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Key Points Question Do older and/or frail patients with advanced gastroesophageal cancer benefit from less intensive palliative chemotherapy, and can a formal geriatric assessment assist treatment decision-making? Findings This phase 3 randomized clinical trial including 559 patients with advanced gastroesophageal cancer found that reducing the intensity of chemotherapy provided an improved patient experience with no significant detriment in cancer control. Baseline frailty, quality of life, and neutrophil/lymphocyte ratio (an inflammation marker) were predictive of outcome and may contribute to treatment decisions. Meaning Decision-making for older and/or frail patients with advanced cancer can be enhanced using geriatric assessment; such patients generally benefit from reducing the intensity of chemotherapy., This randomized clinical trial assesses the efficacy of reduced-intensity chemotherapy for patient quality of life and cancer control in the treatment of older and/or frail patients, Importance Older and/or frail patients are underrepresented in landmark cancer trials. Tailored research is needed to address this evidence gap. Objective The GO2 randomized clinical trial sought to optimize chemotherapy dosing in older and/or frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making. Design, Setting, and Participants This multicenter, noninferiority, open-label randomized trial took place at oncology clinics in the United Kingdom with nurse-led geriatric health assessment. Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable because of advanced age and/or frailty. Interventions There were 2 randomizations that were performed: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (oxaliplatin 130 mg/m2 on day 1, capecitabine 625 mg/m2 twice daily on days 1-21, on a 21-day cycle), Level B (doses 0.8 times A), or Level C (doses 0.6 times A). Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, the patient could instead enter CHEMO-BSC, comparing Level C vs best supportive care. Main Outcomes and Measures First, broad noninferiority of the lower doses vs reference (Level A) was assessed using a permissive boundary of 34 days reduction in progression-free survival (PFS) (hazard ratio, HR = 1.34), selected as acceptable by a forum of patients and clinicians. Then, the patient experience was compared using Overall Treatment Utility (OTU), which combines efficacy, toxic effects, quality of life, and patient value/acceptability. For CHEMO-BSC, the main outcome measure was overall survival. Results A total of 514 patients entered CHEMO-INTENSITY, of whom 385 (75%) were men and 299 (58%) were severely frail, with median age 76 years. Noninferior PFS was confirmed for Levels B vs A (HR = 1.09 [95% CI, 0.89-1.32]) and C vs A (HR = 1.10 [95% CI, 0.90-1.33]). Level C produced less toxic effects and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in younger or less frail patients. A total of 45 patients entered the CHEMO-BSC randomization: overall survival was nonsignificantly longer with chemotherapy: median 6.1 vs 3.0 months (HR = 0.69 [95% CI, 0.32-1.48], P = .34). In multivariate analysis in 522 patients with all variables available, baseline frailty, quality of life, and neutrophil to lymphocyte ratio were independently associated with OTU, and can be combined in a model to estimate the probability of different outcomes. Conclusions and Relevance This phase 3 randomized clinical trial found that reduced-intensity chemotherapy provided a better patient experience without significantly compromising cancer control and should be considered for older and/or frail patients. Baseline geriatric assessment can help predict the utility of chemotherapy but did not identify a group benefiting from higher-dose treatment. Trial Registration isrctn.org Identifier: ISRCTN44687907

Aim To determine if a positive circumferential resection margin (CRM) can be predicted in patients with esophageal adenocarcinoma undergoing neo-adjuvant chemotherapy prior to surgery Methods 223 patients were included in this study. Multivariable analyses of clinico-pathological and computed tomography (CT) imaging predictors were performed to evaluate the likelihood of a positive CRM at initial staging and following neoadjuvant chemotherapy, with prediction models constructed. Area under curve (AUC) with 95% confidence interval (CI) from 1000 bootstrapping was assessed. Results Advanced clinical T-stage (T3-4) (odds ratio, OR 2.93 95%CI 1.03-9.48) and poor tumor differentiation (OR 2.84, 95%CI 1.39-6.01) were independently associated with an increased risk of a positive CRM. Non response to chemotherapy as estimated by CT independently corresponded with an increased risk of CRM positivity (OR 3.38 95% CI 1.43-8.50). Additional CT evidence of local invasion/pleural thickening and higher CT tumor volume (14cm3) improved the performance of a prediction model, including all above parameters; with AUC (c-index) of 0.76 (0.68-0.83). Conclusion Combining advanced clinical T-stage, poor tumor differentiation, CT non-response to chemotherapy, higher CT tumor volume and local invasion may be helpful in selecting patients for intensification of neo-adjuvant treatment prior to resection.

Background: The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy (NAC) and surgery is contentious. In UK practice, surgical resection margin status is often used to classify patients into receiving adjuvant treatment. This study aimed to assess any survival benefit of adjuvant therapy in patients with clear resection margins. Methods: This was a retrospective collaborative cohort study combining two prospectively collected UK institutional databases of patients with oesophageal adenocarcinoma. Multivariable Cox regression and propensity matched analyses were used to compare overall and recurrence-free survival according to the adjuvant treatment. Results: Of 374 patients with clear resection margins, 221 patients (59%) had no adjuvant treatment, 137 patients (37%) had adjuvant chemotherapy and 16 patients (4%) had adjuvant chemoradiotherapy. For patients who had received NAC (290, 76%), when adjuvant chemotherapy was compared to no adjuvant treatment, hazard ratios (HRs) favoured adjuvant chemotherapy but did not reach independent significance (overall survival [OS] HR 0.65 95% confidence interval [CI] 0.40–1.06; p.0.087). Responders to NAC (Mandard 1–3) were seemingly more likely to demonstrate a survival benefit from adjuvant chemotherapy (HR 0.42 95% CI 0.15–1.11; p.1.081). Conclusions: Although no independent survival benefit was observed, the point estimates favoured adjuvant treatment, predominantly in patients with chemo-responsive tumours. Refereed/Peer-reviewed