Prognostic Relevance of the Proximal Resection Margin Distance in Distal Gastrectomy for Gastric Adenocarcinoma.

BACKGROUND: The risk for recurrence in patients with distal gastric cancer can be reduced by surgical radicality. However, dispute exists about the value of the proposed minimum proximal margin distance (PMD). Here, we assess the prognostic value of the safety distance between the proximal resection margin and the tumor. PATIENTS AND METHODS: This is a single-center cohort study of patients undergoing distal gastrectomy for gastric adenocarcinoma (2001-2021). Cohorts were defined by adequacy of the PMD according to the European Society for Medical Oncology (ESMO) guidelines (≥ 5 cm for intestinal and ≥ 8 cm for diffuse Laurén's subtypes). Overall survival (OS) and time to progression (TTP) were assessed by log-rank and multivariable Cox-regression analyses. RESULTS: Of 176 patients, 70 (39.8%) had a sufficient PMD. An adequate PMD was associated with cancer of the intestinal subtype (67% vs. 45%, p = 0.010). Estimated 5-year survival was 63% [95% confidence interval (CI) 51-78] and 62% (95% CI 53-73) for adequate and inadequate PMD, respectively. Overall, an adequate PMD was not prognostic for OS (HR 0.81, 95% CI 0.48-1.38) in the multivariable analysis. However, in patients with diffuse subtype, an adequate PMD was associated with improved oncological outcomes (median OS not reached versus 131 months, p = 0.038, median TTP not reached versus 88.0 months, p = 0.003). CONCLUSION: Patients with diffuse gastric cancer are at greater risk to undergo resection with an inadequate PMD, which in those patients is associated with worse oncological outcomes. For the intestinal subtype, there was no prognostic association with PMD, indicating that a distal gastrectomy with partial preservation of the gastric function may also be feasible in the setting where an extensive PMD is not achievable.

Is neoadjuvant chemotherapy followed by surgery the appropriate treatment for esophagogastric signet ring cell carcinomas? A systematic review and meta-analysis.

Background: The impact of neoadjuvant chemotherapy (nCTX) on survival and tumor response in patients with esophagogastric signet ring cell carcinoma (SRCC) is still controversial. Methods: Two independent reviewers performed a systematic literature search in Medline, CENTRAL, and Web of Science including prospective and retrospective two-arm non-randomized and randomized controlled studies (RCTs). Data was extracted on overall survival (OS) and tumor regression in resected esophagogastric SRCC patients with or without nCTX. Survival data was analyzed using published hazard ratios (HR) if available or determined it from other survival data or survival curves. OS and histopathological response rates by type of tumor (SRCC vs. non-SRCC) were also investigated. Results: Out of 559 studies, ten (1 RCT, 9 non-RCTs) were included in this meta-analysis (PROSPERO CRD42022298743) investigating 3,653 patients in total. The four studies investigating survival in SRCC patients treated with nCTX + surgery vs. surgery alone showed no survival benefit for neither intervention, but heterogeneity was considerable (HR, 1.01; 95% CI, 0.61-1.67; p = 0.98; I2 = 89%). In patients treated by nCTX + surgery SRCC patients showed worse survival (HR, 1.45; 95% CI, 1.21-1.74; p < 0.01) and lower rate of major histopathological response than non-SRCC patients (OR, 2.47; 95% CI, 1.78-3.44; p < 0.01). Conclusion: The current meta-analysis could not demonstrate beneficial effects of nCTX for SRCC patients. Histopathological response to and survival benefits of non-taxane-based nCTX seem to be lower in comparison to non-SRC esophagogastric cancer. However, certainty of evidence is low due to the scarcity of high-quality trials. Further research is necessary to determine optimal treatment for SRCC patients. Systematic Review Registration: https://www.crd.york.ac.uk/, PROSPERO (CRD42022298743).

Low microsatellite instability: A distinct instability type in gastric cancer?

PURPOSE: We recently showed that low microsatellite instability (MSI-L) is associated with a good response to platinum/5-fluorouracil (5-FU) neoadjuvant chemotherapy (CTx) in gastric cancer. The purpose of this study was to characterize the instability pattern and to investigate an association of MSI-L tumors with mutations in genes of DNA repair pathways and with total tumor mutation burden (TMB). METHODS: MSI patterns were compared between 67 MSI high (-H) and 35 MSI-L tumors. Whole-exome sequencing was performed in 34 microsatellite stable (MSS) and 20 MSI-L tumors after or without neoadjuvant CTx. RESULTS: Of the 35 MSI-L tumors, 33 tumors had instability at a dinucleotide repeat marker. In the homologous recombination (HR) pathway, 10 of the 34 (29%) MSS and 10 of the 20 (50%) MSI-L tumors showed variants (p = 0.154). In the DNA damage tolerance pathway, 6 of the 34 (18%) MSS and 7 of the 20 (35%) MSI-L tumors had variants (p = 0.194). The HR deficiency score was similar in both tumor groups. TMB was significantly higher in MSI-L compared to MSS tumors after CTx (p = 0.046). In the MSS and MSI-L tumors without CTx no difference was observed (p = 1.00). CONCLUSION: MSI-L due to instability at dinucleotide repeat markers was associated with increased TMB after neoadjuvant CTx treatment, indicating sensitivity to platinum/5-FU CTx. If confirmed in further studies, this could contribute to refined chemotherapeutic options including immune-based strategies for GC patients with MSI-L tumors.

Age-dependent benefit of neoadjuvant treatment in adenocarcinoma of the esophagus and gastroesophageal junction: a multicenter retrospective observational study of young versus old patients.

OBJECTIVES: The objective was to provide evidence for age-dependent use of neoadjuvant treatment by clinical comparisons of young (lower quartile, <56.6 years) versus old (upper quartile, >71.3 years) patients with esophageal and esophagogastric-junction adenocarcinoma. BACKGROUND: Neoadjuvant treatment is the standard of care for locally advanced and node-positive EAC. However, the effect of age on oncological outcomes is disputable as they are underrepresented in treatment defining randomized controlled trials. METHODS: Patients with EAC undergoing esophagectomy between 2001 and 2022 were retrospectively analyzed from three centers. Patients having distant metastases or clinical UICC-stage I were excluded. Cox proportional hazards regression was used to identify the variables associated with survival benefit. RESULTS: Neoadjuvant treatment was administered to 185/248 (74.2%) young and 151 out of 248 (60.9%) elderly patients ( P =0.001). Young age was associated with a significant overall survival (OS) benefit (median OS: 85.6 vs. 29.9 months, hazard ratio 0.62, 95% CI: 0.42-0.92) after neoadjuvant treatment versus surgery alone. In contrast, elderly patients did only experience a survival benefit equaling the length of neoadjuvant treatment itself (median OS: neoadjuvant 32.8 vs. surgery alone 29.3 months, hazard ratio 0.89, 95% CI: 0.63-1.27). Despite the clear difference in median OS benefit, histopathological regression was similar ((Mandard-TRG-1/2: young 30.7 vs. old 36.4%, P= 0.286). More elderly patients had a dose reduction or termination of neoadjuvant treatment (12.4 vs. 40.4%, P <0.001). CONCLUSION: Old patients benefit less from neoadjuvant treatment compared to younger patients in terms of gain in OS. Since they also experience more side effects requiring dose reduction, upfront surgery should be considered as the primary treatment option in elderly patients.

Pattern and time point of relapse in locally advanced esophagogastric adenocarcinoma after multimodal treatment: implications for a useful structured follow-up.

PURPOSE: Despite improvements in multimodal treatment of locally advanced esophagogastric adenocarcinoma, the majority of patients still relapses. The impact of structured follow-up for early detection of recurrence is unclear and controversially discussed. METHODS: Patients with locally advanced esophagogastric adenocarcinoma having received neoadjuvant/perioperative chemotherapy followed by tumor resection between 2009 and 2021, underwent a structured follow-up including three-monthly imaging during the first 2 years, followed by semiannual and annual examinations in year 3-4 and 5, respectively. Clinical outcome including pattern and time point of relapse was analyzed. RESULTS: Two hundred fifty-seven patients were included in this analysis. In 50.2% (n = 129) of patients, recurrent disease was diagnosed, with the majority (94.6%) relapsing within the first 2 years. The most common site of relapse were lymph node metastases followed by peritoneal carcinomatosis and hepatic and pulmonary metastases. 52.7% of patients presented with symptoms at the time of relapse. Cumulative risk and time point of relapse differed significantly between patient with a node-positive tumor (ypN+) after neoadjuvant treatment (high-risk group) and patients with node-negative primary tumor (ypN0) (low-risk group). High-risk patients had a significantly inferior disease-free survival (DFS) and overall survival (OS) with 11.1 and 29.0 months, respectively, whereas median DFS and OS were not reached for the low-risk group. CONCLUSIONS: The risk of relapse differs significantly between high- and low-risk patients. Only a part of relapses is associated with clinical symptoms. An individualized follow-up strategy is recommended for high- and low-risk patients considering the individual risk of relapse.

Clinical Characteristics and Oncological Outcomes of Surgically Treated Early-Onset Gastric Adenocarcinoma - a Retrospective Cohort Study.

Introduction: The incidence of early-onset gastric adenocarcinoma (patients <50 years, EOGA) is rising. Tumors in younger patients are associated with prognostically unfavorable features. The impact of EOGA on patient survival, however, remains unclear. The aim of this study is to evaluate early-onset age as a prognostic factor compared to late-onset gastric adenocarcinoma (LOGA, >50years) in a surgical cohort and assess treatment options. Methods: We analyzed 738 patients (129 early-onset/609 late-onset) operated in curative intent from 2002 to 2021. Data was extracted from a prospectively managed database of an academic tertiary referral hospital. Differences in perioperative as well as oncological outcomes were calculated by chi-square test. Cox regression analysis was performed to assess disease-free survival (DFS) and overall survival (OS). Results: EOGA patients were more often treated with neoadjuvant therapy (62.8% vs. 43.7%, p<0.001) and extended surgical resections e.g. through additional resections (36.4% vs. 26.8%, p=0.027). EOGA was more often metastasized into regional lymph nodes (pN+ 67.4% vs. 55.3%, p=0.012) and to distant sites (pM+: 23.3% vs. 12.0%, p=0.001) and was more often poorly differentiated (G3/G4: 91.1% vs. 67.2%, p<0.001). There were no significant differences in overall complication rates (31.0% vs. 36.6%, p=0.227). Survival analysis showed shorter DFS (median DFS 25.6 months vs. not reached, p=0.006) but similar OS (median OS: 50.5 months vs. not reached, p=0.920) in EOGA compared to LOGA. Conclusions: This analysis confirmed that EOGA is associated with more aggressive tumor characteristics. Early-Onset was not a prognostic factor in the multivariate analysis. EOGA patients may be more capable to undergo intensive multimodal therapy including perioperative chemotherapy and extended surgery.

Microsatellite instability and sex-specific differences of survival in gastric cancer after neoadjuvant chemotherapy without and with taxane: An observational study in real world patients.

PURPOSE: To investigate the prognostic role of microsatellite instability (MSI) in association with sex of patients treated with platinum/fluoropyrimidine neoadjuvant chemotherapy (CTx) with or without a taxane-containing compound. METHODS: Of the 505 retrospectively analyzed patients with gastric or gastroesophageal adenocarcinoma, 411 patients were treated without taxane and 94 patients with a taxane-containing compound. MSI was determined using standard assays. RESULTS: Females demonstrated a better overall survival (OS) than males in the non-taxane group (HR, 0.59; 95% CI 0.41-0.86; p = 0.005), whereas no significant difference was found in the taxane group (HR 1.22; 95% CI 0.55-2.73, p = 0.630). MSI-High (-H) was associated with a better prognosis in both groups (without taxane: HR 0.56; 95% CI 0.33-0.97; p = 0.038; with taxane: HR 0.28; 95% CI 0.04-2.02, p = 0.204). In the non-taxane group, female MSI-H patients showed the best OS (HR 0.18, 95% CI 0.05-0.73; p = 0.016), followed by the female microsatellite stable (MSS) (HR 0.67, 95% CI 0.46-0.98, p = 0.040) and the male MSI-H group (HR 0.76; 95% CI 0.42-1.37, p = 0.760) taken the male MSS group as reference. In the taxane group, female and male MSI-H patients demonstrated the best OS (female MSI-H: HR 0.05, 95% CI 0.00-240.46; male MSI-H: HR 0.45, 95% CI 0.61-3.63, p = 0.438), whereas the female MSS group showed a decreased OS (HR 1.39 95% CI 0.62-3.12, p = 0.420) compared to male MSS patients. CONCLUSION: OS in gastric/gastroesophageal cancer after CTx might depend on sex and MSI status and may differ between patients treated with or without a taxane compound in the chemotherapeutic regimen.