SummaryBackgroundIn the UK, chemotherapy is the standard treatment for inoperable, locally advanced, non-metastatic pancreatic cancer. Chemoradiotherapy is also an acceptable treatment option, for which gemcitabine, fluorouracil, or capecitabine can be used as concurrent chemotherapy agents. We aimed to assess the activity, safety, and feasibility of both gemcitabine-based and capecitabine-based chemoradiotherapy after induction chemotherapy for patients with locally advanced pancreatic cancer.MethodsIn this open-label, randomised, two-arm, phase 2 trial, patients aged 18 years or older with histologically proven, locally advanced pancreatic cancer (with a tumour diameter of 7 cm or less) were recruited from 28 UK centres between Dec 24, 2009 and Oct 25, 2011. After 12 weeks of induction gemcitabine and capecitabine chemotherapy (three cycles of gemcitabine [1000 mg/m2 on days 1, 8, 15 of a 28-day cycle] and capecitabine [830 mg/m2 twice daily on days 1–21 of a 28-day cycle]), patients with stable or responding disease, tumour diameter of 6 cm or less, and WHO performance status 0–1 were randomly assigned to receive a further cycle of gemcitabine and capecitabine chemotherapy followed by either gemcitabine (300 mg/m2 once per week) or capecitabine (830 mg/m2 twice daily, Monday to Friday only), both in combination with radiation (50·4 Gy in 28 fractions). Randomisation (1:1) was done via a central computerised system and used stratified minimisation. The primary endpoint was 9-month progression-free survival, analysed by intention to treat including only those patients with valid CT assessments. This trial is registered with ISRCTN, number 96169987.Findings114 patients were registered and 74 were randomly allocated (38 to the gemcitabine group and 36 to the capecitabine group). After 9 months, 22 of 35 assessable patients (62·9%, 80% CI 50·6–73·9) in the capecitabine group and 18 of 35 assessable patients (51·4%, 39·4–63·4) in the gemcitabine group had not progressed. Median overall survival was 15·2 months (95% CI 13·9–19·2) in the capecitabine group and 13·4 months (95% CI 11·0–15·7) in the gemcitabine group (adjusted hazard ratio [HR] 0·39, 95% CI 0·18–0·81; p=0·012). 12-month overall survival was 79·2% (95% CI 61·1–89·5) in the capecitabine group and 64·2 (95% CI 46·4–77·5) in the gemcitabine group. Median progression-free survival was 12·0 months (95% CI 10·2–14·6) in the capecitabine group and 10·4 months (95% CI 8·9–12·5) in the gemcitabine group (adjusted HR 0·60, 95% CI 0·32–1·12; p=0·11). Eight patients in the capecitabine group had an objective response at 26 weeks, as did seven in the gemcitabine group. More patients in the gemcitabine group than in the capecitabine group had grade 3–4 haematological toxic effects (seven [18%] vs none, p=0·008) and non-haematological toxic effects (ten [26%] vs four [12%], p=0·12) during chemoradiation treatment; the most frequent events were leucopenia, neutropenia, and fatigue. Two patients in the capecitabine group progressed during the fourth cycle of induction ch...
4004 Background: The optimum combination curative approach to locally advanced adenocarcinoma of the esophagus and esophago-gastric junction (AEG) is unknown. A key question is whether neoadjuvant multimodal therapy, specifically CROSS (carboplatin/paclitaxel, 41.4Gy radiation therapy), is superior to optimum peri-operative chemotherapeutic regimens including modified MAGIC (epirubicin, cisplatin (oxaliplatin), 5-FU (capecitabine)) and more latterly FLOT (docetaxel, 5-FU, leucovorin, oxaliplatin). Neo-AEGIS was designed as the first randomised controlled trial to address this question. Methods: 377 patients with cT2-3N0-3M0 AEG were randomly assigned to CROSS or peri-operative chemotherapy (ECF/ECX/EOF/EOX pre-2018, FLOT option 2019/20) at 24 sites (Ireland, UK, Denmark, France, Sweden). The primary outcome was overall survival. The initial power calculation was based on CROSS superiority of 10%. This was modified after the first futility analysis (70 events) to a non-inferiority margin of 5%. Secondary end points included toxicity, pathologic measures of response, and postoperative complications as per the Esophageal Complications Consensus Group (ECCG) definitions and Clavien-Dindo severity grade. Results: Of 362 evaluable patients, 178 CROSS, 184 MAGIC/FLOT (157/27), 90% were male, median (range) age 64 (35-83), 84% were cT3, and 58% cN1. At a median (range) follow up of 24.5 (1-92) months, at the second futility analysis (60% of planned events), there were 143 deaths, 70 CROSS and 73 MAGIC/FLOT arm, with 3-year estimated survival probability of 56% (95% CI 47,64) and 57% (95% CI 48,65), respectively [(HR 1.02 (95%CI. 0.74-1.42))]. Based on the absence of futility evidenced in this data the DSMB recommended closure of recruitment in December 2020. Conclusions: This RCT reveals no evidence that peri-operative chemotherapy is unacceptably inferior to multimodal therapy, notwithstanding greater proxy markers of local tumour response in the CROSS arm. Oncologic and operative outcomes were consistent with optimum modern benchmarks. These data strongly suggest non-inferiority and support equipoise in decision making in modern practice. Clinical trial information: NCT01726452. [Table: see text]
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 PARTICIPANTSThis 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 2 on day 1, capecitabine 625 mg/m 2 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 MEASURESFirst, 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.
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