Key nodal stations for predicting splenic hilar nodal metastasis in upper advanced gastric cancer without invasion of the greater curvature.

Background: Standard surgery for upper advanced gastric cancer without invasion of the greater curvature (UGC-GC) is spleen-preserving D2 total gastrectomy without dissection of the splenic-hilar nodes (#10). However, some patients with nodal metastasis to #10 survive more than 5 years due to nodal dissection of #10. If nodal metastasis to #10 is predictable based on the positivity of other nodes dissected by the current standard surgery without #10 nodal dissection, physicians may be able to consider #10 dissection. Methods: This study retrospectively reviewed data from the National Cancer Center Hospital in Japan between 2000 and 2012. We selected cases that met the following criteria: (1) D2 or more total gastrectomy with splenectomy, (2) UGC-GC, and (3) histological type is gastric adenocarcinoma. We performed univariate and multivariate analyses concerning lymph node stations associated with #10 metastasis. Results: A total of 366 patients were examined. A multivariate analysis revealed that #10 metastasis was associated with positivity of the nodes along the short gastric arteries (#4sa) and distal nodes along the splenic artery (#11d) (#4sa: p = 0.003, #11d: p = 0.016). When either key node was positive, the metastatic rate of #10 was 24.4%, and the therapeutic value index was 13.3. Conclusions: #4sa and #11d were key lymph nodes predicting #10 nodal metastasis in UGC-GC. When these key nodes are positive on computed tomography before surgery or according to a rapid pathological examination during surgery, dissection of #10 should be considered even if upper advanced tumors are not invading the greater curvature.

Prognostic Impact of Post-operative Infectious Complications in Gastric Cancer Patients Receiving Neoadjuvant Chemotherapy: Post Hoc Analysis of a Randomized Controlled Trial, JCOG0501.

PURPOSE: Post-operative infectious complication (IC) is a well-known negative prognostic factor, while showing neoadjuvant chemotherapy (NAC) may cancel out the negative influence of IC. This analysis compared the clinical impacts of IC according to the presence or absence of NAC in gastric cancer patients enrolled in the phase III clinical trial (JCOG0501) which compared upfront surgery (arm A) and NAC followed by surgery (arm B) in type 4 and large type 3 gastric cancer. METHODS: The subjects were 224 patients who underwent R0 resection out of 316 patients enrolled in JCOG0501. The prognoses of the patients with or without ICs in each arm were investigated by univariable and multivariable Cox regression analyses. RESULTS: There were 21 (20.0%) IC occurrences in arm A and 15 (12.6%) in arm B. In arm A, the overall survival (OS) of patients with ICs was slightly worse than those without IC (3-year OS, 57.1% in patients with ICs, 79.8% in those without ICs; adjusted hazard ratio (95% confidence interval), 1.292 (0.655-2.546)). In arm B, patients with ICs showed a trend of better survival than those without ICs (3-year OS, 80.0% in patients with IC, 74.0% in those without IC; adjusted hazard ratio, 0.573 (0.226-1.456)). CONCLUSION: This study could not indicate the negative prognostic influence of ICs in gastric cancer patients receiving NAC, which might be canceled by NAC. To build exact evidence, further investigation with prospective and large numbers of data might be expected.

Clinical impact of skeletal muscle mass change during the neoadjuvant chemotherapy period in patients with gastric cancer: An ancillary study of JCOG1002.

BACKGROUND: Recent studies have revealed that sarcopenia is associated with postoperative complications and poor prognosis. Although neoadjuvant chemotherapy is a promising treatment for gastric cancer, its toxicity may lead to the loss of skeletal muscle mass. This study investigates the changes in skeletal muscle mass during neoadjuvant chemotherapy and its clinical impact on patients with locally advanced gastric cancer. METHODS: Fifty patients who completed two courses of neoadjuvant chemotherapy followed by surgery were included. Skeletal muscle mass was measured using computed tomography images before and after chemotherapy. The proportion of skeletal muscle mass change (%SMC) during neoadjuvant chemotherapy and its cutoff value was explored using the receiver operating characteristic for the overall survival of patients undergoing R0 resection. Risk factors of skeletal muscle mass loss were also evaluated. RESULTS: Overall, 64% of patients had skeletal muscle mass loss during neoadjuvant chemotherapy (median %SMC -3.4%; range: -18.9% to 10.3%). Multivariable analysis identified older age (≥70 years) as an independent predictor of skeletal muscle mass loss (mean [95% confidence interval]: -4.70% [-8.83 to -0.58], p = 0.026). Among 43 patients undergoing R0 resection, %SMC <-6.9% was an independent poor prognostic factor for overall survival (hazard ratio, 11.53; 95% confidence interval, 2.78-47.80) and relapse-free survival (hazard ratio 4.54, 95% confidence interval 1.50-13.81). CONCLUSIONS: Skeletal muscle mass loss occurs frequently during neoadjuvant chemotherapy for locally advanced gastric cancer and could adversely affect survival outcomes.

Impact of D2 Total Gastrectomy Including Splenectomy for Scirrhous Gastric Cancer in the Era of Effective Adjuvant Chemotherapy.

BACKGROUND: Total gastrectomy with D2 dissection including splenectomy (TGS) is usually selected for locally resectable scirrhous gastric cancer (SGC), which was established in the era of surgery alone. However, it remains unclear whether TGS for SGC is justified in the era of effective adjuvant chemotherapy. METHODS: This study included 112 SGC patients, consisting of 60 cases treated between January 2000 and December 2006 (Former group), and 52 cases treated between January 2007 and December 2016 (Latter group). We collected clinicopathological data and then examined the survival and the therapeutic value indexes. RESULTS: The background characteristics were well-balanced, except for sex and physical status. The Latter group might be characterized by frequent female (P = 0.037) and poorer physical status (P = 0.048). Adjuvant chemotherapy was administered to 86.5% of the Latter group and was 11.7% of the Former group (P < 0.001). The 5-year-overall survival rate of the Latter group was 58.7% (95% confidence interval: 43.5-71.1), seems better than that of the Former group (44.5%; 95% confidence interval 31.7-56.6) (hazard ratio = 0.758, P = 0.291). Improvement of the index from the Former group was observed in the Latter group at almost all stations. The ratio of the index between two groups was 1.42 at the D1 station and 1.67 at the D2 station. Index of splenic hilar node ranked similarly high in both groups. CONCLUSION: The therapeutic value index was improved in almost all nodal stations by S-1 adjuvant chemotherapy, especially in D2 nodes. TGS would be more important for locally resectable SGC in the era of effective adjuvant chemotherapy.

Adjuvant and post-recurrent treatment patterns in patients with resectable gastric cancer in japan: a retrospective database cohort study.

BACKGROUND: This study examined temporal shifts in adjuvant therapy patterns in Japanese patients with resectable gastric cancer (GC) and treatment patterns of first-line and subsequent therapy among those with recurrent disease. METHODS: This retrospective analysis of hospital-based administrative claims data (April 1, 2008 to March 31, 2022) included adults (aged ≥ 20 years) with GC who started adjuvant therapy on or after October 1, 2008 (adjuvant cohort) and patients in the adjuvant cohort with disease recurrence (recurrent cohort), further defined by the time to recurrence (≤ 180 or > 180 days after adjuvant therapy). RESULTS: In the adjuvant cohort (n = 17,062), the most common regimen during October 2008-May 2016 was tegafur/gimeracil/oteracil potassium (S-1; 95.7%). As new standard adjuvant regimen options were established, adjuvant S-1 use decreased to 65.0% and fluoropyrimidine plus oxaliplatin or docetaxel plus S-1 use increased to 15.0% and 20.0%, respectively, in September 2019-March 2022. In the recurrent cohort with no history of trastuzumab/trastuzumab deruxtecan treatment (n = 1257), the most common first-line regimens were paclitaxel plus ramucirumab (34.0%), capecitabine plus oxaliplatin (CapeOX; 17.0%), and nab-paclitaxel plus ramucirumab (10.1%) in patients with early recurrence, and S-1 plus oxaliplatin (26.3%), S-1 plus cisplatin (15.3%), CapeOX (14.0%), S-1 (13.2%), and paclitaxel plus ramucirumab (10.8%) in those with late recurrence. CONCLUSIONS: This study demonstrated temporal shifts in adjuvant treatment patterns that followed the establishment of novel regimens, and confirmed that post-recurrent treatment patterns were consistent with the Japanese Gastric Cancer Association guideline recommendations.

Short-term outcomes of preoperative chemotherapy with docetaxel, oxaliplatin, and S-1 for gastric cancer with extensive lymph node metastasis (JCOG1704).

BACKGROUND: The prognosis for marginally resectable gastric cancer with extensive lymph node metastasis (ELM) remains unfavorable, even after R0 resection. To assess the safety and efficacy of preoperative docetaxel, oxaliplatin, and S-1 (DOS), we conducted a multicenter phase II trial. METHODS: Eligibility criteria included histologically proven HER2-negative gastric adenocarcinoma with bulky nodal (bulky N) involvement around major branched arteries or para-aortic node (PAN) metastases. Patients received three cycles of docetaxel (40 mg/m2, day 1), oxaliplatin (100 mg/m2, day 1), and S-1 (80-120 mg/body, days 1-14), followed by gastrectomy with D2 plus PAN dissection. Subsequently, patients underwent postoperative chemotherapy with S-1 for 1 year. The primary endpoint was major (grade ≥ 2a) pathological response rate (pRR) according to the Japanese Classification of Gastric Carcinoma criteria. RESULTS: Between October 2018 and March 2022, 47 patients (bulky N, 20; PAN, 17; both, 10) were enrolled in the trial. One patient was ineligible. Another declined any protocol treatments before initiation. Among the 45 eligible patients who initiated DOS chemotherapy, 44 (98%) completed 3 cycles and 42 (93%) underwent R0 resection. Major pRR and pathological complete response rates among the 46 eligible patients, including the patient who declined treatment, were 57% (26/46) and 24% (11/46), respectively. Common grade 3 or 4 toxicities were neutropenia (24%), anorexia (16%), febrile neutropenia (9%), and diarrhea (9%). No treatment-related deaths occurred. CONCLUSIONS: Preoperative chemotherapy with DOS yielded favorable pathological responses with an acceptable toxicity profile. This multimodal approach is highly promising for treating gastric cancer with ELM.

Early endpoints of a randomized phase II trial of preoperative chemotherapy with S-1/CDDP with or without trastuzumab followed by surgery for HER2-positive resectable gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301C (Trigger Study).

BACKGROUND: This randomized phase II study explored the superiority of trastuzumab plus S-1 plus cisplatin (SP) over SP alone as neoadjuvant chemotherapy (NAC) for HER2-positive resectable gastric cancer with extensive lymph node metastasis. METHODS: Eligible patients with HER2-positive gastric or esophagogastric junction cancer and extensive lymph node metastasis were randomized to receive three or four courses of preoperative chemotherapy with SP (arm A) or SP plus trastuzumab (arm B). Following gastrectomy, adjuvant chemotherapy with S-1 was administered for 1 year in both arms. The primary endpoint was overall survival, and the sample size was 130 patients in total. The trial is registered with the Japan Registry of Clinical Trials, jRCTs031180006. RESULTS: This report elucidates the early endpoints, including pathological findings and safety. The study was terminated early due to slow patient accruals. In total, 46 patients were allocated to arm A (n = 22) and arm B (n = 24). NAC was completed in 20 patients (91%) in arm A and 23 patients (96%) in arm B, with similar incidences of grade 3-4 hematological and non-hematological adverse events. Objective response rates were 50% in arm A and 84% in arm B (p = 0·065). %R0 resection rates were 91% and 92%, and pathological response rates (≥ grade 1b in Japanese classification) were 23% and 50% (p = 0·072) in resected patients, respectively. CONCLUSIONS: Trastuzumab can be safely added to platinum-containing doublet chemotherapy as NAC, and it has the potential to contribute to higher antitumor activity against locally advanced, HER2-positive gastric or esophagogastric junction cancer with extensive nodal metastasis.

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.

Association between the antiadhesion membrane and small bowel obstruction after open gastrectomy: A supplemental analysis of the randomized controlled JCOG1001 trial.

Aim: Postoperative small bowel obstruction (SBO) is one of the major complications that is mainly caused by postoperative adhesion. Recently, the antiadhesion membrane has become popular for postoperative SBO prevention. However, its efficacy is yet to be confirmed in the gastric cancer surgery field. Here, we conducted the supplemental analysis of the randomized controlled trial JCOG1001 to investigate the efficacy of the antiadhesion membrane on SBO prevention in patients with open gastrectomy for gastric cancer. Methods: Of the 1204 patients enrolled in JCOG1001, 1200 patients were included. The development of SBO of Grade ≥ IIIa according to the Clavien-Dindo classification was recorded. Univariable and multivariable analyses were performed using the Fine and Gray model to determine the risk factors for SBO. Results: Fifty-one patients developed SBO (median follow-up duration: 5.6 years). Total gastrectomy, combined resection, and blood loss significantly increased the risk for SBO development in the univariable analysis. Large amount of blood loss was independently associated with SBO development in the multivariable analysis (hazard ratio [HR], 3.089; 95% confidence interval [CI], 1.562-6.109, p = 0.0012). Antiadhesion membrane did not reduce the risk for SBO (HR, 1.299; 95% CI 0.683-2.470; p = 0.4246). In the patients belonging to subgroup analyses who received distal and total gastrectomy, the antiadhesion membrane was not associated with the incidence of SBO. Conclusions: Antiadhesion membrane did not decrease SBO occurrence rate after open gastrectomy. Therefore, the use of antiadhesion membrane would not be effective for preventing SBO in gastric cancer surgery.

Protocol digest of a randomized controlled adaptive Phase II/III trial of neoadjuvant chemotherapy for Japanese patients with oesophagogastric junction adenocarcinoma: Japan Clinical Oncology Group Study JCOG2203 (NEO-JPEG).

Treatment strategies for oesophagogastric junction adenocarcinoma have not been standardized despite its poor prognosis due to differences in the incidence rates between Western countries and Asia. This randomized Phase II/III trial was initiated in June 2023 to determine which neoadjuvant chemotherapy regimen, docetaxel, oxaliplatin and S-1 or fluorouracil, oxaliplatin and docetaxel, is a more promising treatment in Phase II and confirm the superiority of neoadjuvant chemotherapy with docetaxel, oxaliplatin and S-1 or fluorouracil, oxaliplatin and docetaxel followed by surgery and postoperative chemotherapy over upfront surgery and postoperative chemotherapy in terms of overall survival in patients with Clinical Stage III or IVA oesophagogastric junction adenocarcinoma in Phase III. A total of 460 patients, including 150 patients in Phase II and 310 patients in Phase III, are planned to be enrolled from 85 hospitals in Japan over 5 years. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031230182 (https://jrct.niph.go.jp/latest-detail/jRCTs031230182).

Precancerous nature of intestinal metaplasia with increased chance of conversion and accelerated DNA methylation.

OBJECTIVE: The presence of intestinal metaplasia (IM) is a risk factor for gastric cancer. However, it is still controversial whether IM itself is precancerous or paracancerous. Here, we aimed to explore the precancerous nature of IM by analysing epigenetic alterations. DESIGN: Genome-wide DNA methylation analysis was conducted by EPIC BeadArray using IM crypts isolated by Alcian blue staining. Chromatin immunoprecipitation sequencing for H3K27ac and single-cell assay for transposase-accessible chromatin by sequencing were conducted using IM mucosa. NOS2 was induced using Tet-on gene expression system in normal cells. RESULTS: IM crypts had a methylation profile unique from non-IM crypts, showing extensive DNA hypermethylation in promoter CpG islands, including those of tumour-suppressor genes. Also, the IM-specific methylation profile, namely epigenetic footprint, was present in a fraction of gastric cancers with a higher frequency than expected, and suggested to be associated with good overall survival. IM organoids had remarkably high NOS2 expression, and NOS2 induction in normal cells led to accelerated induction of aberrant DNA methylation, namely epigenetic instability, by increasing DNA methyltransferase activity. IM mucosa showed dynamic enhancer reprogramming, including the regions involved in higher NOS2 expression. NOS2 had open chromatin in IM cells but not in gastric cells, and IM cells had frequent closed chromatin of tumour-suppressor genes, indicating their methylation-silencing. NOS2 expression in IM-derived organoids was upregulated by interleukin-17A, a cytokine secreted by extracellular bacterial infection. CONCLUSIONS: IM cells were considered to have a precancerous nature potentially with an increased chance of converting into cancer cells, and an accelerated DNA methylation induction due to abnormal NOS2 expression.

A nonrandomized controlled trial: long-term outcomes of LATG/LAPG for cStage I gastric cancer: Japan Clinical Oncology Group Study JCOG1401.

BACKGROUND: A previous report confirmed the safety of laparoscopy-assisted total and proximal gastrectomies (LATG and LAPG) (JCOG1401). This report demonstrates the 5-year relapse-free survival (RFS) and overall survival (OS) after long-term follow-up to confirm the efficacy of these surgical methods as key secondary endpoints for cStage I gastric cancer. METHODS: This study enrolled patients who had histologically proven gastric adenocarcinoma and were diagnosed with clinical T1N0, T1N(+), or T2N0 tumors according to the 14th edition of the Japanese Classification of Gastric Carcinoma (3rd English edition). RESULTS: Between April 2015 and February 2017, 246 patients were enrolled, although one patient was excluded because of misregistration. Meticulous follow-up was continued for > 5 years for each patient, and the data were analyzed in March 2022. The 5-year RFS was 90.0% (95% confidence interval [CI] 85.5-93.2%), and the 5-year OS was 91.2% (95% CI 86.9-94.2%) in all enrolled patients. Grade 3 or 4 late postoperative complications were detected in 12.7% of patients. CONCLUSIONS: This single-arm study showed that the long-term outcomes of LATG/LAPG for cStage I gastric cancer were acceptable, which is considered one of the standard treatments when performed by experienced surgeons. Trail registration UMIN000017155 ( http://www.umin.ac.jp/ctr/ ).

5-year follow-up results of a JCOG1104 (OPAS-1) phase III non-inferiority trial to compare 4 courses and 8 courses of S-1 adjuvant chemotherapy for pathological stage II gastric cancer.

BACKGROUND: Postoperative adjuvant chemotherapy with S-1 for 1 year (corresponding to eight courses) is the standard treatment for pathological stage II gastric cancer. The phase III trial (JCOG1104) investigating the non-inferiority of four courses of S-1 to eight courses was terminated due to futility at the first interim analysis. To confirm the primary results, we reported the results after a 5-years follow-up in JCOG1104. METHODS: Patients histologically diagnosed with stage II gastric cancer after radical gastrectomy were randomly assigned to receive S-1 for eight or four courses. In detail, 80 mg/m2/day S-1 was administered for 4 weeks followed by a 2-week rest as a single course. RESULTS: Between February 16, 2012, and March 19, 2017, 590 patients were enrolled and randomly assigned to 8-course (295 patients) and 4-course (295 patients) regimens. After a 5-years follow-up, the relapse-free survival at 3 years was 92.2% for the 8-course arm and 90.1% for the 4-course arm, and that at 5 years was 87.7% for the 8-course arm and 85.6% for the 4-course arm (hazard ratio 1.265, 95% CI 0.846-1.892). The overall survival at 3 years was 94.9% for the 8-course arm, 93.2% for the 4-course arm, and that at 5 years was 89.7% for the 8-course arm, and 88.6% for the 4-course arm (HR 1.121, 95% CI 0.719-1.749). CONCLUSIONS: The survival of the four-course arm was slightly but consistently inferior to that of the eight-course arm. Eight-course S-1 should thus remain the standard adjuvant chemotherapy for pathological stage II gastric cancer.

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.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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]). INTERPRETATION: 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. FUNDING: Merck Sharp & Dohme.

A discrimination model by machine learning to avoid gastrectomy for early gastric cancer.

Aim: Gastrectomy is recommended for patients with early gastric cancer (EGC) because the possibility of lymph node metastasis (LNM) cannot be completely denied. The aim of this study was to develop a discrimination model to select patients who do not require surgery using machine learning. Methods: Data from 382 patients who received gastrectomy for gastric cancer and who were diagnosed with pT1b were extracted for developing a discrimination model. For the validation of this discrimination model, data from 140 consecutive patients who underwent endoscopic resection followed by gastrectomy, with a diagnosis of pT1b EGC, were extracted. We applied XGBoost to develop a discrimination model for clinical and pathological variables. The performance of the discrimination model was evaluated based on the number of cases classified as true negatives for LNM, with no false negatives for LNM allowed. Results: Lymph node metastasis was observed in 95 patients (25%) in the development cohort and 11 patients (8%) in the validation cohort. The discrimination model was developed to identify 27 (7%) patients with no indications for additional surgery due to the prediction of an LNM-negative status with no false negatives. In the validation cohort, 13 (9%) patients were identified as having no indications for additional surgery and no patients with LNM were classified into this group. Conclusion: The discrimination model using XGBoost algorithms could select patients with no risk of LNM from patients with pT1b EGC. This discrimination model was considered promising for clinical decision-making in relation to patients with EGC.

Randomized controlled phase III trial to investigate superiority of robot-assisted gastrectomy over laparoscopic gastrectomy for clinical stage T1-4aN0-3 gastric cancer patients (JCOG1907, MONA LISA study): a study protocol.

BACKGROUND: Laparoscopic gastrectomy (LG) is considered a standard treatment for clinical stage I gastric cancer. Nevertheless, LG has some drawbacks, such as motion restriction and difficulties in spatial perception. Robot-assisted gastrectomy (RG) overcomes these drawbacks by using articulated forceps, tremor-filtering capability, and high-resolution three-dimensional imaging, and it is expected to enable more precise and safer procedures than LG for gastric cancer. However, robust evidence based on a large-scale randomized study is lacking. METHODS: We are performing a randomized controlled phase III study to investigate the superiority of RG over LG for clinical T1-2N0-2 gastric cancer in terms of safety. In total, 1,040 patients are planned to be enrolled from 46 Japanese institutions over 5 years. The primary endpoint is the incidence of postoperative intra-abdominal infectious complications, including anastomotic leakage, pancreatic fistula, and intra-abdominal abscess of Clavien-Dindo (CD) grade ≥ II. The secondary endpoints are the incidence of all CD grade ≥ II and ≥ IIIA postoperative complications, the incidence of CD grade ≥ IIIA postoperative intra-abdominal infectious complications, relapse-free survival, overall survival, the proportion of RG completion, the proportion of LG completion, the proportion of conversion to open surgery, the proportion of operation-related death, and short-term surgical outcomes. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in January 2020. Approval from the institutional review board was obtained before starting patient enrollment in each institution. Patient enrollment began in March 2020. We revised the protocol to expand the eligibility criteria to T1-4aN0-3 in July 2022 based on the results of randomized trials of LG demonstrating non-inferiority of LG to open surgery for survival outcomes in advanced gastric cancer. DISCUSSION: This is the first multicenter randomized controlled trial to confirm the superiority of RG over LG in terms of safety. This study will demonstrate whether RG is superior for gastric cancer. TRIAL REGISTRATION: The protocol of JCOG1907 was registered in the UMIN Clinical Trials Registry as UMIN000039825 ( http://www.umin.ac.jp/ctr/index.htm ). Date of Registration: March 16, 2020. Date of First Participant Enrollment: April 1, 2020.

Randomized phase II study comparing neoadjuvant 5-fluorouracil/oxaliplatin/docetaxel versus docetaxel/oxaliplatin/S-1 for patients with type 4 or large type 3 gastric cancer.

Macroscopic type 4 and large type 3 gastric cancer, mostly overlapping with scirrhous or linitis plastica type, exhibit a highly invasive nature and show unfavorable prognosis after curative surgery, even with adjuvant chemotherapy. A randomized phase III trial (JCOG0501) failed to demonstrate a survival advantage of neoadjuvant chemotherapy with S-1 plus cisplatin for this population. The current authors initiated a randomized phase II study comparing neoadjuvant chemotherapy with 5-fluorouracil/oxaliplatin/docetaxel versus docetaxel/oxaliplatin/S-1 for type 4 and large type 3 gastric cancer. 76 patients are planned to be enrolled over two years. The primary end point is the proportion of patients with a pathological response (grade 1b or higher) and secondary end points include overall survival and adverse events. Clinical Trial Registration: jRCTs031230231 (rctportal.niph.go.jp).

Role of reduction gastrectomy in patients with gastric cancer with a single non-curable factor: Supplementary analysis of REGATTA trial.

Background: REGATTA trial failed to demonstrate the survival benefit of reduction gastrectomy in patients with advanced gastric cancer with a single non-curable factor. However, a significant interaction was found between the treatment effect and tumor location in the subset analysis. Additionally, the treatment effect appeared to be different between Japan and Korea. This supplementary analysis aimed to elucidate the effect of reduction surgery based on tumor location and country. Methods: Multivariable Cox regression analyses in each subgroup were performed to estimate the hazard ratio (HRadj), including the following variables as explanatory variables: country, age, sex, incurable factor, cT, cN, primary tumor, performance status, histological type, and macroscopic type. Results: Patients (95 in Japan and 80 in Korea) were randomized to chemotherapy alone (86 patients) or gastrectomy plus chemotherapy (89 patients). The subgroup analysis according to the country revealed a worse overall survival in gastrectomy plus chemotherapy arm in Japan (hazard ratio: 1.32, 95% confidence interval: 0.85-2.05), but not in Korea (hazard ratio: 0.85.95% confidence interval: 0.52-1.40). Overall survival was better in distal gastrectomy plus chemotherapy compared with chemotherapy alone (hazard ratio = 0.69, 95% confidence interval: 0.42-1.13), and worse in total gastrectomy plus chemotherapy compared with chemotherapy alone (hazard ratio = 1.34, 95% CI: 0.93-1.94), which was more remarkable in Korea than in Japan. Conclusions: Primary chemotherapy is a standard of care for advanced gastric cancer; however, the survival benefits from reduction by distal gastrectomy remained controversial.

Meta-analysis of three randomized trials of capecitabine plus cisplatin (XP) versus S-1 plus cisplatin (SP) as first-line treatment for advanced gastric cancer.

BACKGROUND: S-1 plus cisplatin (SP) and capecitabine plus cisplatin (XP) are standard first-line regimens for advanced gastric cancer (AGC) worldwide. We conducted a meta-analysis using individual participant data (IPD) to investigate which is more suitable. METHODS: IPD from three randomized trials were collected. In these trials, patients with AGC were randomly allocated to SP (S-1 80-120 mg for 21 days plus cisplatin 60 mg/m2 (q5w)) or XP (capecitabine 2000 mg/m2 for 14 days plus cisplatin 80 mg/m2 (q3w)). RESULTS: In 211 eligible patients, median overall survival (OS) for SP versus XP was 13.5 and 11.7 months (hazard ratio [HR], 0.787; p = 0.114), progression-free survival (PFS) was 6.2 and 5.1 months (HR, 0.767; P = 0.076), and TTF was 5.1 and 4.0 months (HR, 0.611; P = 0.001). The most common grade ≥ 3 adverse events with SP or XP were neutropenia (18% vs. 29%) and anorexia (16% vs.18%). Subgroup analysis demonstrated significant interaction between treatment effect and performance status > 1 (HR, 0.685; P = 0.036), measurable lesion (HR, 0.709; P = 0.049), primary upper third tumor (HR, 0.539; P = 0.040), and differentiated type (HR, 0.549; interaction, 0.236; P = 0.019). For the differentiated type, OS was significantly longer in the SP group (13.2 months) than in the XP group (11.1 months) (HR, 0.549; P = 0.019). For the undifferentiated type, OS was similar in the SP group (14.2 months) and in the XP group (12.4 months) (HR, 0.868; P = 0.476). CONCLUSIONS: SP and XP were both effective and well tolerated. SP might be suitable for the pathological differentiated subtype of AGC. CLINICAL TRIAL REGISTRATION: The HERBIS-2, HERBIS-4A, and XParTS II trials were registered with UMIN-CTR as UMIN000006105, UMIN000006755, and UMIN000006045, respectively.

Acceleration of sarcopenia in elderly patients who develop asymptomatic pneumonia shadow within one year after surgery for early gastric cancer.

BACKGROUND: Although early gastric cancer is curable with local treatment, the overall survival in elderly patients did not reach 80% at five years after surgery. The major cause of death in elderly patients with early gastric cancer is not cancer itself but is related to postoperative sarcopenia. Elderly patients frequently develop postoperative asymptomatic pneumonia shadow, which is associated with a poor prognosis. However, why asymptomatic pneumonia shadow worsens the prognosis remains unclear. We investigated whether sarcopenia is accelerated in patients who developed asymptomatic pneumonia shadow. METHODS: We retrospectively examined patients of > 75 years of age who underwent R0 gastrectomy for gastric cancer and were diagnosed with T1 disease at National Cancer Center Hospital between 2005 and 2012. The diagnosis of asymptomatic pneumonia shadow was defined by diagnostic findings of pneumonia (consolidation type, reticular type, and nodular type) which were newly observed on chest computed tomography performed one year after surgery in comparison to preoperative computed tomography. Postoperative muscle loss was assessed by a computed tomography-based analysis using the L3 skeletal muscle index before and two years after surgery and the rate of decrease was calculated. Patients were classified into two groups according to the rate of decrease (cut-off value: 10%). RESULTS: Of the 3412 patients who underwent gastrectomy in our hospital during the study period, 142 were included in this study. Asymptomatic pneumonia shadow was found in 26 patients (18%). Patients who developed asymptomatic pneumonia shadow showed a significantly greater loss of muscle volume in comparison to patients who did not develop asymptomatic pneumonia shadow. In the multivariate analysis, total gastrectomy and asymptomatic pneumonia shadow were the independent risk factors for severe muscle loss. However, there was no significant difference in prognosis between the two groups. CONCLUSIONS: Sarcopenia was accelerated in elderly patients who developed asymptomatic pneumonia shadow after surgery for early gastric cancer. However, the poor prognosis in these patients may not be related to accelerated sarcopenia.