Varlitinib and Paclitaxel for EGFR/HER2 Co-Expressing Advanced Gastric Cancer: a Multicenter Phase Ib/II Study (K-MASTER-13).

Purpose: Varlitinib is a pan-human epidermal growth (HER) inhibitor targeting epidermal growth factor receptor (EGFR), HER2, and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC). Materials and Methods: Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (IHC) (≥1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity. Results: RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median PFS and overall survival (OS) were 3.3 months and 7.9 months, respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), AST/ALT elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D. Conclusion: A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy.

Evaluating the effect of a mobile-based symptom monitoring system for improving physical function in patients with cancer during chemotherapy: study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Symptoms due to chemotherapy are common in patients with cancer. Cancer-related symptoms are closely associated with the deterioration of physical function which can be associated with decreased quality of life and increased mortality. Thus, timely symptom identification is critical for improving cancer prognosis and survival. Recently, remote symptom monitoring system using digital technology has demonstrated its effects on symptom control or survival. However, few studies examined whether remote monitoring would contribute to retaining physical function among patients with cancer. Therefore, this study aimed to evaluate the effectiveness of mobile-based symptom monitoring in improving physical function among patients with cancer under chemotherapy. METHODS AND ANALYSIS: This study is a multicentre, open-label, parallel-group, randomised controlled trial. We will recruit 372 patients at three tertiary hospitals located in Seoul, South Korea. Study participants will be randomly assigned to either an intervention group receiving the ePRO-CTCAE app and a control group receiving routine clinical practice only. The primary outcome is changes in physical function from commencement to completion of planned chemotherapy. A linear mixed model will be performed under the intention-to-treat principle. The secondary outcomes include physical activity level; changes in pain interference; changes in depressive symptom; unplanned clinical visits; additional medical expenditure for symptom management; completion rate of planned chemotherapy; changes in symptom burden and health-related quality of life; and 1-year overall mortality. ETHICS AND DISSEMINATION: The study has been approved by the institutional review board and ethics committee at the three university hospitals involved in this trial. Written informed consent will be obtained from all the participants. The results of the trial will be submitted for publication in peer-reviewed academic journals and disseminated through relevant literatures. TRIAL REGISTRATION NUMBER: KCT0007220.

Real-world outcomes of third-line immune checkpoint inhibitors versus irinotecan-based chemotherapy in patients with advanced gastric cancer: a Korean, multicenter study (KCSG ST22-06).

BACKGROUND: Immune checkpoint inhibitor (ICI) or irinotecan-based chemotherapy is frequently used after failure of second-line paclitaxel plus ramucirumab treatment for patients with locally advanced unresectable or metastatic advanced gastric cancer (AGC). This study aimed to compare the efficacy between ICI and irinotecan-based chemotherapy as third-line treatment in patients with AGC. METHODS: We retrospectively reviewed patients with AGC, whose third-line treatment started between July 2019 and June 2021 at 17 institutions in Korea. The ICI group included patients who received nivolumab or pembrolizumab, and the irinotecan-based chemotherapy group included patients who received irinotecan or FOLFIRI (5-fluorouracil, leucovorin and irinotecan). RESULTS: A total of 363 patients [n = 129 (ICI) and n = 234 (irinotecan-based chemotherapy)] were analyzed. The median progression-free survival was 2.3 and 2.9 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.802). The median overall survival (OS) was 5.5 and 6.0 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.786). For all patients included in this study, multivariable analysis showed that weight loss, peritoneal metastasis, low serum sodium or albumin, and short duration of second-line treatment were associated with inferior OS (p < 0.05). ICI showed significantly longer OS than irinotecan-based chemotherapy in patients without peritoneal metastasis. Whereas ICI showed significantly shorter OS in patients without PD-L1 expression than irinotecan-based chemotherapy. CONCLUSIONS: No significant difference in survival outcome was observed between ICI and irinotecan-based chemotherapy as third-line treatment for AGC patients. ICI might be preferred for patients without peritoneal metastasis and irinotecan-based chemotherapy for patients with tumors without PD-L1 expression. TRIAL REGISTRATION: This study was registered in the Clinical Trial Registry of Korea ( https://cris.nih.go.kr : KCT 0007732).

Open-Label, Multicenter, Randomized, Biomarker-Integrated Umbrella Trial for Second-Line Treatment of Advanced Gastric Cancer: K-Umbrella Gastric Cancer Study.

PURPOSE: This study aimed to screen targeted agents as second-line treatment with a standard-of-care (SOC) controlled umbrella trial design in advanced gastric cancer (AGC). PATIENTS AND METHODS: Patients with HER2-negative AGC from eight Korean cancer centers were screened for druggable targets using immunohistochemistry (IHC) and in situ hybridization, and randomly assigned to the biomarker versus control group at a 4:1 ratio. In the biomarker group, patients were treated with specific targeted agent plus paclitaxel: pan-ERBB inhibitor for epidermal growth factor receptor (EGFR) 2+/3+ patients (afatinib; EGFR cohort), PIK3Cß inhibitor for phosphatase and tensin homolog (PTEN) loss/null patients (GSK2636771; PTEN cohort), and anti-PD-1 inhibitor for PD-L1+, deficient mismatch repair/microsatellite instability-high, or Epstein-Barr virus-related cases (nivolumab; NIVO cohort). NONE cohort in the biomarker group without predefined biomarkers and control group received SOC (paclitaxel with or without ramucirumab). The primary end point was progression-free survival (PFS), and the secondary end points were efficacy and safety. RESULTS: A total of 318 patients were randomly assigned into the control (n = 64) and biomarker (n = 254; EGFR, n = 67; PTEN, n = 37; NIVO, n = 48; NONE, n = 102) groups. Median follow-up was 35 months. Median PFS and overall survival (OS) were 3.7 (95% CI, 3.1 to 4.1) and 8.6 (95% CI, 7.6 to 9.8) months in the biomarker group and 4.0 (95% CI, 3.0 to 4.6) and 8.7 (95% CI, 7.1 to 9.9) months in the control group. Afatinib addition led to marginal survival benefits to patients with EGFR 3+ compared with SOC (PFS, 4.0 v 2.2 months; P = .09), but GSK2636771 did not prolong the survival of patients with PTEN loss. Addition of nivolumab showed a durable survival benefit (median OS, 12.0 v 7.6 months; P = .08). CONCLUSION: Although biomarker group did not show better survival than the control group, IHC-based screening and allocation of patients with AGC to the second-line treatment in an umbrella design were feasible for effective early screening of novel agents.

Second-line chemoimmunotherapy with nivolumab and paclitaxel in immune-related biomarker-enriched advanced gastric cancer: a multicenter phase Ib/II study.

BACKGROUND: We conducted a trial to evaluate the efficacy and safety of nivolumab and paclitaxel as second-line therapy for immune-related biomarker-enriched advanced gastric cancer (AGC). METHODS: This open-label, single-arm, phase Ib/II study was a part of multi-institutional, biomarker-integrated umbrella study conducted in Korea. In phase Ib, patients received nivolumab (3 mg/kg) on Days 1 and 15 and paclitaxel (dose level 1, 70 mg/m2 or dose level 2, 80 mg/m2) on Days 1, 8, 15 every four weeks. In phase II, patients with Epstein-Barr virus-related, deficient mismatch repair or programmed cell death-ligand-1-positive AGC were enrolled. The primary endpoints were recommended phase II dose (RP2D, phase Ib) and progression-free survival (PFS, phase II). Secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and exploratory biomarker analysis. RESULTS: Dose level 2 was selected as RP2D. In phase II, 48 patients were enrolled. The median PFS and OS were 3.9 and 11.2 months, respectively. The ORR was 23.3%, and the median response duration was 16.7 months. Grade 3 or higher treatment-related adverse events, mainly neutropenia, occurred in 20 patients (41.7%). Targeted sequencing revealed that patients with RTK/RAS pathway alterations or the HLA-A02 supertype had better survival. Patients with elevated baseline interleukin-1 receptor antagonist levels had worse survival. CONCLUSIONS: Although the study did not meet its primary end point, nivolumab and paclitaxel for AGC demonstrated a durable response with manageable toxicity profiles. Genomic analysis or plasma cytokine analysis may provide information for the selection of patients who would benefit more from immunotherapy combined with chemotherapy.

Trastuzumab Combined With Ramucirumab and Paclitaxel in Patients With Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Advanced Gastric or Gastroesophageal Junction Cancer.

PURPOSE: Trastuzumab-containing chemotherapy is the recommended first-line regimen for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction (G/GEJ) cancer. We evaluated the safety and efficacy of trastuzumab combined with ramucirumab and paclitaxel as second-line treatment for HER2-positive G/GEJ cancer. PATIENTS AND METHODS: Patients with HER2-positive advanced G/GEJ cancer who progressed after first-line treatment with trastuzumab-containing chemotherapy were enrolled from five centers in the Republic of Korea. Patients were administered a 28-day cycle of trastuzumab (once on days 1, 8, 15, and 22: 2 mg/kg followed by 4 mg/kg loading dose), ramucirumab (once on days 1 and 15: 8 mg/kg), and paclitaxel (once on days 1, 8, and 15: dose level 1, 80 mg/m2; or dose level -1, 70 mg/m2). Phase II was conducted with the recommended phase II dose (RP2D). Primary end points were determination of RP2D during phase Ib and investigator-assessed progression-free survival (PFS) in patients treated with RP2D. RESULTS: Dose-limiting toxicity at dose level 1 was not documented during phase Ib, and a full dose combination was selected as the RP2D. Among 50 patients with a median follow-up duration of 27.5 months (95% CI, 17.4 to 37.6), median PFS and overall survival were 7.1 months (95% CI, 4.8 to 9.4) and 13.6 months (95% CI, 9.4 to 17.7), respectively. Objective response rate was 54% (27 of 50, including one complete response), and disease control rate was 96% (48 of 50). Loss of HER2 expression was observed in 34.8% (8 of 23) patients after first-line treatment, and no definite association between HER2 expression and the outcome was revealed. Safety profiles were consistent with previous reports. CONCLUSION: Trastuzumab combined with ramucirumab and paclitaxel showed appreciable efficacy with manageable safety profiles in patients with previously treated HER2-positive G/GEJ cancer.

A Phase 3 Randomized Clinical Trial to Compare Efficacy and Safety between Combination Therapy and Monotherapy in Elderly Patients with Advanced Gastric Cancer (KCSG ST13-10).

PURPOSE: This study evaluated whether combination therapy is more effective than monotherapy in elderly patients with metastatic or recurrent gastric cancer (MRGC) as first-line chemotherapy. MATERIALS AND METHODS: Elderly (≥ 70 years) chemo-naïve patients with MRGC were allocated to receive either combination therapy (group A: 5-fluorouracil [5-FU]/oxaliplatin, capecitabine/oxaliplatin, capecitabine/cisplatin, or S-1/cisplatin) or monotherapy (group B: 5-FU, capecitabine, or S-1). In group A, starting doses were 80% of standard doses, and they could be escalated to 100% at the discretion of the investigator. Primary endpoint was to confirm superior overall survival (OS) of combination therapy vs. monotherapy. RESULTS: After 111 of the planned 238 patients were randomized, enrollment was terminated due to poor accrual. In the full-analysis population (group A [n=53] and group B [n=51]), median OS of combination therapy vs. monotherapy was 11.5 vs. 7.5 months (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.56 to 1.30; p=0.231). Median progression-free survival (PFS) was 5.6 vs. 3.7 months (HR, 0.53; 95% CI, 0.34 to 0.83; p=0.005). In subgroup analyses, patients aged 70-74 years tended to have superior OS with combination therapy (15.9 vs. 7.2 months, p=0.056). Treatment-related adverse events (TRAEs) occurred more frequently in group A vs. group B. However, among severe TRAEs (≥ grade 3), there were no TRAEs with a frequency difference of > 5%. CONCLUSION: Combination therapy was associated with numerically improved OS, although statistically insignificant, and a significant PFS benefit compared with monotherapy. Although combination therapy showed more frequent TRAEs, there was no difference in the frequency of severe TRAEs.

Progranulin and Breast Cancer Mortality: 13-Year Follow-Up of a Cohort Study.

Background: We have reported that serum progranulin (PGRN) levels are clinically significant in predicting recurrence in patients with HR-positive breast cancer. The aim of the present study was to examine whether PGRN levels might be associated with breast cancer mortality. Methods: This was a cohort study of 695 newly diagnosed breast cancer patients who underwent curative surgery between 2001 and 2004. The relationship between breast cancer mortality and pre-operative serum PGRN levels in these patients with a median follow-up of 12.7 years was evaluated until May 2020. Results: A total of 118 (17%) deaths were identified in the cohort. According to the HR status, (10, 15, and 20)-year overall survival (OS) rates were (91.4, 81.1, and 75.9) % for HR-positive patients, and (76.5, 74.2, and 69.8) % for HR-negative patients, respectively (p = 0.003). Higher levels of PGRN were significantly associated with poor OS in the HR-positive group (p for trend = 0.001). In particular, hazard ratios for PGRN quartiles suggested a dose-response relationship, with the highest quartile having the worst OS in the HR-positive group (highest vs lowest: 15-year OS, (68.3 vs 90.0) %; 20-year OS, (62.3 vs 84.8) %, even after adjusting for age, tumor stage, and metabolic confounders. Conclusion: Pre-operative serum PGRN levels had clinical significance for predicting cancer mortality in breast cancer patients independent of tumor stage and metabolic parameters, especially in HR-positive tumors.

A Multicenter, Prospective, Observational Study to Evaluate Ethanol-Induced Symptoms in Patients Receiving Docetaxel Chemotherapy.

PURPOSE: Several previous studies and case reports have reported ethanol-induced symptoms in patients receiving anticancer drugs containing ethanol. Most docetaxel formulations contain ethanol as a solvent. However, there are insufficient data on ethanol-induced symptoms when docetaxel-containing ethanol is administered. The primary purpose of this study was to investigate the frequency and pattern of ethanol-induced symptoms during and after docetaxel administration. The secondary purpose was to explore the risk factors for ethanol-induced symptoms. MATERIALS AND METHODS: This was a prospective, multicenter, observational study. The participants filled out ethanol-induced symptom questionnaire on the day of chemotherapy and the following day. RESULTS: Data from 451 patients were analyzed. The overall occurrence rate of ethanol-induced symptoms was 44.3% (200/451 patients). The occurrence rate of facial flushing was highest at 19.7% (89/451 patients), followed by nausea in 18.2% (82/451 patients), and dizziness in 17.5% (79/451 patients). Although infrequent, unsteady walking and impaired balance occurred in 4.2% and 3.3% of patients, respectively. Female sex, presence of underlying disease, younger age, docetaxel dose, and docetaxel-containing ethanol amount were significantly associated with the occurrence of ethanol-induced symptoms. CONCLUSION: The occurrence of ethanol-induced symptoms was not low in patients receiving docetaxel-containing ethanol. Physicians need to pay more attention to the occurrence of ethanol-induced symptoms and prescribe ethanol-free or low-ethanol-containing formulations to high-risk patients.

Evaluation of Pretreatment Albumin-Bilirubin Grade as a Better Prognostic Factor Compared to Child-Pugh Classification in Patients with Hepatocellular Carcinoma Receiving Transarterial Chemoembolization Combined with Radiotherapy.

This study assessed the use of pretreatment albumin--bilirubin (ALBI) grade as a prognostic factor in patients with hepatocellular carcinoma (HCC) receiving combined transarterial chemoembolization (TACE) and radiotherapy (RT). Patients who underwent RT following TACE between January 2011 and December 2020 were analyzed retrospectively. The survival outcomes of patients in regard to the ALBI grade and Child-Pugh (C-P) classification were evaluated. A total of 73 patients with a median follow-up of 16.3 months were included. Thirty-three (45.2%) and forty patients (54.8%) were categorized into ALBI grades 1 and 2-3, respectively, while sixty-four (87.7%) and nine (12.3%) were C-P classes A and B, respectively (p = 0.003). The median progression-free survival (PFS) and overall survival (OS) for ALBI grade 1 vs. 2-3 were 8.6 months vs. 5.0 months (p = 0.016) and 27.0 months vs. 15.9 months (p = 0.006), respectively. The median PFS and OS for C-P class A vs. B were 6.3 months vs. 6.1 months (p = 0.265) and 24.8 months vs. 19.0 months (p = 0.630), respectively. A multivariate analysis showed that ALBI grades 2-3 were significantly associated with worse PFS (p = 0.035) and OS (p = 0.021). In conclusion, the ALBI grade could be a good prognosticator in HCC patients who were treated with combined TACE-RT.

Predicting tolerability of high-dose fentanyl buccal tablets in cancer patients.

BACKGROUND & AIMS: Fentanyl buccal tablets (FBTs) are a rapid-onset opioid indicated for breakthrough cancer pain (BTcP) and FBT titration is needed to optimize BTcP management. We aimed to predict which patients could tolerate a high dose of FBT (400 µg or more at a time). METHODS: A retrospective analysis was performed to assess the final FBT dose. The final FBT doses were compared according to the clinical features. The prediction accuracy of patients tolerant of 400 µg or higher FBT was compared using the area under the receiver operating characteristic (ROC) curves. A risk scoring model based on the odds ratio (OR) was developed from the final multivariable model, and patients were assigned into two groups: low tolerance (0-1 point) and high tolerance (2-3 points). RESULTS: Among 131 patients, the most frequently effective dose of FBT was 200 µg (54%), followed by 100 µg (30%). The median value of morphine equivalent daily doses (MEDD) was 60 mg/day, and the most common daily use was 3-4 times/day. In multivariable analysis, male sex, younger age, and use of FBTs three or more times per day were independently associated with high-dose FBT. According to the risk scoring model, the patients with a final FBT of 400 µg or higher were significantly more in the high tolerance group (17%) compared to the low tolerance group (3%; p = 0.023). CONCLUSIONS: According to the dose relationship between the final FBT dose and the clinical features, three factors (sex, age, daily use of FBT) were independently associated with the final dose of FBT. Our risk score model could help predict tolerance to high-dose FBT and guide the titration plan for BTcP.

Clinical outcomes and prognostic factors of cone-beam CT-guided radiofrequency ablation for pulmonary metastases in colorectal cancer patients.

AIM: Radiofrequency ablation (RFA) has been increasingly used for the treatment of pulmonary metastases in various malignancies. METHODS: A retrospective analysis was performed to establish the safety and efficacy of cone-beam computed tomography (CBCT)-guided RFA in patients with metastatic colorectal cancer between 2016 and 2019, and the prognostic factors of local tumor control were assessed. RESULTS: A total of 31 patients with colorectal cancer underwent 48 sessions of lung RFA. The mean diameter of metastases targeted for RFA was 11 mm (range: 4-32), and the RFA was technically successful in 43 sessions (90%). There were 14 complications (29%), the majority of which required no intervention, with no cases of mortality. The median follow-up duration from RFA in the surviving 29 patients was 18.0 months. Only two patients (6%) died of disease progression, and the 3-year overall survival rate was 91% (95% CI: 83-99). Local tumor progression (LTP) of the RFA site was observed in 27%, and the LTP-free survival rates at 1 and 2 years were 81% (95% CI: 70-82) and 64% (95% CI: 50-77), respectively. Multivariate analysis showed that the progression of extra-RFA sites and the presence of extrapulmonary metastasis were independent prognostic factors significantly associated with LTP at RFA site. CONCLUSION: Lung RFA using CBCT guidance is a comparatively safe and effective option for the treatment of lung metastases from colorectal cancer. However, the control of extrapulmonary metastases should be accompanied by combined or sequential systemic treatment and local treatment.

Impact of cumulative hyperglycemic burden on the pancreatic cancer risk: A nationwide cohort study.

AIMS: We aimed to investigate how much cumulative hyperglycemia exposure increases pancreatic cancer risk. METHODS: This study used the National Health Insurance Service Database of Claims and included 3,138,099 individuals who underwent four consecutive annual health screenings between 2009 and 2013. We defined hyperglycemic burden in two ways. First, the hyperglycemic burden was given a score from 0 to 4, with one point assigned for each time blood glucose was ≥100 mg/dL or the use of an antidiabetic drug. Furthermore, we performed semiquantitative scoring of a pre-diabetic (100-125; 1 point) and diabetic level (≥126; 2 points) and categorized into one of nine groups (hyperglycemic score 0-8). RESULTS: During the median 6.2 years of follow-up, groups with a hyperglycemic burden of 1, 2, 3, and 4 had a 15%, 30%, 26%, and 67% increased pancreatic cancer risk compared with normal subjects. In semiquantitative analyses, individuals with a pre-diabetic glucose level on at least one occasion had a 14% increased the risk. Furthermore, individuals with a burden score of 8 had an 89% higher risk than subjects with a normal range. CONCLUSIONS: The pancreatic cancer incidence increased significantly according to the hyperglycemic burden, defined as sustained hyperglycemic exposure, including pre-diabetic levels.

A Pilot Study of Peritumor Administration of 5-FU for Preventing Bleeding in Advanced Gastric Cancer.

Five-FU is a potent chemotherapeutic agent for suppressing endothelial cell growth. The purpose of this study was to investigate the usefulness of local peritumor injection of 5-FU for patients with advanced gastric cancer (AGC) for the prevention of anemia. Between January 2020 and January 2022, patients aged 18 years or older with AGC and moderate anemia were included. A total of 200 mg of 5-FU was injected per session at ten points of the lesion (20 mg at each point) every 7 days for 4 to 12 weeks. Patients received a blood test for toxicity at every cycle. From one of these patients, endoscopic biopsy specimens were taken from gastric cancer before and after injecting 5-FU for immunostaining. A total of five AGC patients participated in this study. For most patients, hemoglobin levels were maintained without transfusions during 5-FU injection, and expression levels of thrombospondin-1 was increased after injection compared to those before injection. Blood test results during 5-FU injection showed no significant change in serum glutamic oxalacetic transaminase/glutamic pyruvic transaminase, total bilirubin, or creatinine level. The results of this study showed the possibility of local peritumor 5-FU injection as a treatment for relieving anemia of patients with gastric cancer.

A single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer.

In this multi-center phase II trial, we evaluated the efficacy and safety of a quadruplet regimen (pembrolizumab, trastuzumab, and doublet chemotherapy) as first-line therapy for unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) (NCT02901301). The primary endpoints were recommended phase 2 dose (RP2D) for phase Ib and objective response rate (ORR) for phase II. The secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to response and safety. Without dose-limiting or unexpected toxicities, the starting dose in the phase Ib trial was selected as RP2D. In 43 patients, the primary endpoint was achieved: the objective response rate was 76.7% (95% confidence interval [CI]: 61.4-88.2), with complete and partial responses in 14% and 62.8% of patients, respectively. The median progression-free survival, overall survival, and duration of response were 8.6 months, 19.3 months, and 10.8 months, respectively. No patients discontinued pembrolizumab because of immune-related adverse events. Programmed death ligand-1 status was not related to survival. Post hoc analyses of pretreatment tumor specimens via targeted sequencing indicated that ERBB2 amplification, RTK/RAS pathway alterations, and high neoantigen load corrected by HLA-B were positively related to survival. The current quadruplet regimen shows durable efficacy and safety for patients with HER2-positive AGC.

Potential anticancer effect of sodium caprate on human gastric cancer cells.

The role of sodium caprate (C10) in enhancing drug absorption is well established; however, little information is available on its role as an anticancer drug. This study aimed to evaluate the anticancer effect of C10 in gastric cancer cells. The mechanism of cytotoxicity of C10 was evaluated by western blotting following treatment of the gastric cancer cells with various concentrations of C10. C10 cytotoxicity was measured via MTS (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium), lactate dehydrogenase (LDH), cAMP, and ATP assays. Gastric cancer cells were observed by electron microscopy following treatment with C10. Then, xenograft mice that were inoculated with gastric cancer cells were treated with C10 for 4 weeks, after which the changes in tumor size were measured. C10 triggered apoptosis in the gastric cancer cells through the mitochondrial pathway at concentrations of more than 0.2 mM. However, 15 mM of C10 induced necrosis in gastric cancer cells by causing cellular swelling and the formation of holes in the cell membrane. Levels of cAMP and ATP decreased significantly following exposure to 15 mM C10 for 1 h. Additionally, the size of the xenograft tumors was significantly reduced by 24% after 4 weeks of C10 treatment (p < 0.05). This study indicates that C10 induces apoptosis and necrosis in a concentration-dependent manner and has clear anticancer effects on gastric cancer cells.

Pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer (KEYNOTE-063): A randomized, open-label, phase 3 trial in Asian patients.

BACKGROUND: KEYNOTE-063 (NCT03019588) investigated pembrolizumab versus paclitaxel as second-line therapy in Asian patients with advanced programmed death ligand 1 (PD-L1)-positive (combined positive score ≥1) gastric/gastroesophageal junction (GEJ) cancer. METHODS: This randomized, open-label, phase 3 study was conducted at 36 medical centers in China (mainland), Malaysia, South Korea, and Taiwan. Patients were randomly assigned 1:1 to 200 mg of pembrolizumab intravenously every 3 weeks for ≤2 years or 80 mg/m2 of paclitaxel intravenously every week. Primary end points were overall survival (OS) and progression-free survival (PFS). Secondary end points were objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 and safety. RESULTS: Between February 16, 2017, and March 12, 2018, 94 patients were randomly assigned (47 pembrolizumab/47 paclitaxel) after screening; enrollment was stopped on March 12, 2018, based on the results of the global KEYNOTE-061 study, and patients were followed until the last patient's last visit. Median OS was 8 months (95% confidence interval [CI], 4-10 months) with pembrolizumab versus 8 months (95% CI, 5-11 months) with paclitaxel (hazard ratio [HR], 0.99; 95% CI, 0.63-1.54). Median PFS was 2 months (95% CI, 1-3 months) with pembrolizumab versus 4 months (95% CI, 3-6 months) with paclitaxel (HR, 1.62; 95% CI, 1.04-2.52). ORR was 13% for pembrolizumab versus 19% for paclitaxel. Any-grade treatment-related adverse events occurred in 28 pembrolizumab-treated patients (60%) and 42 paclitaxel-treated patients (96%); grades 3 to 5 events occurred in 5 patients (11%) and 28 patients (64%), respectively. CONCLUSIONS: Definitive conclusions about the efficacy of second-line pembrolizumab in Asian patients with advanced PD-L1-positive gastric/GEJ cancer are limited because of insufficient power, but pembrolizumab was well tolerated in this patient population. Efficacy followed a trend similar to that observed in the phase 3 KEYNOTE-061 trial.

Prospective multicentre randomised clinical trial comparing survival rates, quality of life and nutritional status between advanced gastric cancer patients with different follow-up intensities: study protocol for the STOFOLUP trial.

INTRODUCTION: Patients who underwent curative gastrectomy for gastric cancer are regularly followed-up for the early detection of recurrence and postoperative symptom management. However, there is a lack of evidence with regard to proper surveillance intervals and diagnostic tools. This study aims to evaluate whether frequent surveillance tests have a survival benefit or improve the quality of life in patients who underwent curative resection for advanced gastric cancer. METHODS AND ANALYSIS: The STOFOLUP trial is an investigator-initiated, parallel-assigned, multicentre randomised controlled trial involving 16 hospitals in the Republic of Korea. Patients (n=886) diagnosed with pathological stage II or III gastric adenocarcinoma will be randomised to either the 3-month or the 6-month group at a 1:1 ratio, stratified by trial site and tumour stage. Patients allocated to the 3-month group will undergo an abdominal CT scan every 3 months postoperatively and those allocated to the 6-month group will undergo CT every 6 months. The primary endpoint is 3-year overall survival and the secondary endpoints are quality of life, as assessed using KOrean QUality of life in Stomach cancer patients Study group-40, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the stomach cancer-specific module (STO22), and nutritional outcomes. Other survival data including data concerning 3-year disease-free survival, recurrence-free survival, gastric cancer-specific survival and postrecurrence survival will also be estimated. The first patient was enrolled on July 2021 and active patient enrolment is currently underway. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board of eight of the participating hospitals (NCC 2021-0085, KBSMC2021-01-059, SMC 2021-01-140, KC21OEDE0082, 4-2021-0281, AJIRB-MED-INT-20-608, 2021-0515 and H-2102-093-1198). This study will be disseminated through peer-reviewed publications, national or international conferences. TRIAL REGISTRATION NUMBER: NCT04740346.

Venous Invasion and Perineural Invasion as Upstaging and Poor Prognostic Factors in N0 Gastric Cancers.

BACKGROUND/AIM: Lymph node metastasis is an important prognostic factor in gastric cancer patients. In node-negative (N0) gastric cancer patients, additional prognostic factors are needed to reinforce TNM staging. PATIENTS AND METHODS: We semi-quantitatively recorded the presence of lymphatic, venous, and perineural invasion and evaluated the possibility that they could be used as upstaging factors in N0 gastric cancer by comparing N0 gastric cancer cases with N1 cases. RESULTS: Venous (p<0.001) and perineural (p<0.001) invasion were important factors in the relapse-free survival of N0 patients, but lymphatic invasion was not. N0 cases with venous or perineural invasion had survival curves similar to those of N1 patients. In addition, the number of invasive features (lymphatic, venous, or perineural) was an important factor in predicting poor patient survival. CONCLUSION: Venous and perineural invasion were significant prognostic factors in N0 gastric cancer cases. It is necessary to record lymphatic, venous, and perineural invasion separately in the pathology report, especially in cases of N0 gastric cancer.

Value Frameworks: Adaptation of Korean Versions of Value Frameworks for Oncology.

This study sought to adapt the existing value framework (VF) to produce a reliable and valid Korean oncology VF. Two VFs developed by The American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) were selected for examination in the present study. Forward and backward translations were conducted for six high-priced drugs indicated for non-small-cell lung cancer and multiple myeloma. Inter-rater reliability was measured based on the intraclass correlation coefficient (ICC) and variation was described using the coefficient of variation. The relative weights of factors critically considered by Korean oncologists were derived following the analytic hierarchy process (AHP), and focus group interviews (FGIs) were used to obtain qualitative data regarding the applications of these two VFs in the Korean setting. The ICCs of the Korean VFs were 0.895 (0.654-0.983) for ASCO and 0.726 (0-0.982) for ESMO translations, suggesting excellent reliability for ASCO and good reliability for ESMO. AHP demonstrated that clinical benefit has the highest priority, which is consistent with the ASCO VF. The FGIs suggested that the result for AHP is acceptable and that both ESMO and ASCO VFs should be used complementarily. Although further evaluation with a larger sample size is needed, the Korean versions of ESMO/ASCO VFs are valid and reliable tools and are acceptable to Korean stakeholders, yet they should be applied with caution.