Long-Term Effects of Oral Nutritional Supplements After Gastrectomy for Gastric Cancer: A Survival Analysis from a Multicenter, Open-Label, Randomized Controlled Trial.

BACKGROUND: Weight loss (WL) after gastrectomy for gastric cancer is associated with both decreased compliance with adjuvant chemotherapy and impaired survival. This study examined the effects of administering oral nutritional supplements (ONS) for 3 months after gastrectomy in terms of compliance with adjuvant chemotherapy and survival outcomes. METHODS: This large-scale, multicenter, open-label, randomized controlled trial enrolled 1,003 gastric cancer patients undergoing curative gastrectomy. Patients were assigned to the control group (n = 503) or ONS group (n = 500). In the ONS group, 400 kcal/day of ONS was recommended in addition to a regular diet for 3 months after gastrectomy. Compliance with adjuvant chemotherapy and survival outcomes were compared between the two groups. RESULTS: Compared with the control group, the ONS group showed significantly decreased WL at 3 months after gastrectomy (8.6 ± 6.1 vs. 7.2 ± 5.7%, respectively, P = 0.0004). The control and ONS groups did not differ regarding the induction rate of adjuvant chemotherapy (84.9 vs. 82.8%, respectively, P = 0.614) or the continuation rate at 3 months postoperatively (75.3 vs. 76.6%, respectively, P = 0.809). Oral nutritional supplements for 3 months showed no survival benefit; the 3- and 5-year overall survival (OS) rates were 91.3% and 87.6% in the control group and 89.6% and 86.4% in the ONS group, respectively, indicating no significant difference (P = 0.548). Subgroup analysis could not detect a population in which ONS administration increased OS. CONCLUSIONS: Administration of ONS for 3 months after gastrectomy was not associated with increased compliance with adjuvant chemotherapy or with improved prognosis.

Nivolumab plus chemotherapy in patients with HER2-negative, previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: 3-year follow-up of the ATTRACTION-4 randomized, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Nivolumab + chemotherapy is now a standard of care for HER2-negative, previously untreated, unresectable or recurrent gastric/gastroesophageal junction cancer (advanced gastric cancer), but long-term follow-up data of clinical trials are limited. METHODS: ATTRACTON-4 was a phase 3, double-blind, placebo-controlled trial in Japan, South Korea, and Taiwan. Patients were randomized to either nivolumab or placebo, both combined with the physician's choice of SOX (oral S-1 [tegafur-gimeracil-oteracil potassium] + oxaliplatin) or CAPOX (capecitabine + oxaliplatin). We report the primary endpoints-centrally assessed progression-free survival (PFS) and overall survival (OS)-and landmark analyses of OS among patients alive using 3-year follow-up data. RESULTS: At the cutoff date (May 10, 2021), 17/359 patients in the nivolumab + chemotherapy group and 6/358 in the placebo + chemotherapy group were continuing study treatment. PFS (centrally assessed) was longer in the nivolumab + chemotherapy group (median 10.94 vs. 8.48 months; hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.55-0.82). Although OS did not differ between the two groups (median 17.45 vs. 17.15 months; HR 0.89, 95% CI 0.75-1.05), the landmark analysis of OS, calculating HRs at each landmark time point (every month), was getting numerically better in the nivolumab + chemotherapy group over time. Approximately 80% of patients who achieved complete response in the nivolumab + chemotherapy group were alive at 3 years. No new safety signals or major late-onset select treatment-related adverse events were observed for nivolumab + chemotherapy. CONCLUSION: This 3-year follow-up of ATTRACTION-4 confirmed the long-term clinical benefit and manageable safety of nivolumab + chemotherapy in patients with previously untreated advanced gastric cancer. TRIAL REGISTRATION: NCT02746796.

The integration of the intracorporeal triangular anastomotic technique in robotic distal gastrectomy: advancing patient safety and procedural simplicity.

BACKGROUND: Robotic distal gastrectomy (RDG) with Billroth I (BI) reconstruction is predominantly performed due to its physiological congruence and simplicity. The Intracorporeal Triangular Anastomotic Technique (INTACT) aims to reduce ischemic areas compared to the conventional Delta-shaped anastomosis using the unique characteristics of robotic surgery to standardize procedures, thereby ensuring safe, simple, and reliable reconstruction. This study aims to investigate the efficacy of the INTACT in RDG with BI reconstruction, focusing on its robotic precision in minimizing ischemic zones and improving surgical reliability. SURGICAL TECHNIQUE: The posterior duodenal wall is dissected before reconstruction, and the hepatoduodenal ligament is severed to facilitate passive duodenal manipulation. A quarter-circumference incision is created centrally on the anterior wall of the duodenal stump to avoid excessive tension during anastomosis and to ensure an adequate anastomotic diameter. A small opening is established on the greater curvature of the remaining stomach, and the posterior walls of the stomach and duodenum are joined using a Linear stapler in the first fire. A V-shape is created, and two EndoWrist instruments (robotic first and fourth arms) are utilized to grip and extend the anastomosis diameter, completing the anastomosis with a shared hole closure using the Linear stapler. The robotic arms' features improve the physiological integrity and stability of the BI reconstruction. RESULTS: A total of 81 patients underwent RDG with INTACT from September 2020 to January 2024. The median age was 72 years (range: 31-91), with 49 males and 32 females. The median blood loss was 0 ml (range: 0-200 ml), and the median postoperative hospital stay was 8 days (range: 6-20 days). No cases required reanastomosis during surgery, and no postoperative anastomotic leakage, surgery-related reoperations, or anastomotic strictures were reported. CONCLUSION: INTACT in RDG can be safely performed. The characteristics of the EndoWrist instruments helped in stabilizing the technique, making it a viable option in robotic-assisted surgeries.

Measuring line tension: Thermodynamic integration during detachment of a molecular dynamics droplet.

The contact line (CL) is where solid, liquid, and vapor phases meet, and Young's equation describes the macroscopic force balance of the interfacial tensions between these three phases. These interfacial tensions are related to the nanoscale stress inhomogeneity appearing around the interface, and for curved CLs, e.g., a three-dimensional droplet, another force known as the line tension must be included in Young's equation. The line tension has units of force, acting parallel to the CL, and is required to incorporate the extra stress inhomogeneity around the CL into the force balance. Considering this feature, Bey et al. [J. Chem. Phys. 152, 094707 (2020)] reported a mechanical approach to extract the value of line tension τℓ from molecular dynamics (MD) simulations. In this study, we show a novel thermodynamics interpretation of the line tension as the free energy per CL length, and based on this interpretation, through MD simulations of a quasi-static detachment process of a quasi-two-dimensional droplet from a solid surface, we obtained the value τℓ as a function of the contact angle. The simulation scheme is considered to be an extension of a thermodynamic integration method, previously used to calculate the solid-liquid and solid-vapor interfacial tensions through a detachment process, extended here to the three-phase system. The obtained value agreed well with the result by Bey et al. and showed the validity of thermodynamic integration at the three-phase interface.

Prognostic impact of nodal status and lymphovascular invasion in patients undergoing neoadjuvant chemotherapy for esophageal squamous cell carcinoma.

Nodal status is well known to be the most important prognostic factor for esophageal cancer patients, even if they are treated with neoadjuvant therapy. To establish an optimal postoperative adjuvant strategy for patients, we aimed to more accurately predict the prognosis of patients and systemic recurrence by using clinicopathological factors, including nodal status, in patients with esophageal cancer who received neoadjuvant chemotherapy. The clinicopathological factors associated with survival and systemic recurrence were investigated in 488 patients with esophageal squamous cell carcinoma who received neoadjuvant chemotherapy. Overall survival differed according to tumor depth, nodal status, tumor regression, and lymphovascular (LV) invasion. In the multivariate analysis, nodal status and LV invasion were identified as independent prognostic factors (P < 0.0001, P = 0.0008). Nodal status was also identified as an independent factor associated with systemic recurrence, although LV invasion was a borderline factor (P = 0.066). In each pN stage, patients with LV invasion showed significantly worse overall survival than those without LV invasion (pN0: P = 0.036, pN1: P = 0.0044, pN2: P = 0.0194, pN3: P = 0.0054). Patients with LV invasion were also more likely to have systemic, and any recurrence than those without LV invasion in each pN stage. Pathological nodal status and LV invasion were the most important predictors of survival and systemic recurrence in patients with esophageal cancer who underwent neoadjuvant chemotherapy followed by surgery. This finding could provide useful information about selecting candidates for adjuvant therapy among these patients. Our analysis showed that LV invasion was an independent prognostic factor in patients with esophageal cancer who underwent neoadjuvant chemotherapy and that combining LV invasion with pathological nodal status makes it possible to stratify the prognosis in those patients.

Prognostic factors and significance of postoperative adjuvant chemotherapy in patients with advanced gastric cancer undergoing neoadjuvant chemotherapy followed by gastrectomy.

PURPOSE: In Japan, gastrectomy with D2 lymph node dissection and postoperative adjuvant chemotherapy are the standard treatments for locally advanced gastric cancer. Neoadjuvant chemotherapy (NAC) is not affected by postgastrectomy syndromes or postoperative complications. This multicenter retrospective study investigated the prognostic factors and significance of postoperative adjuvant chemotherapy in patients with advanced gastric cancer who underwent NAC followed by gastrectomy. METHODS: Consecutive patients (n = 221) with advanced gastric cancer who underwent NAC followed by curative surgery were enrolled in this study. Prognostic factors including postoperative adjuvant chemotherapy were investigated using univariate and multivariate analyses. RESULTS: A multivariate analysis revealed that pathological lymph node metastasis (ypN) status and postoperative adjuvant chemotherapy were independent prognostic factors for the overall and relapse-free survival. Forty-five patients (20.4%) did not receive postoperative adjuvant chemotherapy. There were no significant differences between patients with and without adjuvant chemotherapy for all factors, except age. The most common reason for not undergoing postoperative adjuvant chemotherapy was a poor condition (n = 23). CONCLUSIONS: ypN status and postoperative adjuvant chemotherapy were independent prognostic factors in gastric cancer patients who underwent NAC followed by curative gastrectomy. It is important to maintain the patient's condition during NAC and the perioperative period so that they can receive postoperative adjuvant chemotherapy.

The preliminary analysis of lymphatic flow around the connective tissues surrounding SMA and SpA elucidates patients' oncological condition in borderline-resectable pancreatic cancer.

BACKGROUND: In pancreatic ductal adenocarcinoma (PDAC), invasion of connective tissues surrounding major arteries is a crucial prognostic factor after radical resection. However, why the connective tissues invasion is associated with poor prognosis is not well understood. MATERIALS AND METHODS: From 2018 to 2020, 25 patients receiving radical surgery for PDAC in our institute were enrolled. HyperEye Medical System (HEMS) was used to examine lymphatic flow from the connective tissues surrounding SMA and SpA and which lymph nodes ICG accumulated in was examined. RESULTS: HEMS imaging revealed ICG was transported down to the paraaortic area of the abdominal aorta along SMA. In pancreatic head cancer, 9 paraaortic lymph nodes among 14 (64.3%) were ICG positive, higher positivity than LN#15 (25.0%) or LN#18 (50.0%), indicating lymphatic flow around the SMA was leading directly to the paraaortic lymph nodes. Similarly, in pancreatic body and tail cancer, the percentage of ICG-positive LN #16a2 was very high, as was that of #8a, although that of #7 was only 42.9%. CONCLUSIONS: Our preliminary result indicated that the lymphatic flow along the connective tissues surrounding major arteries could be helpful in understanding metastasis and improving prognosis in BR-A pancreatic cancer.

Prognostic value of a novel index combining the prognostic nutritional index and D-dimer levels for gastric cancer after gastrectomy.

INTRODUCTION: The prognostic nutritional index and D-dimer level are two useful measures for gastric cancer prognosis. Since they each comprise different factors, it is possible to employ a more useful combined indicator. This study therefore aimed to establish a prognostic nutritional index-D score-which combines the prognostic nutritional index and D-dimer level-and validate its usefulness as a prognostic marker. METHODS: We collected data from 1,218 patients with gastric cancer who had undergone radical gastrectomy (R0) between January 2004 and December 2015. Patients were divided into three prognostic nutritional index-D score groups based on the following criteria: score 2, low prognostic nutritional index (≤46) and high D-dimer levels (>1.0 µg/ml); score 1, either a low prognostic nutritional index or high D-dimer levels; and score 0, no abnormality. We then defined the PNI-D score as low (score 0 or 1) and high (score 2). RESULTS: The prognostic nutritional index-D score was significantly associated with overall, recurrence-free, and disease-specific survival (all log-rank P<0.0001). The 5-year overall survival rates of the patients with prognostic nutritional index-D scores of low and high were 88.1% and 64.7%, respectively; their 5-year recurrence-free survival rates were 86.7% and 61.3%, respectively; and their 5-year disease-specific survival rates were 99.3% and 76.5%, respectively. Cox multivariate analysis revealed that a high prognostic nutritional index-D score was an independent, statistically significant prognostic factor for poor overall (P=0.01) survival in the patients with gastric cancer. CONCLUSIONS: The prognostic nutritional index-D is an independent prognostic factor for patients with gastric cancer.

Prognostic factors of conversion surgery for stage IV gastric cancer: A multi-institutional retrospective analysis.

Background: Conversion surgery (CS) is a highly anticipated strategy for stage IV advanced gastric cancer (AGC) with a good response to chemotherapy. However, prognostic factors limiting R0 resection remain unclear. In this multi-institutional study, we investigated the clinical outcomes of CS for stage IV AGC and the prognostic factors of CS-limiting R0 resection and analyzed them according to metastatic patterns. Methods: Clinical data on 210 patients who underwent CS for stage IV AGC at six institutions between 2007 and 2017 were retrospectively retrieved. The patient background, preoperative treatment, operative outcomes, and survival times were recorded. Prognostic factors for overall and recurrence-free survival were investigated using univariate and multivariate analyses for patients who underwent R0 resection. Results: R0 resection was achieved in 146 (70%) patients. The median survival time was 32 months, and the 3-year survival rate was 45%. Patients who achieved R0 resection had significantly longer survival than those with R1/2 resection (median survival time: 41.5 months vs. 20.7 months). Multivariate analysis identified pathological N positivity for overall and relapse-free survival and pathological T4 for relapse-free survival as significant independent poor prognostic factors of R0 resected patients. There was no significant difference in survival among the peritoneum, liver, and lymph node groups regarding the initial metastatic sites. Conclusions: CS with R0 resection for patients with stage IV AGC can lead to longer survival. Patients with pathological T4 and pathological N positivity were eligible for intensive adjuvant therapy after CS with R0 resection.

Comparison of the effects of open and laparoscopic approach on body composition in gastrectomy for gastric cancer: A propensity score-matched study.

Aim: To compare the effects of open (OG) and laparoscopic gastrectomy (LG) on body composition and muscle strength. Methods: This study performed a propensity score matching analysis using cases from a large-scale, multicenter, phase III randomized controlled trial concerning oral nutritional supplements after gastrectomy and analyzed both the whole and matched cohorts. Measurements of body composition and hand grip strength (HGS) were performed at baseline (preoperatively) and at 1, 2, 3, 6, and 12 months after gastrectomy. Results: Of 835 patients, 275 and 560 underwent OG and LG, respectively. Skeletal muscle mass (SMM) and HGS loss were significantly lesser in the LG group than in the OG group. The propensity score-matched analysis, including 120 pairs of patients, confirmed that the % SMM loss values at 1, 2, 3, 6, and 12 POM were -4.5%, -4.0%, -4.7%, -4.6%, and -5.8% in the OG group and -3.0%, -1.9%, -2.4%, -2.2%, and -2.7% in the LG group, respectively. The % SMM loss was significantly lesser in the LG group than in the OG group (repeated measures ANOVA p < 0.001). The HGS loss was non-significantly smaller in the LG group than in the OG group. Conclusion: Skeletal muscle mass loss was significantly lesser in the LG group than in the OG group in both cohorts, indicating that LG may be more effective than OG for maintaining muscle mass.

Risk factors for abdominal surgical infectious complications after distal gastrectomy for gastric cancer: A post-hoc analysis of a randomized controlled trial (JCOG0912).

BACKGROUND: Abdominal surgical infectious complications (ASIC) after gastrectomy for gastric cancer impair patients' survival and quality of life. JCOG0912 was conducted to compare laparoscopy-assisted distal gastrectomy with open distal gastrectomy for clinical stage IA or IB gastric cancer. The present study aimed to identify risk factors for ASIC using prospectively collected data. METHODS: We performed a post-hoc analysis of the risk factors for ASIC using the dataset from JCOG0912. All complications were evaluated according to the Clavien-Dindo classification (CD). ASIC was defined as CD grade I or higher anastomotic leakage, pancreatic fistula, abdominal abscess, and wound infection. Analyses were performed using the logistic regression model for univariable and multivariable analyses. RESULTS: A total of 910 patients were included (median age, 63 years; male sex, 61 %). Among them, ASIC occurred in 5.8 % of patients. In the univariable analysis, male sex (odds ratio [OR] 2.855, P = 0.003), diabetes (OR 2.565, P = 0.029), and Roux-en-Y (R-Y) reconstruction (vs. Billroth Ⅰ, OR 2.707, P = 0.002) were significant risk factors for ASIC. In the multivariable analysis, male sex (OR 2.364, P = 0.028) and R-Y reconstruction (vs. Billroth Ⅰ, OR 2.310, P = 0.015) were independent risk factors for ASIC. CONCLUSIONS: Male sex and R-Y reconstruction were risk factors for ASIC after distal gastrectomy. Therefore, when performing surgery on male patients or when R-Y reconstruction is selected after gastrectomy for gastric cancer, surgeons should pay special attention to prevent ASIC.

Clinical impact of postoperative changes in body composition on long-term outcomes in patients with esophageal cancer.

BACKGROUND & AIMS: This study aimed to investigate the temporal changes in body composition following esophagectomy in patients with esophageal cancer using bioelectrical impedance analysis and to assess the prognostic implications of these changes. METHODS: Our study included 528 patients who underwent esophagectomy and preoperative body composition measurements between January 2013 and June 2020. Postoperative body composition was measured in 493 patients at discharge as follows: 184 at 1 month, 144 at 2 months, 143 at 3 months, 103 at 6 months, 58 at 9 months, and 78 at 12 months. RESULTS: Body weight (BW) continuously decreased until the 6 postoperative months (POMs), reaching -11.5% compared with preoperative levels. Subsequently, almost no change was observed at 12 POMs. Skeletal muscle mass (SMM) decreased until 3 POMs but gradually recovered after 3 POMs. Conversely, body fat mass (BFM) consistently decreased over time post-esophagectomy. The patients were categorized into moderate (>-10%) and severe (≤-10%) groups based on % BW, % SMM, and % BFM losses at 3 POMs. Severe SMM loss at 3 POMs correlated with reduced overall survival (OS) (3-year OS: 85.9% in moderate vs. 75.1% in severe, p = 0.035). BFM loss was associated with reduced recurrence-free survival (3-year RFS: 83.3% in moderate vs. 62.0% in severe, p = 0.011). Multivariate analysis identified pStages Ⅲ and Ⅳ, % SMM loss ≤ -10%, and % BFM loss ≤ -10% as independent factors for worse OS. CONCLUSION: Post-esophagectomy, distinct temporal changes in BW, SMM, and BFM are observed. Significant reductions in SMM and BFM 3 POMs indicate a poor long-term prognosis.

Survival Impact of Inflammation-based Prognostic Scores in Metastatic or Unresectable Esophageal Cancer Treated With Pembrolizumab Plus Chemotherapy.

Pembrolizumab plus chemotherapy has been indicated as the first-line treatment for metastatic or unresectable locally advanced esophageal cancer. However, pretreatment biomarkers for predicting clinical outcomes remain unclear. We investigated the predictive value of inflammation-based prognostic scores in patients treated with pembrolizumab and chemotherapy. The Prognostic Nutritional Index (PNI), C-reactive protein/albumin ratio (CAR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were calculated before initial treatment in 65 eligible patients with metastatic or unresectable locally advanced esophageal cancer receiving pembrolizumab plus CF therapy, and the relationship between these biomarkers and clinical outcomes was analyzed. The objective response rate (ORR) and progression disease (PD) were observed in 51% and 21% of all patients. Patients with PNI<39 have significantly worse treatment responses than those with PNI≥39 (ORR; 28% vs. 60%, PD; 44% vs. 13%, P =0.020). Progression-free survival (PFS) is significantly associated with the PNI and CAR ( P <0.001 and P =0.004, respectively). Overall survival (OS) is associated with PNI, CAR, and PLR ( P <0.001, P =0.008, and P =0.018, respectively). The PNI cutoff value of 39 is identified as an independent factor for PFS (odds ratio=0.27, 95% CI: 0.18-0.81, P =0.012) and OS (odds ratio=0.22, 95% CI: 0.08-0.59, P =0.003). Patients with PNI<39 have significantly worse 6-month PFS and 1-year OS than those with PNI≥39 (27.8% vs. 66.7%, 27.2% vs. 81.1%, respectively). In conclusion, inflammation-based prognostic scores are associated with survival in patients treated with pembrolizumab plus CF therapy. Pretreatment PNI is a promising candidate for predicting treatment response and survival.

Short-term Outcomes of Adjuvant Nivolumab After Neoadjuvant Chemotherapy in Patients With Resected Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIM: CheckMate 577 evaluated adjuvant nivolumab therapy after neoadjuvant chemoradiotherapy and surgery for esophageal cancers. However, the efficacy of this treatment in patients who received neoadjuvant chemotherapy remains unknown. This study investigated the short-term outcomes of adjuvant nivolumab therapy in patients with advanced esophageal squamous cell carcinoma post-neoadjuvant chemotherapy. PATIENTS AND METHODS: Out of 956 patients with thoracic esophageal cancer who underwent radical esophagectomy, 227 who exhibited ypN1-3 after neoadjuvant chemotherapy and surgery were included in this study. RESULTS: Among 227 patients, 30 received adjuvant nivolumab and 197 received non-nivolumab adjuvant therapy. The nivolumab group displayed a higher number of lymph node metastases compared to the control group. Patients with ypN1-2 tended to have longer recurrence-free survival (RFS) in the nivolumab group than in the non-nivolumab group (p=0.095). In the propensity score-matched cohort, no differences in patient characteristics were observed. Adjuvant nivolumab therapy significantly prolonged RFS in patients who received neoadjuvant chemotherapy (p=0.013). Patients with ypN1-2 in the nivolumab group had significantly longer RFS than their counterparts in the non-nivolumab group (p=0.001), but not in ypN3 (p=0.784). The 1-year postoperative recurrence rates were 59% for the non-nivolumab group and 24% for the nivolumab group (p=0.007). Nivolumab-related adverse events in patients receiving neoadjuvant chemotherapy were mostly consistent across all grades, while the frequency of increased aspartate aminotransferase (AST) levels was relatively higher compared to CheckMate577. CONCLUSION: Adjuvant nivolumab was more likely to prolong 1-year RFS in patients receiving neoadjuvant chemotherapy, especially in those with ypN1-2, and had acceptable adverse events.

A striking elevation of CA19-9 after preoperative therapy negates prognostic benefit from radical surgery in resectable and borderline resectable pancreatic cancer.

BACKGROUND: Identifying patients who can be spared nonbeneficial surgery is crucial, as pancreatic cancer surgery is highly invasive, with substantial negative effects on quality of life. The study objective was to investigate a useful indicator of patients who do not gain prognostic benefit from radical surgery after neoadjuvant therapy for resectable and borderline resectable pancreatic cancer. METHOD: We compared factors among 609 patients with resectable or borderline resectable pancreatic cancer receiving neoadjuvant therapy during 2005-2019. Patients were divided into a poor-prognosis group (no surgery or postresection recurrence within a year) and a good-prognosis group (no recurrence or recurrence >1 year after resection). RESULTS: Patients who experience a recurrence within a year of resection (poor-prognosis group) did no better than patients who received neoadjuvant therapy and progressed but never made it to surgery. The value of carbohydrate antigen 19-9 after neoadjuvant therapy was the most significant indicator to predict the poor prognosis group and the elevation of carbohydrate antigen 19-9 (>200 U/mL) identified only poor prognosis group with high specificity of 96.6%. The overall survival of patients with more than 200 of carbohydrate antigen 19-9 after neoadjuvant therapy was significantly very poor and their 2-year survival rate was only 41.4%. CONCLUSION: A striking elevation of carbohydrate antigen 19-9 after neoadjuvant therapy for resectable or borderline resectable pancreatic cancer is a good indicator of poor prognosis. Patients with carbohydrate antigen 19-9 >200 U/mL after neoadjuvant therapy should not undergo radical surgery.

Adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy for stage III gastric or gastro-oesophageal junction cancer after gastrectomy with D2 or more extensive lymph-node dissection (ATTRACTION-5): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In Asia, adjuvant chemotherapy after gastrectomy with D2 or more extensive lymph-node dissection is standard treatment for people with pathological stage III gastric or gastro-oesophageal junction (GEJ) cancer. We aimed to assess the efficacy and safety of adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy administered in this setting. METHODS: ATTRACTION-5 was a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial conducted at 96 hospitals in Japan, South Korea, Taiwan, and China. Eligible patients were aged between 20 years and 80 years with histologically confirmed pathological stage IIIA-C gastric or GEJ adenocarcinoma after gastrectomy with D2 or more extensive lymph-node dissection, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and available tumour tissue for PD-L1 expression analysis. Patients were randomly assigned (1:1) to receive either nivolumab plus chemotherapy or placebo plus chemotherapy via an interactive web-response system with block sizes of four. Investigational treatment, either nivolumab 360 mg or placebo, was administered intravenously for 30 min once every 3 weeks. Adjuvant chemotherapy was administered as either tegafur-gimeracil-oteracil (S-1) at an initial dose of 40 mg/m2 per dose orally twice per day for 28 consecutive days, followed by 14 days off per cycle, or capecitabine plus oxaliplatin consisting of an initial dose of intravenous oxaliplatin 130 mg/m2 for 2 h every 21 days and capecitabine 1000 mg/m2 per dose orally twice per day for 14 consecutive days, followed by 7 days off treatment. The primary endpoint was relapse-free survival by central assessment. The intention-to-treat population, consisting of all randomly assigned patients, was used for analysis of efficacy endpoints. The safety population, defined as patients who received at least one dose of trial drug, was used for analysis of safety endpoints. This trial is registered with ClinicalTrials.gov (NCT03006705) and is closed. FINDINGS: Between Feb 1, 2017, and Aug 15, 2019, 755 patients were randomly assigned to receive either adjuvant nivolumab plus chemotherapy (n=377) or adjuvant placebo plus chemotherapy (n=378). 267 (71%) of 377 patients in the nivolumab group and 263 (70%) of 378 patients in the placebo group were male; 110 (29%) of 377 patients in the nivolumab group and 115 (31%) of 378 patients in the placebo group were female. 745 patients received assigned treatment (371 in the nivolumab plus chemotherapy group; 374 in the placebo plus chemotherapy group), which was the safety population. Median time from first dose to data cutoff was 49·1 months (IQR 43·1-56·7). 3-year relapse-free survival was 68·4% (95% CI 63·0-73·2) in the nivolumab plus chemotherapy group and 65·3% (59·9-70·2) in the placebo plus chemotherapy group; the hazard ratio for relapse-free survival was 0·90 (95·72% CI 0·69-1·18; p=0·44). Treatment-related adverse events occurred in 366 (99%) of 371 patients in the nivolumab plus chemotherapy group and 364 (98%) of 374 patients in the placebo plus chemotherapy group. Discontinuation due to adverse events was more frequent in the nivolumab plus chemotherapy group (34 [9%] of 371 patients) than the placebo plus chemotherapy group (13 [4%] of 374 patients). The most common treatment-related adverse events were decreased appetite, nausea, diarrhoea, neutrophil count decreased, and peripheral sensory neuropathy. INTERPRETATION: The results of this trial do not support the addition of nivolumab to postoperative adjuvant therapy for patients with untreated, locally advanced, resectable gastric or GEJ cancer. FUNDING: Ono Pharmaceutical and Bristol Myers Squibb.