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Background The standard preoperative treatment for resectable locally advanced esophageal squamous cell carcinoma (LAESCC) in Japan is docetaxel, cisplatin (CDDP), and 5-fluorouracil. However, patients with renal or cardiac dysfunction and elderly patients are ineligible for a CDDP-containing regimen because of toxicities. Oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) therapy has less renal toxicity than CDDP-containing regimens and does not require hydration. However, there are limited data on preoperative FOLFOX therapy in these patients. Methods This retrospective study analyzed patients with resectable LAESCC who were aged ≥ 75 years or had renal or cardiac dysfunction and received preoperative FOLFOX between 2019 and 2021. FOLFOX was administered every 2 weeks for 3 or 4 cycles and was followed by surgery. Adverse events associated with chemotherapy, the complete resection (R0) rate, relative dose intensity (RDI), and histopathological response were evaluated. Results Thirty-five patients were eligible. Median age was 77 (range 65–89) years; 68.6% were aged ≥ 75 years, 74.3% had renal dysfunction, and 17.1% had cardiac dysfunction. The RDI was 70.2% and 87.1% for bolus and continuous intravenous 5-fluorouracil, respectively and 85.2% for oxaliplatin. The most common grade ≥ 3 adverse events were neutropenia (60.0%) and leucopenia (28.6%). Two patients (5.7%) had febrile neutropenia and grade 3 pneumonia. Thirty-one patients underwent surgery. The R0 resection rate was 87.1%, and there was no histopathological evidence of residual tumor in 16.1%. There were no treatment-related deaths. Conclusions Preoperative FOLFOX had a manageable safety profile and showed favorable short-term efficacy in patients with resectable LAESCC who were ineligible for CDDP-containing treatment.

The standard preoperative treatment for resectable locally advanced esophageal squamous cell cancer (LAESCC) in Japan is a cisplatin (CDDP)-containing chemotherapy. However, patients with renal or cardiac dysfunction and elderly patients are not candidates for CDDP because of renal toxicity and the need for hydration. Oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX) therapy causes less renal toxicity and does not require hydration. We evaluated the preoperative FOLFOX therapy in patients who are unsuitable for CDDP remains unknown. The subjects of this retrospective study were histologically confirmed LAESCC patients unsuitable for CDDP because of an age ≥ 75 years or a creatinine clearance (CCr) Thirty-five patients were eligible for inclusion in the study (median age 77 years [range, 65–89]; performance status 0/1, 40%/60%; clinical stage I/II/III/IVB [only supraclavicular lymph node], 11%/29%/57%/3%). The reasons for selecting FOLFOX were renal dysfunction (74%), age ≥ 75 years (69%), and cardiac dysfunction (17%). Four patients (11.4%) discontinued chemotherapy because of progression (n = 2), febrile neutropenia (n = 1), or neutropenia (n = 1). The most common grade ≥ 3 adverse events were neutropenia (60%) and leucopenia (29%). 31 patients underwent surgery. The complete resection rate was 87% (27/31) and the pathological complete resection rate was 16% (5/31). There were no treatment-related deaths. Preoperative FOLFOX therapy was well tolerated and showed promising short-term efficacy in patients with resectable LAESCC who were not candidates for CDDP.

ObjectivesThe prognostic factors in patients with malignancy-related ascites (MA) have been poorly investigated. This study aimed to evaluate both the prognostic impact of MA on terminally ill patients with cancer and the prognostic factors in those with MA.MethodsThis was a post hoc analysis of a multicentre, prospective cohort study. Patients with advanced cancer admitted to palliative care units at 23 institutions and aged≥18 years were enrolled between January and December 2017. Overall survival (OS) was compared according to MA. A multivariate analysis was conducted to explore prognostic factors in patients with MA.ResultsOf 1896 eligible patients, gastrointestinal and hepatobiliary pancreatic cancers accounted for 42.5%. 568 (30.0%) of the total had MA. Patients with MA had significantly shorter OS than those without MA (median, 14 vs 22 days, respectively; HR, 1.55; 95% CI, 1.39 to 1.72; pConclusionsMA had a negative impact on survival in terminally ill patients with cancer. A multivariate analysis revealed several prognostic factors in patients with terminal cancer and MA.

Esophageal cancer is the seventh most common cancer worldwide and continues to have a poor prognosis. Starting with the development of immune checkpoint inhibitors for patients with metastatic melanoma, many clinical trials have been conducted to evaluate the efficacy and safety of immune checkpoint inhibitors against various malignancies. Although few effective drugs are available for patients with advanced esophageal cancer, two immune checkpoint inhibitors, nivolumab and pembrolizumab, have been approved as second-line treatments for advanced esophageal squamous cell carcinoma. Recently, immune checkpoint inhibitors have shown promising results as post-operative therapies and first-line treatments for advanced esophageal cancer. Nivolumab has been approved as a post-operative therapy based on the CheckMate-577 trial, and nivolumab, ipilimumab and pembrolizumab have been approved as first-line treatments based on the CheckMate-648 trial and the KEYNOTE-590 trial. In addition, many trials of immune checkpoint inhibitors plus pre-operative treatment or definitive chemoradiotherapy are ongoing. The Japan Esophageal Oncology Group was established in 1978 and has conducted numerous clinical trials, most of which have examined multimodality treatments. In the era of immunotherapy, Japan Esophageal Oncology Group is conducting a clinical trial studying multimodality treatment with an immune checkpoint inhibitor. JCOG1804E (FRONTiER) is a phase I trial to evaluate the safety and efficacy of nivolumab plus pre-operative chemotherapy followed by surgery. These results might improve the clinical outcomes of esophageal cancer patients.

375 Background: Neoadjuvant chemotherapy with docetaxel, cisplatin plus 5-FU (Neo DCF) is one of the standard treatment for resectable esophageal cancer (EC) based on the results of the JCOG1109 study, however, a high frequency (5-30%) of febrile neutropenia (FN) has been reported with NeoDCF and the elderly (patients) pts have higher risk for FN. A single arm phase II study indicated that use of primary prophylactic pegfilgrastim (PG) on day 3 of NeoDCF might prevent FN. We compared the frequency of neutropenia and FN with or without primary prophylactic administration of PG on day 3 of NeoDCF in elderly resectable EC pts. Methods: EC pts who had received NeoDCF between 2009 and 2022, were ≥70 years old, and had adequate organ functions and PS were selected for this retrospective study. Pts were divided into two groups with Day 3 PG-containing DCF (day3 prophylactic PG: D3PG) or No PG DCF (non-prophylactic PG: NPG). Three courses of DCF (DTX [day 1]: 70 mg/m2, CDDP [day 1]: 70 mg/m2, 5-FU [continuous infusion on days 1-5]: 750 mg/m2, every 3 weeks) were planned, and prophylactic antibiotics was administered on days 5-15 in each group if possible. We retrospectively evaluated the relative dose intensity (RDI), histopathological and clinical benefit, and adverse events. Results: A total of 67 pts (D3PG, 32; NPG, 35) with a median age of 73 years were identified. The PS (0/1/2) and clinical stage (I-II/III/ IVA-B [only supraclavicular lymph node]) were 18 (56.3%)/12 (37.5%)/2 (6.2%) and 1 (3.1%)/18 (56.3%)/13 (40.6%) in the D3PG group and 20 (57.1%)/15 (42.9%)/0 and 7 (20.0%)/24 (68.6%)/4 (11.4%) in the NPG group, respectively. Six pts in the D3PG group and 3 pts in the NPG group discontinued NeoDCF because of toxicity and progression. All pts except 1 in the D3PG group underwent surgery. The RDIs (DTX/CDDP/5-FU) were 0.90/0.83/0.90 in the D3PG group and 0.83/0.83/0.83 in the NPG group. Pts who achieved a pCR (D3PG/NPG) were 7/3 (22.6%/28.6%). The common grade ≥3 adverse events (D3PG/NPG) were neutropenia (12.5%/71.4%) and FN (6.3%/20.0%). Three-year relapse-free survival rate (D3PG/NPG) was 70.8%/54.4% (hazard ratio [HR] 0.525 [95% confidence interval (CI) 0.189-1.457], p=0.216). Three-year survival rate (D3PG/NPG) was 91.8%/70.5% (HR 0.497 [95%CI 0.104-2.35], p=0.378), respectively. Conclusions: The use of primary prophylactic PG on day 3 of preoperative DCF improved the safety and maintained the RDI in the D3PG group. The efficacy was comparable between the D3PG and NPG groups despite the higher number of pts with more advanced disease in the D3PG group.

322 Background: Ramucirumab (RAM), nivolumab (NIVO), and trifluridine/tipiracil (FTD/TPI) were approved for advanced gastric cancer (AGC) between 2010 and 2020 in Japan. However, the impact of these newly approved drugs on survival in the real-world clinical setting is not clear. Methods: This retrospective study investigated the effectiveness of RAM, NIVO, and FTD/TPI in patients with performance status (PS) 0 to 2 who received doublet or triplet chemotherapy including platinum agents in first-line (1L) for advanced gastric adenocarcinoma at our hospital between 2010 and 2020. Patients were divided into two groups before or after 2017 to compare the effectiveness. Results: From a total of 825 patients, 533 were assigned to the pre-2017 group and 292 to the post-2017 group. Baseline characteristics of the pre- and post-2017 groups were, respectively, as follows: median age, 64 (range, 20-83) and 65 (25-85) years; PS 0, 206 (39%) and 89 (31%), and PS 1-2, 327 (61%) and 202 (69%); peritoneal metastasis, 334 (63%) and 189 (65%); liver metastasis, 157 (30%) and 68 (23%); and HER2 positive, 82 (15%) and 57 (20%). There was no difference in the proportion of fluoropyrimidine and platinum agents between the two groups. For the pre- and post-2017 groups, 1L chemotherapy comprised fluoropyrimidine plus platinum agents (FP) for 71% and 68% of patients, FP plus taxanes for 15% and 1%, FP plus trastuzumab for 11% and 15%, and FP plus immune checkpoint inhibitors (ICIs) for 1% and 10%, respectively. Taxanes and irinotecan were used significantly more often in any treatment line in the pre-2017 group (taxanes, 74% vs. 64%, p

438 Background: Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein which is associated with cancer growth. Overexpression of TROP2 in advanced gastric cancer (AGC) is known as a poor prognostic factor. However, the association between TROP2 expression and prognosis in patient with AGC treated with nivolumab (NIVO) is not known. Methods: Patients who received NIVO monotherapy as third- or later-line treatment (NIVO group) and those who received only fluoropyrimidine, platinum and taxanes (non-NIVO group) at our hospital between 2015 and 2019 were enrolled. High TROP2 expression was defined as ≥50% positive tumor cells with weak to moderate membranous staining or ≥10% tumor cells with strong membranous staining using immunohistochemistry. Overall survival from first-line chemotherapy (OS) and progression-free survival (PFS) from starting of NIVO were compared according to TROP2 expression and combined positivity score (CPS). Results: Of 111 patients, 61 were in the NIVO group and 50 were in the non-NIVO group. Patient characteristics in the NIVO/non-NIVO groups were median age 67 (range, 41-83)/64.5 (29-80) years; performance status 0, 20 (33%)/23 (46%); lymph node metastasis 41 (67%)/23 (46%); peritoneal metastasis 32 (53%)/26 (52%); liver metastasis 11 (18%)/6 (12%); lung metastasis 4 (7%)/4 (8%); TROP2 high 55 (90%)/43 (86%). Patient characteristics at starting of NIVO did not differ between TROP2 high and low in the NIVO group. Of 55 patients with TROP2 high, 22 patients (40%) were CPS≥1. In the non-NIVO group, OS from first-line chemotherapy did not differ between TROP2 high and low (median, 16.2 months [95%CI, 13.6-19.2] vs. 26.2 months [95%CI, 7.7-NA], HR 0.97, p=0.946). Meanwhile, in the NIVO group, patients with TROP2 high had significantly longer OS from first line chemotherapy than those with TROP2 low (median survival, 23.5 months [95%CI, 17.2-31.2] vs. 19.2 months [95%CI, 10.7-NA], HR 0.40, p=0.04). Progression-free survival (PFS) from starting of NIVO tended to be longer in TROP2 high group than those in TROP2 low group (median, 1.9 months [95%CI, 1.6-2.3] vs. 0.6 months [95%CI, 0.2-NA], HR 0.62, p=0.26). OS from first-line chemotherapy and PFS from starting of NIVO in patients with TROP2 high did not differ between CPS≥1 and CPS

312 Background: CheckMate 577 trial demonstrated efficacy of adjuvant nivolumab (Ad-Nivo) therapy in locally advanced esophageal cancer patients (pts) who underwent surgery after neoadjuvant chemoradiotherapy and did not achieve pathologic complete response. In Japan, neoadjuvant docetaxel plus cisplatin, 5-FU (NeoDCF) therapy is the standard care for locally advanced resectable esophageal squamous cell carcinoma (ESCC) based on the results of the JCOG1109 study. The efficacy and safety of Ad-Nivo therapy after NeoDCF therapy were unknown, so guidelines recommendations have not been determined. Methods: The subjects of this retrospective study were pts with histologically confirmed resectable locally advanced ESCC who received Ad-Nivo (480mg/body, every 4 weeks for 12 times) after NeoDCF in our hospital from Jan 2022 to Sep 2022. We evaluated safety as adverse events during treatments and clinical outcomes. Results: Twenty pts were selected in this study. Characteristics were median age (range) 65 (51–75) years, male/female 70/30%, PS 0/1 85/15%, Ce/Ut/Mt/Lt 5/15/50/30%, clinical stage II/III/IVA/IVB (supraclavicular lymph node) 10/70/0/20%, pathological stage IIB/IIIA/IIIB/IVA/IVB 30/5/40/10/15%. The pathological response according to Japanese Classification of Esophageal Cancer was Grade 0/1a/1b/2/3 5/20/20/40/15%. Median time (range) from surgery to Ad-Nivo was 9 weeks (4-20 weeks). The adverse events included fatigue (30%), increase AST (30%), increase ALT (15%), pruritus (15%), hyperthyroidism (15%), diarrhea (10%), decreased appetite (10%), and pneumonitis (10%). Grade >3 adverse events were not observed. Recurrence was observed in three pts (15%), which site was regional lymph node (2 pts of pathological stage III and IVB) and anastomosis (1pt of pathological stage IVA). Three pts with recurrence received definitive chemoradiotherapy, and still continue the treatment. Conclusions: The short-term toxicity of Ad-Nivo after NeoDCF was well-tolerated and acceptable.

317 Background: Nivolumab monotherapy was established as the standard second-line treatment of advanced esophageal squamous cell carcinoma (ESCC) based on the results of the ATTRACTION-3 trial. Initially, fixed dosing of 240 mg every two weeks (240) was used according to the results of the ATTRACTION-3 trial in Feb 2020. After that, fixed dosing of 480 mg every four weeks (480) was available in clinical practice according to pharmacokinetic data on advanced melanoma in Sep 2020. However, there were little data on the efficacy and safety of these dosing for advanced ESCC patients. Methods: We retrospectively reviewed data from ESCC patients who received nivolumab monotherapy for second or later-line at our institution. We evaluated progression-free survival (PFS), objective response rate (ORR), and the incidence rate of adverse events (AEs) compared between 240 and 480. Cox proportional regression model, Fisher’s exact tests, and t-tests were used for analysis. Results: We identified 117 patients as the subject of this study. Patients characteristics in 2nd line were as followed (240 vs 480); the median age (range): 68(46-85) vs 68.5(51-84) years old, PS (0/1/2): 34/61/5% vs 54/42/4%, taxane refractory cases: 18.6 vs 53.8%. In 3rd or later line; the median age (range): 63.5(47-85) vs 58(46-80) years old, PS (0/1/2): 28/60/12% vs 14/86/0%, taxane refractory cases: 72 vs 71.4%. The ORR were 11.9 vs 24.0% in 2nd line (p=0.19), and 0 vs 14.3% in 3rd or later line (p=0.22). The median PFS was 1.7 vs 4.1 months in 2nd line (HR = 0.60; [95% CI: 0.35-1.01; p = 0.056]), and 1.4 vs 1.8 months in 3rd or later line (HR = 0.58; [95% CI: 0.23-1.46; p = 0.25]). The all-grade AEs in 58.3 vs 69.7 were observed; rash 16.7 vs 6.1%, diarrhea 9.5 vs 6.1%, adrenal insufficiency 3.6 vs 6.1%, and interstitial pneumonia 3.6 vs 15.2%. There were no treatment-related deaths. Conclusions: In this study, fixed dosing of nivolumab in 240mg and 480mg showed comparable outcomes on efficacy and safety.

439 Background: Claudin-18.2 (CLDN 18.2) is the components of tight junction and one of the therapeutic targets in advanced gastric cancer (AGC). It has been reported that the tumor microenvironment in CLDN18.2 high AGC contains more PD-1 negative CD8+ T cells than in CLDN18.2 low, which may make anti-PD-1 antibodies less effective. However, the data on the association between CLDN18.2 expression and prognosis in patients with AGC treated with nivolumab (NIVO) is limited. Methods: Patients who received NIVO monotherapy as third- or later-line treatment (NIVO group) and those who received only fluoropyrimidine, platinum and taxanes (non-NIVO group) at our hospital between 2015 and 2019 were enrolled. High CLDN18.2 expression was defined as ≥40% positive tumor cells with moderate to strong membranous staining on immunohistochemistry. Overall survival (OS) and progression-free survival (PFS) were compared according to CLDN18.2 expression and combined positivity score (CPS). Results: There were 71 and 50 patients in the NIVO and non-NIVO groups, respectively. Patient characteristics at first-line chemotherapy in the NIVO/non-NIVO groups were median age 67 (range, 34-83)/64.5 (29-80) years; performance status 0, 22 (31%)/23 (46%); peritoneal metastasis 38 (54%)/26 (52%); liver metastasis 15 (21%)/6 (12%); CLDN18.2 high 31 (44%)/25 (50%). In the NIVO group, patient characteristics did not differ between CLDN18.2 high and low except for peritoneal metastasis (25 [81%]/22 [55%]). Nine patients (29%) were CLDN18.2 high with CPS≥1, and 14 (35%) were CLDN18.2 low with CPS≥1. OS from first-line chemotherapy did not differ between CLDN18.2 high and low in the non-NIVO group (median, 18.4 months [95%CI, 10.7-32.4] vs. 16.9 months [95%CI, 14.8-21.4], HR 0.94 [95%CI, 0.50-1.78], p=0.847). In the NIVO group, OS from first-line chemotherapy and OS and PFS after starting NIVO did not differ between CLDN18.2 high and low; however, patients with CLDN18.2 high and CPS≥1 had longer OS after starting NIVO (median, 14.8 months [95%CI, 4.2-NR] vs. 3.6 months [95%CI, 2.0-6.9], HR 0.27 [95%CI, 0.11-0.68], p=0.012) and PFS after starting NIVO (median, 3.5 months [95%CI, 0.7-NR] vs. 1.7 months [95%CI, 1.1-3.1], HR 0.38 [95%CI, 0.15-0.97], p=0.033) than those with CLDN 18.2 high and CPS

373 Background: Docetaxel and cisplatin, 5-FU (DCF) is a standard neoadjuvant treatment for resectable esophageal squamous cell carcinoma (ESCC) based on the results of the JCOG1109 study. However, DCF therapy showed that 18.6% of patients achieved pathological complete response but 16.3% had febrile neutropenia (FN) and needed hydration. In Western countries, 5-FU plus leucovorin, oxaliplatin, docetaxel (FLOT) is a standard perioperative treatment for resectable gastric and esophagogastric junction adenocarcinoma patients. FLOT therapy showed that 2% of patients had FN and did not need hydration. However, safety and efficacy of neoadjuvant FLOT (NeoFLOT) in locally advanced ESCC patients was unclear. Methods: The subjects for this study were patients with resectable ESCC diagnosed as cT1N1-3M0, cT2-3N0-3M0, and cT1-3N0-3M1 (UICC-TNM 8th) and received NeoFLOT therapy between Feb 2021 to July 2022 at our hospital. NeoFLOT therapy (oxaliplatin: 85 mg/m2, leucovorin: 200 mg/m2, 5-FU: 2600 mg/m2, docetaxel: 50 mg/m2, every 2 weeks) was administered for 4 courses. We evaluated adverse events (CTCAE ver. 5.0) and histopathological response. Results: We identified 16 eligible patients and 12 of all patients (75%) underwent surgery. 4 patients (25%) resulted in progressive disease (1 patient underwent chemoradiotherapy and 3 patients underwent surgery). R0 resection rate was 75% and complete pathologic response in primary tumor was seen in 2 patients (17%). The most common adverse events were hematologic toxicity, with grade 3 or 4 leukopenia in 6 patients (38%), neutropenia in 9 patients (56%). The common non-hematological toxicity, with all grades deceased appetite in 7 patients (44%) and malaise in 8 patients (50%), peripheral neuropathy in (44%). Furthermore, the incidence of FN was 6%. In patients with grade 2 or higher renal failure, no one (0%) had worsened renal function. Conclusions: NeoFLOT therapy showed well-tolerated and comparable efficacy with DCF therapy.

An advanced small bowel mucinous adenocarcinoma with Peutz-Jeghers syndrome was resected, and we started capecitabine plus oxaliplatin (CapeOX) as adjuvant therapy. However, local recurrence was noted, and the tumor increased even after CapeOX plus bevacizumab and fluorouracil plus leucovorin plus irinotecan plus panitumumab (FOLFIRI plus panitumumab). Pembrolizumab was administered after confirming high-frequency microsatellite instability, and the tumor shrank markedly and remained shrunk for 20 months.