Resectable Advanced Gastric Cancer Research Articles

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 <0.1; lower limit of the 90% CI >0). Subgroup analysis showed that age <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 .

Machine Learning Radiomics Liver Function Model for Prognostic Prediction After Radical Resection of Advanced Gastric Cancer: A Retrospective Study.

We aimed to establish a machine learning radiomics liver function model to explore how liver function affects the prognosis of patients with gastric cancer (GC). Patients with advanced GC were retrospectively enrolled in this study. Eight machine learning radiomic models were constructed by extracting radiomic features from portal-vein-phase contrast-enhanced computed tomography (CE-CT) images. Clinicopathological features were determined using univariate and multifactorial Cox regression analyses. These features were used to construct a GC survival nomogram. A total of 510 patients with GC were split into training and test cohorts in an 8:2 ratio. Kaplan-Meier analysis showed that patients with typeI liver function had a better prognosis. Fifteen significant features were retained to establish the machine learning model. LightBGM showed the best predictive performance in the training (area under the receiver operating characteristic curve [AUC] 0.978) and test cohorts (AUC 0.714). Multivariate analysis revealed that gender, age, liver function, Nutritional Risk Screening 2002 (NRS-2002) score, tumor-lymph node-metastasis stage, tumor size, and tumor differentiation were independent risk factors for GC prognosis. The survival nomogram based on machine learning radiomics, instead of liver biochemical indicators, still had high accuracy (C-index of 0.771 vs. 0.773). The machine learning radiomics liver function model has high diagnostic value in predicting the influence of liver function on prognosis in patients with GC.

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.

Neoadjuvant docetaxel, oxaliplatin, and S-1 plus surgery and adjuvant S-1 for resectable advanced gastric cancer: Final survival outcomes of the randomized phase 3 PRODIGY trial.

30 Background: The phase 3 PRODIGY study compared neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy followed by surgery followed by adjuvant S-1 with surgery followed by adjuvant S-1 for Korean patients with resectable locally advanced gastric cancer (LAGC) (Kang et al. J Clin Oncol. 2021). The planned analysis of the primary endpoint of PRODIGY showed that the addition of neoadjuvant DOS to surgery and adjuvant S-1 improved progression-free survival (PFS). We herein report the long-term follow-up outcomes, including overall survival (OS), from this trial. Methods: Patients with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma with clinical T2-3N+ or T4Nany disease were enrolled from 18 Korean study sites. Patients were randomly assigned to D2 surgery followed by adjuvant S-1 (40–60 mg orally twice a day, days 1–28 q6w for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1–14 q3w for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary endpoint was PFS. OS was the secondary endpoint. This analysis presents the final assessment of the outcomes after 5 years. Results: A total of 266 and 264 patients were randomly assigned to the CSC and SC arms, respectively, among which 238 and 246 patients were treated and included in the full analysis set. As of the data cut-off date (SEP-2022), the median follow-up duration of the surviving patients was 99.5 months (range, 68.6–127.7 months). As compared to SC, CSC significantly increased the OS (adjusted hazard ratio, 0.72; 95% CI, 0.54 to 0.97; stratified log-rank P=0.028) with a 5-year OS rate of 66.8% and 63.0% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (adjusted hazard ratio, 0.71; 95% CI, 0.53 to 0.94; stratified log-rank P=0.019) with a 5-year PFS rate of 60.6% and 56.9% for the CSC and SC arms, respectively. Among the patient subgroups determined based on different clinical T/N categories, a patient subgroup with cT4Nany disease showed the greatest relative risk reduction in OS with neoadjuvant chemotherapy (HR 0.69, 95% CI 0.51–0.95). Conclusions: The addition of neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy, as part of perioperative chemotherapy, to surgery and adjuvant S-1 prolonged the OS and PFS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1 alone. Neoadjuvant DOS chemotherapy should be considered one of the standard treatment options for patients with LAGC in Asia. Unlike in the Western setting, neoadjuvant chemotherapy may be preferentially considered for patients with cT4 disease in Asia. Clinical trial information: NCT01515748 .

Perioperative PD-1 antibody toripalimab plus SOX or XELOX chemotherapy versus SOX or XELOX alone for locally advanced gastric or gastro-oesophageal junction cancer: Results from a prospective, randomized, open-label, phase II trial.

4001 Background: The combination of PD-1 antibody and chemotherapy was shown to be effective in advanced gastric or gastro-oesophageal junction (GEJ) cancer, but has not yet been investigated in the context of locally advanced patients. In this study, we conducted a prospective, randomized, open-label phase II trial to evaluate the effectiveness of adding PD-1 antibody to perioperative chemotherapy in patients with locally advanced resectable gastric or GEJ cancer. Methods: In this randomized, open-label, phase II study, patients with resectable gastric or GEJ cancer clinically staged as cT3-4a N+M0 were randomized (1:1) to three preoperative and five postoperative 3-week cycles of SOX/XELOX (C arm) or PD-1 antibody toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for 6 months (C+T arm). The primary endpoint was pathological complete regression/moderate regression rate (TRG 0/1). The secondary endpoints were pathological complete response (pCR), R0 resection rate, recurrence-free survival, event-free survival, objective response rate, disease control rate, overall survival and treatment safety. The study had been completed enrollment, and here, we analyzed the primary endpoint. Mantel-Haenszel test was used to test the difference of pathological regression between the two arms. The trial was registered at ClinicalTrials.gov, identifier: NCT04250948. Results: Between Oct 2019 and June 2022, 108 patients (C+T arm, n=54; C arm, n=54) were enrolled and assessed using intention-to-treat analysis. Patients in the toripalimab plus chemotherapy arm achieved higher proportion of TRG 0/1 than those in the chemotherapy arm (44.4% [24/54, 95% CI: 30.9%-58.6%] vs 20.4% [11/54, 95% CI: 10.6%-33.5%]; P=0.009). A higher pCR rate was observed in the C+T arm (24.1% [13/54, 95% CI:13.5%-37.6%] vs 9.3% [5/54, 95% CI: 3.1%-20.3%]; P=0.039). Preoperative therapies (3 cycles) were completed in 96.3% of patients and postoperative cycles (&gt;3 cycles) in 81.5%, with no significant differences observed between these two arms. A higher proportion of downstaging was observed in the C+T arm (ypT0-2: 46.3% vs 22.2% [P=0.002]; ypstage 0-1: 38.9% vs 16.7% [P=0.024]). Surgical morbidity (11.8% in the C+T arm vs 13.5% in the C arm) and mortality (1.9% vs 0%) and treatment-related grade 3-4 adverse events (27.8% vs 25.9%) were comparable between the arms. Conclusions: Perioperative PD-1 antibody toripalimab plus chemotherapy demonstrated a significantly improved pathological regression and might be a promising option for patients with locally advanced resectable gastric or GEJ cancer. Clinical trial information: NCT04250948 .

P-33 The role of preoperative immune-chemotherapy in locally advanced resectable gastric cancer with microsatellite instability

P-33 The role of preoperative immune-chemotherapy in locally advanced resectable gastric cancer with microsatellite instability

Neoadjuvant docetaxel, oxaliplatin, and s-1 plus surgery and adjuvant s-1 for resectable advanced gastric cancer: Final survival outcomes of the randomized phase 3 PRODIGY trial.

4067 Background: The phase 3 PRODIGY study compared neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy followed by surgery followed by adjuvant S-1 with surgery followed by adjuvant S-1 for Korean patients with resectable locally advanced gastric cancer (LAGC) (Kang et al. J Clin Oncol. 2021). The planned analysis of the primary endpoint of PRODIGY showed that the addition of neoadjuvant DOS to surgery and adjuvant S-1 improved progression-free survival (PFS). We herein report the long-term follow-up outcomes, including overall survival (OS), from this trial. Methods: Patients with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma with clinical T2-3N+ or T4Nany disease were enrolled from 18 Korean study sites. Patients were randomly assigned to D2 surgery followed by adjuvant S-1 (40–60 mg orally twice a day, days 1–28 q6w for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1–14 q3w for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary endpoint was PFS. OS was the secondary endpoint. This analysis presents the final assessment of the outcomes after 5 years. Results: A total of 266 and 264 patients were randomly assigned to the CSC and SC arms, respectively, among which 238 and 246 patients were treated and included in the full analysis set. As of the data cut-off date (SEP-2022), the median follow-up duration of the surviving patients was 99.5 months (range, 68.6–127.7 months). As compared to SC, CSC significantly increased the OS (adjusted hazard ratio, 0.72; 95% CI, 0.54 to 0.97; stratified log-rank P=0.028) with a 5-year OS rate of 66.8% and 63.0% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (adjusted hazard ratio, 0.71; 95% CI, 0.53 to 0.94; stratified log-rank P=0.019) with a 5-year PFS rate of 60.6% and 56.9% for the CSC and SC arms, respectively. Conclusions: The addition of neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy, as part of perioperative chemotherapy, to surgery and adjuvant S-1 prolonged the OS and PFS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1 alone. Neoadjuvant DOS chemotherapy should be considered one of the standard treatment options for patients with LAGC in Asia. Clinical trial information: NCT01515748 .

Molecular markers as predictors of response to perioperative chemotherapy in locally advanced gastric cancer

Introduction. Perioperative FLOT chemotherapy has improved prognosis in patients with locally advanced resectable gastric cancer (GC). However, in 80 % of cases, the tumor is resistant to the therapy, resulting in unnecessary toxicity and delayed surgical treatment.Aim. Evaluation of clinico-morphological patterns of microsatellite instability, HER2 gene amplification, changes in gene copy number and their relationship with the response to perioperative FLOT chemotherapy in patients with locally advanced resectable GC.Materials and methods. The retrospective study included 185 patients. All tumor samples were assessed for HER2 and microsatellite instability status. Among all cases there were 45 patients with locally advanced T2–4N1–2 M0 GC, who underwent a total or subtotal gastrectomy with D2 lymphadenectomy and perioperative chemotherapy with FLOT. Microsatellite instability detection was performed using fragment analysis, HER2 gene amplification testing – fluorescent in situ hybridization. Also 19 patients were tested for copy number changes of the FGFR1, FGFR2, KRAS, MET, EGFR, CCND1, MYC genes using Multiplex ligation-dependent probe amplification. The endpoints were progression-free survival and objective response rate.Results. Microsatellite instability was detected in 4.8 % (9/185) of GC cases. Microsatellite instability was associated with advanced age (p = 0.005), low grade of differentiation (p = 0.011), presence of tumor-infiltrating lymphocytes (p = 0.0004), and high preoperative CA 72–4 levels (p = 0.025). Prevalence of HER2 amplification was 7.5 % (14/185). It was associated with low grade of differentiation (p = 0.048) and metastasis in regional lymph nodes (p = 0.037). PFS in patients with HER2-positive (HER2 – human epidermal growth factor receptor 2) GC treated with perioperative FLOT chemotherapy (4/45) was significantly lower than in patients with HER2-negative GC: the median was 156 and 317 days, respectively (hazard ratio 0.49; 95 % confidence interval 0.16–1.47; p = 0.0006). There was no correlation between the presence of the alteration and ORR (p = 1.0). Progression-free survival in GC patients with KRAS amplification (3/19) was significantly lower comparing with patients without it: the median was 98 and 327 days, respectively (hazard ratio 0.29; 95 % confidence interval 0.07–1.19; p &lt;0.0001). There was no association between an increase in KRAS copy number and objective response rate (p = 1.0). For microsatellite instability and other studied markers no statistically significant correlation with progression-free survival and objective response rate was found (p &gt;0.05).Conclusion. The presence of HER2 and KRAS amplification have been shown as promising predictive markers of the treatment failure in patients treated with perioperative FLOT chemotherapy for locally advanced resectable GC.

Current trends in perioperative treatment of resectable gastric cancer.

In the last few decades, the treatment strategy for locally advanced resectable gastric cancer (GC) has shifted to a multimodal approach, which potentially decreases recurrence risk and improves survival rates. Perioperative therapy leads to downstaging, increased curative resection rates, and prolonged disease-free and overall survival, by preventing micrometastases in patients with resectable GC. Application of neoadjuvant therapy provides information about tumor biology and in vivo sensitivity. A consensus regarding the therapeutic approach for non-metastatic GC does not exist, and many clinical trials aim to clarify this aspect. Advances in precision medicine and the role of immunotherapy have been the focus of research in GC treatment. Herein, the current status and possible future developments of perioperative therapy for locally advanced resectable GC are reviewed, based on the most recent randomized clinical trials.

Prognostic value of the preoperative albumin-bilirubin score among patients with stages I-III gastric cancer undergoing radical resection: A retrospective study.

The albumin-bilirubin (ALBI) score was originally used to accurately assess liver dysfunction and predict the prognoses of patients with hepatocellular carcinoma. Following its more recent application to patients with gastrointestinal tumors, this study analyzed the prognostic value of the ALBI score in Chinese patients with advanced resectable (tumor-node-metastasis [TNM] stages I-III) gastric cancer (GC). This study investigated 1185 patients with advanced GC, including 429 with TNM stage I. The patients were divided into training and verifications groups (593 and 592 patients, respectively) in which these patients were classified as high risk (ALBI score ≥ -2.65) or low risk (ALBI score < -2.65). Univariate and multivariate Cox regression analyses were performed, and a visual survival prediction model (nomogram) was created. On Kaplan-Meier analysis, patients who were low-risk and high-risk according to their ALBI scores had significantly different survival rates in both the training and verification groups (p < 0.01). The difference was also significant when analyzing only patients with TNM stage I GC (p=0.031). Univariate and multivariate analyses showed that the ALBI score (p=0.014), age (p < 0.001), Nutritional Risk Screening 2002 score (p=0.024), sarcopenia (p=0.049), tumor differentiation (p=0.027), and TNM stage (p < 0.001) were independent risk factors for survival. Our survival prediction model that incorporated the ALBI score accurately predicted the 5-year survival rate of Chinese patients with GC. Therefore, the ALBI score is a valid clinical indicator and good predictor of survival after surgery for progressive GC. Moreover, this score is simple to derive and does not burden patients with additional costs.

Early experience of laparoscopic-assisted distal gastrectomy in resectable advanced gastric cancer: a single-center analysis

Early experience of laparoscopic-assisted distal gastrectomy in resectable advanced gastric cancer: a single-center analysis

Low-dose apatinib combined with camrelizumab and the SOX regimen in the neoadjuvant treatment of locally advanced gastric/gastroesophageal junction adenocarcinoma (SPACE-neo): a protocol for an open-label, single-arm, clinical trial

Neoadjuvant chemotherapy with S-1 plus oxaliplatin (SOX regimen) has shown promising results in pathological response rate and survival rate in patients with locally advanced resectable gastric cancer (LAGC). We previously carried out the SPACE study to assess efficacy and safety of low-dose apatinib combined with camrelizumab and the SOX regimen as a first-line treatment of advanced gastric/gastroesophageal junction adenocarcinoma (AGC/GEJC). The preliminary results demonstrated a high objective response rate. However, the SPACE study was conducted in patients with AGC, but the efficacy of LAGC patients is not yet known. The SPACE-neo study is designed to investigate whether this combination could improve outcomes in patients with locally advanced gastric/gastroesophageal junction cancer (LAGC/GEJC) as neoadjuvant therapy. SPACE-neo is a prospective, open-label, single-arm study conducted in China at the First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital). Thirty-two patients with human epidermal growth factor receptor 2 (HER2)-negative or HER2-unknown LAGC/GEJC confirmed by histopathology or cytology will be recruited. Included patients shall be clinically staged as M0 and either T3 to T4 or N+ assessed by ultrasound endoscopy and thoracoabdominal-enhanced computed tomography or magnetic resonance imaging. The patients will receive three cycles of this combined regimen as a neoadjuvant treatment. Each patient will receive screening visits within 2 weeks before the first cycle and planned visits before every cycle of treatment. Key monitoring data include imaging data, pathological findings, and adverse events associated with neoadjuvant and surgical treatment. The primary endpoints are major pathological response (MPR) and safety. MPR is the proportion of patients whose residual tumor cells make up less than 10% of the primary tumor from among the total cohort. Clopper-Pearson method will be used to estimate the 95% confidence interval of MPR and safety data will be reported as descriptive statistical analysis. The SPACE-neo trial aims to evaluate the safety and preliminary efficacy of this regimen in the neoadjuvant treatment of LAGC/GEJC. It is hoped that the study can achieve a higher pathological response rate and longer survival rate. ChiCTR.gov.cn: ChiCTR2100049305.

Neoadjuvant Chemo-Radiation Using IGRT in Patients with Locally Advanced Gastric Cancer.

The goal of this study was to see how effective and safe neoadjuvant chemoradiation with image-guided IMRT was in patients with locally advanced resectable gastric cancer. Between January 2013 and June 2019, patients with locally advanced (cT3/cT4 or N+) gastric cancer treated with neoadjuvant chemoradiotherapy at PUMCH (Peking Union Medical College Hospital) were retrospectively studied. Using concurrent chemotherapy (Capecitabine alone or XELOX*2 cycles), radiotherapy (IMRT (intensity-modulated radiation therapy) 45 Gy, 25#, 5 weeks) was delivered with IGRT (image-guided radiotherapy) before the start of each weeks therapy to ensure accuracy and repeatability. A total of 95 patients were enrolled in the study, 93 (97.9%) stage cT3/T4 and 85 (89.5%) stage N+. Of these, 85 patients (89.5%) had a tumor located in the upper 1/3 of the stomach, and 93/95 patients (97.9%) completed neoadjuvant chemoradiation, with 80 patients (84.2%) undergoing stomach resection (58 D2 and 22 D1 gastrostomies). Pathology downstaging was found in 68 patients (85.0%), with 66 patients (82.5%) receiving T downstaging and 56 patients (70.0%) receiving N downstaging. There were 11 individuals (13.8%) who had a pathological complete response (PCR). The average period of follow-up was 44.7 months (19–96 months). The 5-year OS (overall survival), LRFS (local recurrence-free survival), and DMFS (distant metastasis free survival) rates of patients were 47.0% (95% CI: 38.6–55.4), 86.55% (95% CI: 79.1–93.99) and 60.71% (95% CI: 51.49–69.93%), respectively. Thirteen (13.7%) patients had grade 3–4 leukopenia, anemia, and thrombocytopenia, while 9 (9.5%) patients had grade 3–4 anemia, and 5 (5.3%) patients had grade 3–4 thrombocytopenia. PCR was found to be a significant predictive factor for OS in multivariate analysis (HR = 11.211, 95% CI: 1.500–83.813, p = 0.024). The method of using IGRT image-guided IMRT (45 Gy, 25 fractions, 5 weeks) combined with concurrent chemotherapy in patients with locally advanced resectable gastric cancer was equally effective when compared to the clinical efficacy of neoadjuvant chemoradiotherapy, with clinical outcomes achieving equal efficacy, with similar PCR rates and high rates of OS, LRFS, and DMFS, as well as good tolerances of concurrent chemoradiotherapy with acceptable side effects.

Clinicopathological Characteristics of Advanced Epstein-Barr Virus-associated Gastric Cancer Highlighting Aberrant p53 Expression.

Epstein-Barr virus (EBV)-associated gastric cancer is a distinct subtype of stomach adenocarcinoma. Although previous studies have investigated its clinicopathological characteristics, there is a lack of research focusing on advanced EBV-associated gastric cancer. In this study, we performed a comprehensive review of advanced EBV-associated gastric cancer cases. We retrospectively collected 18 consecutive cases of surgically resected advanced EBV-associated gastric cancer. Clinicopathological parameters were investigated using histological review, immunohistochemistry, and a review of the electronic medical records of the hospital. The predominant histological pattern of advanced EBV-associated gastric cancer, according to the Laurén classification, was intestinal-type adenocarcinoma with varying degrees of differentiation. However, focal areas showing conventional gastric carcinoma with a lymphoid stromal pattern were found in all cases except one. In addition to the previously described histological patterns of EBV-associated gastric cancer, one case displayed chronic granulomatous inflammation-like histology with barely identifiable malignant epithelial cells. Another case had a pure signet-ring cell carcinoma component showing nuclear positivity for the EBV-encoded RNA in situ hybridization assay. Remarkably, five out of 18 cases (27.8%) showed aberrant p53 expression on immunostaining, which is known to occur rarely in EBV-associated gastric cancer. All cases with aberrant p53 expression had intestinal-type adenocarcinoma-like components. Advanced EBV-associated gastric cancer had distinct histology and a higher rate of aberrant p53 immunostaining pattern than conventional EBV-associated gastric cancer. Therefore, their biological behavior should be investigated separately.

63P Molecular markers as predictors of response to perioperative FLOT chemotherapy in gastric cancer

Perioperative FLOT chemotherapy has improved the prognosis in patients with locally advanced resectable gastric cancer (GC). However, in 80% of cases, the tumor is resistant to the therapy, and the patients are exposed to unnecessary toxicity and delayed surgical treatment. The aim of this study was to identify molecular predictive markers of efficacy of perioperative FLOT chemotherapy in patients with locally advanced resectable GC.

Preoperative prediction of the pathological stage of advanced gastric cancer by 18F-fluoro-2-deoxyglucose positron emission tomography

In recent years, the usefulness of neoadjuvant chemotherapy for resectable advanced gastric cancer, particularly stage III, has been reported. Preoperative staging is mainly determined by computed tomography (CT), and the usefulness of 18F-fluoro-2-deoxyglucose positron emission tomography/CT (FDG-PET/CT) for gastric cancer has been limited in usefulness. The study aimed to evaluate the usefulness of FDG-PET/CT in preoperative diagnosis of advanced gastric cancer. We retrospectively enrolled 113 patients with gastric cancer who underwent preoperative FDG-PET/CT. All patients underwent gastrectomy with lymph-node dissection. The maximum standardized uptake value (SUVmax) of the primary tumor (T-SUVmax) and lymph nodes (N-SUVmax) were measured for all patients. The cutoff values of T-SUVmax for pathological T3/4 from receiver operating characteristic analysis were 8.28 for differentiated and 4.32 for undifferentiated types. The T-SUVmax and N-SUVmax cutoff values for pathological lymph-node metastasis were 4.32 and 1.82, respectively. Multivariate analysis showed that T-SUVmax for differentiated types was a significant predictor of pathological T3/4, and N-SUVmax was a significant predictor of lymph-node metastasis. In conclusion, the SUVmax of FDG-PET/CT was a useful predictor of pathological T3/4 and lymph-node metastasis in gastric cancer. The diagnosis by preoperative FDG-PET/CT is promising to contribute a more accurate staging of gastric cancer than by CT scan alone.

Pattern of recurrence and overall survival in esophagogastric cancer after perioperative FLOT and Clinical Outcomes in MSI-H population: The PROSECCO Study.

e16068 Background: The FLOT4-AIO phase II/III trial established perioperative FLOT regimen as the new standard in Western countries for patients (pts) with locally advanced resectable gastric (GC) or gastroesophageal junction cancer (GEJC). Microsatellite instability (MSI-H) showed a favorable prognostic role and a concomitant negative predictive impact on the benefit of adjuvant and neoadjuvant 5-fluorouracil-based doublets, but its prognostic and predictive role in pts receiving perioperative FLOT treatment still remains unclear. Our study aims to explore the real-world efficacy of FLOT regimen and to describe histopathological features and clinical outcomes in the MSI-H subgroup population. Methods: This is a retrospective multi-center analysis including pts with GC and GEJC, treated with perioperative FLOT regimen in clinical practice and whose microsatellite status and survival data were available. The association of baseline characteristics, biomolecular and pathological features and overall survival (OS) were firstly assessed in univariate analyses by means of log-rank test, and significantly prognostic variables (p &lt; .05) were included in a multivariable COX proportional hazard model. Results: A total of 250 pts (median age, 62, range 37-81, male 71.6%, ECOG PS 0, 82%) were treated at 11 Italian Oncology Units from January 2017 to June 2021. At a median follow-up time of 22.5 months (mos) (2.3 - 66.7 mos), 123/250 (49.2%) patients relapsed and 77/250 (30.8 %) died. In the global population the median disease-free survival (DFS) was 16,7 mos (95% CI 13,8–21,2) and the median OS 34,9 mos [95% confidence interval (CI) 28–NA]. MSI-H phenotype was found in 26 (10.4%) out of 250 analyzed tumors. Compared to MSS cases, MSI-H were more frequently identified in female (50% vs 25.9%, p = .001), elderly pts (age ≥ 70 years, 76.9% vs 9.4%, p = .003), Laurens’s intestinal type (54% vs 12%, p = .0076) and in pts with primary location tumor in antrum (38.5% vs 13.8%, p = .0004). No relevant differences have been noticed in R0 resections (88% and 96%, p = .06) and pathological complete responses (4.9 % and 3.8%, p = .718), however a statistically significant difference in the rate of pathological negative lymph-nodes between MSS and MSI-H cohort emerged (29.3% vs 65.4%, p = .0004). Compared to MSS tumor population, MSI-H subgroup has a tendency to better DFS (median not reached (NR) vs 15.7, p = .06), metastasis free survival (MFS, median NR vs 17.2 mos, p = .06) and OS (median 41 vs 34 mos, p = .07). Conclusions: These real-world data confirm the efficacy of FLOT perioperative regimen in pts with locally advanced GC/GEJC, maintained also in the MSI-H pts. Our study suggests a better outcome of MSI-H GC and GECJ pts treated with FLOT in comparison to MSS, due to increased rate of nodal status downstaging and despite a poor histological response in the resected tumor tissue of MSI-H pts.

Prognostic value and clinicopathological correlation of the tumor regression grade in neoadjuvant chemotherapy for gastric adenocarcinoma: a retrospective cohort study.

Neoadjuvant chemotherapy (NACT) and radical gastrectomy are the gold standard treatments for resectable advanced gastric cancer (GC). However, the prognostic value of the pathological tumor regression grade (TRG) of NACT remains controversial. This retrospective study aimed to investigate the correlation between the TRG after NACT and clinicopathological features as well as its prognostic value in advanced GC. In total, 551 patients with GC who received NACT combined with surgical resection at the Zhejiang Cancer Hospital from April 2004 to December 2019 were included. The demographic characteristics, treatment response, tumor characteristics, treatment regimens, and survival data were reviewed from the medical records of all patients. The Chi-square test was used to analyze the correlation between TRG and clinicopathological factors. Kaplan-Meier univariate analysis and Cox regression multivariate analysis were used to determine the independent risk factors affecting the prognosis of GC patients. Among the 551 patients with advanced GC who accepted NACT treatment, 14 were determined to be in TRG 0, 98 in TRG 1, 257 in TRG 2, and 182 in TRG 3. Also, TRG was significantly correlated with the cT stage (P=0.015), ypT stage (P<0.001), ypN stage (P<0.001), ypTNM stage (P<0.001), vascular tumor thrombus (P<0.001), Borrmann classification (P=0.042), and lymph node ratio (LNR) (P<0.001). Furthermore, patients who had a good pathological response to NACT had a better prognosis, with a 3-year overall survival (OS) of 70.9% versus 48.8% in patients who had a poor pathological response. We also found that TRG (P=0.042, HR =1.65) was an independent prognostic factor affecting the OS of GC patients. TRG plays a significant role in the prognostic value in neoadjuvant chemotherapy for gastric adenocarcinoma. Patients with higher cT stage, higher levels of pre-CA199 and pre-CA125 may have worse pathological response.

Approach to Resectable Gastric Cancer: Evolving Paradigm of Neoadjuvant and Adjuvant Treatment.

Recent therapeutic advances have prolonged survival in patients with metastatic gastric cancer, though the prognosis for patients with locally advanced resectable gastric cancer remains poor. Long-term survival after resection of locally advanced gastric adenocarcinoma is dependent on early eradication of micrometastatic disease and optimal surgical resection. Preoperative therapy with a docetaxel-containing three-drug regimen has recently been shown to be superior to an anthracycline-containing three-drug regimen or two-drug therapy with a fluoropyrimidine and platinum. Chemoradiation is not essential and is reserved for patients with suboptimal resection. Emerging research strategies include introduction of pre- and postoperative checkpoint blockade and biomarker-directed therapy.

Usefulness of an S-1 dosage formula: An exploratory analysis of randomized clinical trial (JCOG1001).

288 Background: Although the S-1 dose is determined by body surface area (BSA), its blood concentration and adverse events are affected by renal function. One study had reported the clinical utility of an S-1 dosage formula for calculating the dose for target blood concentration based on renal function (Booka E. Gastric Cancer 2016;19:876-86.). The present study aimed to explore the usefulness of this formula in adjuvant chemotherapy for gastric cancer. Methods: Ad hoc analyses was performed using data from patients enrolled in a phase III trial, JCOG1001, to evaluate the role of bursectomy for resectable advanced gastric cancer. In the abovementioned trial, patients with stage II/III received adjuvant S-1 chemotherapy based on BSA. The present study calculated the S-1 dose using the following formula: 1447.8 * (14.5+0.301*CLcr+8.23*SEX [male=1, female=0])*BSA (mg/day). Patients were divided into three groups, overdosed (OD), equal dosed (ED), and underdosed (UD), by comparing the initial dosage administered with that recommended by the formula. Results: Among the 686 eligible pts, 324, 304, and 58 were respectively classified as OD/ED/UD, with the following characteristics: median age, 67.5/64/53.5 years; men 188/229/57 (58%/75%/98%); undifferentiated type, 168/172/38 (52%/57%/66%); and pStage III, 212/200/41 (65%/66%/71%). Median relative dose intensity in OD/ED/UD pts was 93.8%/108.8%/75.0% based on the formula-recommended dose. The planned adjuvant S-1 therapy was completed in 69%/74%/74%, dose reduction and treatment schedule alteration were required in 31%/21%/9% and 20%/17%/9%, and treatment was terminated due to adverse events in 25%/18%/12%. The 5-year relapse-free (RFS) and overall survival (OS) OD/ED/UD patients were 66.6%/69.2%/74.0% and 77.0%/74.3%/77.3%, in pStage II 80.2%/85.6%/93.8% and 88.3%/90.1%/100%, and pStage III 59.6%/60.4%/65.8% and 67.0%/70.0%/67.7%, respectively. OD pts had significantly higher incidences of grade 3 or higher anemia, thrombocytopenia, diarrhea, stomatitis than ED and UD pts. Conclusions: Despite no difference in survival, this formula improved treatment compliance in OD patients receiving adjuvant S-1 chemotherapy for gastric cancer.[Table: see text]