Resected Gastric Adenocarcinoma Research Articles

VEGFA locus amplification potentially predicts a favorable prognosis in gastric adenocarcinoma

Gastric adenocarcinoma harbors a range of genetic and epigenetic alterations, including alterations in DNA copy number. However, the key genes that promote the development and progression of gastric adenocarcinoma remain unknown.To identify the key genes amplified in gastric adenocarcinoma, we performed array comparative genomic hybridization on formalin-fixed paraffin-embedded samples of surgically resected gastric adenocarcinoma. We detected a relatively wide genomic region of gain containing the vascular endothelial growth factor A (VEGFA) gene locus on chromosome 6p. VEGFA locus amplification in gastric adenocarcinoma was validated by fluorescence in situ hybridization. To assess the frequency of VEGFA locus amplification in gastric adenocarcinoma, we conducted multiplex ligation-dependent probe amplification (MLPA) assays using homemade probes designed to target the VEGFA gene locus. Eleven of 54 (20 %) gastric adenocarcinomas with MLPA values above 1.3 were defined as having VEGFA locus amplification. Next, we investigated the effect of VEGFA locus amplification on the clinicopathological characteristics of gastric adenocarcinomas and patient survival. VEGFA locus amplification demonstrated a significantly close relationship with pathological intestinal type and lower rates of venous invasion Furthermore, a Kaplan-Meier analysis showed that patients with VEGFA locus amplification had significantly better overall survival than those without amplification (p = 0.038), particularly in the long-term follow-up period. In conclusion, VEGFA locus amplification can predict modest aggressiveness and good outcomes, suggesting the possibility that it may predict a favorable prognosis in patients with gastric adenocarcinoma.

Correlation between postoperative chemotherapy regimen and survival in patients with resectable gastric adenocarcinoma accompanied with vascular cancer thrombus.

Patients with resectable gastric adenocarcinoma accompanied by vascular cancer thrombus (RGAVCT) have a poor prognosis, with a 5-year survival rate ranging from 18.42%-53.57%. These patients need a reasonable postoperative treatment plan to improve their prognosis. To determine the most effective postoperative chemotherapy regimen for patients with RGAVCT. We retrospectively collected the clinicopathological data of 530 patients who underwent radical resection for gastric cancer between January 2017 and January 2022 and who were pathologically diagnosed with gastric adenocarcinoma with a choroidal cancer embolus. Furthermore, we identified the high-risk variables that can influence the prognosis of patients with RGAVCT by assessing the clinical and pathological features of the patients who met the inclusion criteria. We also assessed the significance of survival outcomes using Mantel-Cox univariate and multivariate analyses. The subgroups of patients with stages I, II, and III disease who received single-, dual-, or triple-drug regimens following surgery were analyzed using SPSS 25.0 and the ggplot2 package in R 4.3.0. In all, 530 eligible individuals with RGAVCT were enrolled in this study. The median overall survival (OS) of patients with RGAVCT was 24 months, and the survival rates were 80.2%, 62.5%, and 42.3% at 12, 24, and 59 months, respectively. Preoperative complications, tumor size, T stage, and postoperative chemotherapy were identified as independent factors that influenced OS in patients with RGAVCT according to the Cox multivariate analysis model. A Kaplan-Meier analysis revealed that chemotherapy had no effect on OS of patients with stage I or II RGAVCT; however, chemotherapy did have an effect on OS of stage III patients. Stage III patients who were treated with chemotherapy consisting of dual- or triple-agent regimens had better survival than those treated with single-agent regimens, and no significant difference was observed in the survival of patients treated with chemotherapy consisting of dual- or triple-agent regimens. For patients with stage III RGAVCT, a dual-agent regimen of postoperative chemotherapy should be recommended rather than a triple-agent treatment, as the latter is associated with increased frequency of adverse events.

Correlation between postoperative chemotherapy regimen and survival in patients with resectable gastric adenocarcinoma accompanied with vascular cancer thrombus.

Patients with resectable gastric adenocarcinoma accompanied by vascular cancer thrombus (RGAVCT) have a poor prognosis, with a 5-year survival rate ranging from 18.42%-53.57%. These patients need a reasonable postoperative treatment plan to improve their prognosis. To determine the most effective postoperative chemotherapy regimen for patients with RGAVCT. We retrospectively collected the clinicopathological data of 530 patients who underwent radical resection for gastric cancer between January 2017 and January 2022 and who were pathologically diagnosed with gastric adenocarcinoma with a choroidal cancer embolus. Furthermore, we identified the high-risk variables that can influence the prognosis of patients with RGAVCT by assessing the clinical and pathological features of the patients who met the inclusion criteria. We also assessed the significance of survival outcomes using Mantel-Cox univariate and multivariate analyses. The subgroups of patients with stages I, II, and III disease who received single-, dual-, or triple-drug regimens following surgery were analyzed using SPSS 25.0 and the ggplot2 package in R 4.3.0. In all, 530 eligible individuals with RGAVCT were enrolled in this study. The median overall survival (OS) of patients with RGAVCT was 24 months, and the survival rates were 80.2%, 62.5%, and 42.3% at 12, 24, and 59 months, respectively. Preoperative complications, tumor size, T stage, and postoperative chemotherapy were identified as independent factors that influenced OS in patients with RGAVCT according to the Cox multivariate analysis model. A Kaplan-Meier analysis revealed that chemotherapy had no effect on OS of patients with stage I or II RGAVCT; however, chemotherapy did have an effect on OS of stage III patients. Stage III patients who were treated with chemotherapy consisting of dual- or triple-agent regimens had better survival than those treated with single-agent regimens, and no significant difference was observed in the survival of patients treated with chemotherapy consisting of dual- or triple-agent regimens. For patients with stage III RGAVCT, a dual-agent regimen of postoperative chemotherapy should be recommended rather than a triple-agent treatment, as the latter is associated with increased frequency of adverse events.

Neoadjuvant dual checkpoint inhibition followed by immune-chemoradiation in patients with resectable gastric adenocarcinoma.

4067 Background: Localized gastric cancer is a potentially curable condition and long-term outcomes depend on YP staging. Currently, preferred adjunctive therapy depends on geographic location. Preliminary data from NCT01928394 have shown promising clinical activity of immunotherapy (IO) agents nivolumab (nivo) +/- ipilimumab (ipi) in the metastatic setting. We conducted a single-arm study using IO + chemotherapy followed by immune-chemoradiation prior to surgery, followed by adjuvant IO, in patients with localized gastric adenocarcinoma. Our primary objective was to determine safety and toxicity with this approach. Secondary objectives included efficacy by YP staging and R0 resection rate. Methods: Patients with localized gastric adenocarcinoma were enrolled into NCT03776487 (n=30). Participants received the following: (1) biweekly chemotherapy with 4 doses of 5-Fluorouracil (5-FU)/Oxaliplatin, (2) nivo 240mg q2weeks (x3) and ipi 1mg/kg q6weeks (x1), (3) immune-chemoradiation (biweekly nivo + 5FU Mon-Fri concurrently with a total of 45 Gy given in 25 fractions), and (4) surgical resection. Those with residual disease received adjuvant nivolumab monthly for 6 doses. Correlative studies are planned. To assess preliminary efficacy, the clinical and pathologic complete response rates (pCR) were estimated along with the corresponding exact 95% confidence interval. Adverse events and toxicities were summarized using descriptive statistics. Results: Median follow-up was 27.4 months at the time of data cutoff. Of 30 enrolled, 23 patients completed surgery and seven did not due to progression of disease(n=5) and worsening co-morbidities(n=2). The side effect profile was similar to prior IO studies, with no grade 5 events observed. Three patients (10%) experienced grade 4 events (acute kidney injury, myocarditis, and neutropenia). The most frequent grade 3 toxicity was nausea and vomiting (10%). From the 23 participants that underwent resection, 22 had pathologic data at the time of analysis, with 9 achieving ypT0ypN0 (40.9%, 95% CI: 20.7%, 63.7%). There was an 86% R0 resection rate. Conclusions: Our results are encouraging and support further development of this strategy for localized gastric adenocarcinomas. The regimen is safe and potentially generalizable. Clinical trial information: NCT03776487 .

Longitudinal circulating tumor DNA (ctDNA) analysis during treatment (Tx) of locally advanced resectable (LAR) gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ADENOCA): The PLAGAST prospective biomarker study.

Longitudinal circulating tumor DNA (ctDNA) analysis during treatment (Tx) of locally advanced resectable (LAR) gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ADENOCA): The PLAGAST prospective biomarker study.

Updated results of perioperative PD-1 antibody toripalimab plus FLOT chemotherapy for locally advanced resectable gastric or gastro-esophageal junction adenocarcinoma: A one-arm open-table phase II trial.

e16128 Background: Perioperative chemotherapy is the standard treatment for resectable gastric/gastroesophageal junction (GEJ) adenocarcinoma. Immune checkpoint inhibitors have activity in advanced gastric/GEJ cancer. This trial to assess the efficacy of the addition of toripalimab to FLOT for resectable patients and explore the immune microenvironment prospectively related to treatment response of neoadjuvant immunotherapy by multiplex immunohistochemistry. Methods: This is a prospective, single-arm, investigator-initiated phase II trial. Patients with histologically confirmed, resectable, gastric and GEJ adenocarcinoma (≥ cT2 or cN+) were enrolled to receive 4 pre- and post-operative cycles of toripalimab (240mg, q2w) plus FLOT (docetaxel 50 mg/m2; oxaliplatin 85 mg/m2; leucovorin 200 mg/m2; 5-Fu 2600 mg/m2, q2w). The primary endpoint were 3-year disease-free survival rate, overall survival and pathological complete response rate (pCR). Planned sample size of 36 operated patients. if the pCR rate is greater than 16% (n = 6), an additional 20 cases will be added. Multiplex immunohistochemistry is used to quantify in situ biomarker at subcellular resolution. Results: Study accrual completed at August 2022, 55 patients were enrolled, 40M/15F, age 57 (28-76), ECOG 0 (39) and 1 (16). 4 patients had not received surgery were excluded from efficacy analysis (Three patients withdrew consent after two treatment cycles and one refused surgery after 4 cycles pre-operative treatment). Fifty-one had completely neoadjuvant treatment and received surgery. Pathological response was TRG 0/ 1/ 2/ 3 in 10/ 6/ 21/ 14 patients with pCR seen in 10 (19.6%). Major pathologic response (TRG 0 and 1) was seen in 16 (31.4%) patients. At 36.6 (17.6-57.8) months follow up, the median disease-free survival (DFS) and overall survival (OS) were not reached for all patients. DFS rate at 1, 2, and 3 year is 78.4%, 56.9%, and 54.3%. OS rate at 1, 2, and 3 year is 94.1%, 69.5%, and 65.2%. Compared with TRG 2 or 3, patients with MPR showed significant longer survival (p = 0.01). Twenty-four patients underwent immune microenvironment analysis on their pre-treatment specimens by multiplex immunohistochemisty. Compared with TRG 2 or 3 (n = 11), NK cells with positive CD56 expression in tumor parenchyma microenvironment in patients with MPR (n = 13) were significant decreased (p = 0.024). Conclusions: Perioperative toripalimab in combination with FLOT showed promising efficacy with high pCR and MPR rate in patients with resectable gastric/GEJ adenocarcinoma. MPR rate and NK cells in tumor microenvironment have a predictive on therapeutic efficacy, with deserves further study. Clinical trial information: NCT04354662 .

Overall Volume of Upper Gastrointestinal Surgery Positively Impacts Gastric Cancer Outcomes at Centers with Low Gastrectomy Volume.

The relationship between hospital volume and surgical mortality is well documented. However, complete centralization of surgical care is not always feasible. The present study investigates how overall volume of upper gastrointestinal surgery at hospitals influences patient outcomes following resection for gastric adenocarcinoma. National Cancer Database (2010-2019) patients with pathologic stage 1-3 gastric adenocarcinoma who underwent gastrectomy were identified. Three cohorts were created: low-volume hospitals (LVH) for both gastrectomy and overall upper gastrointestinal operations, mixed-volume hospital (MVH) for low-volume gastrectomy but high-volume overall upper gastrointestinal operations, and high-volume gastrectomy hospitals (HVH). Chi-squared tests were used to analyze sociodemographic factors and surgical outcomes and Kaplan-Meier method for survival analysis. In total, 26,398 patients were identified (LVH: 20,099; MVH: 539; HVH: 5,760). The 5-year survival was equivalent between MVH and HVH for all stages of disease (MVH: 56.0%, HVH 55.6%; p = 0.9866) and when stratified into early (MVH: 69.9%, HVH: 65.4%; p = 0.1998) and late stages (MVH: 24.7%, HVH: 32.0%; p = 0.1480), while LVH had worse survival. After matching patients, postoperative outcomes were worse for LVH, but there was no difference between MVH and HVH in terms of adequate lymphadenectomy, margin status, readmission rates, and 90-day mortality rates. Despite lower gastrectomy volume for cancer, postoperative gastrectomy outcomes at centers that perform a high number of upper gastrointestinal cancer surgeries were similar to hospitals with high gastrectomy volume. These hospitals offer a blueprint for providing equivalent outcomes to high volume centers while enhancing availability of quality cancer care.

Outcomes of locally advanced gastric and gastroesophageal adenocarcinoma cancers treated with neoadjuvant FLOT in a tertiary care hospital in Pakistan.

Docetaxel, oxaliplatin, leucovorin and 5-fluorouracil (FLOT) may improve overall survival (OS) in patients with locally advanced gastric and gastroesophageal cancer. Our study aims to determine the pathological response in these patients with the FLOT chemotherapy in the Neoadjuvant setting. This is the first study conducted in our country. We conducted a retrospective cross-sectional study from March 2018 to December 2020. After ethical review committee approval, all patients who fulfilled the inclusion criteria and received treatment at our tertiary care center were included in the study. SPSS version 22 was used for data analysis. Frequencies and percentages were calculated for categorical. Values were presented as mean ± standard deviation (SD) for continuous variables. The chi-square test was used to determine the difference between categorical variables. A p-value of ≤0.05 was considered the level of significance. Kaplan-Meier curves were used to calculate survival analysis. Out of 41, 35 patients with locally advanced resectable gastric or gastroesophageal adenocarcinoma were included in our study analysis. The entire cohort had a male predominance, with a mean age of 59. All patients received neoadjuvant FLOT. Pathological treatment response achieved was 77%, of which 66% had partial and 11% had complete response. There is a significant association of pathological response with age, gender, stage, grade, co-morbid and number of chemotherapy cycles received (p-value =<0.05). The OS was 80% with the mean OS was 2.6 years (31 months). Our study shows comparable response rates to other studies conducted internationally. Our findings confirm that FLOT is an effective and well-tolerated perioperative regimen with reasonable response rates in the Pakistani population. A more extensive longitudinal study would ensure these preliminary results in the local patient population.

Comparison of the survival outcomes between retrocolic and antecolic Roux-en-Y reconstruction after gastrectomy for gastric cancer.

There are two methods of Roux-en-Y (RY) reconstruction after gastrectomy: the antecolic route (ACR) and retrocolic route (RCR). There is no evidence to support that the ACR achieves comparable long-term survival. This was a multi-center historical cohort study. Patients diagnosed with clinical T3/4a and any N stage who underwent open gastrectomy and R0 resection for gastric adenocarcinoma between January 2006 and December 2012 were enrolled. The primary outcome was the hazard ratio of ACR for overall survival, with adjustment for confounding factors by propensity score matching, and a Cox proportional hazards model. A total of 1758 eligible patients were identified from the database. After matching, 410 patients in the ACR and RCR groups were included in the final analysis. The adjusted hazard ratio (95% CI) for ACR was 1.148 (0.870-1.492). The five-year survival rates in the ACR and RCR groups were 74.3% (69.5-78.4) and 77.3% (72.3-81.2), respectively. The short-term surgical outcomes of the two groups did not differ to a statistically significant extent. The route used to lift the jejunum in RY reconstruction did not affect the incidence of long-term survival or postoperative complications. The ACR and RCR are both acceptable options for RY reconstruction during gastric cancer surgery.

Phase I trial of short-course chemoradiotherapy followed by chemotherapy as total neoadjuvant therapy for patients with potentially resectable gastric cancer.

362 Background: The purpose of this phase I trial was to evaluate the safety and toxicity of preoperative short-course chemoradiotherapy (CXRT) in patients with potentially resectable gastric or gastroesophageal adenocarcinoma as part of a total neoadjuvant therapy (TNT) approach. Methods: Patients with potentially resectable gastric or gastroesophageal adenocarcinoma received CXRT consisting of 30 Gy in 10 fractions with concurrent capecitabine or fluorouracil, followed by systemic therapy for 2 months and then surgery. The primary objective was safety of CXRT with secondary endpoints of pathologic complete response, perioperative complications, and overall survival (OS). Results: A total of 24 patients were treated between March 2021 and December 2022. Ten patients (42%) presented with bleeding and 3 (13%) presented with gastric outlet obstruction. Two patients (8%) had cirrhosis. Clinical nodal involvement was reported in 12 patients (50%). Twenty patients (83%) had poorly differentiated tumors, and 13 (54%) had signet ring cell histology. All patients completed CXRT. CXRT treatment-related toxic effects included grade 3 lymphopenia in 7 patients (29%), grade 4 lymphopenia in 1 (4%), and grade 3 anemia in 1 (4%). After CXRT, 22 patients (92%) completed 2 months of chemotherapy, 1 patient (4%) with a microsatellite-high tumor completed immunotherapy, and 1 patient (4%) underwent resection without systemic therapy. All patients underwent attempted resection, and gastrectomy was performed in 20 (83%). R0 resection rate was 95%. Pathologic complete response was observed in 2 patients (8%), and ≤ 1% viability was observed in an additional 4 (17%). Three patients had surgical complications (grade I in 1 patient [4%], grade IIIb in 1 [4%], and grade IVa in 1 [4%]); there were no deaths within 90 days. The median follow-up time was 20 months, and median OS was not reached. One- and 3-year OS rates from the date of diagnosis were 96% and 80%, respectively. Conclusions: Short-course CXRT (30 Gy in 10 fractions) may be safely used as part of a planned TNT approach. Rates of treatment completion, pathologic response, and survival were promising, supporting further research into TNT for gastric cancer. Clinical trial information: NCT04523818 .

Atezolizumab and trastuzumab plus chemotherapy in patients with HER2+ locally advanced resectable gastric cancer or adenocarcinoma of the gastroesophageal junction: A multicenter, randomized, open-label phase II study.

312 Background: Currently, there are no standard perioperative regimens for human epidermal growth factor receptor 2 positive (HER2+) gastric cancer (GC) or gastroesophageal junction (GEJ) cancer. Furthermore, despite advances in neoadjuvant or perioperative chemotherapy, the efficacy of treatment for locally resectable advanced GC or GEJ cancer remains unsatisfactory. To address this need, we evaluated the effectiveness of adding atezolizumab (programmed death ligand-1 inhibitor) to treatment with trastuzumab (a HER2 antibody) + capecitabine and oxaliplatin (XELOX) compared with trastuzumab + XELOX in patients eligible for surgery with HER2+ locally advanced GC or adenocarcinoma of the GEJ. Methods: Patients aged 18–75 years were randomized 1:1 to atezolizumab + trastuzumab + XELOX (Arm A) or trastuzumab + XELOX (Arm B) and received the regimen for three neoadjuvant cycles (3 weeks per cycle) and five adjuvant cycles. Treatment administration was atezolizumab 1200 mg, trastuzumab 6 mg/kg, oxaliplatin 130 mg/m2 intravenously on Day 1, and capecitabine 1000 mg/m2 orally twice daily on Days 1–14 of each 3-week cycle. The primary endpoint was the pathological complete regression (pCR) rate. Secondary endpoints were the objective response rate (ORR) during neoadjuvant systemic therapy (NAST) and the R0 resection rate. Time-to-event endpoints are not reported because of immaturity. Efficacy endpoints were analyzed in the intention-to-treat population. The clinical cutoff date for the primary analysis was 12 March 2023. Results: Forty-two Asian patients who provided informed consent were screened and randomized to Arm A (n = 21) or Arm B (n = 21); all patients completed NAST. Most patients were male (92.9%), and the median (range) age was 61 (33–72) years in Arm A and 65 (49–72) years in Arm B. The pCR rate was 38.1% (8/21) in Arm A and 14.3% (3/21) in Arm B (treatment difference: 23.8% [90% confidence interval (CI), 1.3%–44.7%]). The pCR rate was significantly better in Arm A than in Arm B (P = 0.079 &lt;0.1; lower limit of the 90% CI &gt;0). Subgroup analysis showed that age &lt;65 years, male sex, and intestinal Lauren classification were associated with a better pCR rate for the atezolizumab inclusive treatment arm (Arm A); however, these results require further confirmation in future studies. No significant difference was detected between the two arms in ORR during NAST or the R0 resection rate. Conclusions: The addition of atezolizumab to trastuzumab + XELOX therapy was effective in patients with HER2+ locally advanced resectable GC or adenocarcinoma of the GEJ. Clinical trial information: NCT04661150 .

Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study

The benefit of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma is unknown. We assess the antitumor activity of neoadjuvant and adjuvant pembrolizumab plus chemotherapy in patients with locally advanced resectable gastric or gastro-oesophageal adenocarcinoma. The KEYNOTE-585 study is a multicentre, randomised, placebo-controlled, double-blind, phase 3 study done at 143 medical centres in 24 countries. Eligible patients were aged 18 years or older with untreated, locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma, and an Eastern Cooperative Oncology Group performance status 0-1. Patients were randomly assigned (1:1) by an interactive voice response system and integrated web response system to neoadjuvant pembrolizumab 200 mg intravenously or placebo (saline) plus cisplatin-based doublet chemotherapy (main cohort) every 3 weeks for 3 cycles, followed by surgery, adjuvant pembrolizumab or placebo plus chemotherapy for 3 cycles, then adjuvant pembrolizumab or placebo for 11 cycles. A small cohort was also randomly assigned (1:1) to pembrolizumab or placebo plus fluorouracil, docetaxel, and oxaliplatin (FLOT)-based chemotherapy (FLOT cohort) every 2 weeks for four cycles, followed by surgery, adjuvant pembrolizumab, or placebo plus FLOT for four cycles, then adjuvant pembrolizumab or placebo for 11 cycles. Patients were stratified by geographic region, tumour stage, and chemotherapy backbone. Primary endpoints were pathological complete response (reviewed centrally), event-free survival (reviewed by the investigator), and overall survival in the intention-to-treat population, and safety assessed in all patients who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT03221426, and is closed to accrual. Between Oct 9, 2017, and Jan 25, 2021, of 1254 patients screened, 804 were randomly assigned to the main cohort, of whom 402 were assigned to the pembrolizumab plus cisplatin-based chemotherapy group and 402 to the placebo plus cisplatin-based chemotherapy group, and 203 to the FLOT cohort, of whom 100 were assigned to the pembrolizumab plus FLOT group and 103 to placebo plus FLOT group. In the main cohort of 804 participants, 575 (72%) were male and 229 (28%) were female. In the main cohort, after median follow-up of 47·7 months (IQR 38·0-54·8), pembrolizumab was superior to placebo for pathological complete response (52 [12·9%; 95% CI 9·8-16·6] of 402 vs eight [2·0%; 0·9-3·9] of 402; difference 10·9%, 95% CI 7·5 to 14·8; p<0·00001). Median event-free survival was longer with pembrolizumab versus placebo (44·4 months, 95% CI 33·0 to not reached vs 25·3 months, 20·6 to 33·9; hazard ratio [HR] 0·81, 95% CI 0·67 to 0·99; p=0·0198) but did not meet the threshold for statistical significance (p=0·0178). Median overall survival was 60·7 months (95% CI 51·5 to not reached) in the pembrolizumab group versus 58·0 months (41·5 to not reached) in the placebo group (HR 0·90, 95% CI 0·73 to 1·12; p=0·174). Grade 3 or worse adverse events of any cause occurred in 312 (78%) of 399 patients in the pembrolizumab group and 297 (74%) of 400 patients in the placebo group; the most common were nausea (240 [60%] vs 247 [62%]), anaemia (168 [42%] vs 158 [40%]), and decreased appetite (163 [41%] vs 172 [43%]). Treatment-related serious adverse events were reported in 102 (26%) and 97 (24%) patients. Treatment-related adverse events that led to death occurred in four (1%) patients in the pembrolizumab group (interstitial ischaemia, pneumonia, decreased appetite, and acute kidney injury [n=1 each]) and two (<1%) patients in the placebo group (neutropenic sepsis and neutropenic colitis [n=1 each]). Although neoadjuvant and adjuvant pembrolizumab versus placebo improved the pathological complete response, it did not translate to significant improvement in event-free survival in patients with untreated, locally advanced resectable gastric or gastro-oesophageal cancer. Merck Sharp & Dohme.

Great Debate: Chemoradiation Should be Added to Chemotherapy as a Neoadjuvant Treatment Strategy for Resectable Gastric Adenocarcinoma.

Most patients with resectable gastric cancer present with locally advanced disease and warrant neoadjuvant chemotherapy based on level 1 evidence. However, the incremental benefit of adding radiation to chemotherapy as a neoadjuvant treatment strategy for these patients is less clear. While awaiting the results of two ongoing randomized clinical trials attempting to specifically address this question (TOPGEAR and CRITICS-II), this article presents the debate between two gastric cancer surgery experts supporting each side of the argument on the use or omission of neoadjuvant radiation in this setting. On the one hand, neoadjuvant radiation may be better tolerated compared with modern triplet chemotherapy and may be associated with higher rates of major pathologic response. Additionally, there is evidence to suggest that radiation may offer a survival benefit when the tumor is located at the gastroesophageal junction or there is concern for a margin-positive resection. However, in the setting of adequate surgery, no survival benefit has been demonstrated by adding radiation to modern chemotherapy, likely reflecting the fact that death from gastric cancer is a result of distant recurrence, which is not addressed by local treatment such as radiotherapy. While awaiting the results of the TOPGEAR and CRITICS-II trials, this discussion of current evidence can facilitate the refinement of an optimal neoadjuvant therapy strategy in patients with resectable gastric cancer.

1512MO Perioperative camrelizumab (C) combined with rivoceranib (R) and chemotherapy (chemo) versus chemo for locally advanced resectable gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The first interim analysis of a randomized, phase III trial (DRAGON IV)

1512MO Perioperative camrelizumab (C) combined with rivoceranib (R) and chemotherapy (chemo) versus chemo for locally advanced resectable gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The first interim analysis of a randomized, phase III trial (DRAGON IV)

Current management of gastric adenocarcinoma: a narrative review.

Gastric adenocarcinoma is a leading cause of cancer death worldwide. The management of this aggressive malignancy largely depends on tumor characteristics especially stage. Superficial early-stage gastric cancer can be safely managed by endoscopic resection, though clear negative deep and lateral margins must be obtained. Optimal surgical resection is an essential part of the treatment for locally advanced gastric adenocarcinoma, with perioperative and adjuvant therapies having significant impact on long-term outcomes. Chemoradiation is reserved for patients with suboptimal surgical resection. Recent therapeutic advances have prolonged survival in patients with metastatic gastric adenocarcinoma, include checkpoint inhibitors and biomarker-directed therapy. Targeted therapies in gastric adenocarcinoma include monoclonal antibodies directed against vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2), and human epidermal growth factor receptor 2 (HER2). While anti-VEGF therapies were not found beneficial in the perioperative setting, the effectiveness of HER2 targeted agents in resectable HER2-positive gastric adenocarcinoma is being studied. Microsatellite instability (MSI) varies greatly in patients with gastric adenocarcinoma between 5-20% based on ethnic origin, tumour heterogeneity and staging. The role chemotherapy in the perioperative setting for patients with MSI-high tumors remains controversial while immunotherapy demonstrates promising results in preliminary studies. Immune checkpoint inhibitors in combination with chemotherapy has been shown to improve outcomes in patients with metastatic gastric adenocarcinoma who express programmed cell death 1 ligand 1 (PD-L1) and is now being investigated in the perioperative setting.

Programmed death-ligand 1 (PD-L1) expression in primary gastric adenocarcinoma and matched metastases

BackgroundCombination of immunotherapy and chemotherapy is recommended for first line treatment of gastric adenocarcinoma (GC) patients with locally advanced unresectable disease or metastatic disease. However, data regarding the concordance rate between PD-L1 combined positive score (CPS) in primary GC and matched regional lymph node metastasis (LNmet) or matched distant metastasis (Dmet) is limited.MethodsTissue microarray sections from primary resected GC, LNmet and Dmet were immunohistochemically stained with anti-PD-L1 (clone SP263). PD-L1 expression was scored separately in tumour cells and immune cells and compared between matched primary GC, LNmet and/or Dmet. CPS was calculated and results for CPS cut-offs 1 and 5 were compared between matched samples.Results275 PD-L1 stained GC were analysed. 189 primary GC had matched LNmet. CPS cut-off 1 concordance rate between primary GC and LNmet was 77%. 23 primary GC had matched Dmet but no matched LNmet, CPS cut-off 1 concordance rate was 70%. 63 primary GC had both matched LNmet and matched Dmet, CPS cut-off 1 concordance rate of 67%. CPS cut-off 5 results were similar. The proportion of PD-L1 positive tumour cells increased from primary GC (26%) to LNmet (42%) and was highest in Dmet (75%).ConclusionOur study showed up to 33% discordance of PD-L1 CPS between primary GC and LNmet and/or Dmet suggesting that multiple biopsies of primary GC and metastatic sites might need to be tested before considering treatment options. Moreover, this is the first study that seems to suggest that tumour cells acquire PD-L1 expression during disease progression.

Pain and Opioid Consumption After Laparoscopic Versus Open Gastrectomy for Gastric Cancer: A Secondary Analysis of a Multicenter Randomized Clinical Trial (LOGICA-Trial)

BackgroundLaparoscopic gastrectomy could reduce pain and opioid consumption, compared to open gastrectomy. However, it is difficult to judge the clinical relevance of this reduction, since these outcomes are reported in few randomized trials and in limited detail. MethodsThis secondary analysis of a multicenter randomized trial compared laparoscopic versus open gastrectomy for resectable gastric adenocarcinoma (cT1-4aN0-3bM0). Postoperative pain was analyzed by opioid consumption in oral morphine equivalents (OME, mg/day) at postoperative day (POD) 1–5, WHO analgesic steps, and Numeric Rating Scales (NRS, 0–10) at POD 1–10 and discharge. Regression and mixed model analyses were performed, with and without correction for epidural analgesia. ResultsBetween 2015 and 2018, 115 patients in the laparoscopic group and 110 in the open group underwent surgery. Some 16 patients (14%) in the laparoscopic group and 73 patients (66%) in the open group received epidural analgesia. At POD 1–3, mean opioid consumption was 131, 118, and 53 mg OME lower in the laparoscopic group, compared to the open group, respectively (all p < 0.001). After correcting for epidural analgesia, these differences remained significant at POD 1–2 (47 mg OME, p = 0.002 and 69 mg OME, p < 0.001, respectively). At discharge, 27% of patients in the laparoscopic group and 43% patients in the open group used oral opioids (p = 0.006). Mean highest daily pain scores were between 2 and 4 at all PODs, < 2 at discharge, and did not relevantly differ between treatment arms. ConclusionIn this multicenter randomized trial, postoperative pain was comparable between laparoscopic and open gastrectomy. After laparoscopic gastrectomy, this was generally achieved without epidural analgesia and with fewer opioids. Trial RegistrationNCT02248519.

Concordance of microsatellite instability and mismatch repair status in paired biopsies and surgical specimens of resectable gastroesophageal adenocarcinoma: time for a call to action.

Reliability of mismatch repair proteins and microsatellite instability assessment is essential in order to define treatment strategy and identify candidates to immune checkpoint inhibitors in locally advanced gastroesophageal carcinoma. We evaluated the concordance of deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H) status between endoscopic biopsies and surgical specimens. Consecutive patients with resectable gastric or gastroesophageal junction adenocarcinoma classified as MSI-H/dMMR by polymerase chain reaction (PCR) or immunohistochemistry (IHC) and operated at three referral Institutions were included. The primary endpoint was the rate of concordance between biopsy and surgical samples. If needed, central revision by IHC/PCR was performed by specialized pathologists from coordinating Institutions. Thirteen (19.7%) out of 66 patients showed discordant MSI-H/dMMR results in the original pathology reports. In most cases (11, 16.7%) this was due to the diagnosis of proficient mismatch repair status on biopsies. Among the ten cases available for central review, four were due to sample issues, fourwere reclassified as dMMR, onecase showed dMMR status but was classified as microsatellite stable by PCR, one was linked to misdiagnosis of endoscopic biopsy by the local pathologist. Heterogeneity of mismatch repair proteins staining was observed in two cases. Available methods can lead to conflicting results in MSI-H/dMMR evaluation between endoscopic biopsies and surgical samples of gastroesophageal adenocarcinoma. Strategies aiming to improve the reliability of assessment should be primarily focused on the optimization of tissue collection and management during endoscopy and adequate training of dedicated gastrointestinal pathologists within the multidisciplinary team.

Distal Versus Total D2-Gastrectomy for Gastric Cancer: a Secondary Analysis of Surgical and Oncological Outcomes Including Quality of Life in the Multicenter Randomized LOGICA-Trial

BackgroundDistal gastrectomy (DG) for gastric cancer can cause less morbidity than total gastrectomy (TG), but may compromise radicality. No prospective studies administered neoadjuvant chemotherapy, and few assessed quality of life (QoL). MethodsThe multicenter LOGICA-trial randomized laparoscopic versus open D2-gastrectomy for resectable gastric adenocarcinoma (cT1–4aN0–3bM0) in 10 Dutch hospitals. This secondary LOGICA-analysis compared surgical and oncological outcomes after DG versus TG. DG was performed for non-proximal tumors if R0-resection was deemed achievable, TG for other tumors. Postoperative complications, mortality, hospitalization, radicality, nodal yield, 1-year survival, and EORTC-QoL-questionnaires were analyzed using Χ2-/Fisher’s exact tests and regression analyses. ResultsBetween 2015 and 2018, 211 patients underwent DG (n = 122) or TG (n = 89), and 75% of patients underwent neoadjuvant chemotherapy. DG-patients were older, had more comorbidities, less diffuse type tumors, and lower cT-stage than TG-patients (p < 0.05). DG-patients experienced fewer overall complications (34% versus 57%; p < 0.001), also after correcting for baseline differences, lower anastomotic leakage (3% versus 19%), pneumonia (4% versus 22%), atrial fibrillation (3% versus 14%), and Clavien-Dindo grading compared to TG-patients (p < 0.05), and demonstrated shorter median hospital stay (6 versus 8 days; p < 0.001). QoL was better after DG (statistically significant and clinically relevant) in most 1-year postoperative time points. DG-patients showed 98% R0-resections, and similar 30-/90-day mortality, nodal yield (28 versus 30 nodes; p = 0.490), and 1-year survival after correcting for baseline differences (p = 0.084) compared to TG-patients. ConclusionsIf oncologically feasible, DG should be preferred over TG due to less complications, faster postoperative recovery, and better QoL while achieving equivalent oncological effectiveness. Mini-abstractDistal D2-gastrectomy for gastric cancer resulted in less complications, shorter hospitalization, quicker recovery and better quality of life compared to total D2-gastrectomy, whereas radicality, nodal yield and survival were similar.

Efficacy and safety of perioperative chemotherapy combined with tislelizumab and trastuzumab for HER2-positive resectable gastric/gastroesophageal junction cancer (GC/EGJC): Preliminary results of a phase 2, single-arm trial.

e16084 Background: Recently, immunotherapy combined with trastuzumab and chemotherapy have been recommended by the clinical guidelines of many countries as the first-line treatment for advanced HER2-positive G/GEJ adenocarcinoma. Combining chemotherapy with tislelizumab and trastuzumab in the neoadjuvant/adjuvant setting may benefit patients with locally advanced, resectable HER2-positive GC/GEJC. Methods: This study is a multicenter, single-arm, open-label phase 2 study (NCT04819971). Patients with histologically confirmed cT2-4NxM0 or cTxN+M0, (TNM 8th edition), resectable gastric adenocarcinoma are eligible for this study. Neoadjuvant therapy will be administered for four cycles. The patients will receive tislelizumab and trastuzumab for 1 cycle (Q3W), followed by tislelizumab and trastuzumab combined with DOS (Docetaxel + Oxaliplatin + S-1) for 3 cycles (Q3W). Surgery is planned 4-6 weeks after preoperative treatment. Patients who have complete surgical resection will receive adjuvant therapy starting within 4–6 weeks after surgery for 6 cycles (three cycles of tislelizumab and trastuzumab combined with DOS regimen, followed by 6 weeks of tislelizumab and trastuzumab for 6 cycles. The primary endpoint was pathological complete response rate (pCR). Secondary endpoints included R0 resection rate, 1-year and 2-year event-free survival (EFS), overall survival (OS) and safety. Results: From September 13, 2021 to February 01, 2023, 12 patients were enrolled (58.0% male, median age 61 years old), and the median follow up time was 7.3 months (0.4-16.9). Seven patients completed surgery, and 5 patients were undergoing neoadjuvant therapy. The R0 resection rate was 100%, 3 patients (42.9%) achieved pCR, and 4 patients (57.1%) achieved major pathological remission (MPR). Postoperative pathology showed tumor downstaging in 5 cases after neoadjuvant therapy, with a decrease rate of 71.4%. Median OS and EFS have not been reached. The most common AEs (all grades, grade ≥3) were anemia in 1 (8.3%) and neutropenia in 1 case (8.3%). The immune-related adverse events were all grade 1 included 2 thyroid dysfunction (16.7%), 1 abnormal liver function (8.3%), and 1 of elevated blood sugar (8.3%). No grade 3 or higher immune-related AE was observed. No treatment related deaths were reported. Conclusions: According to the preliminary results, tislelizumab combined with trastuzumab and standard chemotherapy in the perioperative period of HER2-positive GC and EGJ have a good clinical benefit trend and controllable security. Clinical trial information: NCT04819971 .