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Background: The optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration., Methods: We analyzed cases from the AGAMENON-SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors., Results: Among 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58-0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG-PS (Eastern Cooperative Oncology Group-Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand-foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%)., Conclusions: FOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin., (© 2024. The Author(s).)

Background: Gastroesophageal adenocarcinoma in young adults (GCYA) counts for 10-15% of diagnoses. Previous studies have mainly focused on surgical outcomes in patients with resectable tumors; however, systemic therapy for advanced GCYA remains under-evaluated. This study aims to assess the efficacy-related outcomes and safety of first-line chemotherapy (CT) in younger versus older patients with advanced gastroesophageal adenocarcinoma., Methods: Patients with advanced gastroesophageal adenocarcinoma from the AGAMENON-SEOM registry treated with first-line polychemotherapy between January 2008 and October 2022 were included. We compared clinicopathological features, therapies received, efficacy-related outcomes, and toxicity between individuals aged < and ≥ 45 years., Results: Out of 3386 patients, 263 (7.8%) were < 45 years. Young patients exhibited a higher proportion of females affected, lower ECOG-PS ≥ 2, fewer comorbidities, and more aggressive disease-related features, such as higher proportion of diffuse subtype, signet-ring cells, plastic linitis, grade 3, peritoneal metastases and metastatic disease at diagnosis. They received more triple-agent combinations and underwent more surgeries in metastatic setting. No significant differences were observed between groups in overall response rate (53.1% vs. 52.3% in < and ≥ 45 years, respectively, p = 0.579), progression-free survival (6.1 vs. 6.83 months, p = 0.158) and overall survival (11.07 vs. 10.81 months, p = 0.82), even after adjusting for potential confounding factors. Grade 3-4 adverse events were comparable in both groups, although toxicity leading to treatment discontinuation was more frequent in older patients., Conclusions: In the AGAMENON-SEOM registry, younger patients with GCYA exhibited more aggressive clinicopathological features, and despite receiving more aggressive treatments, similar efficacy outcomes and toxicity profiles were achieved compared to their older counterparts. In the AGAMENON-SEOM registry, GEAC in < 45 years showed more aggressive clinicopathological features and, although treated with more intense first-line CT regimens, similar efficacy outcomes and toxicity were achieved compared to older patients., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Purpose: This study aimed to compare ramucirumab-paclitaxel versus chemotherapy in second-line (2L) advanced gastroesophageal cancer (aGEC) based on HER2 status and analyze prognostic factors., Methods: The study includes patients from the AGAMENON-SEOM registry with aGEC and known HER2 status who received 2L between 2016 and 2021. The Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS) and multivariable Cox regression analysis was done to adjust for confounding variables., Results: Of the 552 patients who met the selection criteria, 149 (26.9%) had HER2-positive aGEC, 89 were treated with chemotherapy, and 60 with ramucirumab-paclitaxel, and 403 had an HER2-negative aGEC, 259 were treated with chemotherapy, and 144 with ramucirumab-paclitaxel. In the whole sample, 2L PFS was 3.0 months (95% CI 2.8-3.2), 2L OS, 5.7 months (5.2-6.3), and ramucirumab-paclitaxel versus chemotherapy was associated with increased PFS (HR 0.64, 95% CI 0.53-0.78, p < 0.0001) and OS (HR 0.68, 0.55-0.83, p = 0.0002). Median PFS of ramucirumab- paclitaxel versus chemotherapy was 3.5 vs 2.8 months (HR 0.67, 0.54-0.83, p = 0.0004) in HER2-negative, and 4.7 vs 2.7 months (HR 0.57, 0.40-0.82, p = 0.0031) in HER2-positive aGEC, respectively. Median OS for ramucirumab-paclitaxel versus chemotherapy was 6.6 vs 5 months (HR 0.67, 0.53-0.85, p = 0.0007) in HER2-negative, and 7.4 vs 5.6 months (HR 0.70, 0.53-1.04, p = 0.083) in HER2-positive aGEC, respectively. ECOG-PS, tumor burden, Lauren subtype, and neutrophil-lymphocyte ratio were prognostic factors., Conclusions: In patients with an aGEC from the AGAMENON-SEOM registry, 2L treatment with ramucirumab-paclitaxel was superior to chemotherapy in PFS, OS and response rate, independent of HER2 status., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Trastuzumab and chemotherapy is the standard first-line treatment in human epidermal growth factor receptor 2 (HER2)-positive advanced gastro-oesophageal cancer. The objective was to develop a predictive model for overall survival (OS) and progression-free survival (PFS) in patients treated with trastuzumab., Methods: Patients with HER2-positive advanced gastro-oesophageal adenocarcinoma (AGA) from the Spanish Society of Medical Oncology (SEOM)-AGAMENON registry and treated first line with trastuzumab and chemotherapy between 2008 and 2021 were included. The model was externally validated in an independent series (The Christie NHS Foundation Trust, Manchester, UK)., Results: In all, 737 patients were recruited (AGAMENON-SEOM, n  = 654; Manchester, n  = 83). Median PFS and OS in the training cohort were 7.76 [95% confidence interval (CI), 7.13-8.25] and 14.0 months (95% CI, 13.0-14.9), respectively. Six covariates were significantly associated with OS: neutrophil-to-lymphocyte ratio, Eastern Cooperative Oncology Group performance status, Lauren subtype, HER2 expression, histological grade and tumour burden. The AGAMENON-HER2 model demonstrated adequate calibration and fair discriminatory ability with a c-index for corrected PFS/OS of 0.606 (95% CI, 0.578-0.636) and 0.623 (95% CI, 0.594-0.655), respectively. In the validation cohort, the model is well calibrated, with a c-index of 0.650 and 0.683 for PFS and OS, respectively., Conclusion: The AGAMENON-HER2 prognostic tool stratifies HER2-positive AGA patients receiving trastuzumab and chemotherapy according to their estimated survival endpoints., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Globally, small and medium-sized enterprises (SMEs) compete and work on their sustainability in order to survive and thrive. SMEs rely only on their internal strength, and this strength lies mainly in their employees. Maintaining employees and their engagement increases productivity not only in terms of employee performance but also in terms of organizational performance. Based on social bond theory, the link between leaders and employees empowers the employees; in this context, the present research addresses how SMEs' potential effectiveness is derived from the employees when leadership plays its role efficiently and promotes voluntary work among employees. Using a sample of 405 employees from Pakistani SMEs, this paper assesses the effect on them of organizational citizenship behavior and transformational leadership, in terms of engaging them in voluntary work that ultimately improves performance; this helps SMEs flourish domestically and internationally. The present research also expands the literature by examining the mediating effect of organizational citizenship behavior and provides new directions for researchers to study transformational leadership and organizational citizenship behavior., Competing Interests: The authors declare no conflict of interest., (© 2022 Published by Elsevier Ltd.)

Background: Recommendations for research articles include the use of the term sex when reporting biological factors and gender for identities or psychosocial or cultural factors. There is an increasing awareness of incorporating the effect of sex and gender on cancer outcomes. Thus, these types of analyses for advanced gastroesophageal adenocarcinoma are relevant., Patients and Methods: Patients with advanced gastroesophageal adenocarcinoma from the Spanish AGAMENON-SEOM registry treated with first-line combination chemotherapy were selected. Epidemiology, characteristics of the disease, treatment selection, and results were examined according to sex., Results: This analysis included 3274 advanced gastroesophageal adenocarcinoma patients treated with combination chemotherapy between 2008 and 2021: 2313 (70.7%) men and 961 (29.3%) women. Tumors in females were more frequently HER2-negative (67.8% versus 60.8%; P < 0.0001), grade 3 (45.4% versus 36.8%; P < 0.001), diffuse (43.3% versus 26.5%; P < 0.0001), and signet ring cell histology (40.5 versus 23.9%; P < 0.0001). Peritoneal spread was more common in women (58.6% versus 38.9%; P < 0.0001), while liver burden was lower (58.9% versus 71.1%; P < 0.0001). There were no significant differences in treatment recommendation. Treatment doses, density, and duration were comparable between sexes. Women experienced more diarrhea (46% versus 37%; P < 0.0001), neutropenia (51% versus 43%; P < 0.0001), and anemia (62% versus 57%; P < 0.0001). After a median 59.6-month follow-up [95% confidence interval (CI) 54.5-70.8], there were no statistically significant differences between the sexes in progression-free survival [6.21 months (95% CI 5.8-6.5 months) versus 6.08 months (95% CI 5.8-6.3 months); log-rank test, χ 2  = 0.1, 1 df, P = 0.8] or in overall survival [10.6 months (95% CI 9.8-11.1 months) versus 10.9 months (95% CI 10.4-11.4 months); log-rank test: χ 2  = 0.6, 1 df, P = 0.5]., Conclusion: This sex analysis of patients with advanced gastroesophageal adenocarcinoma from the AGAMENON-SEOM registry receiving first-line polychemotherapy found no differences in survival. Although women had worse prognostic histopathology, metastatic disease pattern, and greater toxicity, treatment allocation and compliance were equivalent., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Advanced esophageal adenocarcinoma (EAC) is generally treated similarly to advanced gastroesophageal junction (GEJ-AC) and gastric (GAC) adenocarcinomas, although GAC clinical trials rarely include EAC. This work sought to compare clinical characteristics and treatment outcomes of advanced EAC with those of GEJ-AC and GAC and examine prognostic factors., Patients and Methods: Participants comprised patients with advanced EAC, intestinal GEJ-AC, and GAC treated with platin and fluoropyrimidine (plus trastuzumab when HER2 status was positive). Overall and progression-free survival were estimated using the Kaplan-Meier method. Cox proportional hazards regression gauged the prognostic value of the AGAMENON model., Results: Between 2008 and 2019, 971 participants from the AGAMENON-SEOM registry were recruited at 35 centers. The sample included 67.3% GAC, 13.3% GEJ-AC, and 19.4% EAC. Pulmonary metastases were most common in EAC and peritoneal metastases in GAC. Median PFS and OS were 7.7 (95% CI 7.3-8.0) and 13.9 months (12.9-14.7). There was no difference in PFS or OS between HER2- and HER2+ tumors from the three locations (p > 0.05). Five covariates were found to be prognostic for the entire sample: ECOG-PS, histological grade, number of metastatic sites, NLR, and HER2+ tumors treated with trastuzumab. In EAC, the same variables were prognostic except for grade. The favorable prognosis for HER2+ cancers treated with trastuzumab was homogenous for all three subgroups (p = 0.351) and, after adjusting for the remaining covariates, no evidence supported primary tumor localization as a prognostic factor (p = 0.331)., Conclusion: Our study supports the hypothesis that EAC exhibits clinicopathological characteristics, prognostic factors, and treatment outcomes comparable to intestinal GEJ-AC and GAC.

Background: Trastuzumab combined with cisplatin and fluoropyrimidines, either capecitabine or 5-fluorouracile (XP/FP), is the standard first-line treatment for advanced, HER2-positive, gastric cancer patients based on the ToGA trial. Despite the lack of phase III trials, many clinicians administer trastuzumab with alternative regimens. One meta-analysis suggests that substituting cisplatin for oxaliplatin might lead to greater efficacy and less toxicity., Methods: 594 patients with HER2-positive gastroesophageal adenocarcinoma were recruited from the AGAMENON-SEOM registry. The objective was to evaluate the external validity of clinical trials with chemotherapy and trastuzumab., Results: The regimens used in at least 5% of the patients were XP (27%), oxaliplatin and capecitabine (CAPOX) (26%), oxaliplatin and 5-fluorouracil (FOLFOX) (14%), FP (14%), triplet with anthracycline/docetaxel (7%), and carboplatin-FU (5%). Median exposure to trastuzumab was longer with FOLFOX (11.4 months, 95% CI, 9.1-21.0) versus ToGA regimens (7.5, 6.4-8.5), p  < 0.001. Patients with HER2-IHC 3+ cancers had higher response rates than those with IHC 2+/FISH+, odds-ratio 1.97 (95% CI, 1.25-3.09). The results achieved with CAPOX-trastuzumab were comparable to those attained with ToGA regimens. FOLFOX-trastuzumab was superior to ToGA schemes in terms of overall survival (OS), with a greater magnitude of effect in IHC 2+/FISH+ tumors (HR 0.47, 0.24-0.92) compared with IHC 3+ (HR 0.69, 0.49-0.96), and in diffuse (HR 0.37, 0.20-0.69) versus intestinal-type tumors (HR 0.76, 0.54-1.06)., Conclusion: We have updated the external validity of clinical trials with trastuzumab in first-line treatment of gastric cancer. Our data confirm the comparable outcomes of ToGA regimens and CAPOX-trastuzumab in clinical practice and point toward a possible benefit of FOLFOX-trastuzumab, contingent on the subtypes typically less sensitive to trastuzumab, to be confirmed in clinical trials., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

Background: The purpose of our study was to develop an online calculator to estimate the effect of docetaxel triplets (DPF) in first line of advanced gastric cancer (AGC), and to assess the external validity of docetaxel trials in individual patients., Methods: The study includes patients with HER2(-) AGC treated with platin and fluoropyrimidine (PF) or with DPF in first line. Treatment effect and interactions were assessed using Bayesian accelerated failure time models., Result: The series comprises 1376 patients; 238 treated with DPF and 1138 with PF between 2008 and 2019. DPF was associated with increased progression-free survival (PFS) and overall survival (OS) with time ratio (TR) 1.27 (95% credible interval [CrI], 1.15-1.40), and TR 1.19 (95% CrI, 1.09-1.27), respectively. Serious adverse events were more common with DPF, particularly hematological effects (32% vs 22%). Younger participants received greater DPF dose density without achieving greater disease control, while severe toxicity was likewise higher. DPF yielded superior OS in Lauren intestinal (TR 1.27, 95% CrI, 1.08-1.11) vs diffuse subtype (TR 1.17, 95% CrI, 1.09-1.24) and the probability of increasing OS > 15% was 90% vs 67% in each subtype, respectively. The effect dwindles over time, which can be attributed to pathological changes and clinical practice changes., Conclusion: Our study confirms the effect of DPF is highly dependent on several clinical-pathological variables, with discreet and gradually declining benefit over platinum doublets in later years, at the expense of increased toxicity. These results may help to underpin the idea that external validity of AGC trials should be revised regularly.

Introduction: Perioperative chemotherapy improves overall survival (OS) and disease-free survival (DFS) compared with surgery alone in patients with resectable gastric adenocarcinoma (GA) or gastro-oesophageal junction adenocarcinoma (GEJA). The addition of trastuzumab to chemotherapy improves outcomes in patients with HER2-positive advanced gastric cancer (GC), and we aimed to explore its role in the perioperative setting., Material and Methods: This Spanish, multicentre, open-label phase II trial evaluated the efficacy and toxicity of perioperative capecitabine, oxaliplatin and trastuzumab (XELOX-T) in patients with HER2-positive resectable GA or GEJA. The primary end-point was 18-months DFS; and secondary end-points included pathological complete response (pCR) rate, R0 resection rate, OS and toxicity (NCT01130337)., Results: Thirty-six patients were included. After three cycles of preoperative treatment, 14 patients (38% of the intention-to-treat population) had partial response and 18 (50%) had stable disease. Surgery was performed in 31 patients: 28 (90%) had R0 resection, three (9.6%) had a pCR and three (9.6%) died due to surgical complications. A total of 24 patients received post-operative XELOX-T, 22 of whom completed trastuzumab maintenance. Main grade III/IV toxicities included diarrhoea (33%), nausea and vomiting (8%). After a median follow-up of 24.1 months, 18-month DFS was 71% (95% confidence interval [CI], 53-83%); and an update after 102 months of follow-up showed a median OS of 79.9 months and a 60-month OS of 58% (95% CI, 40-73%)., Conclusions: These data suggest that perioperative XELOX-T in patients with HER2-positive GA and GEJA is feasible and active. Further investigation in randomised studies is warranted., Competing Interests: Conflict of interest statement Paula Jimenez-Fonseca declares travel grants from Ipsen and consulting/advisory role for Roche, Celgene, Bristol, Mylan, Rovi, LeoPharma, all outside of the scope of this work. Maria Alsina declares disclosures in terms of scientific consultancy from Bristol Myers Squibb, Lilly, Merck Sharp and Dohme, and Servier; honoraria from Amgen, Bristol Myers Squibb, Lilly, Merck Sharp and Dohme, Roche, and Servier; and travel expenses (partial coverage) from Amgen, Lilly, and Roche. Enrique Aranda disclosures consultant or advisory role for Roche, Merck, Angem, Bayer and Sanofi. Carlos López disclosures Honoraria for Roche, Merck, Sanofi, Novartis, Pfizer, Eisai, Ipsen, Bayer, AstraZeneca, and Servier; Consulting or Advisory Role for Amgen, Roche, Sanofi, Merck, Servier, Pfizer, Ipsen, Bayer, Eisai; research funding from Amgen, Roche, Merck, Merck Sharp & Dohme, AstraZeneca, Sanofi, Bayer, Ipsen, Eisai, Celgene Travel, Accommodations, Expenses Roche, Pfizer, Merck, Servier, Amgen, Ipsen Fernando Rivera disclosures consultant or advisory role for Roche, Merck-Serono, Amgen, MSD, BMS, Lilly, Celgene, Sanofi-Aventis, Servier, Astra-Zeneca, and Bayer; research Funding from Roche, Merck-Serono, Amgen, MSD, Lilly, Celgene, Sanofi-Aventis, Bayer, Servier; speaker roles for Roche, Merck-Serono, Amgen, MSD, BMS, Lilly, Celgene, Sanofi-Aventis, Servier, and Bayer; and grant support from Amgen. The rest of the authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Second-line treatments boost overall survival in advanced gastric cancer (AGC). However, there is a paucity of information as to patterns of use and the results achieved in actual clinical practice., Materials and Methods: The study population comprised patients with AGC in the AGAMENON registry who had received second-line. The objective was to describe the pattern of second-line therapies administered, progression-free survival following second-line (PFS-2), and post-progression survival since first-line (PPS)., Results: 2311 cases with 2066 progression events since first-line (89.3%) were recorded; 245 (10.6%) patients died during first-line treatment and 1326/2066 (64.1%) received a second-line. Median PFS-2 and PPS were 3.1 (95% CI, 2.9-3.3) and 5.8 months (5.5-6.3), respectively. The most widely used strategies were monoCT (56.9%), polyCT (15.0%), ramucirumab+CT (12.6%), platinum-reintroduction (8.3%), trastuzumab+CT (6.1%), and ramucirumab (1.1%). PFS-2/PPS medians gradually increased in monoCT, 2.6/5.1 months; polyCT 3.4/6.3 months; ramucirumab+CT, 4.1/6.5 months; platinum-reintroduction, 4.2/6.7 months, and for the HER2+ subgroup in particular, trastuzumab+CT, 5.2/11.7 months. Correlation between PFS since first-line and OS was moderate in the series as a whole (Kendall's τ = 0.613), lower in those subjects who received second-line (Kendall's τ = 0.539), especially with ramucirumab+CT (Kendall's τ = 0.413)., Conclusion: This analysis reveals the diversity in second-line treatment for AGC, highlighting the effectiveness of paclitaxel-ramucirumab and, for a selected subgroup of patients, platinum reintroduction; both strategies endorsed by recent clinical guidelines., Competing Interests: Dr. Javier Gallego declares advisory role for Amgen, Bayer, BMS, Ipsen, Lilly, Merck, Roche, Servier, and travel grants from Novartis, Amgen. No other authors have competing interests to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The optimal duration of first-line chemotherapy for patients with advanced gastric cancer is unknown. Diverse clinical trials have proposed different strategies including limited treatment, maintenance of some drugs, or treatment until progression., Method: The sample comprises patients from the AGAMENON multicenter registry without progression after second evaluation of response. The objective was to explore the optimal duration of first-line chemotherapy. A frailty multi-state model was conducted., Results: 415 patients were divided into three strata: discontinuation of platinum and maintenance with fluoropyrimidine until progression (30%, n = 123), complete treatment withdrawal prior to progression (52%, n = 216), and full treatment until progression (18%, n = 76). The hazard of tumor progression decreased by 19% per month with the full treatment regimen. However, we found no evidence that fluoropyrimidine maintenance (hazard ratio [HR] 1.07, confidence interval [CI] 95%, 0.69-1.65) worsened progression-free survival (PFS) with respect to treatment until progression. Predictive factors for PFS were ECOG performance status, ≥ 3 metastatic sites, prior tumor response, and bone metastases. Toxicity grade 3/4 was more common in those who continued the full treatment until progression vs fluoropyrimidine maintenance (16% vs 6%)., Conclusion: The longer duration of the full initial regimen exerted a protective effect on the patients of this registry. Platinum discontinuation followed by fluoropyrimidine maintenance yields comparable efficacy to treatment up to PD, with a lower rate of serious adverse events.

Introduction: We used European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) data from the LUME-Colon 1 study to illustrate different methods of statistical analysis for health-related quality of life (HRQoL), and compared the results., Patients and Methods: Patients were randomized 1:1 to receive nintedanib 200 mg twice daily plus best supportive care (n = 386) or matched placebo plus best supportive care (n = 382). Five methods (mean treatment difference averaged over time, using a mixed-effects growth curve model; mixed-effects models for repeated measurements (MMRM); time-to-deterioration (TTD); status change; and responder analysis) were used to analyze EORTC QLQ-C30 global health status (GHS)/QoL and scores from functional scales., Results: Overall, GHS/QoL and physical functioning deteriorated over time. Mean treatment difference slightly favored nintedanib over placebo for physical functioning (adjusted mean, 2.66; 95% confidence interval [CI], 0.97-4.34) and social functioning (adjusted mean, 2.62; 95% CI, 0.66-4.47). GHS/QoL was numerically better with nintedanib versus placebo (adjusted mean, 1.61; 95% CI, -0.004 to 3.27). MMRM analysis had similar results, with better physical functioning in the nintedanib group at all timepoints. There was no significant delay in GHS/QoL deterioration (10%) and physical functioning (16%) with nintedanib versus placebo (TTD analysis). Status change analysis showed a higher proportion of patients with markedly improved GHS/QoL and physical functioning in the nintedanib versus placebo groups. Responder analysis showed a similar, less pronounced pattern., Conclusion: Analyses of EORTC QLQ-C30 data showed that HRQoL was not impaired by treatment with nintedanib versus placebo. Analysis and interpretation of HRQoL endpoints should consider symptom type and severity and course of disease., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Research into cancer-associated thrombosis (CAT) entails managing dynamic data that pose an analytical challenge. Thus, methods that assume proportional hazards to investigate prognosis entail a risk of misinterpreting or overlooking key traits or time-varying effects. We examined the AGAMENON registry, which collects data from 2,129 patients with advanced gastric cancer. An accelerated failure time (AFT) multistate model and flexible competing risks regression were used to scrutinize the time-varying effect of CAT, as well as to estimate how covariates dynamically predict cumulative incidence. The AFT model revealed that thrombosis shortened progression-free survival and overall survival with adjusted time ratios of 0.72 and 0.56, respectively. Nevertheless, its prognostic effect was nonproportional and disappeared over time if the subject managed to survive long enough. CAT that occurred later had a more pronounced prognostic effect. In the flexible competing risks model, multiple covariates were seen to have significant time-varying effects on the cumulative incidence of CAT (Khorana score, secondary thromboprophylaxis, high tumor burden, and cisplatin-containing regimen), whereas other predictors exerted a constant effect (signet ring cells and primary thromboprophylaxis). The model that assumes proportional hazards was incapable of capturing the effect of these covariates and predicted the cumulative incidence in a biased way. This study evinces that flexible and multistate models are a useful and innovative method to describe the dynamic effect of variables associated with CAT and should be more widely used., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Angiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies., Patients and Methods: Eligible patients (Eastern Cooperative Oncology Group performance status 0-1, with histologically/cytologically confirmed metastatic/locally advanced CRC adenocarcinoma unamenable to surgery and/or radiotherapy) were randomized 1 : 1 to receive nintedanib (200 mg twice daily) or placebo (twice daily), until disease progression or undue toxicity. Patients were stratified by previous regorafenib, time from onset of metastatic disease to randomization, and region. Co-primary end points were overall survival (OS) and progression-free survival (PFS) by central review. Secondary end points included objective tumor response and disease control by central review., Results: From October 2014 to January 2016, 768 patients were randomized; 765 were treated (nintedanib n = 384; placebo n = 381). Median follow-up was 13.4 months (interquartile range 11.1-15.7). OS was not improved [median OS 6.4 months with nintedanib versus 6.0 months with placebo; hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.86-1.19; P = 0.8659]. There was a significant but modest increase in PFS with nintedanib versus placebo (median PFS 1.5 versus 1.4 months, respectively; HR 0.58; 95% CI 0.49-0.69; P < 0.0001). There were no complete or partial responses. Adverse events (AEs) occurred in 97% of 384 nintedanib-treated patients and 93% of 381 placebo-treated patients. The most frequent grade ≥3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%)., Conclusions: The study failed to meet both co-primary end points. Nintedanib did not improve OS and was associated with a significant but modest increase in PFS versus placebo. Nintedanib was well tolerated., Clinicaltrials.gov Number: NCT02149108 (LUME-Colon 1).

Introduction: The effect of surgery for metastases in patients with esophagogastric cancer is unknown, given the lack of randomized clinical trials; likewise, the criteria for selecting eligible patients remain to be determined., Methods: This registry evaluates the results of patients with advanced adenocarcinoma of the stomach, distal esophagus, or gastro-esophageal junction from 32 centers. To assess selection criteria and prognostic factors, a state arrival extended Markov proportional hazards (PH) model was used., Results: 1792 subjects were analyzed, 5% of whom (n = 92) underwent surgery for metastasis. The most common surgeries were peritoneal (29%), hepatic (24%), and distant lymph nodes (11%). Subjects chosen for metastasectomy had higher survival rates, HR 0.34 (95% CI, 0.06-0.80, p = 0.021). Patients who underwent surgery had a mOS since metastasectomy of 16.7 months (95% CI, 12.5-22.4). The 1- and 3-year relapse rates following R0 resection were 58% and 65%, respectively. Median time since R0 metastasectomy until relapse was 8.4 months (95% CI, 7.6-23.7). The 3-year OS after surgery was 30.6% (95% CI, 19.3-40.4). Duration of chemotherapy prior to surgery (months) increased mortality (HR 1.04 [95% CI, 1.01-1.07]), p = 0.009. The only significant interaction involved the use of anti-HER2 therapy., Conclusion: The AGAMENON registry suggests that subjects with limited metastatic disease, selected on a clinical basis, can benefit from early surgeries. Prospective trials are needed to confirm these data., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Introduction: The aim of this study was to evaluate the efficacy and safety of maintenance therapy with axitinib versus placebo following induction therapy in patients with metastatic colorectal cancer (mCRC)., Patients and Methods: In this double-blinded, phase II trial, patients with mCRC who had not progressed after 6 to 8 months of first-line chemotherapy were randomized to receive axitinib (5 mg twice a day) (arm A) or placebo (arm B)., Results: Forty-nine patients were included: 25 in arm A and 24 in arm B. The median follow-up was 26.07 months (95% confidence interval [CI], 18.44-31.73 months). Progression-free survival (PFS) rate at 6 months was 40.00% (95% CI, 21.28%-58.12%) in the axitinib arm versus 8.33% (95% CI, 1.44%-23.30%) in the placebo arm (P = .0141). The median PFS was statistically significantly longer in the axitinib group than in the placebo group (4.96 vs. 3.16 months; hazard ratio, 0.46; 95% CI, 0.25-0.86; P = .0116). Median overall survival was also longer in the axitinib arm but did not reach statistical significance (27.61 vs. 19.99 months; hazard ratio, 0.68; 95% CI, 0.31-1.48; P = .3279). Grade 3 to 4 treatment-related toxicities were experienced by 7 patients (28%) in cohort A and 1 patient (4%) in cohort B (P = .0488). The most frequent grade 3 to 4 treatment-related toxicities were hypertension, diarrhea, and asthenia. There were no toxic deaths. The study was prematurely closed because of slow recruitment., Conclusions: In our study, maintenance treatment with axitinib monotherapy showed a significant increase in PFS and a good safety profile. Axitinib should be further explored as a possible option for first-line chemotherapy maintenance treatment in patients with mCRC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Although anthracycline-based triplets are one of the most widely used schedules to treat advanced gastric cancer (AGC), the benefit of including epirubicin in these therapeutic combinations remains unknown. This study aims to evaluate both the efficacy and tolerance of triplets with epirubicin vs. doublets with platinum-fluoropyrimidine in a national AGC registry., Methods: Patients with AGC treated with polychemotherapy without trastuzumab at 28 hospitals in Spain between 2008 and 2016 were included. The effect of anthracycline-based triplets against doublets was evaluated by propensity score matching (PSM) and Cox proportional hazards (PH) regression., Result: A total of 1002 patients were included (doublets, n = 653; anthracycline-based triplets, n = 349). The multivariable Cox PH regression failed to detect significantly increased OS in favor of triplets with anthracyclines: HR 0.90 (95% CI, 0.78-1.05), p = 0.20035. After PSM, the sample contained 325 pairs with similar baseline characteristics. This method was also unable to reveal an increase in OS: 10.5 (95% CI, 9.7-12.3) vs. 9.9 (95% CI, 9.2-11.4) months, HR 0.91 (CI 95%, 0.76-1.083), and (log-rank test, p = 0.226). Response rates (42.1 vs. 33.1%, p = 0.12) and PFS (HR 0.95, CI 95%, 0.80-1.13, log-rank test, p = 0.873) were not significantly higher with epirubicin-based regimens. The triplets were associated with greater grade 3-4 hematological toxicity, and increased hospitalization due to toxicity by 68%. The addition of epirubicin is viable, but 23.7% discontinued treatment because of adverse effects or patient decision., Conclusion: Anthracyclines added to platinum-fluoropyrimidine doublets did not improve the response rate or survival outcomes in patients with AGC but entailed greater toxicity.

Background: The choice of chemotherapy in HER2-negative gastric cancer is based on centre's preferences and adverse effects profile. No schedule is currently accepted as standard, nor are there any factors to predict response, other than HER2 status. We seek to evaluate whether Lauren type influences the efficacy of various chemotherapies and on patient overall survival (OS)., Methods: We have conducted a multicenter study in 31 hospitals. The eligibility criteria include diagnosis of stomach or gastroesophageal junction adenocarcinoma, HER2 negativity, and chemotherapy containing 2-3 drugs. Cox proportional hazards regression adjusted for confounding factors, with tests of 'treatment-by-histology' interaction, was used to estimate treatment effect., Results: Our registry contains 1303 tumours analysable for OS end points and 730 evaluable for overall response rate (ORR). A decrease in ORR was detected in the presence of a diffuse component: odds ratio 0.719 (95% confidence interval (CI), 0.525-0.987), P=0.039. Anthracycline- or docetaxel-containing schedules increased ORR only in the intestinal type. The diffuse type displayed increased mortality with hazard ratio (HR) of 1.201 (95% CI, 1.054-1.368), P=0.0056. Patients receiving chemotherapy with docetaxel exhibited increased OS limited to the intestinal type: HR 0.65 (95% CI, 0.49-0.87), P=0.024, with no increment in OS for the subset having a diffuse component. With respect to progression-free survival (PFS), a significant interaction was seen in the effect of docetaxel-containing schedules, with better PFS limited to the intestinal type subgroup, in the comparison against any other schedule: HR 0.65 (95% CI, 0.50-0.85), P=0.015, and against anthracycline-based regimens: HR 0.64 (95% CI, 0.46-0.88), P=0.046., Conclusions: As a conclusion, in this registry, Lauren classification tumour subtypes predicted survival and responded differently to chemotherapy. Future clinical trials should stratify effect estimations based on histology.

Background: To develop and validate a nomogram and web-based calculator to predict overall survival (OS) in Caucasian-advanced oesophagogastric adenocarcinoma (AOA) patients undergoing first-line combination chemotherapy., Methods: Nine hundred twenty-four AOA patients treated at 28 Spanish teaching hospitals from January 2008 to September 2014 were used as derivation cohort. The result of an adjusted-Cox proportional hazards regression was represented as a nomogram and web-based calculator. The model was validated in 502 prospectively recruited patients treated between October 2014 and December 2016. Harrell's c-index was used to evaluate discrimination., Results: The nomogram includes seven predictors associated with OS: HER2-positive tumours treated with trastuzumab, Eastern Cooperative Oncology Group performance status, number of metastatic sites, bone metastases, ascites, histological grade, and neutrophil-to-lymphocyte ratio. Median OS was 5.8 (95% confidence interval (CI), 4.5-6.6), 9.4 (95% CI, 8.5-10.6), and 14 months (95% CI, 11.8-16) for high-, intermediate-, and low-risk groups, respectively (P<0.001), in the derivation set and 4.6 (95% CI, 3.3-8.1), 12.7 (95% CI, 11.3-14.3), and 18.3 months (95% CI, 14.6-24.2) for high-, intermediate-, and low-risk groups, respectively (P<0.001), in the validation set. The nomogram is well-calibrated and reveals acceptable discriminatory capacity, with optimism-corrected c-indices of 0.618 (95% CI, 0.591-0.631) and 0.673 (95% CI, 0.636-0.709) in derivation and validation groups, respectively. The AGAMENON nomogram outperformed the Royal Marsden Hospital (c-index=0.583; P=0.00046) and Japan Clinical Oncology Group prognostic indices (c-index=0.611; P=0.03351)., Conclusions: We developed and validated a straightforward model to predict survival in Caucasian AOA patients initiating first-line polychemotherapy. This model can contribute to inform clinical decision-making and optimise clinical trial design.

Background: Trastuzumab significantly improves overall survival (OS) when added to cisplatin and fluoropyrimidine as a treatment for HER2-positive advanced gastric cancers (AGC). The aim of this study was to evaluate the impact of the gradual implementation of HER2 testing on patient prognosis in a national registry of AGC., Methods: This Spanish National Cancer Registry includes cases who were consecutively recruited at 28 centers from January 2008 to January 2016. The effect of missing HER2 status was assessed using stratified Cox proportional hazards (PH) regression., Results: The rate of HER2 testing increased steadily over time, from 58.3 % in 2008 to 92.9 % in 2016. HER2 was positive in 194 tumors (21.3 %). In the stratified Cox PH regression, each 1 % increase in patients who were not tested for HER2 at the institutions was associated with an approximately 0.3 % increase in the risk of death: hazard ratio, 1.0035 (CI 95 %, 1.001-1.005), P = 0.0019. Median OS was significantly lower at institutions with the highest proportions of patients who were not tested for HER2., Conclusion: Patients treated at centers that took longer to implement HER2 testing exhibited worse clinical outcomes. The speed of implementation behaves as a quality-of-care indicator. Reviewed guidelines on HER2 testing should be used to achieve this goal in a timely manner.

Purpose: TAS-102 is a combination of the thymidine-based nucleoside analog trifluridine and the thymidine phosphorylase inhibitor tipiracil. Efficacy and safety of TAS-102 in patients with metastatic colorectal cancer (mCRC) refractory or intolerant to standard therapies were evaluated in the phase 3 RECOURSE trial. Results of RECOURSE demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 versus placebo [hazard ratio (HR) = 0.68 and 0.48 for OS and PFS, respectively; both P < 0.001]. The current analysis evaluates efficacy and safety of TAS-102 in the RECOURSE Spanish subgroup., Methods: Primary and key secondary endpoints were evaluated in a post hoc analysis of the RECOURSE Spanish subgroup, using univariate and multivariate analyses. Safety and tolerability were reported with descriptive statistics., Results: The RECOURSE Spanish subgroup included 112 patients (mean age 61 years, 62 % male). Median OS was 6.8 months in the TAS-102 group (n = 80) versus 4.6 months in the placebo group (n = 32) [HR = 0.47; 95 % confidence interval (CI): 0.28-0.78; P = 0.0032). Median PFS was 2.0 months in the TAS-102 group and 1.7 months in the placebo group (HR = 0.47; 95 % CI: 0.30-0.74; P = 0.001). Eighty (100 %) TAS-102 versus 31 (96.9 %) placebo patients had adverse events (AEs). The most common drug-related ≥Grade 3 AE was neutropenia (40 % TAS-102 versus 0 % placebo). There was 1 (1.3 %) case of febrile neutropenia in the TAS-102 group versus none in the placebo group., Conclusions: In the RECOURSE Spanish subgroup, TAS-102 was associated with significantly improved OS and PFS versus placebo, consistent with the overall RECOURSE population. No new safety signals were identified. CLINICALTRIALS., Gov Study Number: NCT01607957., Competing Interests: Author A reports employment at Taiho Oncology Inc. Author B reports providing scientific advice to Bayer. Author C reports consulting/advisory fees from Amgen, Boehringer Ingelheim, Celgene, Chugai, Imclone Systems Inc., Eli Lilly and Company, Merck & Co., Merck Serono, Millennium, Novartis, F. Hoffmann-La Roche Ltd., Sanofi, Symphogen, and Taiho Oncology Inc. All other authors declare that they have no conflicts of interest. Informed consent Informed consent was obtained from all individual participants included in the study. Research involving human participants All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Fluoropyrimidine-based chemotherapy (CT) has been the mainstay of care of metastatic colorectal cancer (mCRC) for years. Response rates are only observed, however, in about half of treated patients, and there are no reliable tools to prospectively identify patients more likely to benefit from therapy. The purpose of our study was to identify a gene expression profile predictive of CT response in mCRC. Whole genome expression analyses (Affymetrix GeneChip HG-U133 Plus 2.0) were performed in fresh frozen tumor samples of 37 mCRC patients (training cohort). Differential gene expression profiles among the two study conditions (responders versus non-responders) were assessed using supervised class prediction algorithms. A set of 161 differentially expressed genes in responders (23 patients; 62%) versus non-responders (14 patients; 38%) was selected for further assessment and validation by RT-qPCR (TaqMan Low Density Arrays (TLDA) 7900 HT Micro Fluidic Cards) in an independent multi-institutional cohort (53 mCRC patients). Seven of these genes were confirmed as significant predictors of response. Patients with a favorable predictive signature had significantly greater response rate (58% vs. 13%, p = 0.024), progression-free survival (61% vs. 13% at 1 year, HR = 0.32, p = 0.009) and overall survival (32 vs. 16 months, HR = 0.21, p = 0.003) than patients with an unfavorable gene signature. This is the first study to validate a gene-expression profile predictive of response to CT in mCRC patients. Larger and prospective confirmatory studies are required, however, in order to successfully provide oncologists with adequate tools to optimize treatment selection in routine clinical practice.

Preclinical and clinical data suggest a protective role for estrogens on colon cancer (CRC) risk. estrogen receptor (ER) β is the prevalent ER in normal colonic mucosa, whereas its expression is significantly reduced in CRC. An increased ERα/β ratio has been documented in colon carcinomas and is associated with increased proliferation and decreased apoptosis. The aim of our study was to evaluate the expression of activated ERα and its prognostic implications in patients with stage II-III CRC. Phospho-ERα(Ser167) (pERα(Ser167)) expression was assessed by immunohistochemistry in 218 CRC paraffin-embedded tumor samples. A high pERα(Ser167) expression was more commonly observed in women, older patients, and patients with high baseline glucose levels. This higher pERα(Ser167) expression was associated with decreased 5-year disease-free interval (DFI; 66% versus 78%, P = .07) and overall survival (65% versus 73%, P = .46). The negative impact of high pERα(Ser167) expression on DFI was particularly significant (P < .05) in women (85% versus 60%), young (82% versus 61%), nondiabetic (85% versus 66%), and stage II patients (86% versus 72% and low versus high pERα(Ser167), respectively). Multivariate analysis confirmed that pERα(Ser167) score was a significant prognostic factor for both DFI and overall survival, independent of sex, age, glucose levels, tumor stage, bowel obstruction/perforation, or adjuvant chemotherapy. These findings illustrate the relevance of estrogen pathways in colon cancer biology and may provide novel therapeutic avenues to be explored in this context., (Copyright © 2014 Elsevier Inc. All rights reserved.)