CA125 Kinetics as a Potential Biomarker for Peritoneal Metastasis Progression following Taxane-Plus-Ramucirumab Administration in Patients with Advanced Gastric Cancer.

Currently, no established marker exists for predicting peritoneal metastasis progression during chemotherapy, although they are major interruptive factors in sequential chemotherapy in patients with advanced gastric cancer (AGC). This multicenter retrospective study was conducted from June 2015 to July 2019, analyzing 73 patients with AGC who underwent taxane-plus-ramucirumab (TAX/RAM) therapy and had their serum carbohydrate antigen 125 (CA125) concentrations measured. Of 31 patients with elevated CA125 levels above a cutoff of 35 U/mL, 25 (80.6%) had peritoneal metastasis. The CA125 concentrations before TAX/RAM treatment were associated with ascites burden. The overall survival was significantly shorter in the CA125-elevated group. CA125 kinetics, measured at a median of 28 days after chemotherapy, were associated with the ascites response (complete or partial response: -1.86%/day; stable disease: 0.28%/day; progressive disease: 2.33%/day). Progression-free survival in the CA125-increased group, defined by an increase of 0.0067%/day using receiver operating characteristic curve analysis, was significantly poorer among patients with peritoneal metastases. In conclusion, this study highlights that CA125 kinetics can serve as an early predictor for the progression of peritoneal metastasis during TAX/RAM treatment.

The Efficacy and Safety of Nivolumab Plus mFOLFOX6 in Gastric Cancer with Severe Peritoneal Metastasis.

(1) Background: Nivolumab plus chemotherapy is established as a first-line treatment for advanced gastric cancer (AGC). While mFOLFOX6 is commonly used for AGC with severe peritoneal metastasis, the efficacy of nivolumab combined with it remains uncertain. We evaluated the outcomes of nivolumab plus mFOLFOX6 for AGC with severe peritoneal metastasis in clinical practice. (2) Methods: This multicenter retrospective study was conducted between December 2021 and June 2023. We investigated AGC patients with massive ascites or inadequate oral intake due to severe peritoneal metastasis and who received nivolumab plus mFOLFOX6. (3) Results: Among 106 patients treated with nivolumab plus chemotherapy, 21 (19.8%) had severe peritoneal metastasis, with 14 receiving nivolumab plus mFOLFOX6. The median progression-free survival was 7.4 months (95%CI 1.9-10.1), and the median overall survival was 10.7 months (95%CI 5.3-NA), with four patients (28.5%) surviving more than 12 months. Improved ascites and oral intake were observed in 6/14 patients (42.8%) and 10/11 patients (90.9%), respectively. The major grade 3 or more adverse events included leukopenia (28.5%) and neutropenia (21.4%), with no severe immune-related adverse events reported. (4) Conclusions: The safety and moderate efficacy of nivolumab plus mFOLFOX6 were suggested even in AGC patients with severe peritoneal metastasis.

Liver metastasis affects progression pattern during immune checkpoint inhibitors monotherapy in gastric cancer.

Introduction: The efficacy of immune checkpoint inhibitors (ICIs) is heterogeneous at each metastatic site, and tumor progression pattern is associated with survival; however, it remains unclear in gastric cancer (GC). Therefore, we aimed to clarify the progression pattern in response to ICIs in patients with GC, and we analyzed its mechanism focusing on the intratumoral immune cells. Methods: Patients who received ICIs were retrospectively classified into non-systemic and systemic progression groups based on their radiological assessments. Moreover, the best percentage change in target lesions from each organ was compared. Results: Among 148 patients, the non-systemic progression group showed a significant improvement in overall survival (OS) compared with the systemic progression group (median, 5.6 months vs. 3.3 months; HR, 0.53; 95%CI, 0.32-0.89; p = 0.012). Poor performance status (HR, 1.73, 95%CI, 1.00-2.87) and systemic progression (HR, 3.09, 95%CI, 1.95-4.82) were associated with OS. Of all metastatic sites, the liver showed the poorest percentage change, and liver metastasis (OR, 2.99, 95%CI, 1.04-8.58) was associated with systemic progression. Hence, intratumoral CD8+ T-cell density was lower in patients with liver metastasis than in those without liver metastasis after ICIs, although the density of CD4+ T-cells (Th1, Th17, and Treg) and CD163+ cells (TAM) were not significantly different. Conclusion: The new progression pattern was associated with OS in GC. Liver metastasis may be a predictive factor of systemic progression during ICIs by regulating intratumoral CD8+ T-cells.

Factors, Including Clinical Trial Eligibility, Associated with Induction of Third-Line Treatment for Advanced Gastric Cancer.

INTRODUCTION: Third-line chemotherapy has been suggested to improve survival in patients with gastric cancer. This study aimed to identify factors associated with the induction of third-line chemotherapy for advanced gastric cancer, focusing on patient eligibility for clinical trial. METHODS: We retrospectively analyzed 335 patients treated for unresectable or recurrent gastric cancer between April 2009 and May 2020. The patients were grouped into those that met the key eligibility criteria for clinical trial (136 patients, 40.6%) and those that did not (199 patients, 59.4%) before receiving first-line chemotherapy. RESULTS: The overall survival (OS) was 16.8 months (95% CI: 14.0-19.6) and 9.3 months (95% CI: 7.8-11.0) in the eligible and ineligible group, respectively. Multivariate analyses to identify the risk factors associated with the induction of third-line chemotherapy revealed ineligibility of clinical trial (OR 1.95; 95% CI: 1.15-3.31), number of metastatic sites (OR 1.99; 95% CI: 1.23-3.22), low albumin concentration (OR 2.24; 95% CI: 1.14-4.38), and a lack of complete or partial response to first-line treatment (OR 1.85; 95% CI: 1.05-3.26). Indeed, in responders to first-line treatment for ineligible patients, the median OS was 17.7 months (95% CI: 10.6-27.9), respectively. CONCLUSIONS: Treatment outcomes were different for those eligible for clinical trials and those who were not. However, this study suggested that patients who responded to first-line treatment have more favorable prognosis when treated with salvage chemotherapy, even if they were deemed ineligible for clinical trials.

Prognosis of Immune-related Adverse Events in Patients With Advanced Gastric Cancer Treated With Nivolumab or Pembrolizumab: A Multicenter Retrospective Analysis.

BACKGROUND: Immune-checkpoint inhibitors (ICI), including nivolumab and pembrolizumab, are among the standard treatments for previously treated advanced gastric cancer (AGC). This study aimed to evaluate the frequency of immune-related adverse events (irAEs) and the correlation between irAEs and their efficacy in AGC cases. PATIENTS AND METHODS: Patients were divided into two groups according to irAE occurrence. The frequency of irAEs and the treatment outcome (response rate [RR], progression-free survival [PFS], and overall survival [OS]) were evaluated. The survival rates were evaluated by landmark analysis considering lead-time bias. RESULTS: Among 108 patients who received nivolumab or pembrolizumab, 17 (15.7%) had irAEs. In a 4-week landmark analysis, the RR, median PFS, and median OS were 28.5%, 3.9 months (95% CI=2.8-9.3), and 12.2 months (95% CI=3.8-NA) in patients with irAEs, while 3.0% (2/65), 1.8 months (95% CI=1.4-2.1), and 3.5 months (95% CI, 2.9-5.1) in patients without irAEs, respectively. In multivariate analysis, irAEs were associated with better PFS (HR=2.08, 95% CI=1.34-3.21). CONCLUSION: The occurrence of irAEs was associated with a better clinical outcome of ICIs in patients with AGC.

[A Case of Advanced Gastric Cancer with Severe Jaundice from Multiple Liver Metastases That Was Significantly Improved after Capecitabine plus Oxaliplatin Treatment].

A 74-year-old man with advanced gastric cancer was admitted to our hospital. His liver function was impaired(total bilirubin 1.6mg/dL)with multiple liver metastases. He was treated with chemotherapy of S-1 plus cisplatin but it was discon- tinued due to severe diarrhea(CTCAE Grade 3)on day 6 and his liver dysfunction progressed(total bilirubin 10.3mg/dL). After his diarrhea improved, he was treated with capecitabine plus oxaliplatin(capecitabine 3,600mg/day on day 1-14, oxaliplatin 130mg/m2 on day 1, q3 weeks). His severe jaundice and general condition improved without severe non-hematological toxicity, and he was ultimately discharged. He achieved a partial response(RECIST v1.1)after capecitabine plus oxaliplatin treatment, and this therapy has been continued for 15 months. This case suggests that capecitabine plus oxaliplatin may be beneficial even in advanced gastric cancer patients with impaired liver function from multiple liver metastases.

[A case of a gastrointestinal stromal tumor of the rectum effectively treated with continuously-administered regorafenib after failure of imatinib and sunitinib].

Regorafenib is recommended as a third-line treatment for unresectable gastrointestinal stromal tumors (GIST). It is usually administered in a repeating cycle of three-weeks on and one-week off. We describe a patient with an unresectable GIST in the pelvic cavity who complained of pelvic pain while taking the one-week break from regorafenib administration. Subsequently, we reduced the dosage to one level and regorafenib was continuously administered. As a result, the adverse events were improved and the antitumor effect against the GIST was retained. The continuous administration of reduced-dose regorafenib could be considered a viable dosage adjustment in specific situations.