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Alpha-Fetoprotein Producing Gastric Cancer (AFPGC) is an aggressive subgroup of gastric cancer. Recently ramucirumab has shown survival benefits in hepatocellular carcinoma, but only in those with higher Alpha-Fetoprotein (AFP) levels. However, the efficacy of ramucirumab-containing chemotherapy in AFPGC remains unclear.We retrospectively assessed 352 patients who received ramucirumab-containing chemotherapy between June 2015 and December 2019. AFPGC was defined when serum AFP levels were elevated at diagnosis and correlated with the disease state during treatment. Non-AFPGC was defined when serum AFP levels were normal at diagnosis.Among the 352 patients, 28 patients were defined as AFPGC and 246 patients were defined as non-AFPGC. AFPGC was characterized by high frequency of liver metastasis and low frequency of peritoneal metastasis compared to non-AFPGC. Ramucirumab containing chemotherapy showed higher response rates in AFPGC (39.1% vs 24.8%, p = 0.198) and disease control rates (86.9% vs 61.5%, p = 0.028) than those of non-AFPGC, respectively. Median progression-free survival (PFS) was 5.5 months (95%CI 3.9-7.1) in AFPGC and 4.0 months (95%CI 3.6-4.6) in non-AFPGC (HR: 0.91, 95% CI 0.61-1.36, p = 0.66), and median overall survival (OS) was 10.7 months (95% CI 7.4-20.8) in AFPGC and 9.2 months (95% CI 8.1-10.4) in non-AFPGC (HR: 0.72, 95% CI 0.48-1.08, p = 0.11), respectively. In multivariate analysis, AFPGC was not a negative prognostic factor both for PFS and OS.Ramucirumab containing chemotherapy showed higher response and comparable survival in AFPGC compared to those of non-AFPGC. Considering the generally poor prognosis of AFPGC, ramucirumab-containing chemotherapy might be a promising treatment option in AFPGC.

Colorectal cancer with liver metastasis (CLM) has high postoperative recurrence rates; therefore, optimizing perioperative treatment is imperative. Postoperative carcinoembryonic antigen (CEA) can aid in detecting minimal residual disease in colon cancer following curative resection. This study aimed to identify the potential role of serum CEA following liver resection in patients with CLM.This retrospective study was conducted at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from 2004 to 2018 and enrolled patients with CLM who underwent complete resection of primary tumors and CLM. Associations between perioperative CEA levels and characteristics of recurrence were investigated.Recurrence was detected during a median follow-up period of 90.1 months in 343 (54.2%) out of 633 analyzed patients. Patients in the postoperative CEA level5 ng/ml group had a significantly higher recurrence rate (75.7% versus 50.0%, p0.01) and shorter time until recurrence (4.4 versus 36.9 months, p0.01) than those in the postoperative CEA level ≤ 5 ng/ml group. Multivariate analysis revealed that postoperative CEA level5 ng/ml was an independent predictor, with hazard ratios of 2.77 (p0.01) for recurrence-free survival (RFS) and 3.18 (p0.01) for overall survival (OS). Additionally, RFS was significantly shorter among patients in the postoperative CEA level5 ng/ml group who did not have normalized CEA levels following adjuvant chemotherapy than among those in the normalized CEA group.The postoperative and post-adjuvant chemotherapy CEA levels in the CEA level5 ng/ml group may be predictors of RFS and OS.

Background We investigated the feasibility of perioperative chemotherapy with S-1 and leucovorin (TAS-118) plus oxaliplatin in patients with locally advanced gastric cancer. Methods Patients with clinical T3–4N1–3M0 gastric cancer received four courses of TAS-118 (40–60 mg/body, orally, twice daily for seven days) plus oxaliplatin (85 mg/m2, intravenously, day one) every two weeks preoperatively followed by gastrectomy with D2 lymphadenectomy, followed by postoperative chemotherapy with either 12 courses of TAS-118 monotherapy (Step 1) or eight courses of TAS-118 plus oxaliplatin (Step 2). The primary endpoints were completion rates of preoperative chemotherapy with TAS-118 plus oxaliplatin and postoperative chemotherapy with TAS-118 monotherapy (Step 1) or TAS-118 plus oxaliplatin (Step 2). Results Among 45 patients enrolled, the preoperative chemotherapy completion rate was 88.9% (90% CI 78.0–95.5). Major grade ≥ 3 adverse events (AEs) were diarrhoea (17.8%) and neutropenia (8.9%). The R0 resection rate was 95.6% (90% CI 86.7–99.2). Complete pathological response was achieved in 6 patients (13.3%). Dose-limiting toxicity was not observed in 31 patients receiving postoperative chemotherapy (Step 1, n = 11; Step 2, n = 20), and completion rates were 90.9% (95% CI 63.6–99.5) for Step 1 and 80.0% (95% CI 59.9–92.9) for Step 2. No more than 10% of grade ≥ 3 AEs were observed in patients receiving Step 1. Hypokalaemia and neutropenia occurred in 3 and 2 patients, respectively, receiving Step 2. The 3-year recurrence-free and overall survival rates were 66.7% (95% CI 50.9–78.4) and 84.4% (95% CI 70.1–92.3), respectively. Conclusions Perioperative chemotherapy with TAS-118 plus oxaliplatin with D2 gastrectomy is feasible.

Background: A relationship between dietary folate intake and efficacy of fluorouracil (FU) is supported by preclinical data. Furthermore, there are several reports that evaluated genetic polymorphisms of MTHFR (methylenetetrahydrofolate reductase) or TYMS (thymidylate synthase) and efficacy of FU. However, to our knowledge, there are no reports that evaluate simultaneously the effects of folate intake and genetic polymorphisms on clinical outcome of gastric cancer patients.Methods: We retrospectively analyzed the survival impact of estimated folate intake by a food frequency questionnaire and MTHFR and TYMS polymorphisms in 132 patients with advanced gastric cancer who were treated with first-line FU-based chemotherapy.Results: Median overall survival was 11.3 months (95% confidence interval, 9.4-13.4 mo) and median progression-free survival was 5.2 months (95% confidence interval, 4.1-6.3 mo). Patients with folate intake of >260 μg/day (n = 88) showed longer overall survival compared with low folate intake (n = 44; overall survival, 12.2 versus 8.4 mo). In a multivariate Cox model, patients who had folate intake of >260 μg/day, MTHFR 677 TT polymorphism, and TYMS-3′ untranslated region 6-bp insertion were associated with better survival. Similar tendency was observed in progression-free survival. No interaction was observed between folate intake and favorable genotypes.Conclusion: Folate intake and genetic polymorphisms of MTHFR and TYMS were associated with better clinical outcome by FU-based chemotherapy in advanced gastric cancer.Impact: Our results suggested folate intake and folate-related genetic polymorphisms may play an important role in efficacy of FU-based chemotherapy in advanced gastric cancer. Cancer Epidemiol Biomarkers Prev; 19(5); 1311–9. ©2010 AACR.

Supplementary Tables 1-3 from Folate Intake along with Genetic Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase in Patients with Advanced Gastric Cancer

Background In the past decade, several successful clinical trials provided new therapeutic agents approved for advanced gastric cancer (AGC). This study evaluated whether these practice-changing results actually altered the clinical practice. Patients and Methods We retrospectively reviewed medical records of treatment-naive AGC patients who received combination chemotherapy of fluoropyrimidine and platinum between 2007 and 2018 and divided them into three groups: Groups A (2007-10), B (2011-14), and C (2015-2018), respectively. We compared the clinicopathological features, treatment details, and clinical outcomes among the three groups. Results In total, 1004 consecutive patients were enrolled (A; n = 254, B; n = 300, and C; n = 450). The number of patients with poor performance status, older age, esophagogastric junction adenocarcinoma, and primary tumor increased during the study period. All groups had similar median overall survival (OS); ~16 months) without any statistical difference but steady prolongation of survival was observed in the adjusted with imbalance prognostic factors among groups (B/A; hazard ratio, HR 0.82, 95% C.I 0.68-0.98, C/A; HR 0.72, 95% CI 0.60-0.86); OS of HER2-positive AGC patients was clearly improved (HER2-positive vs HER2-negative in Group B, HR 0.80, 95% CI 0.60-1.06; Group C, HR 0.68, 95% CI 0.51-0.90) but that of diffuse-type AGC patients remained dismal. Conclusions The increasing availability of chemotherapy options potentially contributed to improved survival of AGC patients, but expanded chemotherapeutic indications made the survival benefit inconspicuous in the whole population. Future therapeutic development for the AGC subset not adequately receiving benefit from previous clinical trials is warranted.

After curative gastrectomy followed by 1-year adjuvant S-1 monotherapy for pathological stage (pStage) II or III gastric cancer, some patients experience peritoneal, hematogenous, or lymph nodal recurrence. However, risk factors for each recurrence pattern despite completed adjuvant S-1 monotherapy remain unclear. The aim of this study was to determine which factors influence each recurrence type after curative gastrectomy followed by 1-year adjuvant S-1 monotherapy.A total of 380 patients with pStage II or III gastric cancer who completed 1-year adjuvant S-1 monotherapy after R0 gastrectomy between January 2008 and December 2013 were enrolled in this study. The risk factors that were associated with peritoneal, hematogenous, and lymph nodal recurrence were investigated by univariate and multivariate analyses.Eighty (21.1%) of 380 patients developed recurrence. As the first site, peritoneal, hematogenous, and lymph nodal recurrence occurred in 42 (11.1%), 26 (6.8%), and 12 (3.2%) patients, respectively. In multivariate analysis, peritoneal metastasis was associated with signet ring cell carcinoma (P 0.001), pT4 (P = 0.001), and pN3 (P 0.001), while hematogenous recurrence was associated with pN3 (P = 0.019) and later initiation of S-1 (P = 0.013), and lymph nodal recurrence was associated with pN3 (P = 0.002).The risk factors for peritoneal, hematogenous, and lymph nodal recurrence in pStage II or III gastric cancer patients who complete adjuvant S-1 monotherapy differ. This information may be helpful for daily surveillance of recurrence in post-operative and chemotherapeutic patients. Furthermore, it may be a useful reference to develop novel perioperative chemotherapy.

Background Circulating tumor DNA (ctDNA) is a biomarker with potential to reflect comprehensive genomic information and overcome intratumor heterogeneity. In contrast, carcinoembryonic antigen (CEA) is a conventional tumor marker for predicting recurrence, survival, and chemotherapeutic efficacy in patients with metastatic colorectal cancer (mCRC). However, the relationship between them remains unclear. Here, the relationship between plasma ctDNA and CEA levels was evaluated to clarify the advantages and disadvantages of their clinical use. Methods A total of 110 patients with mCRC underwent chemotherapy were enrolled. Amplicon‐based plasma genomic profiling of 14 genes that are commonly mutated in CRC by next‐generation sequencing was compared to the CEA level and tumor diameter using Spearman’s correlation coefficient. Results The overall concordance rate between the ctDNA and CEA levels was 75.5% (83/110). The correlation coefficient between the ctDNA and CEA levels was lower in the group of patients without liver and lymph node metastases (r = 0.18, p = 0.44) than in the group of patients with liver metastasis (r = 0.48, p, Tumor diameter and ctDNA and CEA levels highly correlated in metastatic colorectal cancer patients with liver metastases. Status of ctDNA and CEA may not be consistent in metastatic colorectal cancer (mCRC) patients without liver metastasis or with low tumor volume. Both results should be considered when deciding a treatment strategy for mCRC patients without liver metastases.

Purpose Morphologic response (MR) is a novel predictor of chemotherapeutic efficacy in solid tumors, especially those treated with anti-vascular endothelial growth factor (VEGF) antibodies. Nevertheless, the importance of MR in systemic chemotherapy for colorectal liver metastases (CLM) remains unclear. This study aimed to evaluate the usefulness of MR as a factor associated with the therapeutic effects of chemotherapy plus bevacizumab for initially unresectable CLM. Methods We retrospectively evaluated the associations among MR and/or Response Evaluation Criteria in Solid Tumors(RECIST), progression-free survival (PFS), and overall survival (OS) in patients who received first-line capecitabine, oxaliplatin, and bevacizumab treatment for initially unresectable CLM using multivariate analysis. Patients who showed a complete or partial response based on the RECIST, or an optimal response based on MR, were defined as “responders.” Results A total of 92 patients were examined, including 31 (33%) patients who showed an optimal response. PFS and OS estimates were comparable in MR responders and non-responders (13.6 vs 11.6 months, p=0.47; 26.6 vs 24.6 months, p=0.21, respectively). RECIST responders showed better PFS and OS than non-responders (14.8 vs 8.6 months, pConclusion MR predicts neither PFS nor OS; nevertheless, it may be useful when combined with the RECIST. Approval by the Ethics Committee of The Cancer Institute Hospital of JFCR in 2017 (No. 2017-GA-1123): retrospectively registered

Hypertension is one of the main side effects of ramucirumab(RAM)plus paclitaxel(PTX)therapy. Although dihydropyridine calcium channel blockers(D-CCBs)are considered to cause drug-drug interactions with PTX based on the inhibition of cytochrome P450, D-CCBs are often administered to patients receiving RAM plus PTX therapy in clinical practice. We retrospectively studied the actual usage of antihypertensive drugs in 133 advanced or recurrent gastric cancer patients who received RAM plus PTX therapy. Antihypertensive drugs were administered to 34(25.6%)patients. Among them, 13 (38.2%)received antihypertensive drugs during the first course, and 19(55.9%)received D-CCBs. We also investigated whether D-CCBs affect the expression of Grade 3 or higher neutropenia caused by PTX. Results of multivariate analysis indicated that D-CCBs did not increase the risk of neutropenia caused by PTX.

Background/aim Primary tumor location and RAS and BRAF V600E mutations are predictors of the efficacy of epidermal growth factor receptor (EGFR) inhibitors. However, there are limited reports on their effects on the outcomes of third-line chemotherapy with EGFR inhibitors in metastatic colorectal cancer (mCRC) patients. Patients and methods We retrospectively collected the clinical data of KRAS exon 2 wild type (WT) mCRC patients treated with EGFR inhibitor monotherapy or EGFR inhibitor plus irinotecan as third-line chemotherapy. The association between primary tumor location, RAS (KRAS exon 3, 4 or NRAS), BRAF V600E, and PIK3CA mutational status, and treatment outcome was evaluated. Results A total of 72 patients were included in this study. In multivariate analysis, RAS (p=0.004) and BRAF mutations (p=0.00008) were independent factors for shorter PFS. Poor performance status (p=0.01) and BRAF mutation (p=0.00002) were independent factors for shorter OS, whereas primary tumor location and PIK3CA mutation did not influence survival. Conclusion Additional analysis of RAS and BRAF mutations could contribute to the selection of patients who are likely to benefit from third-line EGFR inhibitors, regardless of primary tumor location.

The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer (CRC). However, there is a lack of consensus on CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with metastatic CRC (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors.We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment. We analyzed the incidence and clinicopathological characteristics of highly methylated CRC (HMCC) and associations between genome-wide DNA methylation status and response rate (RR), progression-free survival (PFS), and overall survival (OS).In total, 169 patients were included in the final analyses. The frequency of HMCC was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAF V600E mutation (P 0.0001). Patients with HMCC showed worse clinical outcomes than those with low-methylated CRC in terms of RR (P = 0.017), PFS (P = 0.004), and OS (P = 0.019). In the multivariate analysis, peritoneal metastasis (P = 0.017), methylation status (P = 0.037), and BRAF V600E mutations (P = 0.0001) were independent factors for shorter PFS.Genome-wide DNA methylation status is an independent factor associated with PFS in patients with mCRC treated with first-line EGFR inhibitors.

The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (Ctrough) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer. The Ctrough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2, SLCO1B1, and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5. We analyzed 43 patients who received regorafenib 40–120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the Ctrough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 (p = 0.010). The M5 Ctrough levels were significantly associated with the severity of hypertension or rash (p

348 Background: CapeOX is a standard regimen for treating advanced gastric cancer (AGC). However, limited data are available for its use in the elderly patients. Geriatric assessment (GA) assessment is also considered important other than the age. Therefore, we conducted a multicenter, single-arm, phase II study to evaluate the efficacy and safety of CapeOX as a first-line therapy for AGC in elderly patients. We performed GA assessments using the G8, and the MINI-COG. Methods: The inclusion criteria were: HER2-negative or unknown status, age 70 years or older, PS 0 or 1, no history of chemotherapy or radiotherapy, and an evaluable lesion based on the RECIST v1.1 guidelines. The initial treatment plan consisted of capecitabine (1,000 mg/m2, b.i.d., on days 1–14), and oxaliplatin (130 mg/m2, on day 1) every three weeks. After the initial feasibility assessment, the treatment plan was modified and consisted of capecitabine (750 mg/m2, b.i.d., on days 1–14) and oxaliplatin (100 mg/m2, on day 1) every three weeks. The primary endpoint was overall survival (OS). G8 assessments were performed before the beginning of the treatment, every three months after the start of the treatment, and at the end of the treatment. MINI-COG assessments were performed before the beginning of the treatment, and at the end of the treatment. Results: Between November 2016 and June 2020, 108 patients were enrolled, out of which 104 were evaluated. Thirty-nine patients received the initial treatment whereas sixty-five patients received the modified treatment. The primary endpoint was met. The median OS, progression-free survival (PFS), and time-to-treatment failure (TTF) were 12.9 (95% CI: 11.7–14.8), 5.8 (95% CI: 5.1–7.1), and 4.3 (95% CI: 3.9–5.7) months, respectively, for all patients. The median OS, PFS, and TTF for the initial treatment plan were 13.4 (95% CI: 9.6–16.0), 5.8 (95% CI: 4.1–7.9), and 5.3 (95% CI: 3.5–7.3) months, respectively, and for the modified treatment plan were 12.8 (95% CI: 11.3–15.3), 5.7 (95% CI: 4.4–7.0), and 4.2 (95% CI: 3.7–5.7) months, respectively. The most common grade 3/4 toxicities in the initial treatment plan patients were neutropenia (17.9%), anemia (12.8%), thrombocytopenia (12.8%), anorexia (10.3%), and nausea (10.3%) and in the modified treatment plan patients were (13.8%) and anorexia (12.3%). Mean G8 score was 11.4 before the treatment, 13.4 during the treatment and 11.6 at the end of the treatment. Mean MINI-COG score was 4.0 before the treatment, and 4.1 at the end of the treatment and the positive screen for dementia was 13.5% before the treatment and 11.4% at the end of the treatment. Conclusions: Our results show that the modified treatment plan is favorable for the elderly patients with gastric cancer based on the OS and the toxicities. Clinical trial information: 000022450 .

49 Background: Oxaliplatin (OXA) is one of the major cytotoxic agents for the treatment of gastrointestinal tumors. Hypersensitivity reaction (HSR) is one of major reasons of not continuing OXA-based chemotherapy, similar to chemotherapy-induced peripheral neuropathy (CIPN). We developed prevention of the HSR protocol and evaluated its clinical application. Methods: We have retrospectively evaluated and characterized HSR reaction in metastatic colorectal cancer patients exposed to an OXA-containing regimen between 2005 and 2019. We also evaluated the clinical utility of a prevention of the HSR protocol for mCRC patients occurred in grade 1, grade 2 or grade 3 HSR after administration of OXA-based chemotherapy. The prevention of HSR protocol is based on increasing the dose of dexamethasone to 16.5 mg/body, chlorpheniramine to 5 mg, famotidine to 20mg, and the administration time of OXA is extended to 4 hours. Results: A total of 209 patients (median age 61 years, range: 27 to 80) were experienced grade 1 (106 patients, 50.7%), grade 2 (98 patients, 46.0%), or grade 3 HSR (5 patients, 3.3%). Most of the patients had been treated with the FOLFOX4 or modified FOLFOX6 regimen (86.6%). The median number of cycles of OXA administration until the initial onset of HSR was 11 (range: 2 to 48). 111 patients (53.1%) succeeded in OXA re-administration under the prevention of HSR protocol. The median OXA free interval was 23 days (range: 13 to 890). The median progression-free survival after OXA re-administration was 7.0 months (95%CI: 5.3 to 10.4). The reason for the prevention of HSR protocoldiscontinuation was HSR in 98 patients (46.9%), disease progression in 77 patients (36.9%) and CIPN in 17 patients (8.1%), respectively. Forty-eight patients (49.0%) had HSR during the first cycle of OXA re-administration and the median time to HSR after OXA re-administration was 14 days (95%CI 0-19). Grade 3 HSR after OXA re-administrationwere observed in only 6 patients (6.1%) and no one experienced Grade 4 or 5 HSR. Conclusions: Hi-dose dexamethasone and an increased infusion time may allow for OXA re-administration. The prevention of the HSR protocol may provide an alternative to permanent discontinuation of OXA.

342 Background: We previously reported that performance status (PS) ≥1, no prior gastrectomy, number of metastatic sites ≥2, and high serum ALP level are poor prognosis factors and proposed a JCOG prognostic index by analyzing the data of advanced gastric cancer (AGC) patients enrolled in JCOG9912 (Takahari D et al. Oncologist 2014). Recently, Neutrocyte/ Lymphocyte Ratio (NLR) and diffuse type of cancer have also been reported to be prognostic factors of AGC. Methods: Prognostic factors were assessed in patients with AGC who enrolled in JCOG1013, the phase III study comparing docetaxel, cisplatin, and S-1 (DCS) versus cisplatin and S-1 (CS) in first-line treatment (Yamada Y et al. Lancet Gastroenterol Hepatol. 2019) was retrospectively evaluated using a Cox proportional regression model. The overall adequacy of risk prediction in the modified JCOG prognostic index and the original index were assessed by C-statistics. Results: Among 741 patients, 730 with all data for this analysis were selected. The median overall survival (OS) was 14.9 months (95% confidence interval [CI], 14.1–15.8). The median OS of the good (n=233), moderate (n=444), and poor (n=53) risk groups by the original JCOG index was 19.0, 14.2, and 9.1 months, respectively. The HRs compared with the good group were 1.59 [95% CI, 1.33–1.89; p < 0.0001] in the moderate group, and 2.47 [95% CI, 1.81–3.38; p < 0.0001] in the poor group with C-statistics of 0.572. In the multivariable analysis of 7 factors which showed p

206 Background: The ’’Neo RAS’’ phenomenon, in which tissue rat sarcoma viral oncogene homolog ( RAS) status converts from mutant (MT) to wild-type (WT) after treatment in metastatic colorectal cancer (mCRC), is gaining attention because epidermal growth factor receptor (EGFR) inhibitors, which were originally considered to be ineffective, may converted to be effective. This multi-center study investigated its incidence and clinicopathological characteristics that are still unclear. Methods: 107 mCRC patients with tissue RAS MT, confirmed using MEBGEN RASKET-B, who were refractory or intolerant to previous chemotherapies, including fluoropyrimidines, oxaliplatin, or irinotecan were enrolled in 4 institutions from June 2021 to August 2022. The RAS status in ctDNA was investigated after prior chemotherapy using ONCOBEAMTM RAC CRC. Clinicopathological characteristics were compared between patients with RAS MT and RAS WT (Neo RAS) in ctDNA. Results: The incidence of Neo RAS WT mCRC was 21.5% (23/107). The frequency of Neo RAS in KRAS exon 2 was significantly lower than that in other alleles such as exon 3 and 4 or NRAS (18.2% [18/99] vs 62.5% [5/8], P = 0.011). There were significant differences in frequency of Neo RAS between male vs female (30.6% [19/62] vs 8.9% [4/45], P = 0.008), absence vs presence of liver metastasis (38.6% [17/44] vs 9.5% [6/63], P < 0.001), and between two groups divided at the median: tumor diameter (> 60.9 mm vs ≤, 3.8% [2/53] vs 38.9% [21/54], P < 0.001), carcinoembryonic antigen level (> 38.2 ng/ml vs ≤, 11.3% [6/53] vs 31.5% [17/54], P = 0.018), carbohydrate antigen 19-9 level (> 158.0 U/ml vs ≤, 9.4% [5/53] vs 33.3% [18/54], P = 0.004). Logistic regression multivariate analysis, absence of liver metastasis (Odds ratio [OR], 4.62; P = 0.019), smaller tumor diameter (OR, 7.92; P = 0.012) and tissue RAS MT in other than KRAS exon 2 (OR, 9.04; P = 0.026) were significantly related to the appearance of Neo RAS WT mCRC. Conclusions: Original RAS status in tissue, tumor diameter and liver metastasis are related to conversion to Neo RAS WT mCRC.

459 Background: The DESTINY-Breast04 data demonstrated the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) was also effective for metastatic breast patients (pts) with HER2-low expression. Now that the HER2-low expressed cancer is categorized as an independent subset in breast cancer patients. It is unknown whether patients with the HER2-low expression are distinguishable from the HER2 negative or positive and are potential candidates for the anti-HER2 therapy in advanced gastric cancer (AGC) patients. Methods: We retrospectively reviewed the medical records of AGC pts who received standard chemotherapy with platinum containing regimens as the first-line treatment between Jan, 2011 and Dec, 2018 at the Cancer Institute Hospital of the JFCR. AGC pts were classified according to the HER2 status using immunohistochemistry (IHC) and in situ hybridization (ISH) as follows; HER2 negative (IHC 0), HER2-low (IHC 1+ or 2+/ISH-) and HER2 positive (IHC2+/ISH+ or 3+). This study was conducted to investigate the clinicopathological features and prognosis of HER2-low AGC pts compared with HER2 negative and positive. Results: A total of 734 AGC pts were received HER2 testing and classified into three groups according to HER2 status (HER2 negative; n=410, HER2-low; n=154, HER2 positive; n=170). The proportion of male (negative; 61.5%, low; 63.6% and positive; 69.4%), intestinal histology (negative; 21.0%, low; 44.2% and positive; 59.8%), liver metastases (negative; 18.3%, low; 24.8% and positive; 46.5%), higher serum CEA level (>ULN) (negative; 32.2%, low; 41.6% and positive; 56.5%) and higher serum CA19-9 level (>ULN) (negative; 34.1%, low; 36.7% and positive; 56.5%) were gradually increased along with HER2 expression level. The proportion of peritoneum metastasis (negative; 56.3%, low; 44.8% and positive; 21.8%) was decreased along with the HER2 expression level. One hundred and fifty-two pts (89.4%) received combination chemotherapy with trastuzumab in the first-line treatment. Sixteen pts received trastuzumab in the HER2-low (n=3) and HER2 negative (n=13) in the clinical trial. The median survival time (MST) of pts with HER-low was the same with that of HER2 negative (15.7ms). The statistically significant difference was observed in OS between the HER2-low and HER2 positive (HR 1.43 95% CI: 1.12-1.83, P=0.003). Conclusions: AGC Pts with HER2-low have intermediate clinicopathological features between HER2 negative and positive. A Novel effective anti-HER2 therapy for the HER2-low expressed tumor would be warranted in AGC treatment.

Background Three vascular endothelial growth factor (VEGF) inhibitors, Bevacizumab (BEV), ramucirumab (RAM), and aflibercept (AFL), are widely used for metastatic colorectal cancer (mCRC) patients who are treated with second‐line chemotherapy. The difference in outcome between the three drugs has not been evaluated. In contrast to epidermal growth factor receptor inhibitors, VEGF inhibitors have few candidate predictors of efficacy. Methods Consecutive mCRC patients who were treated with second‐line chemotherapy were retrospectively enrolled. Overall response rate (ORR), progression‐free survival (PFS), overall survival (OS), and safety were assessed. Subgroup analyses of prognostic and predictive efficacy markers were performed. Results A total of 119 (41.2%), 107 (37.0%), and 63 patients (21.8%) were treated with FOLFIRI +BEV, RAM, or AFL, respectively. ORR, PFS, and OS showed no significant differences between three groups. However, the frequency of grade 3 or 4 adverse events (AEs) in the FOLFIRI +AFL group was significantly higher than that in the other groups (p, Chemotherapeutic efficacy did not differ between the groups. Grade 3 or 4 AEs within the first four cycles of treatment may be an effective predictor of treatment efficacy in mCRC patients administered VEGF inhibitors as second‐line chemotherapy

Safety of combination chemotherapy using platinum and fluorouracil has not been evaluated adequately for advanced gastric cancer (AGC) in elderly patients.We initiated a phase II study to evaluate the efficacy and safety of capecitabine plus oxaliplatin (CapeOX) as first-line therapy for patients with AGC aged ≥70 years. Planned assessment of toxicity was made upon recruitment of the first 20 patients.In five out of 20 patients, unacceptable toxicity was observed, including three patients who were unable to complete the initial two courses due to adverse events. Among the other 15 patients, dose reduction due to toxicity were needed in 10 and treatment delay for adverse events also occurred in 12 patients during the first two courses.Early analyses of safety suggest that the CapeOX regimen was not tolerated without dose reduction for elderly patients with AGC in this study.

Background: Prognostic factors for the survival of patients with advanced HER2-positive gastric cancer treated with trastuzumab-based chemotherapy remain controversial. The aim of this study was to reveal the clinical factors that predict prognosis in this patient population.Methods: We retrospectively reviewed the medical records of HER2-positive gastric cancer patients treated with trastuzumab-based chemotherapy in our institution. Clinical features and laboratory test results considered prognostic factors were re-examined. Overall survival (OS) was estimated using the Kaplan-Meier method, univariate analysis was performed with the log-rank test, and multivariate analysis using Cox’s proportional hazard regression model.Results: A total of 133 patients with advanced HER2-positive gastric cancer were enrolled. The median OS in this cohort was 18.7 months. Four prognostic factors: visceral metastasis (lung or liver), and levels of haemoglobin (Hb) (< 11.6 g/dL), lactate dehydrogenase (LDH) (> 222 mg/dL), and C-reactive protein (CRP) (> 0.14 mg/dl) were identified as independent prognostic factors. After classifying the patients in three groups according to their number of prognostic factors, namely low (0,1), moderate (2,3), and high (4) risk, OS curves were separated into three categories with median OS of 32.0, 18.7, and 10.1 months, respectively (p=0.00025). Compared to the low-risk group, hazard ratios for the moderate- and high-risk groups were 1.75 (95% CI: 1.05–2.93) and 3.49 (95% CI: 1.81–6.71), respectively.Conclusion: Visceral metastasis and abnormal Hb, LDH, and CRP test results were associated with unfavourable OS. These findings are helpful for the management of advanced HER2-positive gastric cancer treated with trastuzumab-based chemotherapy.

After failure of first-line chemotherapy with fluoropyrimidines and platinum compounds for advanced gastric cancer, second-line chemotherapy with ramucirumab plus paclitaxel, which elicits a durable response, and third-line or later chemotherapy with nivolumab have been shown to lead to a more favorable prognosis in advanced gastric cancer patients. As new and more effective drugs are now available, sequential chemotherapy would contribute to prolonged survival. From this point of view, the patient’s disease course should be frequently monitored in order to adapt treatment regimens. This review summarizes the points to note in regard to radiological assessment, and discusses the integration of prognostic factors, tumor markers, and clinical symptoms that need to be taken into account to change treatment at an appropriate timing.

Several factors are known to be significantly associated with a low completion rate of 1-year adjuvant S-1 monotherapy for gastric cancer. The present study investigated whether or not the specialties of physicians conducting adjuvant S-1 monotherapy affect the completion rate. A total of 437 patients who underwent curative gastrectomy followed by adjuvant S-1 monotherapy for pathological stage II or III gastric cancer between 2008 and 2013 were retrospectively analyzed. Factors affecting completion of adjuvant S-1 monotherapy, including the physicians (medical oncologists or surgeons) administering S-1, were evaluated by a multivariate analysis. The relationship between patient factors and physicians was analyzed regarding the cumulative incidence of discontinuation. The number of times the dose was reduced, the schedule changed, or administration was suspended or delayed in patients completing adjuvant S-1 monotherapy was also counted. The multivariate analysis showed that old age (≥ 65 years old), excess body weight loss (≥ 15%), and surgeons were independently associated with discontinuation. In older patients, the cumulative incidence of discontinuation by medical oncologists was significantly lower than that by surgeons. Medical oncologists ensured that older patients continued S-1 by frequent suspension or a delay in each course. Medical oncologists may facilitate completion of adjuvant S-1 monotherapy.

Aim: Definitive chemoradiotherapy (dCRT) is the standard treatment for locally advanced unresectable esophageal squamous cell carcinoma (LU-ESCC). This study aimed to describe the results of dCRT for T4 ESCC and evaluate the pretherapeutic predictive factors of the outcomes. Methods: A total of 133 patients with T4 ESCC who received dCRT were grouped into those who achieved a complete response (CR) or those who had residual disease (RD). The clinicopathologic variables were compared between the groups and the overall survival (OS) was evaluated. The predictive factor of RD was assessed and the prognostic factor for OS was identified. Results: Among the 133 patients, 31 (23%) achieved CR. The CR group had a significantly better OS than the RD group (89.9 months vs. 10.7 months; hazard ratio = 0.096; 95% confidence interval: 0.05-0.19; P < 0.001). Multivariate analysis showed that a supracarinal tumor (OR = 3.21; P = 0.016), higher pretherapeutic serum SCC-Ag level (> 1.6 ng/mL) (OR = 2.86; P = 0.018), and metastatic node invasion (OR = 3.19; P = 0.048) were independent predictors of RD. The increased level of pretherapeutic serum squamous cell carcinoma antigen (> 1.6 ng/mL) (OR = 1.61; P = 0.022) was an independent predictor of poor survival. Conclusions: Among the patients who underwent dCRT for LU-ESCC, 23% achieved CR, and the long-term outcome of these patients was favorable. Increased levels of pretherapeutic serum squamous cell carcinoma antigen were also found to be predictive of treatment failure.

The optimal treatment strategy for patients with borderline resectable (BR) esophageal squamous cell carcinoma (ESCC), in which tumors grow very close to the adjacent vital organs, remains unclear. This study evaluated the efficacy of neoadjuvant chemoradiotherapy (NACRT) with cisplatin plus fluorouracil (CF) and irradiation (40 Gy) for these patients. The study cohort included 50 patients with BR-ESCC who received NACRT as the initial treatment and were allocated to one of two groups: patients who achieved curative resection (R0 group) or those who did not (Non-R0 group). The overall survival (OS), relapse-free survival (RFS), and pre-therapeutic predictive factors for Non-R0 were evaluated. Among the 50 patients, 22 (44%) achieved curative resection clinically. The median OS was significantly better in the R0 group than in the Non-R0 group (2.4 vs 0.8 years; hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.12–0.67; p

This study aimed to examine the safety of fixed-dose nivolumab.We retrospectively reviewed the medical records of 113 Japanese patients with gastric cancer who were previously treated with cytotoxic chemotherapy and initiated nivolumab. The endpoints were the incidence of Grade 2 or higher immune-related adverse events (irAEs) in the conventional dose (3 mg/kg) and fixed-dose groups (240 mg).The incidence rates of irAEs in the conventional-dose and fixed-dose groups were 29.9% and 19.4%, respectively, and the rates of Grade 2 or higher irAEs were 23.3% and 19.4%, respectively, with no significant difference between the two groups, suggesting that nivolumab at 240 mg is as safe as the 3 mg/kg dose.This is the first report on the safety of nivolumab at 240 mg in Japanese patients.

Although RAS and PIK3CA mutations have been associated with resistance to anti-EGFR antibody in colorectal cancer or trastuzumab in breast cancer, their implications for trastuzumab resistance in HER2-positive advanced gastric cancer (AGC) remains unclear. We aimed to assess the relationship between trastuzumab efficacy and mutation status in the HER family signaling pathway.This study retrospectively evaluated patients with HER2-positive AGC who received first-line trastuzumab-containing chemotherapy between March 2011 and November 2015. Multiplex genotyping, including KRAS, NRAS, PIK3CA, and BRAF, was then performed using the Luminex Assay, after which KRAS amplification was measured using quantitative real-time reverse transcription-polymerase chain reaction. Thereafter, the association between genetic alterations and clinical outcomes were evaluated.KRAS mutation (MT) was detected in 6 of 77 patients (7.8%), whereas KRAS amplification was found in 15 of 67 patients (22%). No mutations in NRAS, PIK3CA, or BRAF were identified. The KRAS MT group showed significantly worse response rates (16.7% vs. 66.2%, P = 0.016), progression-free survival [median, 4.8 vs. 11.6 months; hazard ratio (HR), 3.95; 95% CI, 1.60-9.76; P = 0.0029], and overall survival (11.5 vs. 23.6 months; HR, 3.80; 95% CI, 1.56-9.28; P = 0.033) compared to the KRAS wild-type group. KRAS amplification had no effect on clinical outcomes.KRAS mutation was an independent prognostic factor for poor survival and might predict insufficient trastuzumab efficacy, whereas KRAS amplification showed no prognostic significance during trastuzumab treatment. Further investigations are warranted to confirm the predictive value of KRAS status in HER2-positive AGC.

Global studies have been planned to achieve early approval of the new agent especially in cancer chemotherapy. On the other hand, it is important to consider the difference in efficacy among each region. As medical approval in Japan means reimbursement of medical cost, new drug is required to show its effectiveness in the medical situation in Japan, and the Japanese subgroup data is important. Especially in the gastric cancer field, where there is a large difference in survival time and surgical outcome between Japan and outside Japan need to consider Japanese domestic data. But characteristic of Japanese subgroup is the number of target patients is small, high censored case due to longer survival and the background factors are not even. So the interpretation of the data requires caution because of these robustness.

The SARS-CoV-2 was first identified in December 2019 in Wuhan, China. Since then, the ongoing COVID-19 pandemic has drastically changed the healthcare system, including cancer treatments worldwide. Since March 2020 in Japan, cancer patients faced a crisis; they suffered from delays or restrictions in cancer treatment during the initial outbreak. At present, we can perform cancer treatment as usual. Most of the treatments depend on continuous infection control by cancer patients and their families. However, the need to recognize cancer treatment management during the COVID-19 pandemic is crucial. Cancer treatment practice, purpose, risk factors, and the evidence during clinical trials should be comprehensively evaluated and adapted for each patient. Moreover, there is a need to discuss care planning between healthcare professionals, patients, and their families in advance. The COVID-19 vaccine could be essential for cancer patients. In this article, we review cancer treatment points for implementing whole-person care, including advanced care planning for patients with gastrointestinal malignancies, during the COVID-19 pandemic.

S-1 plus oxaliplatin (SOX) is an established treatment for advanced gastric cancer. S-1 adherence is the key to successful SOX treatment. This study focused on S-1 adherence by evaluating real-world adherence to S-1 and investigating factors related to decreased S-1 adherence. This study included cases treated between August 1, 2014 and October 12, 2016 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. The S-1 adherence rate per cycle was defined as the number of times a patient took S-1/28. In this study, adherence to S-1 was assessed through pill counts and by asking the patient about the reason for non-adherence at a pharmaceutical outpatient clinic. Univariate and multivariate analyses were performed to investigate factors influencing lower adherence. This analysis included 116 patients evaluated for adherence to S-1 on SOX treatment. The median rate of adherence to S-1 was 92.8% in the first cycle and 90.5% in the seventh cycle. The median relative dose intensity of S-1 was 84.6%. In terms of reasons for nonadherence, patients most commonly cited nausea/vomiting (43.7%), diarrhea (20.8%), missed dose (11.8%), and fever (8.1%). Logistic regression analysis was performed using the most appropriate regression equation, and a significant association was detected with 1 factor, number of combined drugs ≥5 (odds ratio (OR) = 2.50; 95% confidence interval (CI), 1.04-6.03, p = 0.04). Eliminating unnecessary concomitant medications helps maintain proper adherence to S-1 in SOX treatment.

Primary tumor location and RAS and BRAF V600E mutations are predictors of the efficacy of epidermal growth factor receptor (EGFR) inhibitors. However, there are limited reports on their effects on the outcomes of third-line chemotherapy with EGFR inhibitors in metastatic colorectal cancer (mCRC) patients.We retrospectively collected the clinical data of KRAS exon 2 wild type (WT) mCRC patients treated with EGFR inhibitor monotherapy or EGFR inhibitor plus irinotecan as third-line chemotherapy. The association between primary tumor location, RAS (KRAS exon 3, 4 or NRAS), BRAF V600E, and PIK3CA mutational status, and treatment outcome was evaluated.A total of 72 patients were included in this study. In multivariate analysis, RAS (p=0.004) and BRAF mutations (p=0.00008) were independent factors for shorter PFS. Poor performance status (p=0.01) and BRAF mutation (p=0.00002) were independent factors for shorter OS, whereas primary tumor location and PIK3CA mutation did not influence survival.Additional analysis of RAS and BRAF mutations could contribute to the selection of patients who are likely to benefit from third-line EGFR inhibitors, regardless of primary tumor location.

Preoperative chemotherapy with cisplatin plus S-1 (CS) followed by gastrectomy with D2 plus para-aortic lymph node (PAN) dissection is regarded as a standard treatment in Japan for advanced gastric cancer with bulky lymph node (BN) and/or PAN metastasis. In the JCOG1002, we added docetaxel to CS (DCS) to further improve long-term outcomes. However, the primary endpoint, clinical response rate (RR), did not reach the expected level (Ito et al. in Gastric Cancer 20:322–31, 2017). Herein, we report our long-term survival results. Patients with BN and/or PAN metastasis received 2 or 3 cycles of DCS therapy (docetaxel at 40 mg/m2 and cisplatin at 60 mg/m2 on day 1 and S-1 at 80 mg/m2 per day for 2 weeks, followed by a 2-week rest) followed by gastrectomy with D2 plus PAN dissection and postoperative S-1 for 1 year. Between July 2011 and May 2013, 53 patients were enrolled. Clinically, 17.0% had both PAN and BN metastasis, and the rest had either PAN (26.4%) or BN (56.6%) metastasis. Among all eligible patients, the 5-year overall survival was 54.9% (95% confidence interval 40.3–67.3%) at the last follow-up in May 2018. Among 44 eligible patients with R0 resection, the 5-year relapse-free survival was 47.7% (95% confidence interval 32.5–61.5%). Adding docetaxel to CS in preoperative chemotherapy for extensive nodal metastasis improved neither short-term outcomes nor long-term survival. Preoperative chemotherapy with CS followed by D2 + PAN dissection and postoperative S-1 remains the standard of care for patients with extensive nodal metastasis.