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Duodenal cancer is considered to be a small intestinal carcinoma in terms of clinicopathology. In Japan, there are no established treatment guidelines based on sufficient scientific evidence; therefore, in daily clinical practice, treatment is based on the experience of individual physicians. However, with advances in diagnostic modalities, it is anticipated that opportunities for its detection will increase in future. We developed guidelines for duodenal cancer because this disease is considered to have a high medical need from both healthcare providers and patients for appropriate management. These guidelines were developed for use in actual clinical practice for patients suspected of having non-ampullary duodenal epithelial malignancy and for patients diagnosed with non-ampullary duodenal epithelial malignancy. In this study, a practice algorithm was developed in accordance with the Minds Practice Guideline Development Manual 2017, and Clinical Questions were set for each area of epidemiology and diagnosis, endoscopic treatment, surgical treatment, and chemotherapy. A draft recommendation was developed through a literature search and systematic review, followed by a vote on the recommendations. We made decisions based on actual clinical practice such that the level of evidence would not be the sole determinant of the recommendation. This guideline is the most standard guideline as of the time of preparation. It is important to decide how to handle each case in consultation with patients and their family, the treating physician, and other medical personnel, considering the actual situation at the facility (and the characteristics of the patient).

PURPOSE: Liver metastasis (LM) is reported in approximately 40% of patients with advanced/metastatic gastric/gastroesophageal junction adenocarcinoma (metastatic esophagogastric adenocarcinoma; mGEA) and is associated with a worse prognosis. This post-hoc analysis from the RAINBOW trial reported the efficacy, safety, and biomarker outcomes of ramucirumab and paclitaxel combination treatment (RAM+PAC) in patients with (LM+) and without (LM-) LM at baseline. MATERIALS AND METHODS: Patients (n=665) were randomly assigned on a 1:1 basis to receive either RAM+PAC (LM+: 150, LM-: 180) or placebo and paclitaxel (PL+PAC) (LM+: 138, LM-: 197). The overall survival (OS) and progression-free survival (PFS) were evaluated using stratified Kaplan-Meier and Cox regression models. The correlation of dichotomized biomarkers (VEGF-C, D; VEGFR-1,2) with efficacy in the LM+ versus LM- subgroups was analyzed using the Cox regression model with reported interaction P-values. RESULTS: The presence of LM was associated with earlier progression than those without LM, particularly in patients receiving PL+PAC (hazard ratio [HR], 1.68). RAM+PAC treatment improved OS and PFS irrespective of LM status but showed greater improvement in LM+ than that in LM- (OS HR, 0.71 [LM+] vs. 0.88 [LM-]; PFS HR, 0.47 [LM+] vs. 0.76 [LM-]). Treatment-emergent adverse events were similar between patients with and without LM. No predictive relationship was observed between biomarker levels (VEGF-C, D; VEGFR-1,2) and efficacy outcome (OS, PFS) (all interaction P-values >0.05). CONCLUSIONS: RAM provided a significant benefit, irrespective of LM status; however, its effect was numerically stronger in patients with LM. Therefore, RAM+PAC is a clinically meaningful therapeutic option for patients with mGEA and LM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01170663. ispartof: JOURNAL OF GASTRIC CANCER vol:23 issue:2 pages:289-302 ispartof: location:Korea (South) status: published

BACKGROUND: Nivolumab and pembrolizumab are promising therapies for gastric adenocarcinoma. The 22C3 and 28-8 pharmDx immunohistochemistry assays for programmed death ligand-1 scoring criteria have been developed. This study compared the programmed death ligand-1 staining patterns of gastric adenocarcinoma evaluated by the 22C3 and 28-8 pharmDx assays. METHODS: Tissue microarray analysis was performed for 226 patients with gastric adenocarcinoma who underwent curative surgery. Interobserver concordance between the 22C3 and 28-8 pharmDx assays was assessed to compare the dichotomized expression values. Programmed death ligand-1 positivity was assessed by combined positive score and tumor proportion score. Immunohistochemistry for deficient mismatch repair proteins and Epstein-Barr virus-encoded RNA in situ hybridization was examined. RESULTS: Programmed death ligand-1 positivity with a combined positive score ≥5 was detected in 63 patients (28%) by the 22C3 pharmDx assay, and in 45 patients (20%) by the 28-8 pharmDx assay. A pairwise comparison of the 22C3 and 28-8 pharmDx assays showed 87% of pairs were concordant and 11% higher expressions for the 22C3 pharmDx assay, with strong concordance (kappa score =0.881 with a combined positive score cutoff of 5). The programmed death ligand-1 positivity rate (range, 3–5%) of the tumor proportion score was markedly lower than that of the combined positive score in the two assays. Programmed death ligand-1 positivity of the combined positive score in these two assays was associated with mismatch repair proteins and Epstein-Barr virus status. There was no significant difference in the overall survival between programmed death ligand-1, mismatch repair proteins, and Epstein-Barr virus status. CONCLUSIONS: The study findings suggest the potential interchangeability of the 22C3 and 28-8 pharmDx assays to determine programmed death ligand-1 expression levels in gastric adenocarcinoma patients.

ObjectivesEpigenomic alterations in cancer interact with the immune microenvironment to dictate tumour evolution and therapeutic response. We aimed to study the regulation of the tumour immune microenvironment through epigenetic alternate promoter use in gastric cancer and to expand our findings to other gastrointestinal tumours.DesignAlternate promoter burden (APB) was quantified using a novel bioinformatic algorithm (proActiv) to infer promoter activity from short-read RNA sequencing and samples categorised into APBhigh, APBint and APBlow. Single-cell RNA sequencing was performed to analyse the intratumour immune microenvironment. A humanised mouse cancer in vivo model was used to explore dynamic temporal interactions between tumour kinetics, alternate promoter usage and the human immune system. Multiple cohorts of gastrointestinal tumours treated with immunotherapy were assessed for correlation between APB and treatment outcomes.ResultsAPBhigh gastric cancer tumours expressed decreased levels of T-cell cytolytic activity and exhibited signatures of immune depletion. Single-cell RNAsequencing analysis confirmed distinct immunological populations and lower T-cell proportions in APBhigh tumours. Functional in vivo studies using ‘humanised mice’ harbouring an active human immune system revealed distinct temporal relationships between APB and tumour growth, with APBhigh tumours having almost no human T-cell infiltration. Analysis of immunotherapy-treated patients with GI cancer confirmed resistance of APBhigh tumours to immune checkpoint inhibition. APBhigh gastric cancer exhibited significantly poorer progression-free survival compared with APBlow (median 55 days vs 121 days, HR 0.40, 95% CI 0.18 to 0.93, p=0.032).ConclusionThese findings demonstrate an association between alternate promoter use and the tumour microenvironment, leading to immune evasion and immunotherapy resistance.

Gastric cancer treatments are evolving rapidly. For example, immune checkpoint inhibitors, especially those that target PD-1 or PD-L1, have long-term efficacy in a subset of gastric cancer patients, and are currently the first-line therapy. Immunotherapies approved for use in untreated gastric cancer patients include monotherapy and chemotherapy-immunotherapy combinations. Major clinical trials have reported efficacy and safety data suggesting that PD-L1 expression is important for regimen selection, although other biomarkers, clinicopathologic factors, and patient preference might also be relevant in other situations. Currently, several novel biomarkers and therapeutic strategies are being assessed, which might refine the current treatment paradigm. In this review, we describe the current treatment regimens for patients with gastric cancer and detail the approach we use for the selection of first-line immunotherapy regimens.

The triplet-agent (5-fluorouracil/leucovorin, oxaliplatin, and irinotecan; FOLFOXIRI) combined with an anti-epidermal growth factor receptor antibody as a first-line treatment of metastatic colorectal cancer (mCRC) has shown promising results in Western trials. This phase Ib study assessed the safety of FOLFOXIRI plus cetuximab in Japanese patients with RAS wild-type mCRC. Patients with previously untreated RAS wild-type mCRC received weekly cetuximab (400 mg/m2 at week 1 and subsequently 250 mg/m2) plus FOLFOXIRI that consisted of irinotecan (100, 120, and 150 mg/m2 defined as dose levels 0, 1, and 2), followed by oxaliplatin 85 mg/m2 and l-leucovorin 200 mg/m2 and then 5-fluorouracil 2400 mg/m2. The dose level of irinotecan was escalated starting at dose level 1 in a 3 + 3 manner. The primary endpoint was to determine the maximum-tolerated dose (MTD) and the recommended phase-2 dose (RP2D). Secondary endpoints included safety, overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Nine patients were enrolled. The MTD was not reached at dose level 2 and the RP2D was 150 mg/m2 irinotecan. The most frequent grade 3/4 adverse events were neutropenia (44%), fatigue (11%), paronychia (22%), and acneiform rash (11%). No dose-limiting toxicities occurred in any of the enrolled patients. No treatment-related death was observed. The ORR was 89% (95% confidence interval 52–100%). The safety profile of the combination of cetuximab and FOLFOXIRI was acceptable and promising anti-tumor activity was demonstrated, supporting further study in patients with RAS wild-type mCRC.

PurposeNivolumab is recommended for patients with advanced esophageal squamous cell carcinoma (aESCC) who are refractory or intolerant to fluoropyrimidine-based and platinum-based chemotherapy regardless of tumor proportion score (TPS). However, the predictive role of combined positive score (CPS) to predict nivolumab efficacy is unclear.MethodsWe retrospectively collected data from patients with aESCC, who were previously treated with fluoropyrimidines and platinum, and subsequently received nivolumab monotherapy between January 1, 2014 and September 15, 2020. Next, we examined the impact of CPS and TPS on clinical response to nivolumab. The inclusion criteria were refraction or intolerance to fluoropyrimidines and platinum, absence of comorbid malignancies, availability of tissue specimen for immunohistochemistry and programmed cell death-1 analysis results before initiating nivolumab.ResultsFifty patients were included (CPS, ≥ 10/1–10/< 1, n = 23/18/9; TPS, ≥ 10/1–10/< 1%, n = 17/8/25). The median progression-free survival were 4.1, 2.5, and 1.4 months in CPS ≥ 10, 1–10 (hazard ratio [HR] vs. CPS ≥ 10, 1.05; p = 0.90), and < 1 (HR vs. CPS ≥ 10, 3.75; p = 0.003) groups, respectively. Furthermore, among the patients with CPS ≥ 10/1–10/< 1, and TPS ≥ 10/1–10/< 1%, objective response rate were 32/25/0% and 36/0/19%. In addition, disease control rate were 63/50/11% (p = 0.04) and 65/40/38% (p = 0.30).ConclusionsThis study proposes that CPS can predict responses to nivolumab in patients with aESCC better than TPS, making it especially useful for predicting negative outcomes for those with CPS < 1.

The introduction of immune checkpoint inhibitors has redefined the treatment strategy and changed the way tumor assessments are made because of its response pattern. Studies have suggested that initiating chemotherapy after checkpoint inhibitors may have high anti-tumor activity in some cancer types. This response pattern has not been reported in patients with gastric cancer, and particularly for the combination of trifluridine/tipiracil. A 69-year-old man presented at follow-up for metastatic gastric cancer being treated with nivolumab, an anti-PD-1 antibody. Computed tomography of the liver showed a rapid 4-fold growth of the metastasis compared with baseline measurements taken while receiving paclitaxel and ramucirumab. It met the definition of a phenomenon called hyperprogressive disease. Nivolumab was discontinued, and he was switched to trifluridine/tipiracil. The liver metastasis was shrunk markedly after 2 months with improvement in his performance status and laboratory data. Sequential therapy starting with immune checkpoint inhibitors followed by cytotoxic agents such as trifluridine/tipiracil may have an apparent efficacy in gastric cancer even though prior immunotherapy demonstrates hyperprogressive disease.

Trial Information Click here to access other published clinical trials. Lessons Learned The recommended S-1 dose was 40 mg/m2, twice daily on Monday, Wednesday, Friday, and Sunday, with oral leucovorin and bevacizumab. Compared with daily administration, the alternate-day administration of S-1 with oral leucovorin may reduce mucositis with promising antitumor activity in refractory metastatic colorectal cancer. Background Daily S-1 plus oral leucovorin administration in a 1-week-on/1-week-off schedule has promising efficacy in gastrointestinal cancer but is associated with high risk of mucositis and diarrhea. Methods This phase Ib, 3+3 dose-escalation trial included patients with chemorefractory metastatic colorectal cancer (mCRC) receiving S-1 (40 mg/m2) and leucovorin (25 mg) orally twice daily (level 1, even-numbered days; level 2, Monday, Wednesday, Friday, and Sunday) and intravenous bevacizumab (5 mg/kg) every 2 weeks. Enrollment continued at the recommended dose level in the expansion cohort. Results We enrolled 21 patients (3 and 18 patients in levels 1 and 2, respectively). Briefly, 12 and 9 patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 1, respectively, and 8 and 13 patients had 1–3 and ≥4 prior treatment lines, respectively. Dose-limiting toxicity (DLT) was not observed, and level 2 was confirmed as the recommended dose. Common grade 3–4 adverse events at level 2 were anemia (22%), anorexia (6%), and diarrhea (6%). In the entire cohort, response rate, disease control rate, and median progression-free survival were 10%, 71%, and 4.2 months, respectively. Conclusion The recommended S-1 dose was 40 mg/m2, twice daily on Monday, Wednesday, Friday, and Sunday, with 25 mg oral leucovorin twice daily and 5 mg/kg bevacizumab every 2 weeks. Compared with the daily administration, alternate-day administration of S-1 plus leucovorin may reduce mucositis with promising antitumor activity in refractory mCRC.

Sphingobacterium is an aerobic, glucose non-fermenting, Gram-negative rod bacterium that has been isolated from soil, plants, food, and water sources, including in hospitals. Reports of systemic infections caused by Sphingobacterium multivorum (S. multivorum) are rare, and their clinical and microbiological characteristics remain unclear. Moreover, conventional microbiological methods have limited ability to identify S. multivorum. We report the first case of obstructive cholangitis with bacteremia caused by S. multivorum in a patient with gastric cancer.A 68-year-old woman with advanced gastric cancer, hypertension, and hyperlipidemia was admitted with obstructive jaundice, and subsequently developed obstructive cholangitis during the hospital stay. S. multivorum were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and 16S ribosomal RNA sequencing of the patient's blood samples. Based on the antibiotic susceptibility results of the isolates, cefepime was administered intravenously for 14 days, with good therapeutic outcomes.S. multivorum infection is rare, and its microbiology and pathogenicity in humans is mostly unknown. Therefore, multiple diagnostic approaches should be used to identify S. multivorum, and antimicrobial therapy should be selected based on the in vitro susceptibility. This report provides clinicians with novel information on the clinical manifestations and diagnostic methods for an accurate diagnosis of S. multivorum.

PurposeFluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab is the standard second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) who are refractory or intolerant to fluoropyrimidines and oxaliplatin. However, the benefits of incorporating fluoropyrimidines into second-line chemotherapy for patients with mCRC who are refractory to fluoropyrimidines in first-line chemotherapy are unknown.MethodsWe retrospectively evaluated patients with mCRC who were administered irinotecan plus bevacizumab or FOLFIRI plus bevacizumab as second-line chemotherapy at a single institution from January 2010 to April 2020. We compared the efficacy and safety of irinotecan plus bevacizumab (IRI group) with those of FOLFIRI plus bevacizumab (FOLFIRI group).ResultsOf the 255 enrolled patients, 107 (IRI/FOLFIRI group, 31/76 patients) were eligible for analysis. After a median follow-up of 13.1 months (range, 1.2–48.4) and 14.3 months (range, 0.9–46.5) for the IRI and FOLFIRI groups, respectively, the median progression-free survival was 6.4 months and 5.8 months [adjusted hazard ratio (aHR), 0.82; 95% confidence interval (CI), 0.50–1.34, p=0.44] and the median overall survival was 16.6 months and 16.5 months (aHR, 1.01; 95% CI, 0.59–1.69; p=0.97) in the IRI and FOLFIRI groups, respectively. All grade nausea, vomiting, decreased appetite, stomatitis, hand-foot syndrome, neutropenia, thrombocytopenia, increased creatinine, Grade 3/4 neutropenia, and febrile neutropenia occurred more frequently in the FOLFIRI group than in the IRI group.ConclusionOmitting fluorouracil from FOLFIRI plus bevacizumab as second-line chemotherapy may reduce adverse events without affecting antitumor activity in patients with mCRC who are refractory to fluoropyrimidines.

425 Background: Blocking immune checkpoint (IC) pathways, particularly mediated by PD1 and PDL1, has attracted great attention as a promising strategy for treating gastrointestinal cancer. However, the clinical responses are low in many cases, and thus a new treatment strategy and its biomarker are urgently needed for improving the clinical outcome. Blocking other IC molecules, including LAG3, has been evaluated in many clinical trials, while the therapeutic efficacy and the predictive biomarkers remains to be determined due to the same issues as anti-PD1/PDL1 therapy. Methods: We analyzed soluble LAG3 (sLAG3) in sera by ELISA, and LAG3+ cells by flow cytometry, using fresh peripheral blood (PB) obtained from 91 patients with advanced gastric cancer (AGC) before and about one month after nivolumab monotherapy (2 courses) in the WJOG10417GTR study, according to the protocol approved by the IRB (August 2018 - November 2020). Progression-free survival (PFS) and overall survival (OS) were compared between high/low groups divided by the cutoff value determined by visually assessing the continuous trend and change point of log hazard ratios obtained by applying penalized splines to each molecular marker. This study was supported by ONO PHARMACEUTICAL CO., LTD. and Bristol Myers Squibb. Results: Posttreatment values were significantly more associated with patients’ prognosis rather than baseline values, and the sLAG3-high group showed significantly shorter PFS/OS as compared to the low group divided by the median: median PFS (mPFS) 51.5 vs 95.5 days (HR = 2.04, P = 0.002), and median OS (mOS) 188 vs 393 days (HR = 1.81, P = 0.032). Patients with high levels of LAG3+ PBCs after treatment showed worse prognosis as compared to those with low levels divided by the cutoff values: a CD3+CD4+LAG3+ T-cell subset, mPFS 43 vs 72 days (HR = 2.23, P = 0.015) and mOS 178 vs 282 days (HR = 1.56, P = 0.249); a CD3+CD8+LAG3+ T-cell subset, mPFS 57 vs 69 days (HR = 1.89, P = 0.012) and mOS 228 vs 303 days (HR = 1.40, P = 0.233); and a CD56+LAG3+ NK subset, mPFS 57 vs 88 days (HR = 2.15, P = 0.003) and mOS 217 vs 409 days (HR = 1.88, P = 0.031). Patients with sLAG3-high/CD56+LAG3+ NK-high levels showed markedly worse prognosis than those with low/low levels (mPFS-HR = 10.55, P < 0.001; and mOS-HR = 4.59, P < 0.001). Conclusions: Patients with posttreatment high levels of sLAG3 and LAG3+ cells in PB showed poor prognosis of AGC patients after the nivolumab therapy, suggesting that these are useful predictive biomarkers. LAG3 may be a promising target in immunotherapy for AGC. Clinical trial information: UMIN000032686 .

331 Background: Anamorelin is a highly selective ghrelin receptor agonist that improves appetite and increases lean body mass in patients (pts) with cachexia. We aimed to investigate the predictors of therapeutic efficacy of anamorelin in pts with gastrointestinal cancer. Methods: This retrospective study included pts with gastric cancer (GC), pancreatic cancer (PC), and colorectal cancer (CRC) treated with anamorelin at our institution between May 2021 and July 2022. Glasgow Prognostic Score (GPS) was defined as follows: GPS 0: CRP≤1.0 (mg/dL) and Alb≥3.5 (g/dL), GPS 1: either CRP>1.0 or Alb1.0 and Alb2. The treatment line for 1st/2nd/≥3rd/others was 51/13/14/22%, respectively. GPS was 0/1/2 in 21/30/49%, respectively. Except for treatment line, there were no significant differences in patient characteristics according to the cancer type. A total of 12 pts discontinued treatment owing to AEs (nausea, 3; epigastric distress, 2; fatigue, 2; poor physical condition, 2; staggering, 1; pulsation, 1; diarrhea, 1 pts). The RR was 42%. Pts with GPS 2 had less improvement in appetite than those with GPS 0 or 1 (26% vs. 56%, adjusted odds ratio [95% confidence interval (95%CI)]:0.22 [0.07–0.69], p=0.009). The RR of pts with GC, PC, and CRC were 44%, 42%, and 41%, respectively. The cumulative incidence of discontinuation of anamorelin after 12 weeks was higher in pts with GPS 2 than in those with GPS 0 or 1 (46% vs. 30%). The TTF in pts with GPS 2 was significantly shorter than that in pts with a GPS 0 or 1 (adjusted subdistributional hazard ratio [95%CI]:2.80 [1.37–5.72], p=0.005). There was no statistically significant difference in TTF by cancer type, although TTF was shorter in GC and PC than in CRC. Other factors, including age, sex, baseline BMI, ECOG PS, lines of therapy, and cancer type did not correlate with RR and TTF. Conclusions: In pts with a GPS of 0 or 1, anamorelin showed better appetite improvement and a longer treatment effect than in those with GPS 2. TTF was shorter in pts with GC and PC; therefore, the timing of use should be carefully considered.

Background/aim Metastatic small bowel adenocarcinoma (SBA) is a rare disease with poor prognosis. This study aimed to explore the efficacy and safety of second-line chemotherapy for patients with SBA. Patients and methods We retrospectively reviewed the clinical characteristics of 27 metastatic patients with SBA after progression on first-line chemotherapy. The patients were divided into Cohort A, receiving second-line chemotherapy, and Cohort B, receiving best supportive care. Results Patients in Cohort B had higher age, worse performance status, and higher neutrophil-to-lymphocyte ratio compared with those in Cohort A. Cohort A showed significantly better overall survival (OS) compared with Cohort B (median OS, 15.6 vs. 3.4 months; p=0.002). Objective response rate, disease control rate, and median progression-free survival (PFS) for Cohort A were 7%, 74%, and 5.0 months, respectively. Patients who underwent irinotecan-based chemotherapy showed longer PFS and OS compared with those who underwent taxane-based chemotherapy. No significant adverse events were reported. Conclusion Second-line chemotherapy for metastatic SBA demonstrated clinical activity with acceptable toxicities.

Background Esophageal cancer is associated with synchronous or metachronous cancer at other primary sites. However, few studies have evaluated the second malignancies after the treatment of esophageal cancer. The present study aimed to clarify the frequency of and risk factors for the second malignancies after definitive therapy for esophageal cancer. Patients and Methods We included patients with esophageal cancer who received definitive therapy between 2000 and 2010. Exclusion criteria were synchronous cancer or a past history of cancer. Standardized incidence rate (SIR) was calculated using age‐ and sex‐specific incidence rates from the cancer registry data. To conduct risk analyses, we used the competing risk regression model, which defined death and the development of second malignancies as competing risks. Results A total of 758 patients were included, with 131 second malignancies occurring in 106 patients (14%), over a median follow‐up of 3.7 years. Cumulative incidences of second malignancies after 3, 5, and 8 years were 4.0%, 7.6%, and 13.8%, respectively. The risk of second malignancy was significantly elevated [SIR = 1.83, 95% confidence interval (CI): 1.50‐2.22]. The most common sites of primary tumor were the head and neck (20%), followed by the lung (17%), stomach (16%), colon and rectum (11%), and urinary tract (9%). Risk analyses revealed that age ≥ 65 years [subdistribution hazard ratio (sHR): 1.51, 95% CI: 1.01‐2.24, vs age, We conducted risk analyses using the competing risk regression model, which defined death and the development of second malignancies as competing risks. Our study revealed that risk of second primary malignancies was significantly higher compared with the general population. Age, clinical stage, and tumor location were identified as significant factors for the development of second primary malignancies.

PURPOSE We previously reported on the pilot study assessing the feasibility of using the Japanese translation of the Comprehensive Score for Financial Toxicity (COST) tool to measure financial toxicity (FT) among Japanese patients with cancer. In this study, we report the results of the prospective survey assessing FT in Japanese patients with cancer using the same tool. PATIENTS AND METHODS Eligible patients were receiving chemotherapy for a solid tumor for at least 2 months. In addition to the COST survey, socioeconomic characteristics were collected by using a questionnaire and medical records. RESULTS Of the 191 patients approached, 156 (82%) responded to the questionnaire. Primary tumor sites were colorectal (n = 77; 49%), gastric (n = 39; 25%), esophageal (n = 16; 10%), thyroid (n = 9; 6%), head and neck (n = 4; 3%), and other (n = 11; 7%). Median COST score was 21 (range, 0 to 41; mean ± standard deviation, 12.1 ± 8.45), with lower COST scores indicating more severe FT. On multivariable analyses using linear regression, older age (β, 0.15 per year; 95% CI, 0.02 to 0.28; P = .02) and higher household savings (β, 8.24 per ¥15 million; 95% CI, 4.06 to 12.42; P < .001) were positively associated with COST score; nonregular employment (β, −5.37; 95% CI, −10.16 to −0.57; P = .03), retirement because of cancer (β, −5.42; 95% CI, −8.62 to −1.37; P = .009), and use of strategies to cope with the cost of cancer care (β, −5.09; 95% CI, −7.87 to −2.30; P < .001) were negatively associated with COST score. CONCLUSION Using the Japanese version of the COST tool, we identified various factors associated with FT in Japanese patients with cancer. These findings will have important implications for cancer policy planning in Japan.

OBJECTIVES Insufficient oral intake in advanced gastric cancer (AGC) limits the use of several drugs. We aimed to determine the oral intake status of patients with AGC during later-line chemotherapy. MATERIALS AND METHODS We retrospectively evaluated data of patients with AGC who experienced disease progression during first-line chemotherapy administered from January 2012 to December 2018 in a single institution. We defined "insufficient oral intake" as requiring daily intravenous fluids or hyperalimentation. Multivariate logistic regression was performed to identify oral intake-related factors. RESULTS Among 589 included patients, at disease progression during first-line, second-line, and third-line chemotherapy, 78.3% (461), 53.3% (314), and 30.4% (179) of patients, respectively, exhibited sufficient oral intake. Fourth-line chemotherapy was initiated for 22.2% (131) of patients, with 20.0% (118) exhibiting sufficient oral intake. During second-line and third-line chemotherapy, 11/67 (16%) and 2/39 (5%) patients, respectively, exhibited improvements in oral intake; 85/428 (19.9%) and 70/259 (27.0%), respectively, exhibited deteriorations in oral intake. Factors correlated to deterioration in oral intake during second-line chemotherapy were poor Eastern Cooperative Oncology Group Performance Status (odds ratio, 4.32; P

Limited data are available regarding the efficacy of nutrition support in advanced gastric cancer (AGC) patients receiving a standard second-line combination chemotherapy. The BALAST study is conducted as a prospective, multicenter observational study to evaluate the efficacy of nutrition support for patients with AGC treated with ramucirumab plus taxane as second-line treatment. As part of the routine care, patients who are malnourished or at risk of malnutrition will receive nutrition support from dietitians. We will enroll a total of 26 patients to estimate weight control rate at 12 weeks as primary end point. This study will generate valuable data reinforcing the role of nutrition support therapy for AGC patients receiving second-line chemotherapy.Lay abstract Various guidelines recommend that nutrition support therapy should be considered if cancer patients are malnourished or at risk of malnutrition. Several studies have revealed that body weight loss, which is an important factor in determining the nutrition status, may predict survival during second-line standard chemotherapy with ramucirumab and a taxane for advanced gastric cancer (AGC) patients. However, limited data are available regarding the efficacy of nutrition support in AGC patients receiving ramucirumab and a taxane. This study is conducted as a prospective, multicenter observational study to evaluate the efficacy of nutrition support for Japanese patients with AGC treated with ramucirumab and a taxane. This study will generate valuable data reinforcing the role of nutrition support therapy for AGC patients in second-line treatment.

Background Nivolumab (NIVO) and irinotecan (IRI) are standard treatments for refractory advanced gastric cancer (AGC); however, it is unclear which drug should be administered first or in which cases. The tumor growth rate (TGR) during preceding treatment is reported to be associated with tumor response in metastatic colorectal cancer patients treated with regorafenib or trifluridine/tipiracil, suggesting that TGR may be useful for drug selection. Therefore, we evaluated the association between TGR during preceding treatment and the tumor response to NIVO or IRI. Patients and methods We retrospectively evaluated consecutive AGC patients treated with NIVO or IRI and divided them into slow-growing (Slow) and rapid-growing (Rapid) groups according to TGR and the presence or absence of new lesions (NL+/NL−, respectively) during preceding treatment (Slow group: NL− with low TGR, Highlights • NIVO and IRI are standard treatments for refractory AGC, although it is unclear which should be administered first. • TGR may be useful for drug selection, therefore we evaluated the association between TGR and the tumor response to NIVO or IRI. • In the Slow group, the response rate (RR) was significantly higher in patients treated with NIVO compared with IRI. • In the Rapid group, there was no significant difference in RR between the NIVO and IRI groups. • TGR and NL emergence during preceding treatment may be useful for drug selection.

Nivolumab is an increasingly used standard care treatment for heavily pretreated patients with advanced gastric cancer, with increasing clinical use in Japan. Data from retrospective studies on various tumors have shown the objective response rate to cytotoxic chemotherapy potentially improves after an exposure to immune checkpoint inhibitors. Based on these data, we conducted the multicenter observational REVIVE study to evaluate the efficacy and safety of cytotoxic chemotherapy in nivolumab-refractory or nivolumab-intolerant patients with advanced gastric cancer. Patients who are refractory or intolerant to nivolumab and scheduled to receive irinotecan monotherapy, oxaliplatin combination treatment or oral trifluridine/tipiracil hydrochloride therapy will be included. The primary end point is overall survival of nivolumab-pretreated patients with advanced gastric cancer after the cytotoxic chemotherapy. Clinical trial registration: UMIN000032182 ( umin.ac.jp )

Although immune checkpoint inhibitors are commonly less effective for patients with a poor general condition, they can be effective and should be considered for poor general conditions in the case of MSI‐H tumor.

In patients with advanced gastric cancer refractory to chemotherapy, the treatment options are limited. Via this phase II study, we aimed to assess the efficacy and safety of oxaliplatin in combination with 5-fluorouracil and l-leucovorin (modified FOLFOX6). Patients who had histologically confirmed metastatic gastric cancer refractory to ≥ two previous chemotherapy regimens were included. The primary endpoint was the overall response rate (ORR) by an independent central review. According to an assumption of a threshold ORR of 10% and expected ORR of 25%, with α = 0.05 and β = 0.20, at least 33 patients were required. The secondary endpoints included overall survival (OS), progression-free survival (PFS), quality of life measured by EQ-5D, and safety. Among the 35 enrolled patients, 33 were included in the primary analysis. All patients previously received fluoropyrimidines, cisplatin, and taxanes, and 24 (73%) were pretreated with irinotecan. The confirmed ORR was 27% [95% confidence interval (CI) 13–46]. The median PFS and OS were 2.2 (95% CI 1.2–3.2) and 5.6 (95% CI 4.1–7.0) months, respectively. In the multivariate analyses, immunotherapy within 90 days and a Glasgow Prognostic Score of 0 were associated with better treatment outcomes. The most common grade ≥ 3 adverse event was neutropenia (36%), and no febrile neutropenia was observed. The median EQ-5D scores did not change from baseline at 2, 4, and 8 weeks (p value = 0.38, 0.79, and 0.98, respectively). Modified FOLFOX6 (mFOLFOX6) showed substantial activity and acceptable toxicity for chemotherapy-refractory advanced gastric cancer. UMIN Clinical Trial Registry (UMIN000016416).

Background/aim The efficacy of treatment using the anti-programmed cell death-1 (anti-PD-1) antibody for metastatic gastric cancer (mGC) has been established previously. Exploratory analyses in various types of tumours suggest that prior exposure to immune checkpoint inhibitors can enhance the efficacy of subsequent cytotoxic chemotherapy (CTx). Our aim is to evaluate the efficacy and safety of CTx for mGC after progression on anti-PD-(ligand) 1 [anti-PD-(L)1] antibody. Patients and methods We retrospectively evaluated patients with mGC who underwent CTx. The patients received CTx after progression on anti-PD-(L)1 antibody (cohort A) or as a third-line treatment without prior exposure to anti-PD-(L)1 antibody (cohort B). We evaluated: i) clinical characteristics, ii) efficacies, iii) prognoses, and iv) adverse events (AEs). Results In cohorts A and B, 16 and 68 patients fulfilled the criteria, respectively. In the univariate analysis, the overall response rate was significantly higher in cohort A compared to cohort B (31% vs. 10%, respectively; Odds Ratio:3.96, 95% Confidence Interval:1.06-14.8, p=0.040). The multivariate analysis showed a similar trend. Immune-related AEs did not worsen and were manageable, while new immune-related AEs were not observed. Conclusion CTx after progression on anti-PD-(L)1 antibody demonstrated a favourable efficacy in intensively treated patients with mGC.

298 Background: Although FLOT (5-fluorouracil [5-FU]/leucovorin [ l-LV] + oxaliplatin [L-OHP] + docetaxel [DTX]) is globally recognized as the standard treatment for gastric cancer (GC), the safety of FLOT in Japanese patients (pts) is unknown. Moreover, because advanced GC (AGC) pts with severe peritoneal metastasis (SPM) have often been excluded from pivotal clinical trials due to their poor condition, it is necessary to develop standardized treatment for them. Methods: This study is an open-label, multicenter, single-arm, phase I study to determine the recommended phase II dose (RP2D) of FLOT for Japanese AGC pts without (part 1) or with (part 2) SPM using a 3 + 3 design. Main eligibility criteria included histologically confirmed AGC, HER2 negative, and age 20–75 years. In part 2a, pts with ECOG Performance status (PS) 2, who simultaneously had massive ascites and inadequate oral intake, were excluded. Massive ascites was defined as continuous ascites from the pelvic cavity to the upper abdomen, based on computed tomography findings. Inadequate oral intake was defined as the requirement for daily intravenous infusions to supply water or nutrition. The dose limiting toxicity (DLT) was assessed before the start of cycle 2. The fixed dose of L-OHP, l-LV, and 5-FU was 85, 200, and 2600 mg/m2, respectively, and DTX was administered at a dose of 50, 40, and 30 mg/m2 in the level 0, −1, and −2, respectively. Results: In part 1a, one patient died of hemorrhage from the primary tumor on Cycle 1 Day 2 and was replaced. The characteristics were as follows: median age (range), 70 (51–71) years; male/female, 2/1; ECOG PS (0/1), 2/1; histological type (diffuse/intestinal), 3/0; prior gastrectomy (yes/no), 0/3; and measurable lesions (yes/no), 1/2. During DLT evaluation, grade 3 (G3) or higher adverse events (AEs) were neutropenia (n = 1), lymphocytopenia (n = 1), anemia (n = 1), and anorexia (n = 1). During follow-up, the most common G3 or higher AEs included neutropenia (n = 3), lymphocytopenia (n = 1), anemia (n = 1), febrile neutropenia (FN) (n = 1 at cycle 5), diarrhea (n = 1), anorexia (n = 1), fatigue (n = 1), and colonic perforation (n = 1) due to diverticulitis (not treatment-related AE). In part 2a, the characteristics were as follows: median age (range) 64 (49–69) years; male/female, 3/0; ECOG PS (0/1), 0/3; histological type (diffuse/intestinal), 3/0; prior gastrectomy (yes/no), 0/3; and measurable lesions (yes/no), 0/3. Two pts had massive ascites and 1 pt had both massive ascites and inadequate oral intake. During follow-up, only G3 neutropenia (n = 3) was observed. Two pts needed dose modification in cycle 2. Both in part 1a and 2a, no treatment-related deaths and no DLTs were observed and the RP2D was determined in level 0. Conclusions: We determined that DTX 50 mg/m2, L-OHP 85 mg/m2, 5-FU 2600 mg/m2, and l-LV 200 mg/m2 were the RP2D of FLOT for Japanese AGC with/without SPM. Clinical trial information: 041200044.

346 Background: SWI/SNF chromatin-remodeling complex is encoded by multi-gene families that are recurrently mutated in cancer. Previous studies reported that tumors harboring SWI/SNF complex genetic alterations (GA) are sensitive to immune checkpoint inhibitors (ICIs), but the clinical significance of SWI/SNF complex GA in patients with gastrointestinal cancers (GICs) is unclear. Methods: We reviewed patients with metastatic GICs who underwent comprehensive genomic profiling (CGP) and received ICIs at our institution between July 2014–June 2021. SWI/SNF complex GA were defined as ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1 alterations. Results: Of 292 patients receiving CGP, 136 patients received ICIs, of which 10 (7.4%) had SWI/SNF GA, including 8 ARID1A (5.9%), 1 ARID2 (0.7%) and 2 SMARCA4 (1.5%) alterations. The subjects included 50 esophageal cancers, 84 gastric cancers, and 2 small intestine cancers. The patients with SWI/SNF complex GA had significantly higher proportions of microsatellite instability-high ( p = 0.004) and lower proportions of esophageal cancer ( p = 0.002), compared with patients without SWI/SNF complex GA. During the median follow-up time of 7.5 months (M), the median overall survival (OS), time-to-treatment failure (TTF), and progression-free survival (PFS) in all patients was 13.2 M ([95% confidence interval [CI] 7.7-21.8 M), 2.2 M (95%CI, 1.8-2.5 M), and 2.3 M (95%CI, 1.9-2.8 M), respectively. The patients with SWI/SNF complex GA had better OS (median, not reached vs 10.3 M; hazard ratio [HR], 0.40 [95% confidence interval [CI] 0.19–0.86]; p = 0.019) than those without SWI/SNF complex GA. The patients with SWI/SNF complex GA tended to have longer TTF (median, 4.7 M vs 2.1 M; HR, 0.67 [95%CI 0.38–1.17]; p = 0.16) and PFS (median, 5.4 M vs 2.2 M; HR, 0.70 [95%CI 0.39–1.27], p = 0.24) than those without SWI/SNF GA. The objective response rate (ORR) and disease control rate (DCR) in all patients was 13.2% (95%CI, 8.0-20.1) and 40.4% (95%CI, 32.1-49.2), respectively. The ORR and DCR of patients with SWI/SNF complex GA tended to be higher than those without SWI/SNF complex GA (ORR, 30.0% vs 11.9%; p = 0.13: DCR, 70.0% vs 38.1%; p = 0.09), with 1 complete response and 2 partial responses in the patients with SWI/SNF complex GA. Conclusions: The patients with GICs who had SWI/SNF complex GA were more likely to benefit from ICI therapy, suggesting that novel ICI-containing chemotherapies targeting SWI/SNF complex GA are needed for GICs.[Table: see text]

257 Background: NIVO therapy is a standard care treatment for heavily pretreated patients with AGC. Improvement in objective response rate (ORR) to CTx after NIVO therapy for various cancer types has been reported. However, the efficacy and safety of CTx for AGC after progression on NIVO remains unclear. Methods: The REVIVE trial was a prospective, multicenter, observational study that evaluated the efficacy and safety of CTx in NIVO-refractory or NIVO-intolerant patients (pts) with AGC (UMIN000032182). The primary endpoint was overall survival (OS) of CTx following NIVO therapy. The median threshold and expected survival times were set as 4.0 and 7.0 months (M). The secondary endpoints are ORR, disease control rate (DCR), progression-free survival (PFS), and incidence of adverse events (AEs), including immune-related adverse events (irAEs). CTx consisted of irinotecan alone (IRI), trifluridine/tipiracil alone (FT), and oxaliplatin-containing regimens (OX). Results: Of 395 pts treated with NIVO who met the eligibility at formal registration from Jun 2018 to Sep 2020, 199 pts who received CTx after NIVO were evaluated. Pt characteristics were as follows: median age, 69 years; male, 70%; ECOG PS 0/1/2, 38/51/12%; histology (diffuse/intestinal), 39/59%; metastatic lesions (peritoneum/liver/lung), 38/34/15%; number of metastatic organ sites (0–1/≥2), 40/60%; measurable lesions, 83%; and CTx regimens (IRI/FT/OX), 64/31/5%. Median OS and PFS were 7.5 M (95%CI, 6.7–9.7) at 145 events for OS and 2.9 M (95%CI, 2.2–3.5) at 184 events for PFS. The ORR and DCR were 17.0% (95%CI, 11.6–23.6) and 46.7% (95%CI, 38.9–54.6). Median OS, median PFS, ORR, and DCR according to CTx regimens (IRI/FT/OX) were 8.1/7.1/6.2 M, 3.3/2.8/2.4 M, 18.9/10.9/25.0%, and 47.8/43.5/50.0%, respectively. At the start of CTx, 42 pts had irAEs due to prior NIVO therapy. The most common any-grade and grade ≥3 AEs during CTx included decreased appetite (46% and 7.5%), fatigue (26% and 2.5%), nausea (24% and 1.5%), constipation (16% and 0%), and diarrhea (28% and 4.0%). No treatment-related deaths were observed. Conclusions: Prior NIVO therapy may lead to improved prognosis after CTx without unexpected AEs in pts with AGC, warranting further investigations after NIVO is approved as first-line treatment.[Table: see text]

Background Anti-HER2 therapy has not demonstrated a survival advantage in the second-line setting of patients with HER2-positive gastric cancer. We conducted this study to assess changes in HER2 status and to identify possible biomarkers for acquired resistance after the use of trastuzumab as the first-line therapy. Patients and methods Patients with advanced or recurrent HER2-positive gastric adenocarcinoma who were diagnosed with progressive disease after the first-line trastuzumab-based therapy and developed pathologically confirmed adenocarcinoma within 3 months after completion of trastuzumab-based therapy were enrolled in this study. We collected re-biopsied samples from the HER2-positive patients who had developed resistance to trastuzumab and re-evaluated their HER2 status. Amplification of EGFR and c-met, as well as PIK3CA mutation, were comparatively analysed when samples were available. Results Among 33 eligible patients, loss of HER2 was identified in 20 patients (60.6%) with refractory disease. Immunohistochemistry showed that the rate of HER2 overexpression was greatly reduced after therapy (pre-HER2 3+: 24 [72.7%] vs. post-HER2 3+: 13 [39.4%]). We found that the use of fixatives other than 10% neutral buffered formalin significantly reduced the HER2-positive rate. EGFR amplification, c-met amplification and PIK3CA mutation before and after trastuzumab-based therapy were observed in 10.3% and 3.8%, 17.9% and 4.2% and 4.0% and 4.2% of cases, respectively. Conclusion Re-evaluation of HER2 status is needed to determine the appropriate use of anti-HER2–targeted therapy after disease progression. Our results also highlight the importance of formalin fixation conditions for HER2 testing.