Background: Data on the clinicopathological characteristics of mucinous gastric cancer (muc-GC) are limited. This study compares the clinical outcome and response to chemotherapy between patients with resectable muc-GC, intestinal (int-GC), and diffuse (dif-GC) gastric cancer. Methods: Patients from the D1/D2 study or the CRITICS trial were included in exploratory surgery-alone (SA(test)) or chemotherapy test (CTtest) cohorts. Real-world data from the Netherlands Cancer Registry on patients treated between with surgery alone (SA(validation)) and receiving preoperative chemotherapy with or without postoperative treatment (CTvalidation) were used for validation. Histopathological subtypes were extracted from pathology reports filed in the Dutch Pathology Registry and correlated with tumor regression grade (TRG) and relative survival (RS). Results: In the SA(test) (n = 549) and SA(validation) (n = 8062) cohorts, muc-GC patients had a 5-year RS of 39% and 31%, similar to or slightly better than dif-GC (43% and 29%, P = .52 and P = .011), but worse than int-GC (55% and 42%, P = .11 and P < .001). In the CTtest (n = 651) and CTvalidation (n = 2889) cohorts, muc-GC showed favorable TRG (38% and 44% (near-) complete response) compared with int-GC (26% and 35%) and dif-GC (10% and 28%, P < .001 and P = .005). The 5-year RS in the CTtest and CTvalidation cohorts for muc-GC (53% and 48%) and int-GC (58% and 59%) was significantly better compared with dif-GC (35% and 38%, P = .004 and P < .001). Conclusion: Recognizing and incorporating muc-GC into treatment decision-making of resectable GC can lead to more personalized and effective approaches, given its favorable response to preoperative chemotherapy in relation to int-GC and dif-GC and its favorable prognostic outcomes in relation to dif-GC.

BACKGROUND AND OBJECTIVE:This study aims to investigate the impact of sex on outcome measures stratified by histological subtype in patients with resectable gastric cancer (GC). METHODS:A post-hoc analysis of the CRITICS-trial, in which patients with resectable GC were treated with perioperative therapy, was performed. Histopathological characteristics and survival were evaluated for males and females stratified for histological subtype (intestinal/diffuse). Additionally, therapy-related toxicity and compliance were compared. RESULTS:Data from 781 patients (523 males) were available for analyses. Female sex was associated with a distal tumor localization in intestinal (p = 0.014) and diffuse tumors (p < 0.001), and younger age in diffuse GC (p = 0.035). In diffuse GC, tumor-positive resection margins were also more common in females than males (21% vs. 10%; p = 0.020), specifically at the duodenal margin. During preoperative chemotherapy, severe toxicity occurred in 327 (63%) males and 184 (71%) females (p = 0.015). Notwithstanding this, relative dose intensities were not significantly different between sexes. CONCLUSIONS:Positive distal margin rates were higher in females with diffuse GC, predominantly at the duodenal site. Females also experience more toxicity, but this neither impacts dose intensities nor surgical resection rates. Clinicians should be aware of these different surgical outcomes when treating males and females with GC.

(1) Background: Perioperative chemotherapy is the current standard treatment for patients with resectable gastric cancer. Based on studies in patients with metastatic gastric cancer, oxaliplatin has replaced cisplatin in the curative setting as well. However, evidence to prefer oxaliplatin over cisplatin in the curative setting is limited. (2) Methods: We compared patient-related and tumor-related outcomes for cisplatin versus oxaliplatin in patients with resectable gastric cancer treated with perioperative chemotherapy in the CRITICS trial. (3) Results: Preoperatively, 632 patients received cisplatin and 149 patients received oxaliplatin. Preoperative severe toxicity was encountered in 422 (67%) patients who received cisplatin versus 89 (60%) patients who received oxaliplatin (p = 0.105). Severe neuropathy was observed in 5 (1%) versus 6 (4%; p = 0.009) patients, respectively. Postoperative severe toxicity occurred in 109 (60%) versus 26 (51%) (p = 0.266) patients; severe neuropathy in 2 (1%) versus 2 (4%; p = 0.209) for patients who received cisplatin or oxaliplatin, respectively. Diarrhea impacted the quality of life more frequently in patients who received oxaliplatin compared to cisplatin. Complete or near-complete pathological response was achieved in 94 (21%) versus 16 (15%; p = 0.126) patients who received cisplatin or oxaliplatin, respectively. Overall survival was not significantly different in both groups (p = 0.300). (4) Conclusions: Both cisplatin and oxaliplatin are legitimate options as part of systemic treatment in patients with resectable gastric cancer.

Gastric cancer (GC) patients at high risk of developing peritoneal metastasis (PM) as a single site of metastasis after curative treatment may be candidates for adjuvant prophylactic strategies. Here we investigated risk factors for metachronous isolated PM in patients who were treated in the CRITICS trial (NCT00407186). Univariable and multivariable analyses on both metachronous isolated PM and ‘other events’, i.e., (concurrent) distant metastasis, locoregional recurrence or death, were performed using a competing risk model and summarized by cumulative incidences. Isolated PM occurred in 64 of the 606 (11%) included patients. Diffuse or mixed histological subtype, ypT4 tumor stage and LNhigh (ypN3 lymph node stage or a lymph node ratio >20%) were independent risk factors for isolated PM in both univariable and multivariable analyses. Likewise, LNhigh was an independent risk factor for ‘other events’. Patients with tumors who were positive for all three independent risk factors had the highest two-year cumulative incidence of 43% for isolated PM development. In conclusion, diffuse or mixed histological subtype, ypT4 and LNhigh were identified as independent risk factors for isolated PM in patients treated with preoperative chemotherapy followed by surgical resection. The combination of these factors may identify a subgroup that may benefit from PM-preventing treatment strategies.

To evaluate the prognostic value of tumor markers in a European cohort of patients with resectable gastric cancer. We performed a post hoc analysis of the CRITICS trial, in which 788 patients received perioperative therapy. Association between survival and pretreatment CEA, CA 19-9, alkaline phosphatase, neutrophils, hemoglobin and lactate dehydrogenase were explored in uni- and multivariable Cox regression analyses. Likelihoods to receive potentially curative surgery were investigated for patients without elevated tumor markers versus one of the tumor markers elevated versus both tumor markers elevated. The association between tumor markers and the presence of circulating tumor DNA (ctDNA) was explored in 50 patients with available ctDNA data. In multivariable analysis, in which we corrected for allocated treatment and other baseline characteristics, elevated pretreatment CEA (HR 1.43; 95% CI 1.11–1.85, p < 0.001) and CA 19-9 (HR 1.79; 95% CI 1.42–2.25, p < 0.001) were associated with worse OS. Likelihoods to receive potentially curative surgery were 86%, 77% and 60% for patients without elevated tumor marker versus either elevated CEA or CA 19-9 versus both elevated, respectively (p < 0.001). Although both preoperative presence of ctDNA and tumor markers were prognostic for survival, no association was found between these two parameters. CEA and CA 19-9 were independent prognostic factors for survival in a large cohort of European patients with resectable gastric cancer. No relationship was found between tumor markers and ctDNA. These factors could potentially guide treatment choices and should be included in future trials to determine their definitive position. ClinicalTrial.gov identifier: NCT00407186. EudraCT number: 2006-00413032.

4024 Background: Carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 are well-known tumor markers. Most studies on CEA and CA 19-9 in pts with GC were performed in Asia, and/or in the metastatic setting. The aim of this study was to investigate the prognostic value of blood derived laboratory parameters in a cohort of European pts with resectable non-metastatic GC. Methods: In the CRITICS trial, 788 pts with resectable GC underwent perioperative therapy (preoperative chemotherapy plus either postoperative chemotherapy or postoperative chemoradiotherapy). Blood levels of CEA, CA 19-9, alkaline phosphatase (AP), creatinine, neutrophils, hemoglobin (Hb) and lactate dehydrogenase (LDH) were determined prior to treatment. Data for these variables were available for at least 89% of the pts. Factors significant on univariable cox regression analysis were further explored in multivariable analysis. Probabilities to undergo potentially curative surgery was investigated for factors significant on multivariable analysis. The relationship between tumor markers and the presence of circulating tumor DNA (ctDNA) was explored in 50 pts with available ctDNA data. Results: CEA and CA 19-9 were identified as independent prognostic factors for survival (Table). Probabilities to undergo potentially curative surgery were 86%, 77% and 60% for pts with no elevated tumor makers versus those with elevated CEA or elevated CA 19-9 versus those with both tumor markers elevated, respectively (p<0.001). No relationship was found between elevated tumor marker(s) and the presence of ctDNA neither pretreatment nor preoperatively. Conclusions: Pretreatment blood levels of CEA and CA 19-9 were identified as prognostic factors for overall survival in a large cohort of European GC pts with potentially curable disease. These factors may guide treatment choices at an early phase and should be included in future trials to determine their role in clinical decision making.[Table: see text]

Aim: To evaluate treatment-related toxicity, treatment compliance, surgical complications and event-free survival (EFS) in older (>= 70 years) versus younger (<70 years) adults who underwent perioperative treatment for gastric cancer. Methods: In the CRITICS trial, 788 patients with resectable gastric cancer were randomised before start of any treatment and received preoperative chemotherapy (3 cycles of epirubicin, cisplatin or oxaliplatin and capecitabine), followed by surgery, followed by either postoperative chemotherapy or chemoradiotherapy (45Gy + cisplatin + capecitabine). Results: 172 (22%) patients were older adults. During preoperative chemotherapy, 131 (77%) older adults versus 380 (62%) younger adults experienced severe toxicity (p < 0.001); older adults received significantly lower relative dose intensities (RDIs) for all chemotherapeutic drugs. Equal proportions of older versus younger adults underwent curative surgery: 137 (80%) versus 499 (81%), with comparable postoperative complications and postoperative mortality. Postoperative therapy after curative surgery started in 87 (64%) older adults versus 391 (78%) younger adults (p < 0.001). Incidence of severe toxicity during postoperative chemotherapy was 22 (54%) in older adults versus 113 (59%) in younger adults (p = 0.541); older adults received significantly lower RDIs for all chemotherapeutic drugs. Severe toxicity rates for postoperative chemoradiotherapy were 22 (48%) older adults versus 89 (45%) for younger adults (p = 0.703), with comparable chemotherapy RDIs and radiotherapy dose. Two-year EFS was 53% for older adults versus 51% for younger adults. Conclusion: Perioperative treatment compliance, especially in the postoperative phase, was poorer in older adults compared with younger adults. As comparable proportions of patients underwent curative surgery, future studies should focus on neo-adjuvant treatment. (C) 2020 The Author(s). Published by Elsevier Ltd.

Gastric cancer is the fifth most common cancer worldwide and has a high mortality rate. In the last decades, treatment strategy has shifted from an exclusive surgical approach to a multidisciplinary strategy. Treatment options for patients with resectable gastric cancer as recommended by different worldwide guidelines, include perioperative chemotherapy, pre- or postoperative chemoradiotherapy and postoperative chemotherapy. Although gastric cancer is a heterogeneous disease with respect to patient-, tumor-, and molecular characteristics, the current standard of care is still according to a one-size-fits-all approach. In this review, we discuss the background of the different treatment strategies in resectable gastric cancer including the current standard, the specific role of radiotherapy, and describe the current areas of research and potential strategies for personalization of therapy.

Abstract Background The occurrence of a venous thromboembolism (VTE) is common in patients with cancer. Gastric cancer has been associated with one of the highest risks for VTE. Chemotherapy, especially cisplatin has been associated with a high VTE risk. In this study, risk factors for VTE occurrence and their potential impact on subsequent therapeutic interventions were investigated in patients who underwent preoperative chemotherapy, in the CRITICS gastric cancer trial. Patients and methods Patients with resectable gastric cancer were preoperatively treated with three cycles of 3‐weekly epirubicin, cisplatin or oxaliplatin, and capecitabine (ECC/EOC). VTE was defined as any thrombus in the venous system, excluding superficial and/or device related VTEs. Potential risk factors were analyzed in a multivariable regression model with age, gender, Body Mass Index (BMI), tumor localization, Lauren classification, type of chemotherapy (ECC/EOC), (cardiovascular) comorbidity, and previous VTE as independent risk factors. The impact of VTE on completion rate of preoperative chemotherapy, surgical resection rate, postoperative complications, and start of postoperative therapy were investigated. Results Of 781 patients, 78 (10%) of 781 patients developed a VTE during preoperative chemotherapy. On multivariable analysis, BMI ≥ 30 kg/m2 and previous VTE were associated with VTE occurrence (reference BMI < 25 kg/m2; OR 2.190; 95% CI 1.152‐4.164; P = .017/previous VTE; OR 3.617; 95% CI 1.201‐10.890; P = .022). Treatment with cisplatin was, compared to oxaliplatin, not significantly associated with VTE occurrence (OR 1.535; 95% CI 0.761‐3.094; P = .231). VTE occurrence did not affect completion of preoperative chemotherapy, surgical resection rate, postoperative complications, or start of postoperative therapy. Conclusion High BMI and previous VTE were independent risk factors for VTE occurrence during preoperative chemotherapy in patients with resectable gastric cancer. VTE occurrence in the preoperative setting did not affect receipt of further treatment.

81 Background: Although the proportion of elderly cancer patients (pts) increases, few randomized trials provide separate results on this group. Here, we present a sub-analysis of the CRITICS trial, comparing elderly with non-elderly pts. Methods: Preoperative (preop) chemotherapy (CT) included three cycles of epirubicin, cisplatin/oxaliplatin and capecitabine (ECC/EOC); pts were upfront randomized between postoperative (postop) CT (3x ECC/EOC) and chemoradiotherapy (CRT; 45Gy + cisplatin/capecitabine). Elderly pts were defined as age ≥ 70 years at the time of randomization. We present tolerability and outcomes for elderly versus non-elderly pts. Results: Details on baseline characteristics, preop treatment, surgery, postop treatment and survival are shown in Table 1. Tumor type and localization did not differ between both groups. Conclusions: Age had a significant impact on toxicity and tolerability of preop CT, but did not affect surgical resection rates and complications. Although less elderly pts started postop treatment and elderly pts received lower dose in de CT arm, there were no differences in treatment related toxicities. Survival was not significantly different. Clinical trial information: NCT00407186. [Table: see text]

Patient compliance of postoperative chemoradiotherapy (CRT) for gastric cancer is poor. Elderly patients may be at particularly risk. Here, we present a subgroup analysis focusing on the CRT arm of the CRITICS phase III trial, comparing elderly with non-elderly patients. Patients with resectable gastric cancer or gastro-esophageal cancer with tumor bulk in the stomach, were treated with 3 cycles of preoperative chemotherapy (CT) (epirubicin, cisplatin/oxaliplatin, and capecitabine), resection with D2 lymph node dissection and postoperative CRT (45Gy + cisplatin + capecitabine). Elderly patients were defined as those aged ≥70 years at time of randomization. We present tolerability and outcomes, including relative dose intensities (RDIs) with interquartile range (IQR) for elderly versus non-elderly patients. A total of 172 (22%) out of 788 were elderly patients. Median age was 73 years (range 70-82) for elderly patients and 59 years (range 28-69) for non-elderly patients; 104 (60%) versus 249 (40%) had comorbidities (p<0.001). Median start doses for preoperative CT were similar in both groups. Preoperatively, elderly patients experienced significantly more severe (grade 3-5) toxicities: 131 (77%) versus 380 (62%) (p<0.001). All chemotherapy RDIs were lower for elderly patients compared to non-elderly patients (p<0.001); 120 (70%) elderly patients versus 535 (88%) finished preoperative chemotherapy (p<0.001). A total of 137 (80%) elderly and 499 (81%) non-elderly patients underwent curative resection (p=0.941), of whom 14 (11%) versus 53 (11%) had an R1 resection (n=9 unknown; p=0.947) and 111 (84%) elderly patients versus 433 (88%) non-elderly patients had a lymph node D2 resection or more (n=14 unknown; p=0.188). Among patients who were randomized to postoperative CRT, 46 (54%) elderly patients and 199 (64%) non-elderly patients started CRT; more details about postoperative chemoradiotherapy are displayed in the table. Age had a significant impact on completing preoperative CT, with elderly patients having more toxicities and lower RDIs compared to non-elderly patients. Although less elderly patients started postoperative CRT, this part of the treatment was tolerated similarly in elderly versus non-elderly patients. Hence, age alone should not be the reason to withhold patients from postoperative CRT.Abstract 2483; Table 1VariableElderly patientsN=46Non-elderly patientsN=199P valueSevere (grade 3-4) toxicity22 (48%)89 (45%)0.828Median RT dose (Gy; median; IQR)45 (45-45)45 (45-45)0.126Cisplatin (RDI; IQR)97% (78-99%)98% (80-100%)0.437Capecitabine (RDI; IQR)87% (69-100%)91% (80-100%)0.249Completed CRT35 (76%)167 (84%)0.204 Open table in a new tab

Background: Sorafenib has demonstrated survival benefit in first-line treatment of advanced hepatocellular carcinoma (HCC); utility of sorafenib in patients with advanced HCC and Child-Pugh B (CP-B) liver function remains a subject of debate. Methods: A systematic review identified studies using first-line sorafenib in patients with advanced HCC and CP-A/B liver function. Meta-regression analysis comprising linear regression was conducted to explore the association between the baseline factors and overall survival (OS). Differences between efficacy/safety and tolerability parameters were explored using meta-analysis. Results: Thirty studies (12 Asian) comprising 8678 patients (August 2002 - September 2012) were included (four randomised controlled trials, 26 cohort studies). Median age was 61 years and 83% were men. Hepatitis B/C status was positive in 35%/22%, respectively. The CP status was available for 8577 patients (99%); CP-A, 79% and CP-B, 19%. Median OS on sorafenib for entire cohort was 7.2 months; 8.8 months in CP-A and 4.6 months in CP-B. Multivariable meta-regression analysis showed significant negative association between OS and proportion of patients with the Eastern Cooperative Oncology Group performance status 2 (P = 0.04) and CP-B liver function (P = 0.001). Among four studies reporting multivariable comparison of the CP status, CP-B was associated with significantly worse OS (P < 0.001). There were no differences in the response rate to sorafenib between patients with CP-A (4.6%) and CP-B (4.2%) liver function. Safety and tolerability were similar; 35% of patients with CP-A/B liver function developed grade III/IV adverse events (P = 0.7). Meta-regression analysis showed similar rates of treatment discontinuation without progression (P = 0.31) and treatment-related death (P = 0.94) in patients with CP-B liver function. Conclusion: CP-B liver function (versus CP-A) is associated with worse OS (but the similar response rate, safety and tolerability of first-line sorafenib, is unlikely to be clinically meaningful). (C) 2018 Elsevier Ltd. All rights reserved.

BACKGROUND The prognostic significance of lymph nodes (LNs) metastases and the optimum number of LN yield in gastroenteropancreatic neuroendocrine tumours (GEP NETs) undergoing curative resection is still debatable. Many studies have demonstrated that cure rate for patients with GEP NETs can be improved by the resection of the primary tumour and regional lymphadenectomy AIM To evaluate the effect of lymph node (LN) status and yield on relapse-free survival (RFS) and overall survival (OS) in patients with resected GEP NETs. METHODS Data on patients who underwent curative resection for GEP NETs between January 2002 and March 2017 were analysed retrospectively. Grade 3 tumours (Ki67 > 20%) were excluded. Univariate Cox proportional hazard models were computed for RFS and OS and assessed alongside cut-point analysis to distinguish a suitable binary categorisation of total LNs retrieved associated with RFS. RESULTS A total of 217 patients were included in the study. The median age was 59 years (21-97 years) and 51% (n = 111) were male. Primary tumour sites were small bowel (42%), pancreas (25%), appendix (18%), rectum (7%), colon (3%), gastric (2%), others (2%). Median follow up times for all patients were 41 mo (95%CI: 36-51) and 71 mo (95%CI: 63–76) for RFS and OS respectively; 50 relapses and 35 deaths were reported. LNs were retrieved in 151 patients. Eight or more LNs were harvested in 106 patients and LN positivity reported in 114 patients. Three or more positive LNs were detected in 62 cases. The result of univariate analysis suggested perineural invasion (P = 0.0023), LN positivity (P = 0.033), LN retrieval of ≥ 8 (P = 0.047) and localisation (P = 0.0049) have a statistically significant association with shorter RFS, but there was no effect of LN ratio on RFS: P = 0.1 or OS: P = 0.75. Tumour necrosis (P = 0.021) and perineural invasion (P = 0.016) were the only two variables significantly associated with worse OS. In the final multivariable analysis, localisation (pancreas HR = 27.33, P = 0.006, small bowel HR = 32.44, P = 0.005), and retrieval of ≥ 8 LNs (HR = 2.7, P = 0.036) were independent prognostic factors for worse RFS. CONCLUSION An outcome-oriented approach to cut-point analysis can suggest a minimum number of adequate LNs to be harvested in patients with GEP NETs undergoing curative surgery. Removal of ≥ 8 LNs is associated with increased risk of relapse, which could be due to high rates of LN positivity at the time of surgery. Given that localisation had a significant association with RFS, a prospective multicentre study is warranted with a clear direction on recommended surgical practice and follow-up guidance for GEP NETs.

Although radical surgery remains the cornerstone of cure in resectable gastric cancer, survival remains poor. Current evidence-based (neo)adjuvant strategies have shown to improve outcome, including perioperative chemotherapy, postoperative chemoradiotherapy and postoperative chemotherapy. However, these regimens suffer from poor patient compliance, particularly in the postoperative phase of treatment. The CRITICS-II trial aims to optimize preoperative treatment by comparing three treatment regimens: (1) chemotherapy, (2) chemotherapy followed by chemoradiotherapy and (3) chemoradiotherapy.