Survival In Advanced Gastric Cancer Research Articles

CT-derived skeletal muscle change before immunotherapy predicts survival of advanced gastric cancer: associations with inflammatory markers and liver lipid metabolism.

Skeletal muscle (SM) is a key factor in cancer treatment. However, it is unclear whether pretreatment SM change affects the outcome of immune checkpoint inhibitors (ICIs) therapy in gastric cancer (GC). Advanced GCs treated with ICIs were retrospectively investigated. SM evaluated by psoas muscle area at the third lumbar vertebra was measured on CT acquired within 1month from the start of ICIs therapy (CT-1), and on CT acquired 2.8 ± 0.84months before CT-1. Monthly change rate of SM (MCR-SM) was defined as the change rate of SMs between those two CTs divided by the period between those CTs (month). Monthly change rate of body weight (MCR-BW) during the same period was also calculated. They were compared with disease-specific survival (DSS) and progression-free survival (PFS). MCR-SM was compared with pretreatment markers including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), C-reactive protein (CRP), and liver-to-spleen CT attenuation ratio (LSR) as a marker of liver lipid metabolism. This study enrolled eighty-three GC patients. MCR-SM significantly correlated with DSS and PFS (P < 0.0001, 0.001, respectively), whereas MCR-BW did not. Kaplan-Meier analyses demonstrated that higher MCR-SM (MCR-SM ≥ -0.7185%) significantly associated with better DSS and PFS (P = 0.0002, 0.03, respectively). Patients with positive MCR-SM showed significantly lower NLR, MLR, and CRP than those with negative (P = 0.01, 0.006, 0.003, respectively). MCR-SM showed a significant positive correlation with LSR (P = 0.007, R = 0.30). Pretreatment SM loss, associated with high systemic inflammation and hepatic fat accumulation, related to poor outcome of ICIs therapy in GC.

Claudin18.2 in Advanced Gastric Cancer.

Globally, the fifth most common cancer and the fourth leading cause of cancer-related mortality is gastric cancer (GC). Recent clinical trials on solid tumors enrolled patients who possess druggable genetic alterations, protein expression, and immune characteristics. In gastric or gastroesophageal junction (GEJ) cancers, trastuzumab combined with first-line chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive patients and ramucirumab combined with second-line paclitaxel remarkably prolonged overall survival (OS) compared with chemotherapy alone, according to phase 3 trial results. Recently, immune checkpoint inhibitor (ICI) monotherapy was approved as third- or later-line treatment. Chemotherapy plus ICIs as first-line treatment exhibited improved survival compared with chemotherapy alone in HER2-negative patients according to Checkmate 649 trial results. Conversely, systemic chemotherapy prognosis remains poor. although some patients may achieve durable response to treatment and prolonged survival in advanced GC. Recently, a first-in-class, chimeric immunoglobulin G1 monoclonal antibody (zolbetuximab) that targets and binds to claudin 18 isoform 2 (CLDN18.2) has emerged as a new target therapy in GC treatment. Global phase Ⅲ trials revealed that the addition of zolbetuximab to first-line chemotherapy prolonged OS in CLDN18.2-positive and HER2-negative GC patients. This review summarizes recent clinical trials of CLDN18.2-targeted therapy.

Evaluation of peritoneal Carcinoembryonic Antigen as a survival prognostic factor in gastric cancer patients: a single western center experience

The aim of this study is to define the importance of peritoneal CEA (pCEA) as a prognostic factor of overall survival (OS) and disease-free survival (DFS) in gastric cancer (GC) patients surgically treated with a curative intent In our department. A total of 64 patients affected by gastric cancer with intraoperatively measurement of CEA on peritoneal lavage were enrolled in the study. Patients were divided into two groups: (A) the peritoneal lavage CEA ( −) with CEA < 0.5 ng/ml and (B) the peritoneal lavage CEA ( +) with CEA ≥ 0.5 ng/ml. Then we analyzed OS and DFS of the two groups correlating them to others clinico-pathological features. Furthermore, we investigated the correlation between pCEA and peritoneal cytology. We demonstrated a strong significant difference in OS and in DFS in CEA ( +) patients. We emphasized that pCEA had a strong survival impact, in both OS and DFS, in selected patients affected by diffuse histotype GC (p = 0.0048 and p = 0.0030 respectively), stage III (p = 0.015 and p = 0.021, respectively) and distal gastric cancer (p = 0.0036 and p = 0.0017, respectively). There is a strong need to recognize prognostic factors that can help clinicians to stratify patients at high risk to develop post-surgical recurrences and moreover to recognize who could benefit from an aggressive surgical treatment of cytoreductive surgery and intra-peritoneal chemotherapy.pCEA is a good predictor of survival in advanced gastric cancer and could discriminate which patients need a more accurate follow-up program and an intensive therapeutic strategy.

The impact of claudin-18.2 expression in patients with advanced gastric cancer treated with nivolumab.

439 Background: Claudin-18.2 (CLDN 18.2) is the components of tight junction and one of the therapeutic targets in advanced gastric cancer (AGC). It has been reported that the tumor microenvironment in CLDN18.2 high AGC contains more PD-1 negative CD8+ T cells than in CLDN18.2 low, which may make anti-PD-1 antibodies less effective. However, the data on the association between CLDN18.2 expression and prognosis in patients with AGC treated with nivolumab (NIVO) is limited. Methods: Patients who received NIVO monotherapy as third- or later-line treatment (NIVO group) and those who received only fluoropyrimidine, platinum and taxanes (non-NIVO group) at our hospital between 2015 and 2019 were enrolled. High CLDN18.2 expression was defined as ≥40% positive tumor cells with moderate to strong membranous staining on immunohistochemistry. Overall survival (OS) and progression-free survival (PFS) were compared according to CLDN18.2 expression and combined positivity score (CPS). Results: There were 71 and 50 patients in the NIVO and non-NIVO groups, respectively. Patient characteristics at first-line chemotherapy in the NIVO/non-NIVO groups were median age 67 (range, 34-83)/64.5 (29-80) years; performance status 0, 22 (31%)/23 (46%); peritoneal metastasis 38 (54%)/26 (52%); liver metastasis 15 (21%)/6 (12%); CLDN18.2 high 31 (44%)/25 (50%). In the NIVO group, patient characteristics did not differ between CLDN18.2 high and low except for peritoneal metastasis (25 [81%]/22 [55%]). Nine patients (29%) were CLDN18.2 high with CPS≥1, and 14 (35%) were CLDN18.2 low with CPS≥1. OS from first-line chemotherapy did not differ between CLDN18.2 high and low in the non-NIVO group (median, 18.4 months [95%CI, 10.7-32.4] vs. 16.9 months [95%CI, 14.8-21.4], HR 0.94 [95%CI, 0.50-1.78], p=0.847). In the NIVO group, OS from first-line chemotherapy and OS and PFS after starting NIVO did not differ between CLDN18.2 high and low; however, patients with CLDN18.2 high and CPS≥1 had longer OS after starting NIVO (median, 14.8 months [95%CI, 4.2-NR] vs. 3.6 months [95%CI, 2.0-6.9], HR 0.27 [95%CI, 0.11-0.68], p=0.012) and PFS after starting NIVO (median, 3.5 months [95%CI, 0.7-NR] vs. 1.7 months [95%CI, 1.1-3.1], HR 0.38 [95%CI, 0.15-0.97], p=0.033) than those with CLDN 18.2 high and CPS&lt;1. Patients with CLDN18.2 high and CPS≥1 had a trend of longer OS from first-line chemotherapy than those with CLDN 18.2 high and CPS&lt;1 (median, 37.4 months [95%CI, 11.1-NR] vs. 14.8 months [95%CI, 9.4-31.2], HR 0.47 [95%CI, 0.17-1.31], p=0.12). In the CLDN18.2 low group, OS and PFS did not differ between CPS≥1 and &lt;1. Conclusions: With CLDN18.2 high, CPS≥1 was associated with longer survival in AGC treated with NIVO.

Effect of malnutrition as defined by the Global Leadership Initiative on Malnutrition criteria on compliance of adjuvant chemotherapy and relapse-free survival for advanced gastric cancer

ObjectivesThe aim of the present study was to clarify the effect of malnutrition as defined by the Global Leadership Initiative on Malnutrition (GLIM) criteria on compliance with postoperative adjuvant chemotherapy and relapse-free survival (RFS) in patients with gastric cancer. MethodsThis single-center, retrospective cohort study included 281 consecutive patients with gastric cancer who underwent radical gastrectomy for pathologic stages II and III and received postoperative S-1 adjuvant chemotherapy between April 2008 and June 2018. Treatment failure was defined as discontinuation of adjuvant chemotherapy ≤1 y. Nutritional assessment was preoperatively performed according to the GLIM criteria for all patients. We analyzed risk factors for treatment failure and poor prognostic factors for RFS using multivariate analyses. ResultsTreatment failure and recurrence were observed in 50 (17.8%) and 97 (34.5%) of the 281 patients, respectively. The median follow-up period was 52 mo. The treatment failure rate was higher (P = 0.032) and RFS was worse (P = 0.017) in the malnutrition group. In multivariate analyses, GLIM criteria–defined malnutrition was an independent risk factor for treatment failure (odds ratio = 3.110; 95% confidence interval [CI], 1.020–9.470; P = 0.046). Furthermore, severe malnutrition was an independent poor prognostic factor for RFS (hazard ratio = 1.767; 95% CI, 1.132–2.759; P = 0.012). ConclusionsPreoperative malnutrition as defined by the GLIM criteria was an independent risk factor for poor compliance with adjuvant S-1 chemotherapy and a poor prognostic factor for RFS after radical gastrectomy in patients with advanced gastric cancer.

MCEMP1 is a potential therapeutic biomarker associated with immune infiltration in advanced gastric cancer microenvironment

BackgroundOver the last decade, breakthroughs have been made in cancer immunotherapy. However, for advanced gastric cancer (AGC), the complexity and heterogeneity of the tumor microenvironment (TME) has been the biggest challenge for immunotherapy. Therefore, an intensive study on TME of AGC is necessary. MethodsESTIMATE and CIBERSORT algorithms were applied to analyze the transcriptome data of AGC using TCGA database systematically. We identified mast cell-expressed membrane protein 1 (MCEMP1) as a potential prognostic marker by protein–protein interaction (PPI) and Univariate Cox regression. The expression of MCEMP1 was evaluated by immunohistochemistry (IHC) and quantitative real time PCR. We assessed prognostic values of MCEMP1 with use of Kaplan-Meier and Multivariate Cox regression analysis. Gene set enrichment analysis (GSEA) was used to analyze the molecular mechanism of MCEMP1. The correlation between MCEMP1 expression and tumor immune infiltration was analyzed by the TIMER database and CIBERSORT algorithm, which was confirmed by IHC. ResultsThe mRNA and protein expression of MCEMP1 was up-regulated substantially and related to poor survival in AGC. GSEA analysis revealed that MCEMP1 was involved in the immune-related signaling pathways. We further demonstrated that the expression of MCEMP1 was correlated with multiple immune cells and immune checkpoints. The results of IHC indicated that there was a positive correlation between PD-L1 expression and MCEMP1, suggesting that MCEMP1 may affect the prognosis of AGC patients by regulating immune infiltration and the function of immune cells. ConclusionMCEMP1 may serve as a biomarker associated with immune infiltration in TME and could be a potential therapeutic target for AGC patients.

Apatinib: A Novel Antiangiogenic Drug in Monotherapy or Combination Immunotherapy for Digestive System Malignancies.

Digestive system malignancies are one of the primary causes of cancer-related death. Meanwhile, angiogenesis has been proved to play an important role in the process of cancer neovascularization. Apatinib, a novel targeted antiangiogenic molecule, could generate highly selective competition in the vascular endothelial growth factor receptor-2, involved in tumor progression and metastasis. It has been implied as a promising cancer treatment agent that can prevent tumor cell proliferation meanwhile inhibit tumor angiogenesis. Furthermore, completed clinical trials demonstrated that apatinib could prolong the progression-free survival and overall survival in advanced gastric cancer and primary liver cancer. Recent studies revealed that apatinib had a synergistic effect with immunotherapy as a second-line and third-line treatment regimen for some other cancers. In this review, we summarize the pharmacological properties of apatinib and the latest clinical application in chemotherapy-refractory patients with advanced digestive system cancer. Based on the comparable survival results, the molecular mechanisms of apatinib are prospective to include the antiangiogenic, apoptosis-inducing, and autophagy-inducing properties in the corresponding signaling pathway. Treatment of apatinib monotherapy or combination immunotherapy remains the optimal option for patients with digestive system malignancies in the future.

The Effect of Inflammatory Markers on the Survival of Advanced Gastric Cancer Patients Who Underwent Anti-Programmed Death 1 Therapy.

PurposeThis clinical study sought to determine whether the levels of inflammatory markers predicted the survival of advanced gastric cancer (AGC) patients who underwent anti-programmed death 1 (PD-1) therapy.MethodsUsing AGC patient plasma samples and baseline characteristics, we investigated the specific value of inflammatory markers in AGC from a clinical perspective in immunotherapy.ResultsOne hundred and six patients with AGC who underwent anti-PD-1 therapy were enrolled in this study between 20 July 2019 and 16 March 2021. A significant decrease in NLR, dNLR, and SII was noticed among the PR (P=0.023; P=0.036; P=0.001), SD (P=0.048; P=0.022; P=0.023), ORR (P=0.021; P=0.032; P=0.001), and DCR (P=0.003; P=0.001; P<0.001) groups after anti-PD-1 therapy. Additionally, a significant decline of PLR was also observed in PR (P=0.010), ORR (P=0.007), and DCR (P=0.005) after anti-PD-1 therapy. Only MLR levels increased significantly at the time of anti-PD-1 immunotherapy the failure compared to baseline (P=0.039). And statistically significant elevations in NLR (P=0.001), MLR (P=0.020), dNLR (P=0.002), and SII (P=0.019) were found in failure of anti-PD-1 treatment compared to optimal efficacy in AGC patients. In first-line treatment, the number of metastatic sites (P=0.001) was an independent prognostic factor for PFS, and peritoneal metastases (P=0.004) and platelet-to-lymphocyte ratio (PLR) level (P=0.014) were independent prognostic predictors of OS according to Cox regression analysis. In second-line or posterior treatment, the number of metastatic sites (P=0.007), ECOG (P=0.011), and PLR level (P=0.033) were independent prognostic factors for PFS in AGC patients, and the number of metastatic sites (P=0.003), differentiation (P=0.030), and NLR level (P<0.001) were independent prognostic factors for OS according to Cox regression analysis.ConclusionsNLR, PLR, MLR, dNLR, and SII can reflect the short-term efficacy of immunotherapy in patients who underwent anti-PD-1 therapy with AGC. PLR is an independent prognostic factor for OS in AGC patients receiving first-line immunotherapy and PFS in those receiving second-line or posterior immunotherapy. And NLR was an independent prognostic factor for OS in AGC patients receiving second-line or posterior immunotherapy. The number of metastatic sites was significantly associated with the prognosis of AGC patients who received immunotherapy.

1418P Chronological improvement in the survival of advanced gastric cancer patients in the past 15 years

Recent clinical trials have shown that the median overall survival (OS) of advanced gastric cancer (AGC) patients (pts) has reached 11–17 months. However, in practice, the prognosis remains unclear. The objective of this study was to evaluate the clinicopathological features and survival of pts with AGC in the past 15 years. We retrospectively collected data on 1,355 AGC pts who received first-line chemotherapy (CTx) between Jan 2005 and Mar 2019 at a single institution. We compared the survival between four periods: Jan 2005–Dec 2007 (period A); Jan 2008–Feb 2011 (period B; after the establishment of fluoropyrimidines plus platinum agents as standard CTx); Mar 2011–May 2015 (period C; after the approval of trastuzumab); and Jun 2015–Mar 2019 (period D; after approval of ramucirumab [Ram]). With a median follow-up time of 13.1 months, there were 312 pts in period A, 333 pts in period B, 393 pts in period C, and 317 pts in period D. The characteristics in each period were not different, except for the proportion of those with prior gastrectomy (49%, 39%, 38%, and 34%) and HER2 testing (33%, 55%, 93%, and 100%). The rates of receiving second-, third-, and fourth-line CTx were not different between each period. The frequency of exposure to irinotecan (39%, 49%, 39%, and 26%) gradually decreased, whereas that of Ram (0%, 4%, 10%, and 64%) and nivolumab (0%, <1%, 8%, and 43%) increased. Pts in period D had significantly longer OS than those in period A (median OS, 15.7 vs. 12.4 months; adjusted hazard ratio [aHR], 0.79; p=0.02). Over time, the 5-year OS rate significantly improved (2%, 2%, 6%, and 10%). The OS of the pts with liver metastasis (LM) in period D remarkably improved compared with those in period A (median OS, 19.3 vs. 12.4 months; aHR, 0.61; p<0.01).Table: 1418PPeriod APeriod BPeriod CPeriod DMedian OS (months)12.412.713.815.7aHR (95% CI)Ref.0.98 (0.83–1.15)0.94 (0.78–1.14)0.79 (0.65–0.97)Median PFS of first-line (months)4.35.16.06.6aHR (95% CI)Ref.1.00 (0.84–1.18)0.83 (0.69–1.00)0.76 (0.62–0.92)Median PPS of first-line (months)6.26.66.67.5aHR (95% CI)Ref.0.97 (0.82–1.16)1.13 (0.92–1.37)0.99 (0.80–1.23)Median OS of patients with LM (months)12.411.014.319.3aHR (95% CI)Ref.1.11 (0.81–1.53)0.97 (0.67–1.39)0.61 (0.40–0.92) Open table in a new tab A change in clinical strategy, including gastrectomy, HER2 testing, and the approval of new drugs, may be associated with improved OS in pts with AGC. In the last 4 years, a remarkable improvement has been observed in pts with LM.

Nomogram for Predicting Survival in Advanced Gastric Cancer after Neoadjuvant Chemotherapy and Radical Surgery.

Background Neoadjuvant chemotherapy (NAC) with subsequent radical surgery has become a popular treatment modality for advanced gastric cancer (AGC) worldwide. However, the survival benefit is still controversial, and prognostic factors remain undetermined. Aim To identify clinical parameters that are associated with the survival of AGC patients after NAC and radical surgery and to establish a nomogram integrating multiple factors to predict survival. Methods We reviewed the medical profiles of 215 AGC patients who received NAC and radical resection, and clinical parameters concerning NAC, surgery, pathological findings, and adjuvant chemotherapy were analyzed using a Cox regression model to determine their impact on survival. Based on these factors, a nomogram was developed and validated. Results The overall 1-year and 3-year survival rates were 85.8% and 55.6%, respectively. Younger age (<60 years old), increased examined lymph nodes (exLNs), successful R0 resection, the achievement of pathological complete response (pCR), and acceptance of adjuvant chemotherapy were positive predictors of survival. The C-index of the established nomogram was 0.785. The area under receiver operating curve (ROC) at 1/3 years of prediction was 0.694/0.736, respectively. The model showed an ideal calibration following internal bootstrap validation. Conclusion A nomogram predicting survival after NAC and surgery was established. Since this nomogram exhibited satisfactory and stable predictive power, it can be inferred that this is a practical tool for predicting AGC patient survival after NAC and radical surgery.

Assessment of copy number in protooncogenes are predictive of poor survival in advanced gastric cancer

The copy number (CN) gain of protooncogenes is a frequent finding in gastric carcinoma (GC), but its prognostic implication remains elusive. The study aimed to characterize the clinicopathological features, including prognosis, of GCs with copy number gains in multiple protooncogenes. Three hundred thirty-three patients with advanced GC were analyzed for their gene ratios in EGFR, GATA6, IGF2, and SETDB1 using droplet dPCR (ddPCR) for an accurate assessment of CN changes in target genes. The number of GC patients with 3 or more genes with CN gain was 16 (4.8%). Compared with the GCs with 2 or less genes with CN gain, the GCs with 3 or more CN gains displayed more frequent venous invasion, a lower density of tumor-infiltrating lymphocytes, and lower methylation levels of L1 or SAT-alpha. Microsatellite instability-high tumors or Epstein–Barr virus-positive tumors were not found in the GCs with 3 or more genes with CN gain. Patients of this groups also showed the worst clinical outcomes for both overall survival and recurrence-free survival, which was persistent in the multivariate survival analyses. Our findings suggest that the ddPCR-based detection of multiple CN gain of protooncogenes might help to identify a subset of patients with poor prognosis.

Lymph Node Involvement in Advanced Gastric Cancer in the Era of Multimodal Treatment-Oncological and Surgical Perspective.

Simple SummaryGastric cancer (GC) continues to be one of the major oncological challenges on a global scale. The role of neoadjuvant chemotherapy (NAC) in GC is to downstage primary tumour, eliminate potential micrometastases, and increase the chance for radical resection. Although systemic treatment prolongs the survival in advanced GC, persistent lymph node (LN) metastases indicate poor prognosis. Therefore, further identification of prognostic factors after NAC is urgent and could positively influence clinical outcomes. This article aimed to review the actual trends and future perspectives in multimodal therapy of advanced GC, with a particular interest in the post-neoadjuvant pathological nodal stage. Since downstaged and primarily node-negative patients show a similar prognosis, the main target for NAC in advanced GC should be nodal clearance. Adequate staging and personalised perioperative therapy seem to be of great importance in the multimodal treatment of GC.Gastric cancer (GC) continues to be one of the major oncological challenges on a global scale. The role of neoadjuvant chemotherapy (NAC) in GC is to downstage primary tumour, eliminate potential micrometastases, and increase the chance for radical resection. Although systemic treatment prolongs the survival in advanced GC, persistent lymph node (LN) metastases indicate poor prognosis. Further identification of prognostic factors after NAC is urgent and could positively influence clinical outcomes. This article aimed to review the actual trends and future perspectives in multimodal therapy of advanced GC, with a particular interest in the post-neoadjuvant pathological nodal stage. A favourable prognostic impact for ypN0 patients is observed, either due to truly negative LN before the start of therapy or because preoperative therapy achieved a pathologically complete nodal response. Ongoing trials investigating the extent of lymphadenectomy after neoadjuvant therapy will standardise the LN dissection from the multimodal therapy perspective. Since downstaged and primarily node-negative patients show a similar prognosis, the main target for NAC in advanced GC should be nodal clearance. Adequate staging and personalised perioperative therapy seem to be of great importance in the multimodal treatment of GC.

History and emerging trends in chemotherapy for gastric cancer.

Chemotherapy is indispensable for gastric cancer. For unresectable and/or recurrent gastric cancer, first‐line chemotherapy consists of multidrug regimens including oral 5‐FU agents such as S1/Xeloda and platinum preparations, as well as Trastuzumab, which is effective in HER2‐positive cases. Second‐ and third‐line chemotherapy regimens include taxanes, Ramucirumab (R‐mab), and Nivolumab (N‐mab), which have different mechanisms of action from first‐line chemotherapy. R‐mab is molecularly targeted to vascular endothelial growth factor receptor 2 in the host cells, but its indication is not conditional. For resectable gastric cancer, in Eastern countries, postoperative adjuvant chemotherapy has been successful, including S1, Docetaxel/S1 (DS), and Xeloda/Oxaliplatin (Xelox) regimens, whereas, in Western countries, the 5‐FU/Leucovorin/Oxaliplatin/Docetaxel (FLOT) regimen was recently shown to be effective in the perioperative chemotherapy setting. Most recently, however, in Eastern countries, perioperative SOX was demonstrated to be effective in specific advanced gastric cancer. For stage IV gastric cancer, new therapeutic strategies have been proposed such as neoadjuvant chemotherapy and conversion surgery, and cures can be conditionally obtained. Recent genomic understanding of gastric cancer proposed a diversity of molecular targets by molecular profiling. Such optimized chemotherapy regimens, according to the specific clinical situations, have been rigorously established for the best survival of advanced gastric cancer.

The impact of nutrition support in advanced gastric adenocarcinoma patients treated with chemotherapy.

208 Background: Numerous studies have demonstrated how malnutrition and cachexia are associated with poor survival in advanced gastric cancer (AGC). The impact of nutrition support involving multidisciplinary specialists is unclear, particularly among patients with AGC being treated with chemotherapy. This study aimed to clarify the differences in patient characteristics and survival outcomes between patients receiving nutrition support (NS) and routine care (RC). Methods: We retrospectively analyzed 212 consecutive patients with AGC at a single institution between January 2015 and June 2020. Inclusion criteria were: histologically confirmed metastatic or recurrent gastric and adenocarcinoma and gastroesophageal junction patients treated with chemotherapy, ECOG performance status (PS) 0-2, and adequate organ function. Time to treatment failure (TTF) in the entire cohort, patients with a positive Glasgow prognostic score (GPS) (graded as 1 and 2), and hypoalbuminemia (cutoff was 3.5 g/dl) were evaluated. Univariate and multivariate analyses were conducted to identify whether NS was an independent prognostic factor of time to treatment failure (TTF). Multivariate analysis included variables with p-values ≤0.1 in univariate analyses. Results: A total of 97 patients met the inclusion criteria with 67 (69%) and 30 (31%) patients classified into the RC or NS group, respectively. The median age was 71 years (range, 26-92). The median follow-up time was 8.4 months (range, 0.5-66). Patient characteristics revealed that NS was offered to patients with poorer prognostic nutritional index (PNI) (cutoff was 45, p=0.02), GPS positivity (p=0.01), and high neutrophil-lymphocyte ratio (NLR) (cutoff was 3, p=0.01). In the entire cohort, TTF in the RC and NS groups was 4.3 and 5.3 months (p=0.15), respectively. Among the patients with GPS positivity (graded as 1 and 2) and hypoalbuminemia, TTF in the RC and NS group were 2.3 and 5.0 months (p=0.05), and 2.3 and 5.3 months (p=0.02), respectively (Table). Variables with p-values ≤0.1 in univariate analyses for TTF were PS, NS, and prior gastrectomy. As per multivariate analyses, PS and NS were significant positive prognostic factors for TTF. Conclusions: NS was provided to patients with unfavorable clinical features. Among the AGC patients treated with chemotherapy, having GPS positivity or hypoalbuminemia seems to be a good indication for NS. [Table: see text]

The Reprimo-Like Gene Is an Epigenetic-Mediated Tumor Suppressor and a Candidate Biomarker for the Non-Invasive Detection of Gastric Cancer.

Reprimo-like (RPRML) is an uncharacterized member of the Reprimo gene family. Here, we evaluated the role of RPRML and whether its regulation by DNA methylation is a potential non-invasive biomarker of gastric cancer. RPRML expression was evaluated by immunohistochemistry in 90 patients with gastric cancer and associated with clinicopathologic characteristics and outcomes. The role of RPRML in cancer biology was investigated in vitro, through RPRML ectopic overexpression. Functional experiments included colony formation, soft agar, MTS, and Ki67 immunofluorescence assays. DNA methylation-mediated silencing was evaluated by the 5-azacytidine assay and direct bisulfite sequencing. Non-invasive detection of circulating methylated RPRML DNA was assessed in 25 gastric cancer cases and 25 age- and sex-balanced cancer-free controls by the MethyLight assay. Downregulation of RPRML protein expression was associated with poor overall survival in advanced gastric cancer. RPRML overexpression significantly inhibited clonogenic capacity, anchorage-independent growth, and proliferation in vitro. Circulating methylated RPRML DNA distinguished patients with gastric cancer from controls with an area under the curve of 0.726. The in vitro overexpression results and the poor patient survival associated with lower RPRML levels suggest that RPRML plays a tumor-suppressive role in the stomach. Circulating methylated RPRML DNA may serve as a biomarker for the non-invasive detection of gastric cancer.

Second-line treatment in advanced gastric cancer: Data from the Spanish AGAMENON registry.

Second-line treatments boost overall survival in advanced gastric cancer (AGC). However, there is a paucity of information as to patterns of use and the results achieved in actual clinical practice. The study population comprised patients with AGC in the AGAMENON registry who had received second-line. The objective was to describe the pattern of second-line therapies administered, progression-free survival following second-line (PFS-2), and post-progression survival since first-line (PPS). 2311 cases with 2066 progression events since first-line (89.3%) were recorded; 245 (10.6%) patients died during first-line treatment and 1326/2066 (64.1%) received a second-line. Median PFS-2 and PPS were 3.1 (95% CI, 2.9-3.3) and 5.8 months (5.5-6.3), respectively. The most widely used strategies were monoCT (56.9%), polyCT (15.0%), ramucirumab+CT (12.6%), platinum-reintroduction (8.3%), trastuzumab+CT (6.1%), and ramucirumab (1.1%). PFS-2/PPS medians gradually increased in monoCT, 2.6/5.1 months; polyCT 3.4/6.3 months; ramucirumab+CT, 4.1/6.5 months; platinum-reintroduction, 4.2/6.7 months, and for the HER2+ subgroup in particular, trastuzumab+CT, 5.2/11.7 months. Correlation between PFS since first-line and OS was moderate in the series as a whole (Kendall's τ = 0.613), lower in those subjects who received second-line (Kendall's τ = 0.539), especially with ramucirumab+CT (Kendall's τ = 0.413). This analysis reveals the diversity in second-line treatment for AGC, highlighting the effectiveness of paclitaxel-ramucirumab and, for a selected subgroup of patients, platinum reintroduction; both strategies endorsed by recent clinical guidelines.

Peritoneal cancer index is a prognostic indicator of survival in advanced gastric cancer with peritoneal carcinomatosis

Abstract Objective The peritoneal cancer index (PCI) has been used for the detailed evaluation of the peritoneal spread in tumors of a gynecologic origin and has been found to be a prognostic indicator of survival. The aim of this study was to identify the significance of the PCI in advanced gastric cancer (AGC) with peritoneal carcinomatosis (PC). Methods From 2010 to 2018, a retrospective analysis was carried out of 60 AGC patients with PC, including 21 patients with a PCI ≤ 13 and 39 with a PCI &gt; 13. All patients were treated with both surgery and intraoperative peritoneal hyperthermic chemotherapy (IPHC). The performance status (Karnofsky performance status), age, sex, Borromann's classification, differentiation, depth of invasion, lymph node metastasis, PCI, extent of gastrectomy, extent of lymph node dissection, and residual tumor volume were retrospectively evaluated and correlated to survival. Results The overall 5-year survival rate was 43% and mean survival was (54.47 ± 4.53) months. The favorable clinical prognostic indicators of survival were Borromann's classification, differentiation, depth of invasion, PCI, and residual tumor volume on univariate analyses (P &lt; 0.05). The Cox proportional regression hazard model showed that only the volume of residual tumor and PCI were associated with postoperative survival. The median survival time was 69.76 months for patients with a PCI ≤ 13 and 39.96 months for patients with a PCI &gt; 13. There was a significant difference in survival rate between the two group (P = 0.004). Postoperative major morbidity and mortality rates were 23.81% and 4.76% in the PCI ≤ 13 group and 43.59% and 5.12% in the PCI &gt; 13 group, respectively. Conclusion The peritoneal spread in advanced gastric cancer with peritoneal carcinomatosis can be assessed in detail using the PCI. It is also a significant prognostic factor of survival and is useful in identifying subgroups.

Differences in disease status between patients with progression after first-line chemotherapy versus early relapse after adjuvant chemotherapy who undergo second-line chemotherapy for gastric cancer: Exploratory analysis of the randomized phase III TRICS trial

BackgroundSecond-line chemotherapy (SLC) improves survival in advanced gastric cancer (AGC). Patients receiving SLC are categorized into two disease status groups: tumour progression after first-line chemotherapy and early recurrence after adjuvant chemotherapy. Differences between these groups have not yet been clarified. Patients and methodsA total of 163 eligible patients registered in the randomized phase III TRICS trial evaluating SLC for patients with AGC was classified into the progressive disease (PD) group (n = 55) or the early relapse (ER) group (n = 108). We compared overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety. Adjusted OS and adjusted PFS were estimated using inverse probability of treatment weighting (IPTW). ResultsThe ER group had a lower median age than the PD group (66 vs. 72 years; P = 0.016), performance status (PS) 0 was more frequently seen in the ER group (87% vs. 71%; P = 0.012). The adjusted median OS was 13.7 months in the ER group and 13.6 months in the PD group (IPTW hazard ratio [HR]: 1.023; P = 0.854). The adjusted median PFS was 4.9 months in the ER group and 4.4 months in the PD group (IPTW HR: 0.707; P = 0.004). ORR was significantly better in the ER group than the PD group (21.3% vs. 4.9%; P = 0.020). No significant differences were observed in the incidence of adverse events. ConclusionsER was associated with improved PFS and better ORR than PD, although no difference in survival was demonstrated. From the viewpoint of treatment outcome, it seems appropriate to treat patients with ER in the same way as patients with PD. Clinical trial registrationUMIN 000002571.

A clinical scoring system for survival prediction in advanced gastric cancer.

436 Background: We established a scoring system using easily approachable clinical characteristics at the timing of initiating palliative chemotherapy to achieve accurate overall survival prediction to first-line treatment consisting of fluoropyrimidines in patients with advanced gastric cancer. Methods: A total of 1,733 patients were included in the study. The dataset was split into a training (n=1156, 67%) and validation set (n=577, 33%). Top-ranked variables were identified using the Random Forest for Survival algorithm and analyzed into a Cox regression model, thereby constructing the scoring system for predicting overall survival of advanced gastric cancer. Results: Five variables were finally included in the scoring system: serum neutrophil-lymphocyte ratio, alkaline phosphatase, albumin level, performance status, and histologic differentiation. The scoring system determined four distinct risk groups in validation dataset with median overall survival of 17.1 month (95% confidence interval [CI] = 14.9 to 20.5 month), 12.9 month (95% CI = 11.4 to 14.6 month), 8.1 month (95% CI = 5.3 to 12.3 month), and 3.9 month (95% CI = 1.5 to 8.2 month), respectively. AUC to estimate discrimination performance of the scoring system was 66.1 for one-year overall survival. Conclusions: We developed a simple and clinically useful predictive scoring model in a relatively homogenous population who initiate fluoropyrimidine-containing chemotherapy in advanced gastric cancer. Generalized application of the scoring model will require additional independent validation. [Table: see text]

Association between Severe Neutropenia Induced by Ramucirumab Plus Paclitaxel Combination Therapy and Overall Survival in Advanced Gastric Cancer

Association between Severe Neutropenia Induced by Ramucirumab Plus Paclitaxel Combination Therapy and Overall Survival in Advanced Gastric Cancer