef- reason we did not apply the typical stringent noninferiority ficacy and safety end points. The GO2 trial uses modern boundarydemandedbyregulators,butwereinsteadabletowork methods and studies patients—the older frail, older nonfrail, with patients and clinicians to carefully balance the competing and younger frail—who rarely participate in trials. In re- needs for cancer control and good tolerability. sponse to calls to address the deficit in evidence guiding treat- One mechanism for retaining cancer control despite lower ment of vulnerable cancer patients, we offer GO2 as an ex- doses is avoidance of toxicity-induced treatment reductions emplar of real-world, patient-centered research. and stoppages. Toxic effects leading to treatment modifica- Lower-dose chemotherapy improved patients’ experi- tion may be accepted by oncologists as part of standard on- ence without compromising anticancer control. This balance cology practice, but it represents a negative experience for pa- is captured in OTU, an objective measure of a virtual conver- tients and detracts from both quality of life and cancer control; sation between physician and patient and reflecting their joint and these impacts are particularly heightened in patients with assessment of treatment value: “With the benefit of hind- poor baseline reserve. Only 32% patients starting Level A were sight, am I glad I recommended this treatment?” and “Am I glad able to receive 3 cycles without reduction or stoppage, com- that I accepted it?” The GO2 trial also demonstrates that a base- pared with 58% with Level C. line GA can contribute to the doctor-patient decision by esti- The GO2 trial aimed to develop dose individualization mating an individual’s probability of better or worse OTU. guided by baseline geriatric assessment: we anticipated fitter jamaoncology.com (Reprinted) JAMA Oncology June 2021 Volume 7, Number 6 875 Research Original Investigation Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer patients would benefit from higher-dose treatment; however, should embrace the newer concept of Comprehensive Geri- we did not identify any group for whom the higher doses are atric Assessment (CGA): both identification of vulnerabilities preferable. Using the OTU outcome measure, reflecting the bal- and active remedial management to correct them. An out- ance of benefits and harms, goes beyond conventional single- standing research question is whether CGA-based pre- outcome models looking at survival or toxicity in isolation. habilitation will convert a patient from low to high probabil- In so doing, GO2 challenges a pervading assumption of oncol- ity of achieving good OTU. ogy: that within the bounds of tolerability more is better. We hope it will stimulate research exploring lower-dose chemo- therapy, perhaps extending to younger and less frail patients. Conclusion We hope also that those designing trials of novel agents, includ- ing registration studies, will consider the option of lower-dose The GO2 clinical trial shows that the goals of palliative chemotherapyasthereferenceorplatformtowhichnovelagents chemotherapy in the older and/or frail population, includ- are added, to widen access to these trials. ing but not limited to cancer control, may be better achieved The 3-month survival benefit seen in the CHEMO-BSC using treatment at doses well below those currently randomization, though nonsignificant in isolation as a conse- regarded as standard. Careful baseline geriatric health quence of small numbers and an imbalance in patient charac- assessment in the oncology clinic can help predict the likeli- teristics, concurs with previous data and supports consid- hood of achieving those goals, and so contribute to patients’ eration of low-dose chemotherapy in vulnerable patients. and clinicians’ treatment decisions. Assessing the outcome This should, however, be interpreted alongside the baseline of cancer treatment should be multidimensional, including predictor, which helps identify patients at high risk of poor its value to patients and its adverse effects, and we recom- treatment utility, for whom BSC may be a preferable path. mend further development of OTU to capture this complex- ity. The GO2 trial offers a design paradigm for enhancing older patients’ access to research and ensuring that our Limitations A limitation of GO2 is that our GA was purely observational. evidence base embraces the whole population that we Implementation of these findings—and future research— serve. ARTICLE INFORMATION Health Board, Bangor, United Kingdom (Garcia); Statistical analysis: Hall, Cairns, Roy, Marshall, Ow, The Christie National Health Service Foundation Seymour. Accepted for Publication: March 4, 2021. Trust, Manchester, United Kingdom (Waddell); Obtained funding: Hall, Marshall, Howard, Seymour.. Published Online: May 13, 2021. Worcestershire Acute Hospitals National Health Patient participant perspectives: Allmark. doi:10.1001/jamaoncol.2021.0848 Service Trust, Worcester, United Kingdom (Guptal); Conflict of Interest Disclosures: Dr Hall reported Open Access: This is an open access article Guys and St Thomas’s National Health Service grants from Cancer Research UK during the conduct distributed under the terms of the CC-BY License. Foundation Trust, London, United Kingdom of the study and institutional research funding from © 2021 Hall PS et al. JAMA Oncology. (Maisey); York Teaching Hospital National Health Novartis, Pfizer, Eli Lilly, Daiichi-Sanchyo, and Eisai Service Foundation Trust, Scarborough, United Author Affiliations: University of Leeds, Leeds, outside the submitted work. Dr Waters reported Kingdom (Khan); Calderdale and Huddersfield United Kingdom (Hall, Cairns, Ruddock, Katona, nonfinancial support from Ipsen and Mylan outside National Health Service Foundation Trust, Marshall, Grabsch, Velikova, Ow, Handforth, the submitted work. Dr Petty reported personal fees Huddersfield, United Kingdom (Dent); University Howard, Seymour); University of Edinburgh, from Eli Lilly, Bristol Myers Squib, and Servier, and of Oxford, Oxford, United Kingdom (Lord); Edinburgh, United Kingdom (Hall); Leeds Teaching grants from AstraZeneca, Roche, Sanofi, Merck Sharp Maastricht University Medical Center, Maastricht, Hospitals National Health Service Trust, United & Dohme, Five Prime Therapeutics, and Jansen the Netherlands (Grabsch). Kingdom (Swinson, Crossley, Seymour); Maidstone outside the submitted work. Dr Wadsley reported and Tunbridge Wells National Health Service Trust, Author Contributions: Drs Seymour and Hall had grants, personal fees, and nonfinancial support from Maidstone, United Kingdom (Waters); University of full access to all of the data in the study and take AstraZeneca, personal fees and nonfinancial support Dundee, Dundee, United Kingdom (Petty); Bristol responsibility for the integrity of the data and the from Sanofi-Genzyme, and personal fees from Oncology Centre, Bristol, United Kingdom (Falk); accuracy of the data analysis. Novartis (AAA), Lilly, Roche, Eisai, Ipsen, and Celgene Concept and design: Hall, Swinson, Petty, Allmark, outside the submitted work. Dr Chatterjee reported Weston Park Cancer Centre, Sheffield, United Kingdom (Wadsley); Hull University Hospitals Lord, Marshall, Velikova, Seymour. personal fees from Pfizer and AstraZeneca and travel National Health Service Trust, Hull, United Kingdom Recruitment of participants; acquisition, analysis, or grant and accommodation for attending educational (Roy); Royal United Hospitals Bath, Bath, United interpretation of data: Hall, Swinson, Cairns, meeting from Roche and Leo Pharma. Dr Waddell Kingdom (Tillett); North Cumbria University Waters, Petty, Ruddock, Falk, Wadsley, Roy, Tillett, reported research funding, travel expenses, Hospitals National Health Service Trust, Carlisle, Nicol, Cummins, Joseph, Grumett, Stokes, honoraria and advisory board fees from Bristol Myers United Kingdom (Nicoll); Royal Surrey County Kamposioras, Chatterjee, Garcia, Waddell, Gupta, Squibb, research funding, honoraria and advisory Hospital National Health Service Foundation Trust, Maisey, Khan, Dent, Lord, Crossley, Katona, board fees from Pfizer, honoraria and travel expenses Guildford, United Kingdom (Cummins); The Royal Marshall, Grabsch, Velikova, Ow, Handforth, from EUSA pharma, travel expenses, honoraria and Wolverhampton National Health Service Trust, Howard, Seymour. advisory board fees from Ipsen, funding and advisory Wolverhampton, United Kingdom (Mano); The Drafting of the manuscript: Hall, Swinson, Cairns, board fees from Eisai Research, Research grant and Dudley Group National Health Service Foundation Seymour. advisory board fees from Merck Sharpe & Dohme, Trust, Dudley, United Kingdom (Grumett); United Critical revision of the manuscript for important and research funding and advisory board fees from Lincolnshire Hospitals National Health Service intellectual content: Hall, Swinson, Cairns, Waters, Roche Research outside the submitted work. Dr Lord Trust, Lincoln, United Kingdom (Stokes); Mid Petty, Allmark, Ruddock, Falk, Wadsley, Roy, Tillett, reported funding of clinical trial activities from the Yorkshire Hospitals National Health Service Trust, Nicol, Cummins, Joseph, Grumett, Stokes, National Institute for Health Research during the Wakefield, United Kingdom (Konstantinos-Velios); Kamposioras, Chatterjee, Garcia, Waddell, Gupta, conduct of the study; personal fees from Eisai, The Shrewsbury and Telford Hospital National Maisey, Khan, Dent, Lord, Crossley, Katona, Prosigna, Roche, and Shionogi; grants from Pathios Health Service Trust, Shrewsbury, United Kingdom Marshall, Grabsch, Velikova, Ow, Handforth, Therapeutics; travel, accommodation, expenses (Chatterjee); Betsi Cadwaladr University Local Howard, Seymour. from Pfizer; travel, accommodation, expenses from 876 JAMA Oncology June 2021 Volume 7, Number 6 (Reprinted) jamaoncology.com Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer Original Investigation Research Roche; travel, accommodation, expenses, and other fluorouracil, leucovorin, and irinotecan versus module, the EORTC QLQ-OG25, to assess from Sython; and travel, accommodation, and other epirubicin, cisplatin, and capecitabine in advanced health-related quality of life in patients with cancer gastric adenocarcinoma: a French intergroup of the oesophagus, the oesophago-gastric junction expenses from Piqur Therapeutics outside the (Fédération Francophone de Cancérologie and the stomach. Eur J Cancer. 2007;43(14): submitted work; in addition, Dr Lord had a patent Digestive, Fédération Nationale des Centres de 2066-2073. doi:10.1016/j.ejca.2007.07.005 for Mitox Therapeutics issued related to role as Lutte Contre le Cancer, and Groupe Coopérateur co-founder of biotech company. Dr Marshall reported 18. Kind P. The EuroQoL instrument: an index of Multidisciplinaire en Oncologie) study. J ClinOncol. grants from Cancer Research UK during the conduct health-related quality of life. In Spiker B, ed. Quality 2014;32:3520-3526. doi:10.1200/JCO.2013.54.1011 of the study. Dr Grabsch reported personal fees from of life in pharmacoeconomicsin clinical trials. 2nd ed. 6. Seymour MT, Thompson LC, Wasan HS, et al; Philadelphia: Lippincott-Raven; 1996. Merck Sharpe & Dohme outside the submitted work. FOCUS2 Investigators; National Cancer Research Dr Velikova reported personal fees from Roche, Eisai, 19. Handforth C, Clegg A, Young C, et al. Institute Colorectal Cancer Clinical Studies Group. Novartis, and Seattle Genetics, and grants from The prevalence and outcomes of frailty in older Chemotherapy options in elderly and frail patients Breast Cancer Now, European Organisation for cancer patients: a systematic review. Ann Oncol. with metastatic colorectal cancer (MRC FOCUS2): Research and Treatment of Cancer, Yorkshire Cancer 2015;26(6):1091-1101 doi:10.1093/annonc/mdu540 an open-label, randomised factorial trial. Lancet. Research, and Pfizer outside the submitted work. 20. Wildiers H, Mauer M, Pallis A, et al. End points 2011;377(9779):1749-1759. doi:10.1016/S0140-6736 Dr Howard reported grants from Cancer Research UK and trial design in geriatric oncology research: (11)60399-1 during the conduct of the study; grants from Bristol a joint European organisation for research and 7. Hall PS, Lord SR, Collinson M, et al. A randomised Myers Squibb, Servier, and Roche; and nonfinancial treatment of cancer—Alliance for Clinical Trials in phase II trial and feasibility study of palliative support from AstraZeneca and Sanofi outside the Oncology—International Society Of Geriatric chemotherapy in frail or elderly patients with submitted work. Dr Seymour reported grants from Oncology position article. J Clin Oncol. 2013;31(29): advanced gastroesophageal cancer (321GO). Br J 3711-3718. doi:10.1200/JCO.2013.49.6125 Cancer Research UK during the conduct of the study. Cancer. 2017;116(4):472-478. doi:10.1038/bjc.2016.442 No other disclosures were reported. 21. US Food and Drug Administration. Guidance for 8. Handforth C, Hall P, Marshall H, Seymour M. industry: clinical trial endpoints for the approval of Funding/Support: This trial ran within the UK Overall treatment utility: a novel outcome measure cancer drugs and biologics. Federal Register. May 16, National Health Service and was supported by the to convey the balance of benefits and harms from 2007. https://www.federalregister.gov/documents/ National Institute for Health Research (NIHR) cancer treatment. J Geriatr Oncol. 2013 4:S49. 2007/05/16/E7-9345/guidance-for-industry-on- Clinical Research Network. doi:10.1016/j.jgo.2013.09.064 clinical-trial-endpoints-for-the-approval-of-cancer- Role of the Funder/Sponsor: Cancer Research UK 9. Bang YJ, Van Cutsem E, Feyereislova A, et al; drugs-and-biologics had no role in the design and conduct of the study; ToGA Trial Investigators. Trastuzumab in 22. Knobel H, Loge JH, Brenne E, Fayers P, collection, management, analysis, and combination with chemotherapy versus Hjermstad MJ, Kaasa S. 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Clinical randomized, multicenter, phase III study of and psychometric validation of a questionnaire jamaoncology.com (Reprinted) JAMA Oncology June 2021 Volume 7, Number 6 877 j . c. w ebst er @leed s. ac. u k non-inferiority of progression-free survival superiority of patient-reported EORTC fatigue, QoL (EQ-5D/QLQ-C30) & symptom scores superiority of OTU) regression analysis superiority for overall survival superiority for patient-reported EORTC fatigue & QoL (EQ-5D/QLQ-C30) Please ensure that you have completed the Eligibility Checklist (F01), Nurse completed CHA (F02) and Randomisation (F03) CRFs, and the patient has completed the baseline QOL CHA questionnaire before telephoning Brain Natriuretic Peptide The ratio of non-fit:fit patients with colorectal cancer is therefore 5:8 i.e. 63% “some information is better than none when patients are faced with treatment decisions” Best-case scenario: Worst-case scenario: Y Y P ) P P Y ) P ) P ) P P ) P ) P ) P ) P P ) P ) P ) P P P ) P P ) P ) P ) P A ) P ) P ) P ) ) P P ) P ) P P Y ) P ) P ) P ) P P ) P ) P ) P ) P ) P ) P ) P ) P "With the benefit of hindsight, are you glad you gave this treatment?" "With the benefit of hindsight, are you glad you received it?" "How much has your treatment interfered with your normal daily activities?" "How worthwhile do you think your treatment has been?" "How much has your treatment interfered with your normal daily activities?" "How worthwhile do you think your treatment has been?" Briefly justify the risk category selected and your conclusions below (where the table is completed in detail the detail need not be repeated, however a summary should be given): 2.1 Chemotherapy intensity comparison 2.2 Chemotherapy vs. BSC comparison (exploratory) Chemotherapy intensity comparison Chemotherapy vs. BSC comparison (exploratory) The ratio of non-fit:fit patients with colorectal cancer is therefore 5:8 i.e. 63% “some information is better than none when patients are faced with treatment decisions” 2.1 Chemotherapy intensity comparison 2.2 Chemotherapy vs. BSC comparison (exploratory) How much has your treatment interfered with your normal daily activities? How worthwhile do you think your treatment has been? Very much/quite a bit Not at all Very much/quite a bit Not at all Very much/quite a bit Not at all Very much/quite a bit Not at all Chemotherapy intensity comparison Chemotherapy vs. BSC comparison (exploratory) http://info.cancerresearchuk.org/cancerstats Br J Surg http://www.macmillan.org.uk/Documents/AboutUs/Health_professionals/OlderPeoplesProject/CancerSe rvicesComingofAge.pdf N Engl J Med J Clin Oncol Cancer J Clin Oncol Lancet Lancet Statistical power analysis for the behavioural sciences J Eval Clin Pract J Clin Oncol International journal of environmental research and public health European Journal of Cancer Journal of the National Cancer Institute "With the benefit of hindsight, are you glad you gave this treatment?" "With the benefit of hindsight, are you glad you received it?" "How much has your treatment interfered with your normal daily activities?" "How worthwhile do you think your treatment has been?" "How much has your treatment interfered with your normal daily activities?" "How worthwhile do you think your treatment has been?" Supplemental Online Content: Nonauthor Collaborators *Indicates required information. Only first name, last name, and suffix will appear in PubMed. Group Name(s):* The GO2 Trial Investigators First Name and Last Name* Suffix Academic Institution Location (city, Role or Contribution, eg, chair, Group (if more than 1 Middle Initial(s)* (eg, Jr, Degrees state/province, country) principal investigator Group listed in the III)* byline) and/or Subgroup (eg, Steering Committee) Eleanor James Sherwood Forest NHS Foundation Trust Nottingham, UK Recruiting Centre PI Sue Cheeseman Bradford Teaching Hospitals NHS Foundation Trust Bradford, UK Recruiting Centre PI Norfolk and Norwich University Hospitals NHS Foundation Trust Tom Roques Norwich, UK Recruiting Centre PI Nick Reed Imperial College Healthcare NHS Trust London, UK Recruiting Centre PI Charles Candish Gloucestershire Hospitals NHS Foundation Tru Gloucester, UK Recruiting Centre PI University Hospitals of Morecambe Bay NHS Foundation Trust David Fyfe Lancaster, UK Recruiting Centre PI Kim Last York Teaching Hospitals Foundation Trust York, UK Recruiting Centre PI Richard Ellis Royal Cornwall NHS Trust Truro, UK Recruiting Centre PI NHS Grampian, Aberdeen Lesley Samuel Aberdeen, UK Recruiting Centre PI Rebecca Herbertson Western Sussex Hospitals NHS Foundation Trust Brighton, UK Recruiting Centre PI Louise Medley South Devon Healthcare NHS Trust, Torbay, UK Recruiting Centre PI Oxford University Hospitals NHS Trust, Kinnari Patel Oxford, UK Recruiting Centre PI David Sherriff Plymouth Hospitals NHS Trust Plymouth, UK Recruiting Centre PI Angus Robinson East Sussex Healthcare NHS Trust Brighton, UK Recruiting Centre PI Blackpool Teaching Hospitals NHS Trust Pavel Bezecny Preston, UK Recruiting Centre PI Dunca Wilkins Betsi Cadwaldr University LHB Clwyd, UK Recruiting Centre PI Adam McGeoch Hinchingbrooke Healthcare NHS Trust Huntingdon, UK Recruiting Centre PI Barts Cancer Institute Daniel Propper London, UK Recruiting Centre PI Olwyn Williams Ysbyty Gwynedd Bangor, UK Recruiting Centre PI Serena Hilman Western Area Healthcare Trust, Bristol, UK Recruiting Centre PI Barking, Havering & Redbridge University Hospitals NHS Trust Sherif Raouf London, UK Recruiting Centre PI Claire Hobbs Great Western Hospitals NHS Foundation Trust Swindon, UK Recruiting Centre PI Jo Parkinson The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust Bournemouth, UK Recruiting Centre PI South Tees Nick Wadd Hospitals NHS Foundation Trust Middlesborough, UK Recruiting Centre PI Milton Keynes Hospital NHS Trust W Saku Milton Keynes, UK Recruiting Centre PI Victori Kunene Walsall Healthcare NHS Trust Birmingham, UK Recruiting Centre PI Colin Askill Abertawe Bro Morgannwg NHS Trust Swansea, UK Recruiting Centre PI Mid Cheshire Hospitals Foundation Trust Arshad Jamil Crewe, UK Recruiting Centre PI Emma Cattell Taunton and Somerset NHS Foundation Trust Taunton, UK Recruiting Centre PI Lauren Gorf Dorset Country Hospitals NHS Foundation Trust Dorset, UK Recruiting Centre PI Singleton Hospital, Hywel Dda Health Board Vallipuram Vigneswaran Swansea, UK Recruiting Centre PI Erica Beaumont Yeovil District Hospital NHS Foundation Trust Yeovil, UK Recruiting Centre PI Syed Zubair County Durham and Darlington NHS Foundation Trust Darlington, UK Recruiting Centre PI Elin Jones Hywel Dda Health Board Haverfordwest, UK Recruiting Centre PI Nicholas Reed Wye Valley NHS Trust Cheltenham, UK Recruiting Centre PI Alaaeldin Shablak Salisbury NHS Foundation Trust Salisbury, UK Recruiting Centre PI Northern Lincolnshire and Goole NHS Foundation Trust George Bozas Hull, UK Recruiting Centre PI Sheela Rao Royal Marsden NHS Trust London, UK Recruiting Centre PI Michael Bennet University of Leeds, Institute of Health Sciences Leeds, UK TMG Member Joanne Askey Leeds Teaching Hospitals NHS Trust Leeds, UK TMG Member v 11 20 1 of 2 Supplemental Online Content: Nonauthor Collaborators *Indicates required information. Only first name, last name, and suffix will appear in PubMed. 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Copyright 2021 Hall PS et al. JAMA Oncology.
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Abstract

Research JAMA Oncology | Original Investigation 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 Peter S. Hall, PhD; Daniel Swinson, MD; David A. Cairns, PhD; Justin S. Waters, PhD; Russell Petty, PhD; Christine Allmark; Sharon Ruddock, BSc; Stephen Falk, MD; Jonathan Wadsley, MA; Rajarshi Roy, MSc; Tania Tillett, MSc; Jonathan Nicoll, MA; Sebastian Cummins, MBBS; Joseph Mano, MD; Simon Grumett, PhD; Zuzana Stokes, MUDr; Kamposioras Konstantinos-Velios, PhD; Anirban Chatterjee, MBBS; Angel Garcia, MD; Tom Waddell, MD; Kamalnayan Guptal, MD; Nick Maisey, MD; Mohammed Khan, MD; Jo Dent, MSc; Simon Lord, PhD; Ann Crossley, DipHE; Eszter Katona, MA; Helen Marshall, MSc; Heike I. Grabsch, PhD; Galina Velikova, PhD; Pei Loo Ow, MSc; Catherine Handforth, PhD; Helen Howard, PhD; Matthew T. Seymour, MD; for the GO2 Trial Investigators Supplemental content 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/m on day 1, capecitabine 625 mg/m 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 Author Affiliations: Author reduced-intensity chemotherapy provided a better patient experience without significantly affiliations are listed at the end of this compromising cancer control and should be considered for older and/or frail patients. article. Baseline geriatric assessment can help predict the utility of chemotherapy but did not Corresponding Author: Matthew T. identify a group benefiting from higher-dose treatment. Seymour MD, Institute of Oncology, St James’s University Hospital, TRIAL REGISTRATION isrctn.org Identifier: ISRCTN44687907 University of Leeds, Leeds LS9 7TF, JAMA Oncol. 2021;7(6):869-877. doi:10.1001/jamaoncol.2021.0848 United Kingdom (matt.seymour@ Published online May 13, 2021. nihr.ac.uk). (Reprinted) 869 Research Original Investigation Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer ancerismostcommoninolderpeople.InNorthAmerica and Europe, gastroesophageal cancer is the third most Key Points C common cause of cancer death, with more than half Question Do older and/or frail patients with advanced these deaths in people over 75 years, many of whom are frail gastroesophageal cancer benefit from less intensive palliative and with comorbidities. But evidence guiding treatment for chemotherapy, and can a formal geriatric assessment assist vulnerable older patients is poor: standard chemotherapy regi- treatment decision-making? mens were developed in trials involving predominantly non- Findings This phase 3 randomized clinical trial including 2-5 frail, noncomorbid patients of median age less than 65, and 559 patients with advanced gastroesophageal cancer found that although selected older people participated they cannot be reducing the intensity of chemotherapy provided an improved assumed to fully represent the older population. patient experience with no significant detriment in cancer control. Baseline frailty, quality of life, and neutrophil/lymphocyte ratio In 2011, MRC FOCUS2, a national randomized trial de- (an inflammation marker) were predictive of outcome and may signed for frail and older patients with colorectal cancer, was contribute to treatment decisions. reported. It used reduced doses of chemotherapy and intro- duced a novel composite end point, Overall Treatment Utility Meaning Decision-making for older and/or frail patients with advanced cancer can be enhanced using geriatric assessment; (OTU), combining clinical efficacy, tolerability, and the pa- such patients generally benefit from reducing the intensity of tient’s own assessment of treatment value and acceptability. chemotherapy. In the same year we surveyed 50 gastrointestinal oncologists in the UK : 49 reported routinely treating older patients with gastroesophageal cancer with standard schedules at reduced inselectingpatients.Thekeyeligibilitycriterionwasthattheon- doses, or omitting agents. There was wide variation in practice cologist considered full-dose standard combination chemo- and no use of objective geriatric assessment (GA) to guide de- therapy (at that time epirubicin/oxaliplatin/capecitabine or cisions.Thisledto321GO,arandomizedfeasibilitytrialinwhich cisplatin/fluorouracil/trastuzumab ) unsuitable because of the older and/or frail patients with gastroesophageal cancer re- patient’sadvancedageand/orfrailty.Itwasmadecleartopatients ceived 80% doses of the standard 3-drug schedule epirubicin/ and clinicians that GO2 was a trial for older patients, but there oxaliplatin/capecitabine (EOCap), the same treatment omit- were no chronological age limits. Furthermore, since scoring ting epirubicin (OCap), or the same treatment omitting both of performance status (PS) by oncologists in older patients is epirubicin and oxaliplatin (Cap). The best balance of benefits inconsistent, afixedPSthresholdwasnotspecified,butpatients and tolerability was achieved with the OCap doublet. This trial hadtobeconsideredfitforanyofthetreatmentsintheirselected 7,8 allowed further development of the OTU end point. randomization. Patients with moderate renal/hepatic dysfunc- The GO2 randomized clinical trial takes the OCap sched- tion could be entered with dose adjustment to compensate for ule from 321GO and compares 3 dose levels, seeking the best reduced clearance. Medical comorbidity was allowed provided balance of efficacy and patient experience. For patients with the oncologist did not consider this to preclude chemotherapy. uncertainty regarding whether to use chemotherapy at all, ResponseEvaluationCriteriainSolidTumors–assessabledisease an alternative randomization compares the lowest dose level was not mandatory. vs supportive care alone. We ask whether a baseline GA may aid personalized dose selection and perhaps identify patients Randomization unlikelytobenefitfromchemotherapy.Morebroadly,GO2aims If the clinician and/or patient considered chemotherapy defi- to stimulate researchers across all cancer types to evaluate nitely indicated, patients entered the CHEMO-INTENSITY ran- patient-centered assessment, dosing, and outcome measure- domization and were allocated (1:1:1) to OCap dose Level A, B, ment for vulnerable patients. or C. Level A treatment was oxaliplatin 130 mg/m on day 1 and capecitabine 625 mg/m twice daily on days 1-21, on a 21-day cycle; Level B treatment was 80% of Level A doses; and Level C treatment was 60% of Level A doses. If the patient and cli- Methods nician agreed that best supportive care alone (BSC) would be Study Design and Participants an acceptable alternative, patients could instead enter the TheGO2trial(ISRCTN44687907)wasanacademic,multicenter, CHEMO-BSC randomization, with allocation (1:1) to OCap Level open-label randomized trial, approved by the UK National C or BSC. Randomization used an automated telephone/web ResearchEthicsService,overseenbyindependentTrialSteering system and validated minimization algorithm, with age, PS, and Data Monitoring & Ethics Committees. All participants gave metastases, histology, renal function, planned trastuzumab fully informed written consent. The study is closed and use, and center as stratification factors. The treatment alloca- follow-up is complete. The authors assume responsibility for tion was not masked from study investigators or patients. accuracy, completeness, and fidelity to the trial protocol (Supplement 1) and statistical analysis plan (Supplement 2). Procedures Eligibility criteria are detailed in the Trial Protocol. Patients The GA, aligned with the European Organization for Re- had locally advanced and/or metastatic gastroesophageal can- search and Treatment of Cancer (EORTC) Elderly Minimum cer that was not pretreated. In the absence of established objec- Data set, was administered after consent but before random- tive frailty thresholds, and given the complex interrelations of ization; results were not communicated to the clinician. It in- 13 14 frailtyandadvancedage,weusedoncologists’clinicaljudgment cluded G8, Instrumental Activities of Daily Living (IADL), 870 JAMA Oncology June 2021 Volume 7, Number 6 (Reprinted) jamaoncology.com Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer Original Investigation Research 15 16,17 Timed Up and Go test, EORTC QLQ-C30/OG25, and EQ-5D andquality-adjustedsurvival.FatiguewasscoredusingQLQ-C30 and visual analogue scale (EQ-VAS). Frailty was scored by with time-to-deterioration from randomization to a deteriora- assessing impairment (yes/no) in nine domains (weight loss, tionof16percentagepointsormore.IntheCHEMO-BSCrandom- mobility, falls, neuropsychiatric, physical functioning, social ization,theprimaryendpointwasOS;secondaryendpointswere functioning, mood, fatigue, and polypharmacy) and partici- patient-reported fatigue and QL. pants were categorized as not frail (0-1/9 domain impaired), mildly frail (2/9 domains), or severely frail (≥3/9 domains). Statistical Analysis Patients with estimated glomerular filtration rate (eGFR) In the CHEMO-INTENSITY randomization, reducing the dose of 30 to 50 mL/min or bilirubin 1.5 to 2 times the upper limit of of chemotherapy was hypothesized to provide a better patient normal received 75% of their allocated dose of capecitabine. experience without major detriment in PFS. The trial there- Patients with ERBB2 (formerly HER2)-positive cancers could fore used a PFS noninferiority design but with a relatively non- additionally receive trastuzumab. Imaging was repeated every stringent boundary, set following careful discussion at a fo- 9 weeks, and chemotherapy stopped in the event of radiologi- rumofpatientsandclinicians,whereacceptableabsolutePFS/OS cal or clinical progression, unacceptable toxic effects, or pa- losses were considered as a trade-off against toxicity. Patients tient choice. Patients allocated to BSC had access to specialist were prepared to sacrifice 6 weeks or more of PFS in return palliative care, pain and psychosocial services, blood transfu- for reduced treatment toxic effects, but clinicians were more sions,nutritionalsupport,radiotherapy,stenting,orsurgicalpro- conservative and the trial was eventually powered to exclude ceduresasindicated;chemotherapy,althoughnotplanned,was 34 days or greater reduction in median PFS from a predicted 134 allowable if it later became indicated. days,equivalenttohazardratio(HR)atorover1.34.With1-sided Overall Treatment Utility was scored once, 9 weeks after 5% significance and 80% power, this required 284 events or starting chemotherapy. It comprised computed tomography more per pairwise comparison, requiring recruitment of 501 pa- (CT) and clinical assessment of cancer progression status; toxic tients or more. In the CHEMO-BSC randomization, chemo- effects (Common Terminology Criteria for Adverse Events, therapy was hypothesized to improve OS; however, given that CTCAE) and serious adverse events (SAEs); quality of life (QL, the uptake of this randomization was not predicable at the time as scored with QLQ-C30 Global Health Status subscale), and of designing the trial, the sample size could not be predeter- patient value/acceptability, scored from 2 questions posed in mined and only exploratory analysis was planned. a questionnaire before patients received their scan results: Efficacy analyses were by intention to treat (ITT); safety “Since you started chemotherapy, how worthwhile do you and toxic effect analyses in patients who received 1 or more think your treatment has been?” and “How much has your che- dose of protocol therapy. Kaplan-Meier methods were used to motherapy interfered with your normal daily activities?” both estimate survivor functions for time-to-event end points. Cox scored “not at all/a little/quite a bit/very much.” Overall Treat- proportional hazards regression adjusted for minimization fac- ment Utility was not measurable in patients allocated BSC. tors were used to estimate HRs and CIs, using 1-sided 95% CIs Treatment beyond 9 weeks continued until CT progres- for the noninferiority comparison. Proportional hazards were sion or clinical/patient decision. Longitudinal QL comprised assessed using a permutation test of martingale residuals. No weekly EQ-VAS and every 3 weeks EQ-5D and QLQ-C30 violations were observed. Overall Treatment Utility compari- Fatigue Subscale during chemotherapy, then then once every sons used ordinal logistic regression adjusting for minimiza- 9 weeks until a year from randomization. tion factors to estimate odds ratios (ORs) and 95% CIs. ForQLsubscales,wefoundnoevidenceagainstthemissing- at-random assumption using descriptive and logistic regres- Outcomes Endpoints,conformingtothejointEORTC/Alliance/International sion analysis, so we applied multiple imputation by chained 20 26 SocietyofGeriatricOncology(SIOG)Statement, aredefinedin equations (MICE). We compared allocated groups for QL and the trial protocol (Supplement 1) and statistical analysis plan symptom subscales using multiple linear regression adjusted (Supplement 2). In the CHEMO-INTENSITY randomization the for the baseline subscale and minimization factors (excluding primaryendpointwasinvestigator-determinedprogression-free center). For fatigue we compared groups using multilevel re- survival (PFS). The key secondary end point was OTU. A score peated mixed-model analyses allowing for time effects, treat- of “Good OTU” requires no radiological or clinical evidence of ment-time interactions, baseline fatigue (fixed effects), and pa- cancer progression, no major toxic effects (a serious adverse re- tient and patient-time interaction (random effects). These action[SAR],oranygrade≥3non-hematologicaltoxicity),nosig- models were also used to estimate treatment effects and 95% nificantdeteriorationinQL(≥16percentage-pointsdropinEORTC CI. We performed sensitivity analyses for complete cases. GlobalQLsubscale )andnoadverseresponsestopatientvalue/ Subgroupanalysisusedthesamemodelmethodsasprimary acceptability questions (“not at all” worthwhile or “very much” and secondary end point comparisons, prespecified for poten- interference).PoorOTUdenotesevidenceofcancerprogression tiallyprognosticvariables:patientcharacteristics/minimization and at least 1 other negative factor (toxic effects, SAE, QL dete- factors, frailty, QL/symptoms, and laboratory tests. Tests for rioration, or poor value/acceptability), or the patient has died. heterogeneity correspond to 1 degree of freedom for 2-category IntermediateOTUmeanseithercancerprogressionwithoutany subgroups (or continuous scales), 2 degrees of freedom for othernegativefactorornegativefactorswithoutcancerprogres- 3-category subgroups, and so on. Following univariate analyses sion. Other secondary end points were toxic effects; symptoms with ordinal logistic regression, we performed multivariable (QLQ-C30/OG250);QL;RECISTresponse ;overallsurvival(OS); analysis using backward elimination including all variables, jamaoncology.com (Reprinted) JAMA Oncology June 2021 Volume 7, Number 6 871 Research Original Investigation Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer Figure 1. CONSORT Diagrams CONSORT diagram for the CHEMO-INTENSITY pathway 514 Patients were randomized in the CHEMO-INTENSITY pathway 170 Randomized to Level A 171 Randomized to Level B 173 Randomized to Level C 161 Received Level A 163 Received Level B 168 Received Level C 9 Received no treatment 8 Received no treatment 5 Received no treatment 170 Included in ITT analysis 171 Included in ITT analysis 173 Included in ITT analysis 142 Progressed or died 147 Progressed or died 149 Progressed or died 28 Alive and progression-free 24 Alive and progression-free 24 Alive and progression-free CONSORT diagram for the CHEMO-BSC pathway 45 Patients were randomized in the CHEMO-BSC pathway 23 Randomized to Level C 22 Randomized to BSC 18 Received Level C 5 Received no treatment A, CONSORT diagram for the CHEMO-INTENSITY pathway. 23 Included in ITT analysis 22 Included in ITT analysis B, CONSORT diagram for the CHEMO-BSC pathway. Treatment pathways are detailed in the 17 Died 20 Progressed or died Randomization section of Methods. 6 Alive 2 Alive BSC indicates best supportive care alone; ITT, intention to treat. irrespectiveofunivariateresult.Finally,weconstructedanomo- CHEMO-INTENSITY Randomization gram using a transformation of the linear predictor to a scale In the ITT analysis, both lower doses satisfied the prespecified estimating the probability of each OTU outcome. trial definition of noninferior PFS compared with Level A; nei- P values for superiority comparisons are 2-sided and con- ther CI crosses the HR boundary of 1.34 (Figure 2). A total of 438 sidered significant at an overall significance level of 5%. All (85%) patients experienced PFS events, with HR = 1.09 (95% CI, other analyses are described in the statistical analysis plan 0.89-1.32) for B vs A and HR = 1.10 (95% CI, 0.90-1.33) for C vs A. (Supplement 2). For analysis, SAS version 9.4 (SAS Institute) After 373 (73%) deaths, there is no evidence that higher-dose and R version 3.2.3 (R Project) were used. treatment improved OS: B vs A HR = 1.09 (95% CI, 0.88-1.36); C vs A HR = 1.14 (95% CI, 0.92-1.41) (Figure 2). No subgroup was identifieddemonstratingclearbenefitwithLevelAforeitherPFS or OS (eFigures 1-4 in Supplement 3). Among the 349 (68%) Results RECIST-assessable patients there was a lower response rate A total of 514 patients entered the CHEMO-INTENSITY and 45 (CR/PR) in Level B, but not Level C (B vs A OR = 0.53 [90% CI, entered the CHEMO-BSC randomization, between January 0.33-0.85]; C vs A HR = 0.63 [90% CI, 0.36-1.11]), with little dif- 2014 and November 2017, at 61 UK medical centers (Figure 1; ferenceindiseasecontrol(CR/PR/SD)(eTable11inSupplement3). eTable 1 in Supplement 3); cutoff date was February 2019. Slow ResultsforPFSweresimilarintheper-protocolanalysis(n = 492), recruitment in some centers was attributed to patients opting withHR = 1.09(95%CI,0.89-1.34)forBvsAandHR = 1.10(95% for the lower dose levels off-trial. Populations were well- CI, 0.90-1.34) for C vs A (eFigure 13 in Supplement 3). balanced within each randomization but differed between the Overall Treatment Utility, assessed in all 514 patients by two, with CHEMO-BSC patients having higher rates of poor PS ITT, was good in 196 patients (38%), intermediate in 149 (29%), andseverefrailty,drivenespeciallybyimpairedADL,lowmood and poor in 169 (33%). Level C produced more good (43%) and and social care requirements (Table 1;eTable2in Supple- fewer poor (29%) OTU outcomes than A or B, but these differ- ment 3). Of the total 559 patients, 44 (8%) were neither frail ences were not statistically significant (eFigure 1 in Supple- nor aged over 75 years, reflecting the flexibility of the selec- ment 3). Other patient experience end points also trended tion criteria (eTable 3 in Supplement 3). toward better outcomes with lower doses (eTables 4-9 in 872 JAMA Oncology June 2021 Volume 7, Number 6 (Reprinted) jamaoncology.com Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer Original Investigation Research Table 1. Baseline Patient Characteristics No. (%) a a CHEMO-INTENSITY pathway CHEMO-BSC pathway Level A Level B Level C Level C BSC Treatment allocation (n = 170) (n = 171) (n = 173) (n = 23) (n = 22) Age, median (range), y 76 (57-96) 76 (51-91) 77 (56-88) 79 (66-89) 78.5 (58-88) Male gender 131 (77) 129 (75) 125 (72) 14 (61) 13 (59) WHO performance status 0 27 (16) 23 (13) 22 (13) 0 0 1 90 (53) 94 (55) 95 (55) 9 (39) 6 (27) 2 49 (29) 47 (27) 52 (30) 11 (48) 14 (64) >2 3 (1.8) 7 (4.1) 3 (1.7) 3 (13) 2 (9.1) Frailty Not frail (0-1 domains) 23 (14) 30 (18) 41 (24) 2 (8.7) 1 (4.5) Slightly frail (2 domains) 44 (26) 45 (26) 32 (18) 5 (22) 6 (27) Severely frail (≥3 domains) 103 (61) 96 (56) 100 (58) 16 (70) 15 (69) Frailty/age Age ≥75 y and frail 74 (44) 81 (47) 71 (41) 15 (65) 16 (73) Age ≥75 y and nonfrail 16 (9) 15 (9) 20 (12) 1 (4) 1 (4) Age <75 y and frail 73 (43) 60 (35) 61 (35) 6 (26) 5 (23) Age <75 y and nonfrail 7 (4) 15 (9) 21 (12) 1 (4) 0 Squamous histology 20 (12) 18 (11) 20 (12) 4 (17) 5 (23) Site of primary tumor Esophagus 55 (32) 73 (43) 69 (40) 13 (57) 9 (49) GO junction 50 (29) 34 (20) 39 (23) 4 (17) 4 (18) Gastric 64 (38) 64 (37) 64 (37) 6 (26) 9 (41) Distant metastases 115 (68) 118 (69) 121 (70) 11 (48) 10 (46) Trastuzumab use 7 (4.1) 10 (5.8) 10 (5.8) 0 0 Individual domains contributing to the Frailty Score BMI<18.5 7 (4.1) 13 (7.6) 11 (6.4) 2 (8.7) 6 (27) Abbreviations: ADL, activities of daily Weight loss 92 (54) 94 (55) 85 (49) 11 (48) 10 (45) living; BMI, body mass index; Mobility (TUGT) 103 (61) 91 (53) 95 (55) 19 (83) 14 (64) WHO, World Health Organization; Falls 8 (4.7) 9 (5.3) 7 (4.0) 2 (8.7) 0 TUGT, Timed Up and Go Test. BMI is Cognition 22 (13) 25 (15) 26 (15) 4 (17) 3 (14) calculated as weight in kilograms divided by height in meters squared. Function (ADL) 97 (57) 97 (57) 100 (58) 16 (70) 19 (86) Treatment pathways are detailed in Social care 0 2 (1.2) 1 (0.6) 23 (100) 21 (95) the Randomization section of Mood 2 (1.2) 4 (2.3) 3 (1.7) 21 (91) 22 (100) Methods. Fatigue 42 (25) 42 (25) 42 (24) 5 (22) 7 (32) For frailty definitions, see the trial Polypharmacy 127 (75) 129 (75) 116 (67) 19 (83) 14 (64) protocol (Supplement 2). Supplement 3). Time-to-deterioration of fatigue favored Level respectively, and 30 (18%), 36 (21%), and 47 (27%) went on to C (C vs A HR = 0.88 [95% CI, 0.65-1.19]). Global QL (EORTC receive 6 or more cycles. Second-line therapy was recorded Core Quality of Life questionnaire, QLQ-C30, and EuroQoL-5 in 23 (14%), 18 (11%), and 24 (14%) patients. Dimension, EQ-5D) improved between baseline and 9 weeks with Levels B and C, but not A (eFigures 4-7 in Supple- CHEMO-BSC Randomization ment 3). Longitudinal fatigue and QL showed no major differ- A total of 45 patients entered the CHEMO-BSC randomization. ences. Cancer symptoms improved between baseline and Inthoseallocatedchemotherapy,toxicitywashigherthaninpa- 9 weeks in all arms similarly (eFigures 8-12 in Supplement 3). tients allocated the same dose level in the CHEMO-INTENSITY The rate of toxic effects fell markedly with reducing dose randomization (Table 2). Longer OS was observed with chemo- levels (Table 2). Consequently, treatment delivery was more therapy than with BSC, but the difference was not statistically reliable: during the first three 3-week cycles, comparing Lev- significant (HR = 0.69 [95% CI, 0.35-1.48]). Both QL and els A, B, and C, a dose reduction was required in 63 (39%), fatigue were nonsignificantly better with chemotherapy than 39 (24%), and 21 (13%) patients, respectively; 53 (33%), 47 BSC (eFigure 8 and eFigure 9 in Supplement 3). (29%), and 34 (20%) patients stopped treatment wholly or partly owing to toxicity, and 51 (32%), 72 (44%), and 97 (58%) Baseline Predictors of OTU patients respectively completed their first 3 cycles without Univariate analysis in all 537 patients allocated chemo- reduction or stoppage (eTable 15 in Supplement 3). Mean (SD) therapy identified the following baseline factors associated treatment duration was 4.4 (3.3), 4.6 (4.0), and 5.4 (4.1) cycles, with worse OTU (P ≤ .05): distant metastases, raised B-type jamaoncology.com (Reprinted) JAMA Oncology June 2021 Volume 7, Number 6 873 Research Original Investigation Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer Figure 2. Survival Curves A CHEMO-INTENSITY progression-free survival 1.0 Level A 0.8 Level B Level C 0.6 0.4 0.2 0 1 23 4 561 7 8 90 11 12 13 Time since randomization, mo No. at risk Level A 170 153 137 110 100 76 64 38 32 26 23 20 12 0 Level B 171 157 126 97 85 66 58 40 34 27 23 20 8 0 Level B 173 156 125 107 100 79 64 42 31 24 22 17 7 0 B CHEMO-INTENSITY overall survival 1.0 Level A 0.8 Level B Level C 0.6 0.4 0.2 0 1 23 4 561 7 8 90 11 12 13 Time since randomization, mo No. at risk Level A 170 159 145 136 125 115 98 83 66 61 53 48 32 0 Level B 171 163 145 127 113 95 87 78 72 62 50 39 25 0 Level B 173 167 148 131 123 112 97 90 77 64 56 43 31 0 C CHEMO-BSC overall survival 1.0 BSC 0.8 BSC/Level C 0.6 0.4 0.2 A, CHEMO-INTENSITY progression-free survival. B, CHEMO-INTENSITY overall 0 1 23 4 561 7 8 90 11 12 13 survival. C, CHEMO-BSC overall Time since randomization, mo survival. Treatment pathways are No. at risk detailed in the Randomization BSC 22 20 15 10 8 7 5 3 2 2 210 BSC/Level C 23 17 15 14 13 13 12 10 9 7 666 0 section of Methods. BSC indicates best supportive care alone. natriuretic peptide (BNP) or N-terminal prohormone of brain can be used to calculate a predictive score: (0.27 if not se- natriuretic peptide (NT-proBNP), leukocytosis, raised neutro- verely frail) + (0.39 if EQ-VAS ≥ 50) + (0.34 if NLR ≤ 4.0). This phil to lymphocyte ratio (NLR), hypoalbuminaemia, raised score (range 0-1) translates into the probability of good, inter- urea, severe frailty (dementia, activities of daily living [ADL], mediate, or poor OTU at 9 weeks (eTable 10 and eTable 11 and polypharmacy domains), poor global QL, and impaired in Supplement 3). Thus, a slightly frail patient with baseline taste (eFigure 1 in Supplement 3). EQ-VAS = 55 and NLR = 3.0 (predictive score = 1) has a 44% In multivariable analysis, baseline frailty, EQ5D-VAS, and probability of good and 27% probability of poor OTU. Con- NLR were independently associated with OTU. These factors versely, a severely frail patient with baseline EQ-VAS = 45 and 874 JAMA Oncology June 2021 Volume 7, Number 6 (Reprinted) jamaoncology.com Proportion alive Proportion alive Proportion alive and progression free Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer Original Investigation Research Table 2. Toxic Effects Reported Within 9 Weeks of Starting Chemotherapy Randomization, No. (%) a a CHEMO-INTENSITY CHEMO-BSC Allocation Level A (n = 162) Level B (n = 162) Level C (n = 168) Level C (n = 18) Max CTCAE grade (week 1-9) ≥2 ≥3 ≥2 ≥3 ≥2 ≥3 ≥2 ≥3 Nausea or vomiting 47 (29) 14 (8.6) 33 (20) 8 (4.9) 29 (17) 12 (7.1) 2 (11) 0 Anorexia 45 (28) 11 (6.7) 46 (28) 14 (8.6) 32 (19) 3 (1.8) 13 (17) 0 Diarrhea 34 (21) 10 (6.2) 19 (12) 10 (6.2) 7 (4.2) 3 (1.8) 1 (5.6) 1 (5.6) Peripheral neuropathy 24 (15) 4 (2.5) 11 (6.7) 1 (0.6) 6 (3.6) 1 (0.6) 2 (11) 0 Fatigue 86 (53) 24 (15) 72 (44) 20 (12) 67 (40) 18 (11) 6 (33) 4 (22) Infection 7 (4.3) 4 (2.5) 15 (9.3) 9 (5.6) 5 (3.0) 1 (0.6) 0 0 Thrombosis 5 (3.1) 5 (3.1) 4 (2.5) 3 (1.9) 3 (1.8) 2 (1.2) 2 (11) 2 (11) Any nonhematological 125 (77) 62 (38) 116 (72) 58 (36) 101 (60) 38 (23) 10 (56) 7 (39) WBC/neutrophils (×10 /l) 10 (6.2) 1 (0.6) 3 (1.9) 0 5 (3.0) 1 (0.6) 0 0 Anaemia 26 (16) 1 (0.6) 33 (20) 6 (3.7) 22 (13) 3 (1.8) 2 (11) 0 Any hematological 33 (20) 3 (1.9) 36 (22) 6 (3.7) 27 (16) 4 (2.4) 2 (11) 0 Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; “Any nonhematological” is defined as any of the following: nausea, vomiting, WBC, white blood cell count. anorexia, stomatitis, diarrhea, hand-foot syndrome, peripheral neuropathy, a fatigue, infection, thrombosis, or dehydration. Treatment pathways are detailed in the Randomization section of Methods. b “Any hematological” is defined as any of the following: low white blood cell Maximum CTCAE grade experienced weeks 1-9 in patients receiving1 cycle count, low neutrophils/granulocytes, low platelets, or anemia. of their allocated chemotherapy. Individual listings are shown for more common toxic effects. NLR = 5.0 (score = 0) has only 18% probability of good OTU but In designing GO2, decisions were necessary for patient se- 57% probability of poor OTU. lection, treatment, and statistical design, all of which may be In the CHEMO-INTENSITY randomization (n = 514), inter- debated. For example, previous trials could not characterize action was seen between the multivariable predictive score and patients who were not included, but it was precisely those pa- doselevel(P = .01)withgreaterincrementalbenefitoflower-dose tients who were to be selected for GO2. It was therefore nec- treatment in patients with better baseline scores: thus a patient essary to use clinicians’ experience, rather than an objective with score = 1 allocated to Level C has 68% probability of good, tool, to offer trial entry to patients they assessed as unsuited 20% intermediate, and 12% poor OTU, but if the same patient to full-dose combination chemotherapy but able to receive is allocated Level A these probabilities are 41%, 30%, and 29%. reduced-intensity treatment. No baseline score was identified as predicting better OTU with EventhehighestdoseinGO2,LevelA,wasless-than-standard higher-dose treatment (eTables 12-14 in Supplement 3). treatment, comprising just 2 drugs from the standard EOCap triplet. Althoughthisincludesfull-doseoxaliplatin,itiscombined withlow-dosecontinuouscapecitabineratherthantheintensive intermittent schedule typically used in doublet therapy. Level C Discussion thereforerepresentsjust60%of2outof3drugs,around40% The GO2 randomized clinical trial is the first large trial testing of full standard dose intensity. It is also important to recognize the relationship between treatment intensity and patient- that Level A, although a reference schedule for this trial, is not focused outcomes in frail and/or older patients with cancer. standard therapy; indeed, the stimulus for the trial was a survey Previous reports have studied older patients who were fit showing that there is no standard for this population. For this enough to enter all-comer trials, or relied on traditional ef- reason we did not apply the typical stringent noninferiority ficacy and safety end points. The GO2 trial uses modern boundarydemandedbyregulators,butwereinsteadabletowork methods and studies patients—the older frail, older nonfrail, with patients and clinicians to carefully balance the competing and younger frail—who rarely participate in trials. In re- needs for cancer control and good tolerability. sponse to calls to address the deficit in evidence guiding treat- One mechanism for retaining cancer control despite lower ment of vulnerable cancer patients, we offer GO2 as an ex- doses is avoidance of toxicity-induced treatment reductions emplar of real-world, patient-centered research. and stoppages. Toxic effects leading to treatment modifica- Lower-dose chemotherapy improved patients’ experi- tion may be accepted by oncologists as part of standard on- ence without compromising anticancer control. This balance cology practice, but it represents a negative experience for pa- is captured in OTU, an objective measure of a virtual conver- tients and detracts from both quality of life and cancer control; sation between physician and patient and reflecting their joint and these impacts are particularly heightened in patients with assessment of treatment value: “With the benefit of hind- poor baseline reserve. Only 32% patients starting Level A were sight, am I glad I recommended this treatment?” and “Am I glad able to receive 3 cycles without reduction or stoppage, com- that I accepted it?” The GO2 trial also demonstrates that a base- pared with 58% with Level C. line GA can contribute to the doctor-patient decision by esti- The GO2 trial aimed to develop dose individualization mating an individual’s probability of better or worse OTU. guided by baseline geriatric assessment: we anticipated fitter jamaoncology.com (Reprinted) JAMA Oncology June 2021 Volume 7, Number 6 875 Research Original Investigation Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer patients would benefit from higher-dose treatment; however, should embrace the newer concept of Comprehensive Geri- we did not identify any group for whom the higher doses are atric Assessment (CGA): both identification of vulnerabilities preferable. Using the OTU outcome measure, reflecting the bal- and active remedial management to correct them. An out- ance of benefits and harms, goes beyond conventional single- standing research question is whether CGA-based pre- outcome models looking at survival or toxicity in isolation. habilitation will convert a patient from low to high probabil- In so doing, GO2 challenges a pervading assumption of oncol- ity of achieving good OTU. ogy: that within the bounds of tolerability more is better. We hope it will stimulate research exploring lower-dose chemo- therapy, perhaps extending to younger and less frail patients. Conclusion We hope also that those designing trials of novel agents, includ- ing registration studies, will consider the option of lower-dose The GO2 clinical trial shows that the goals of palliative chemotherapyasthereferenceorplatformtowhichnovelagents chemotherapy in the older and/or frail population, includ- are added, to widen access to these trials. ing but not limited to cancer control, may be better achieved The 3-month survival benefit seen in the CHEMO-BSC using treatment at doses well below those currently randomization, though nonsignificant in isolation as a conse- regarded as standard. Careful baseline geriatric health quence of small numbers and an imbalance in patient charac- assessment in the oncology clinic can help predict the likeli- teristics, concurs with previous data and supports consid- hood of achieving those goals, and so contribute to patients’ eration of low-dose chemotherapy in vulnerable patients. and clinicians’ treatment decisions. Assessing the outcome This should, however, be interpreted alongside the baseline of cancer treatment should be multidimensional, including predictor, which helps identify patients at high risk of poor its value to patients and its adverse effects, and we recom- treatment utility, for whom BSC may be a preferable path. mend further development of OTU to capture this complex- ity. The GO2 trial offers a design paradigm for enhancing older patients’ access to research and ensuring that our Limitations A limitation of GO2 is that our GA was purely observational. evidence base embraces the whole population that we Implementation of these findings—and future research— serve. ARTICLE INFORMATION Health Board, Bangor, United Kingdom (Garcia); Statistical analysis: Hall, Cairns, Roy, Marshall, Ow, The Christie National Health Service Foundation Seymour. Accepted for Publication: March 4, 2021. Trust, Manchester, United Kingdom (Waddell); Obtained funding: Hall, Marshall, Howard, Seymour.. Published Online: May 13, 2021. Worcestershire Acute Hospitals National Health Patient participant perspectives: Allmark. doi:10.1001/jamaoncol.2021.0848 Service Trust, Worcester, United Kingdom (Guptal); Conflict of Interest Disclosures: Dr Hall reported Open Access: This is an open access article Guys and St Thomas’s National Health Service grants from Cancer Research UK during the conduct distributed under the terms of the CC-BY License. Foundation Trust, London, United Kingdom of the study and institutional research funding from © 2021 Hall PS et al. JAMA Oncology. (Maisey); York Teaching Hospital National Health Novartis, Pfizer, Eli Lilly, Daiichi-Sanchyo, and Eisai Service Foundation Trust, Scarborough, United Author Affiliations: University of Leeds, Leeds, outside the submitted work. Dr Waters reported Kingdom (Khan); Calderdale and Huddersfield United Kingdom (Hall, Cairns, Ruddock, Katona, nonfinancial support from Ipsen and Mylan outside National Health Service Foundation Trust, Marshall, Grabsch, Velikova, Ow, Handforth, the submitted work. Dr Petty reported personal fees Huddersfield, United Kingdom (Dent); University Howard, Seymour); University of Edinburgh, from Eli Lilly, Bristol Myers Squib, and Servier, and of Oxford, Oxford, United Kingdom (Lord); Edinburgh, United Kingdom (Hall); Leeds Teaching grants from AstraZeneca, Roche, Sanofi, Merck Sharp Maastricht University Medical Center, Maastricht, Hospitals National Health Service Trust, United & Dohme, Five Prime Therapeutics, and Jansen the Netherlands (Grabsch). Kingdom (Swinson, Crossley, Seymour); Maidstone outside the submitted work. Dr Wadsley reported and Tunbridge Wells National Health Service Trust, Author Contributions: Drs Seymour and Hall had grants, personal fees, and nonfinancial support from Maidstone, United Kingdom (Waters); University of full access to all of the data in the study and take AstraZeneca, personal fees and nonfinancial support Dundee, Dundee, United Kingdom (Petty); Bristol responsibility for the integrity of the data and the from Sanofi-Genzyme, and personal fees from Oncology Centre, Bristol, United Kingdom (Falk); accuracy of the data analysis. Novartis (AAA), Lilly, Roche, Eisai, Ipsen, and Celgene Concept and design: Hall, Swinson, Petty, Allmark, outside the submitted work. Dr Chatterjee reported Weston Park Cancer Centre, Sheffield, United Kingdom (Wadsley); Hull University Hospitals Lord, Marshall, Velikova, Seymour. personal fees from Pfizer and AstraZeneca and travel National Health Service Trust, Hull, United Kingdom Recruitment of participants; acquisition, analysis, or grant and accommodation for attending educational (Roy); Royal United Hospitals Bath, Bath, United interpretation of data: Hall, Swinson, Cairns, meeting from Roche and Leo Pharma. Dr Waddell Kingdom (Tillett); North Cumbria University Waters, Petty, Ruddock, Falk, Wadsley, Roy, Tillett, reported research funding, travel expenses, Hospitals National Health Service Trust, Carlisle, Nicol, Cummins, Joseph, Grumett, Stokes, honoraria and advisory board fees from Bristol Myers United Kingdom (Nicoll); Royal Surrey County Kamposioras, Chatterjee, Garcia, Waddell, Gupta, Squibb, research funding, honoraria and advisory Hospital National Health Service Foundation Trust, Maisey, Khan, Dent, Lord, Crossley, Katona, board fees from Pfizer, honoraria and travel expenses Guildford, United Kingdom (Cummins); The Royal Marshall, Grabsch, Velikova, Ow, Handforth, from EUSA pharma, travel expenses, honoraria and Wolverhampton National Health Service Trust, Howard, Seymour. advisory board fees from Ipsen, funding and advisory Wolverhampton, United Kingdom (Mano); The Drafting of the manuscript: Hall, Swinson, Cairns, board fees from Eisai Research, Research grant and Dudley Group National Health Service Foundation Seymour. advisory board fees from Merck Sharpe & Dohme, Trust, Dudley, United Kingdom (Grumett); United Critical revision of the manuscript for important and research funding and advisory board fees from Lincolnshire Hospitals National Health Service intellectual content: Hall, Swinson, Cairns, Waters, Roche Research outside the submitted work. Dr Lord Trust, Lincoln, United Kingdom (Stokes); Mid Petty, Allmark, Ruddock, Falk, Wadsley, Roy, Tillett, reported funding of clinical trial activities from the Yorkshire Hospitals National Health Service Trust, Nicol, Cummins, Joseph, Grumett, Stokes, National Institute for Health Research during the Wakefield, United Kingdom (Konstantinos-Velios); Kamposioras, Chatterjee, Garcia, Waddell, Gupta, conduct of the study; personal fees from Eisai, The Shrewsbury and Telford Hospital National Maisey, Khan, Dent, Lord, Crossley, Katona, Prosigna, Roche, and Shionogi; grants from Pathios Health Service Trust, Shrewsbury, United Kingdom Marshall, Grabsch, Velikova, Ow, Handforth, Therapeutics; travel, accommodation, expenses (Chatterjee); Betsi Cadwaladr University Local Howard, Seymour. from Pfizer; travel, accommodation, expenses from 876 JAMA Oncology June 2021 Volume 7, Number 6 (Reprinted) jamaoncology.com Efficacy of Reduced-Intensity Chemotherapy Among Older and Frail Patients With Advanced Gastroesophageal Cancer Original Investigation Research Roche; travel, accommodation, expenses, and other fluorouracil, leucovorin, and irinotecan versus module, the EORTC QLQ-OG25, to assess from Sython; and travel, accommodation, and other epirubicin, cisplatin, and capecitabine in advanced health-related quality of life in patients with cancer gastric adenocarcinoma: a French intergroup of the oesophagus, the oesophago-gastric junction expenses from Piqur Therapeutics outside the (Fédération Francophone de Cancérologie and the stomach. Eur J Cancer. 2007;43(14): submitted work; in addition, Dr Lord had a patent Digestive, Fédération Nationale des Centres de 2066-2073. doi:10.1016/j.ejca.2007.07.005 for Mitox Therapeutics issued related to role as Lutte Contre le Cancer, and Groupe Coopérateur co-founder of biotech company. Dr Marshall reported 18. Kind P. The EuroQoL instrument: an index of Multidisciplinaire en Oncologie) study. J ClinOncol. grants from Cancer Research UK during the conduct health-related quality of life. In Spiker B, ed. Quality 2014;32:3520-3526. doi:10.1200/JCO.2013.54.1011 of the study. Dr Grabsch reported personal fees from of life in pharmacoeconomicsin clinical trials. 2nd ed. 6. Seymour MT, Thompson LC, Wasan HS, et al; Philadelphia: Lippincott-Raven; 1996. Merck Sharpe & Dohme outside the submitted work. FOCUS2 Investigators; National Cancer Research Dr Velikova reported personal fees from Roche, Eisai, 19. Handforth C, Clegg A, Young C, et al. Institute Colorectal Cancer Clinical Studies Group. Novartis, and Seattle Genetics, and grants from The prevalence and outcomes of frailty in older Chemotherapy options in elderly and frail patients Breast Cancer Now, European Organisation for cancer patients: a systematic review. Ann Oncol. with metastatic colorectal cancer (MRC FOCUS2): Research and Treatment of Cancer, Yorkshire Cancer 2015;26(6):1091-1101 doi:10.1093/annonc/mdu540 an open-label, randomised factorial trial. Lancet. Research, and Pfizer outside the submitted work. 20. Wildiers H, Mauer M, Pallis A, et al. End points 2011;377(9779):1749-1759. doi:10.1016/S0140-6736 Dr Howard reported grants from Cancer Research UK and trial design in geriatric oncology research: (11)60399-1 during the conduct of the study; grants from Bristol a joint European organisation for research and 7. Hall PS, Lord SR, Collinson M, et al. A randomised Myers Squibb, Servier, and Roche; and nonfinancial treatment of cancer—Alliance for Clinical Trials in phase II trial and feasibility study of palliative support from AstraZeneca and Sanofi outside the Oncology—International Society Of Geriatric chemotherapy in frail or elderly patients with submitted work. Dr Seymour reported grants from Oncology position article. J Clin Oncol. 2013;31(29): advanced gastroesophageal cancer (321GO). Br J 3711-3718. doi:10.1200/JCO.2013.49.6125 Cancer Research UK during the conduct of the study. Cancer. 2017;116(4):472-478. doi:10.1038/bjc.2016.442 No other disclosures were reported. 21. US Food and Drug Administration. Guidance for 8. Handforth C, Hall P, Marshall H, Seymour M. industry: clinical trial endpoints for the approval of Funding/Support: This trial ran within the UK Overall treatment utility: a novel outcome measure cancer drugs and biologics. Federal Register. May 16, National Health Service and was supported by the to convey the balance of benefits and harms from 2007. https://www.federalregister.gov/documents/ National Institute for Health Research (NIHR) cancer treatment. J Geriatr Oncol. 2013 4:S49. 2007/05/16/E7-9345/guidance-for-industry-on- Clinical Research Network. doi:10.1016/j.jgo.2013.09.064 clinical-trial-endpoints-for-the-approval-of-cancer- Role of the Funder/Sponsor: Cancer Research UK 9. Bang YJ, Van Cutsem E, Feyereislova A, et al; drugs-and-biologics had no role in the design and conduct of the study; ToGA Trial Investigators. Trastuzumab in 22. Knobel H, Loge JH, Brenne E, Fayers P, collection, management, analysis, and combination with chemotherapy versus Hjermstad MJ, Kaasa S. 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Clinical randomized, multicenter, phase III study of and psychometric validation of a questionnaire jamaoncology.com (Reprinted) JAMA Oncology June 2021 Volume 7, Number 6 877 j . c. w ebst er @leed s. ac. u k non-inferiority of progression-free survival superiority of patient-reported EORTC fatigue, QoL (EQ-5D/QLQ-C30) & symptom scores superiority of OTU) regression analysis superiority for overall survival superiority for patient-reported EORTC fatigue & QoL (EQ-5D/QLQ-C30) Please ensure that you have completed the Eligibility Checklist (F01), Nurse completed CHA (F02) and Randomisation (F03) CRFs, and the patient has completed the baseline QOL CHA questionnaire before telephoning Brain Natriuretic Peptide The ratio of non-fit:fit patients with colorectal cancer is therefore 5:8 i.e. 63% “some information is better than none when patients are faced with treatment decisions” Best-case scenario: Worst-case scenario: Y Y P ) P P Y ) P ) P ) P P ) P ) P ) P ) P P ) P ) P ) P P P ) P P ) P ) P ) P A ) P ) P ) P ) ) P P ) P ) P P Y ) P ) P ) P ) P P ) P ) P ) P ) P ) P ) P ) P ) P "With the benefit of hindsight, are you glad you gave this treatment?" "With the benefit of hindsight, are you glad you received it?" "How much has your treatment interfered with your normal daily activities?" "How worthwhile do you think your treatment has been?" "How much has your treatment interfered with your normal daily activities?" "How worthwhile do you think your treatment has been?" Briefly justify the risk category selected and your conclusions below (where the table is completed in detail the detail need not be repeated, however a summary should be given): 2.1 Chemotherapy intensity comparison 2.2 Chemotherapy vs. BSC comparison (exploratory) Chemotherapy intensity comparison Chemotherapy vs. BSC comparison (exploratory) The ratio of non-fit:fit patients with colorectal cancer is therefore 5:8 i.e. 63% “some information is better than none when patients are faced with treatment decisions” 2.1 Chemotherapy intensity comparison 2.2 Chemotherapy vs. BSC comparison (exploratory) How much has your treatment interfered with your normal daily activities? How worthwhile do you think your treatment has been? Very much/quite a bit Not at all Very much/quite a bit Not at all Very much/quite a bit Not at all Very much/quite a bit Not at all Chemotherapy intensity comparison Chemotherapy vs. BSC comparison (exploratory) http://info.cancerresearchuk.org/cancerstats Br J Surg http://www.macmillan.org.uk/Documents/AboutUs/Health_professionals/OlderPeoplesProject/CancerSe rvicesComingofAge.pdf N Engl J Med J Clin Oncol Cancer J Clin Oncol Lancet Lancet Statistical power analysis for the behavioural sciences J Eval Clin Pract J Clin Oncol International journal of environmental research and public health European Journal of Cancer Journal of the National Cancer Institute "With the benefit of hindsight, are you glad you gave this treatment?" "With the benefit of hindsight, are you glad you received it?" "How much has your treatment interfered with your normal daily activities?" "How worthwhile do you think your treatment has been?" "How much has your treatment interfered with your normal daily activities?" "How worthwhile do you think your treatment has been?" Supplemental Online Content: Nonauthor Collaborators *Indicates required information. Only first name, last name, and suffix will appear in PubMed. Group Name(s):* The GO2 Trial Investigators First Name and Last Name* Suffix Academic Institution Location (city, Role or Contribution, eg, chair, Group (if more than 1 Middle Initial(s)* (eg, Jr, Degrees state/province, country) principal investigator Group listed in the III)* byline) and/or Subgroup (eg, Steering Committee) Eleanor James Sherwood Forest NHS Foundation Trust Nottingham, UK Recruiting Centre PI Sue Cheeseman Bradford Teaching Hospitals NHS Foundation Trust Bradford, UK Recruiting Centre PI Norfolk and Norwich University Hospitals NHS Foundation Trust Tom Roques Norwich, UK Recruiting Centre PI Nick Reed Imperial College Healthcare NHS Trust London, UK Recruiting Centre PI Charles Candish Gloucestershire Hospitals NHS Foundation Tru Gloucester, UK Recruiting Centre PI University Hospitals of Morecambe Bay NHS Foundation Trust David Fyfe Lancaster, UK Recruiting Centre PI Kim Last York Teaching Hospitals Foundation Trust York, UK Recruiting Centre PI Richard Ellis Royal Cornwall NHS Trust Truro, UK Recruiting Centre PI NHS Grampian, Aberdeen Lesley Samuel Aberdeen, UK Recruiting Centre PI Rebecca Herbertson Western Sussex Hospitals NHS Foundation Trust Brighton, UK Recruiting Centre PI Louise Medley South Devon Healthcare NHS Trust, Torbay, UK Recruiting Centre PI Oxford University Hospitals NHS Trust, Kinnari Patel Oxford, UK Recruiting Centre PI David Sherriff Plymouth Hospitals NHS Trust Plymouth, UK Recruiting Centre PI Angus Robinson East Sussex Healthcare NHS Trust Brighton, UK Recruiting Centre PI Blackpool Teaching Hospitals NHS Trust Pavel Bezecny Preston, UK Recruiting Centre PI Dunca Wilkins Betsi Cadwaldr University LHB Clwyd, UK Recruiting Centre PI Adam McGeoch Hinchingbrooke Healthcare NHS Trust Huntingdon, UK Recruiting Centre PI Barts Cancer Institute Daniel Propper London, UK Recruiting Centre PI Olwyn Williams Ysbyty Gwynedd Bangor, UK Recruiting Centre PI Serena Hilman Western Area Healthcare Trust, Bristol, UK Recruiting Centre PI Barking, Havering & Redbridge University Hospitals NHS Trust Sherif Raouf London, UK Recruiting Centre PI Claire Hobbs Great Western Hospitals NHS Foundation Trust Swindon, UK Recruiting Centre PI Jo Parkinson The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust Bournemouth, UK Recruiting Centre PI South Tees Nick Wadd Hospitals NHS Foundation Trust Middlesborough, UK Recruiting Centre PI Milton Keynes Hospital NHS Trust W Saku Milton Keynes, UK Recruiting Centre PI Victori Kunene Walsall Healthcare NHS Trust Birmingham, UK Recruiting Centre PI Colin Askill Abertawe Bro Morgannwg NHS Trust Swansea, UK Recruiting Centre PI Mid Cheshire Hospitals Foundation Trust Arshad Jamil Crewe, UK Recruiting Centre PI Emma Cattell Taunton and Somerset NHS Foundation Trust Taunton, UK Recruiting Centre PI Lauren Gorf Dorset Country Hospitals NHS Foundation Trust Dorset, UK Recruiting Centre PI Singleton Hospital, Hywel Dda Health Board Vallipuram Vigneswaran Swansea, UK Recruiting Centre PI Erica Beaumont Yeovil District Hospital NHS Foundation Trust Yeovil, UK Recruiting Centre PI Syed Zubair County Durham and Darlington NHS Foundation Trust Darlington, UK Recruiting Centre PI Elin Jones Hywel Dda Health Board Haverfordwest, UK Recruiting Centre PI Nicholas Reed Wye Valley NHS Trust Cheltenham, UK Recruiting Centre PI Alaaeldin Shablak Salisbury NHS Foundation Trust Salisbury, UK Recruiting Centre PI Northern Lincolnshire and Goole NHS Foundation Trust George Bozas Hull, UK Recruiting Centre PI Sheela Rao Royal Marsden NHS Trust London, UK Recruiting Centre PI Michael Bennet University of Leeds, Institute of Health Sciences Leeds, UK TMG Member Joanne Askey Leeds Teaching Hospitals NHS Trust Leeds, UK TMG Member v 11 20 1 of 2 Supplemental Online Content: Nonauthor Collaborators *Indicates required information. Only first name, last name, and suffix will appear in PubMed. First Name and Last Name* Suffix Academic Institution Location (city, Role or Contribution, eg, chair, Group (if more than 1 Middle Initial(s)* (eg, Jr, Degrees state/province, country) principal investigator Group listed in the III)* byline) and/or Subgroup (eg, Steering Committee) Gareth Griffiths University of Southampton Southampton, UK Independent TSC Chair Sally Clive Edinburgh Cancer Centre Edinburgh, UK Independent TSC member Vanessa Potter University Hospitals Coventry and Warwickshire NHS Trust Coventry, UK Independent TSC member Jean Gall n/a n/a Independent TSC patient member Chris Twelves Leeds Teaching Hospitals NHS Trust Leeds, UK IDMC Chair Matt Sydes MRC Clinical Trials Unit, University College London, UK IDMC member Juan Valle University of Manchester Manchester, UK IDMC member Jo Webster University of Leeds, Institute of Trials Research Leeds, UK Clinical Trials Unit member Marc Jones University of Leeds, Institute of Trials Research Leeds, UK Clinical Trials Unit member Fiona Collinson University of Leeds, Institute of Trials Research Leeds, UK Clinical Trials Unit member Julia Brown University of Leeds, Institute of Trials Research Leeds, UK Clinical Trials Unit member Louise Brook University of Leeds, Institute of Trials Research Leeds, UK Clinical Trials Unit member v 11 20 2 of 2

Journal

JAMA OncologyAmerican Medical Association

Published: Jun 13, 2021

References