Prognostic relevance of prognostic nutritional indices in gastric or gastro-esophageal junction cancer patients receiving immune checkpoint inhibitors: a systematic review and meta-analysis.

Background: The Prognostic Nutritional Index (PNI) has become an important predictive tool for assessing patients' nutritional status and immune competence. It is widely used in prognostic evaluations for various cancer patients. However, the prognostic relevance of the Prognostic Nutritional Index (PNI) in gastric or gastro-esophageal junction cancer patients (GC/GEJC) undergoing immune checkpoint inhibitors (ICIs) treatment remains unclear. This meta-analysis aimed to determine the prognostic impact of PNI in this specific patient cohort. Methods: We conducted a thorough literature search, covering prominent databases such as PubMed, Embase, Web of Science, SpringerLink, and the Cochrane Library. The search spanned from the inception of these databases up to December 5, 2023. Employing the 95% confidence interval and Hazard Ratio (HR), the study systematically evaluated the relationship between PNI and key prognostic indicators, including the objective remission rate (ORR), disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) in GC/GEJC patients undergoing ICI treatment. Results: Eight studies comprising 813 eligible patients were selected. With 7 studies consistently demonstrating superior Overall Survival (OS) in the high-Prognostic Nutritional Index (PNI) group compared to their low-PNI counterparts (HR 0.58, 95% CI: 0.47-0.71, P<0.001). Furthermore, the results derived from 6 studies pointed out that the significant correlation between he low-PNI and poorer progression-free survival (PFS) (HR 0.58, 95% CI: 0.47-0.71, P<0.001). Subgroup analyses were performed to validate the robustness of the results. In addition, we conducted a meta-analysis of three studies examining the correlation between PNI and objective response rate/disease control rate (ORR/DCR) and found that the ORR/DCR was significantly superior in the high PNI group (ORR: RR: 1.24, P=0.002; DCR: RR: 1.43, P=0.008). Conclusion: This meta-analysis indicates that the low-PNI in GC/GEJC patients undergoing ICI treatment is significantly linked to worse OS and PFS. Therefore, PNI can serve as a prognostic indicator of post-treatment outcomes in patients with GC receiving ICIs. Further prospective studies are required to assess the reliability of these findings. Systematic review registration: https://inplasy.com/, identifier INPLASY202450133.

Updated meta-analysis of randomized controlled trials on primary outpatient thromboprophylaxis in patients with gastric and gastroesophageal junction cancers receiving chemotherapy.

Advanced gastric cancer is a highly thrombogenic cancer per Khorana score. Recent clinical practice guidelines suggest primary outpatient thromboprophylaxis (POTP) for patients with a Khorana score ≥2. We performed an updated meta-analysis to evaluate the benefit of POTP in patients with gastric cancer and gastroesophageal junction cancers receiving chemotherapy. Randomized controlled trials with reduction in venous thromboembolism (VTE) as a primary or secondary endpoint were incorporated. A total of 631 patients from subgroups of three randomized controlled trials were included. The VTE incidence was 1.6% and 5.1% in POTP and control groups, respectively (risk ratio 0.31; confidence interval 0.11 to 0.83; P = 0.02), with a number needed to treat of 29 to prevent one VTE event. Even though the recent clinical practice guidelines suggest POTP in patients with gastric cancer and gastroesophageal junction cancers, our meta-analysis findings do not support the routine use of POTP in those patients.

Treatment- and immune-related adverse events of immune checkpoint inhibitors in esophageal or gastroesophageal junction cancer: A network meta-analysis of randomized controlled trials.

Objective: To systematically evaluate the safety and adverse event profiles of immune checkpoint inhibitors (ICIs) in patients with esophageal cancer (EPC) or gastroesophageal junction cancer (GEJC). Methods: PubMed, Web of Science, Cochrane Library, and major conference proceedings were systematically searched for all phase II or phase III randomized controlled trials (RCTs) in EPC or GEJC using ICIs. Safety outcomes including treatment-related adverse events (trAEs), immune-related adverse events (irAEs), and serious trAEs were evaluated by network meta-analysis or dichotomous meta-analysis based on the random-effects model. Results: Eleven RCTs involving EPC (five RCTs) and GEJC (six RCTs) were included in the final meta-analysis. NMA showed that placebo was associated with the best safety ranking for grade 3-5 trAEs (SUCRA = 96.0%), followed by avelumab (78.6%), nivolumab (73.9%), ipilimumab (57.0%), and pembrolizumab (56.6%). Conventional pairwise meta-analysis (CPM) showed that ICIs have similar grade 3-5 trAE risk compared with chemotherapy (RR = 0.764, 95% CI: 0.574 to 1.016, I 2 = 95.7%, Z = 1.85, P = 0.065). NMA showed that the general safety of grade 3-5 irAEs ranked from high to low is as follows: ChT (85.1%), placebo (76.5%), ipilimumab (56.0%), nivolumab (48.5%), avelumab (48.4%), camrelizumab (41.8%), pembrolizumab (36.4%), and nivolumab + ipilimumab (21.6%). CPM showed that the rates of grade 3-5 irAEs in the ICI group and the chemotherapy group were 7.35% (154/2,095, 95% CI: [6.23%, 8.47%]) versus 2.25% (42/1,869, 95% CI: [1.58%, 2.92%]), with statistical significance (RR = 3.151, 95% CI = 2.175 to 4.563, Z = 6.07, P = 0.000). The most common irAEs in the ICI group were skin reaction (15.76%, 95% CI: [13.67%, 17.84%]), followed by hypothyroidism (9.73%, 95% CI: [8.07%, 11.39%]), infusion-related reactions (5.93%, 95% CI: [4.29%, 7.58%]), hepatitis (5.25%, 95% CI: [4.28%, 6.22%]), and pneumonitis (4.45%, 95% CI: [3.5%, 5.4%]). Conclusion: Different ICIs had different toxicity manifestations and should not be considered as an entity. Compared with chemotherapy, ICIs were more prone to irAEs, but the overall rates remained low and acceptable. For clinicians, it is important to recognize and monitor the adverse events caused by ICIs for patients with EPC or GEJC.

Recent advances in immune-based approaches for the treatment of esophagogastric cancer.

INTRODUCTION: The year 2021 will be remembered as a transformational year in the management of both esophageal and gastric cancers. Decades of failed clinical trials had seen limited therapeutic advances beyond refinement of the traditional combined modality approach. Targeted strategies against specific molecular alterations did not - with the exception of Her2 - yield the desired breakthroughs, and it was unclear what immune-based approaches would bring to this group of cancers. The presence of tumor-infiltrating lymphocytes in esophagogastric cancer demonstrates that an endogenous immune response is already occurring and potentially amplifiable by immune checkpoint inhibition. Recent data have validated this with FDA approvals in both the locoregional (CheckMate 577) and metastatic disease (CheckMate 649, KeyNote 590 and KeyNote 811) setting which have altered the therapeutic landscape. AREAS COVERED: Here we discuss recent data and ongoing research efforts to better define the role of immune-based approaches and select the patient cohorts who might gain the most benefit from them. EXPERT OPINION: Immunotherapy, and specifically the incorporation of the immune checkpoint inhibitors (ICI) drug class, has altered the therapeutic paradigm of many cancers in recent years. Anti-PD-1 therapies are now the new standard of care for patients with local and advanced disease.

Signet ring cell cancer of stomach and gastro-esophageal junction: molecular alterations, stage-stratified treatment approaches, and future challenges.

PURPOSE: There has been an increase in the incidence of signet ring cell cancer (SRCC) of the stomach and gastro-esophageal junction (GEJ). The multistage carcinogenesis involving genetic and epigenetic aberrations may have a major role in the increasing incidence of SRCC. Although there are numerous studies on the prognostic value of SRCC, they are markedly inconsistent in their results, making it impossible to draw any meaningful conclusions. We aimed to examine the available evidences on molecular alterations and stage-stratified treatment approaches in SRCC of the stomach and GEJ. METHODS: A systematic search was carried out in PubMed. Studies available in English related to SRCC of stomach and gastro-esophageal junction were identified and evaluated. RESULTS: This study reviewed the current evidence and provided an insight into the molecular alterations, stage-stratified treatment approaches, and future challenges in the management of SRCC of the stomach and GEJ. Specific therapeutic strategies and personalized multimodal treatment have been recommended based on the tumor characteristics of SRCC. CONCLUSION: Multistage carcinogenesis involving genetic and epigenetic aberrations in SRCC is interlinked with stage-dependent prognosis. Specific therapeutic strategy and personalized multimodal treatment should be followed based on the tumor characteristics of SRCC. Endoscopic resection, radical surgery, and perioperative chemotherapy should be offered in carefully selected patients based on stage and prognostic stratification. Future studies in genetic and molecular analysis, histopathological classification, and options of multimodality treatment will improve the prognosis and oncological outcomes in SRCC of gastric and GEJ.

Harnessing biomarkers of response to improve therapy selection in esophago-gastric adenocarcinoma.

Advanced esophago-gastric (OG) adenocarcinomas have a high mortality rate and new therapeutic options are urgently required. Despite recent advances in understanding the molecular characteristics of OG cancers, tumor heterogeneity poses a challenge in developing new therapeutics capable of improving patient outcomes. Consequently, chemotherapy remains the mainstay of systemic treatment, with the HER2 being the only predictive biomarker routinely targeted in clinical practice. Recent data indicate that immunotherapy will be incorporated into first-line chemotherapy, but further research is required to refine patient selection. This review will summarize the clinical strategies being evaluated to utilize our knowledge of predictive biomarkers with reference to novel therapeutics, and discuss the barriers to implementing precision oncology in OG adenocarcinoma.

COVID-19 Pneumonia on Post-Operative Day 2 after Esophagectomy: Performing Esophago-Gastric Junction Cancer Surgery during the SARS-Cov-2 Second Wave.

The coronavirus disease 2019 (COVID-19) pandemic has had a substantial impact on the provision of medical healthcare. Due to an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) transmission, elective surgical treatment has been suspended in many centers. The effects of COVID-19 in the early post-operative period after esophagectomy remains unknown. In this report, we present three cases of patients diagnosed with esophago-gastric junction cancer who were scheduled for elective esophagectomy with a curative intention during second wave of COVID-19 pandemic in a single high-volume tertiary center. Despite all available safety measures, one of the patients developed COVID-19 pneumonia on post-operative day two, leading to an impaired respiratory function and increased pleural fluid collection from the chest tube, resulting in a prolonged time of hospital stay. Finding a good balance between the COVID-19-related perioperative risks and consequences of delaying surgical treatment in patients diagnosed with esophago-gastric cancer is a challenge. In order to achieve the best possible outcome, care must be taken to ensure availability of necessary treatment options and to reduce the risk of SARS-Cov-2 transmission perioperatively.

Impact of Radiation Dose on Postoperative Complications in Esophageal and Gastroesophageal Junction Cancers.

Introduction: The impact of radiation prescription dose on postoperative complications during standard of care trimodality therapy for operable stage II-III esophageal and gastroesophageal junction cancers has not been established. Methods: We retrospectively reviewed 82 patients with esophageal or gastroesophageal junction cancers treated between 2004 and 2016 with neoadjuvant chemoradiation followed by resection at a single institution. Post-operative complications within 30 days were reviewed and scored using the Comprehensive Complication Index (CCI). Results were compared between patients treated with <50 Gy and ≥ 50 Gy, as well as to published CROSS study neoadjuvant chemoradiation group data (41.4 Gy). Results: Twenty-nine patients were treated with <50 Gy (range 39.6-46.8 Gy) and 53 patients were treated with ≥ 50 Gy (range 50.0-52.5 Gy) delivered using IMRT/VMAT (41%), 3D-CRT (46%), or tomotherapy IMRT (12%). Complication rates and CCI scores between our <50 Gy and ≥ 50 Gy groups were not significantly different. Assuming a normal distribution of the CROSS data, there was no significant difference in CCI scores between the CROSS study neoadjuvant chemoradiation, <50 Gy, or ≥ 50 Gy groups. Rates of pulmonary complications were greater in the CROSS group (50%) than our <50 Gy (38%) or ≥ 50 Gy (30%) groups. Conclusions: In selected esophageal and gastroesophageal junction cancer patients, radiation doses ≥ 50 Gy do not appear to increase 30 day post-operative complication rates. These findings suggest that the use of definitive doses of radiotherapy (50-50.4 Gy) in the neoadjuvant setting may not increase post-operative complications.

Hyperprogression in PDL1 Expressive, Recurrent Gastroesophageal-junction Adenocarcinoma After Pembrolizumab.

Hyperprogression is a pattern of accelerated tumor growth noted uncommonly after the use of immune checkpoint inhibitors in some patients. We present a 56-year-old female with gastroesophageal junction (GEJ) adenocarcinoma who was initially treated with neoadjuvant radiation and chemotherapy with carboplatin and paclitaxel, followed by esophagogastrectomy and postoperative FOLFOX chemotherapy. After a stable two-year course, she was noted to have recurrence at the GEJ which was biopsy confirmed. She was started on pembrolizumab, after which she developed several new metastases noted on the PET/CT. Lesions were noted in iliac bones, spine, retroperitoneal lymph nodes, hilar nodes, mediastinum, and lungs. Postdiscontinuation of the pembrolizumab, she received six cycles of paclitaxel with ramucirumab and showed remarkable improvement on the next imaging scan with resolution of osseous lesions, lung nodules and significant improvement in hilar, mediastinal, and retroperitoneal lymph nodes. We hope that this case report sheds further light on this uncommon complication of immune checkpoint inhibitors.

EORTC-1203-GITCG - the "INNOVATION"-trial: Effect of chemotherapy alone versus chemotherapy plus trastuzumab, versus chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on pathologic response rate: a randomized phase II-intergroup trial of the EORTC-Gastrointestinal Tract Cancer Group, Korean Cancer Study Group and Dutch Upper GI-Cancer group.

BACKGROUND: 10-20% of patients with gastric cancer (GC) have HER2+ tumors. Addition of trastuzumab (T) to cisplatin/fluoropyrimidine-based chemotherapy (CT) improved survival in metastatic, HER2+ GC. When pertuzumab (P) was added to neoadjuvant T and CT, a significant increase in histopathological complete response rate was observed in HER2+ breast cancer. This study aims to investigate the added benefit of using both HER2 targeting drugs (T alone or the combination of T + P), in combination with perioperative CT for localized HER2+ GC. METHODS: This is a prospective, randomized, open-label, phase II trial. HER2 status from patients with resectable GC (UICC TNM7 tumor stage Ib-III) will be centrally determined. Two hundred and-fifteen patients from 52 sites in 14 countries will be centrally randomized (1:2:2 ratio) to one of the following treatment arms: 1. Standard: CT alone. CT regimens will be FLOT (5-FU, leucovorin, oxaliplatin, taxotere) CapOx (capecitabine, oxaliplatin) or FOLFOX (5-FU, leucovorin, oxaliplatin) according to investigator's choice in Europe, and cisplatin/capecitabine in Asia. 2. Experimental arm 1: CT as in control group, plus T (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) at day 1, independent of CT chosen for 3 cycles of 3 weeks before and after surgery. 3. Experimental arm 2: CT plus T as in experimental arm 1, plus P (840 mg every 3 weeks) on day 1. Adjuvant treatment with T or T + P will continue for 17 cycles in total. Stratification factors are: histology (intestinal/non-intestinal); region (Asia vs Europe); location (GEJ vs non-GEJ); HER2 immunohistochemistry score (IHC 3+ vs IHC 2+/FISH+) and chemotherapy regimen. Primary objective is to detect an increase in the major pathological response rate from 25 to 45% either with CT plus T alone, or with CT plus the combination of T and P. DISCUSSION: Depending on the results of the INNOVATION trial, the addition of HER2 targeted treatment with either T or T and P to CT may inform future study designs or become a standard in the perioperative management HER2+ GC. TRIAL REGISTRATION: This article reports a health care intervention on human participants and was registered on July 10, 2014 under ClinicalTrials.gov identifier: NCT02205047 ; EudraCT: 2014-000722-38.

Population pharmacokinetics analysis of nivolumab in Asian and non-Asian patients with gastric and gastro-esophageal junction cancers.

PURPOSE: Nivolumab monotherapy provided clinically meaningful antitumor activity in Asian and non-Asian patients with chemotherapy-refractory gastric cancer (GC) or gastro-esophageal junction cancer (GEJC) in the ATTRACTION-2 and CheckMate 032 studies, respectively. This analysis assessed the population pharmacokinetics (PopPK) of nivolumab, the impact of covariates on pharmacokinetics (PK), and the PK of nivolumab flat dosing in GC/GEJC using samples from these studies. METHODS: PopPK analyses were conducted using data from 1302 patients with solid tumors, including 387 patients with GC/GEJC who had received nivolumab 3 mg/kg once every 2 weeks (Q2W). The impact of covariates on nivolumab PK was assessed in the full model. Nivolumab exposures following a flat dose of 240 mg Q2W in patients with GC/GEJC were simulated and compared with those of 3 mg/kg Q2W. RESULTS: Nivolumab PK was described using a 2-compartment, zero-order intravenous infusion and time-varying clearance (CL) model. Baseline CL in patients with GC/GEJC was ~ 33% greater than in patients with non-small cell lung cancer (NSCLC) in second line or subsequent lines of treatment (2L+). The effect of race was not clinically relevant (< 20% difference). Nivolumab exposures following 240 mg Q2W were similar to 3 mg/kg Q2W in non-Asian patients and 46% higher in Asian patients due to lower body weight. CONCLUSIONS: Nivolumab CL was increased in GC/GEJC relative to NSCLC 2L+. Higher nivolumab exposures achieved with 240 mg Q2W in Asian patients are predicted to be below the acceptable safety margin, supporting the use of a flat dose in both patient populations.

A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2).

BACKGROUND: Nivolumab, an anti-programmed death-1 agent, showed survival benefits in Asian patients, including Japanese, with gastric/gastro-esophageal junction (G/GEJ) cancer. We report the analysis of the Japanese subpopulation from ATTRACTION-2 that evaluated nivolumab versus placebo in unresectable advanced or recurrent G/GEJ cancer after ≥ 2 chemotherapy regimens. METHODS: Data from the Japanese subpopulation in the randomized, double-blind, placebo-controlled, phase 3 trial were analyzed (data cutoff, February 25, 2017). Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). RESULTS: Among the overall study population of 493 patients, 226 (nivolumab 152; placebo 74) were enrolled from 28 sites in Japan. In the Japanese subset, median OS was longer with nivolumab versus placebo (5.4 months, 95% CI 4.6-7.4 versus 3.6 months, 95% CI 2.8-5.0). The risk of death was lower in the nivolumab versus placebo group (hazard ratio 0.58, 95% CI 0.42-0.78; p = 0.0002). Incidences of serious adverse events were 23% (35/152) and 25% (18/72) in the nivolumab and placebo groups, respectively. In the Japanese ITT population, 22% of nivolumab-treated and 28% of placebo-treated patients received prior ramucirumab treatment. Overall, clinical activity of nivolumab was observed regardless of prior ramucirumab use. In the nivolumab group, ORR and PFS were numerically higher in patients with prior ramucirumab use than in those without. CONCLUSIONS: In the Japanese subpopulation, patients receiving nivolumab had longer OS, similar to the overall population, with a manageable safety profile. The interaction between nivolumab and ramucirumab will be clarified in ongoing clinical trials.

EGFR and AKT1 overexpression are mutually exclusive and associated with a poor survival in resected gastric adenocarcinomas.

PURPOSE: The evaluation of molecular targets in gastric cancer has demonstrated the predictive role of HER2 amplification for trastuzumab treatment in metastatic gastric cancer. Besides HER2, other molecular targets are under evaluation in metastatic gastric tumors. However, very little is known about their role in resected tumors. We evaluated the expression of HER2, EGFR, MET, AKT1 and phospho-mTOR in resected stage II-III adenocarcinomas. METHODS: Ninety-two patients with resected stomach (63%) or gastro-esophageal adenocarcinomas (27%) were evaluated. Antibodies anti-HER2, EGFR, MET, AKT1 and phospho-mTOR were used for immunostaining of formalin-fixed paraffin-embedded slides. Using FISH, HER2 amplification was evaluated in cases with an intermediate (+2) staining. RESULTS: EGFR overexpression (11%) was a poor prognostic factor for overall survival (3-year OS: 47% vs 77%; Log-Rank p= 0.033). MET overexpression (36%) was associated with a trend for a worse survival (3-year OS: 65% vs 77%; Log-Rank p= 0.084). HER2 amplification/overexpression and mTOR hyper-phosphorylation were observed in 13% and 48% of tumors, respectively. AKT1 overexpression (8%) was not a prognostic factor by itself (p= 0.234). AKT1 and EGFR overexpression was mutually exclusive and patients with EGFR or AKT1 overexpression experienced a poor prognosis (3-year OS: 52% vs. 79%, Log-Rank p= 0.005). CONCLUSIONS: EGFR is confirmed a poor prognostic factor in resected gastric cancers. We firstly describe a mutually exclusive overexpression of EGFR and AKT1 with potential prognostic implications, suggesting the relevance of this pathway for the growth of gastric cancers.

Proximal gastrectomy versus total gastrectomy for proximal third gastric cancer: total gastrectomy is not always necessary.

BACKGROUND: The appropriate extent of gastric resection for patients with proximal third gastric cancer is controversial. This study addresses whether the choice of surgical strategy (proximal gastrectomy [PG] versus total gastrectomy [TG]) influences the outcomes for proximal third gastric adenocarcinoma. MATERIALS AND METHODS: Review of prospective database at Tata Memorial Hospital from January 2010 to December 2012 identified 343 patients diagnosed and treated for gastric cancer. Of these, 75 underwent curative resections with D2 lymphadenectomy for proximal third gastric adenocarcinoma, which entailed proximal gastrectomy in 43 and total gastrectomy in 32 patients, depending on the epicenter of the primary and its relation with the mid-body of the stomach. Morbidity, lymph node yield, resection margins, patterns of recurrence, and survival were compared between these two groups. RESULTS: 41/75 tumors were pT3 (23 cases [53.4 %] in the PG and 18 cases [56.3 %] in the TG group). Thirty-six patients [83.7 %] in PG and 29 patients [90.6 %] in TG group received neoadjuvant chemotherapy (NACT). There were no significant differences with regard to median blood loss, general complication rates and length of hospitalization between the two groups. The lymph node yield was comparable between the two procedures [PG = 14; TG = 15]. Positive proximal resection margin rates were comparable between the two groups [PG = 4.7 %; TG = 9.4 %], and there was no statistical difference observed in the distal resection margin positivity rates [PG = 4.7 %; TG = 3.1 %]. Regarding the patterns of recurrence, local recurrence in PG was 4.7 % and there was no local recurrence in the TG group (p = 0.08). Distant recurrence rates was dominant in TG [PG = 30.2 % versus TG = 53.1 %]. The overall 2-year survival following PG and TG was 73.8 and 49.9 %, respectively, and not statistically different (p = 0.10). CONCLUSIONS: The extent of resection for proximal third gastric cancer does not influence the clinical outcome. PG and TG have similar survival rates. Both procedures can be accomplished safely. Therefore, PG should be an alternative to TG, even in locally advanced proximal gastric cancers treated by NACT, provided that the tumor size and location permit preservation of adequate remnant of stomach without compromising oncological resection margins. Future QOL studies would further lend credence to the concept of PG for proximal third gastric cancer.

Potential role of rilotumumab in the treatment of gastric cancer.

In 2014, outcomes for patients with advanced gastric cancer remain extremely poor with a high level of unmet need regarding effective therapeutic options. However, recent years have seen increasing interest in the role of the MET signaling pathway in this disease subtype, leading to the development and evaluation of MET-targeted therapeutics. Rilotumumab is a monoclonal antibody directed against hepatocyte growth factor, the only known ligand for the MET receptor. It is an unlicensed product which is currently undergoing evaluation in a randomized Phase III trial in 'MET-positive' gastric cancer. Here we discuss the background to the treatment of gastric cancer as well as the characteristics of rilotumumab and reported results with this agent in the trials performed to date.