Eg5, also known as KIF11, is a motor protein essential for establishing a bipolar spindle and ensuring proper chromosome congression during mitosis. It is amplified in various human cancers and serves as a critical oncogene driving tumour progression. However, the role and clinical significance of Eg5 in gastric cancer has remained elusive. In this study, we showed that Eg5 is upregulation in gastric cancer tissues and is negatively associated with patient prognosis. The ablation of Eg5 inhibits the proliferation and migration of gastric cancer cells and suppresses tumour growth in xenograft mice. Mechanistically, Eg5 ablation induces the formation of monopolar spindle, leading to cell apoptosis and consequent inhibition of tumour growth. Furthermore, Arry520 is demonstrated as a potent Eg5 inhibitor which blocks tumour growth by increasing the formation of cell monopolar spindle and inducing apoptosis. Arry520 exhibits efficiently therapeutic effects on gastric cancer in tumour organoid models, cell-derived xenografts and patient-derived xenografts (PDX) in mice. Collectively, our findings provide evidence for the oncogenic properties of the mitotic protein Eg5 and identify Arry520 as a promising strategy to combat gastric cancer.

Efficacy of 2nd line treatment in advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma remains limited with no identified strong predictor of treatment efficacy. We evaluated the prognostic value of circulating tumor DNA (ctDNA) in predicting the efficacy of immune checkpoint inhibitors (ICI) plus chemotherapy in the randomized PRODIGE 59-FFCD 1707-DURIGAST trial.

ctDNA was evaluated before treatment (baseline) and at 4 weeks (before the third cycle of treatment, C3) using droplet-digital PCR assays based on the detection of CpG methylation.

Progression-free survival (PFS) and overall survival (OS) were shorter in patients with a high (>1.1 ng/mL) versus low (<1.1 ng/mL) ctDNA concentration at baseline (2.3 vs. 5.8 months; HR = 2.19; 95% CI, 1.09-4.41; p = 0.03 and 4.5 vs. 12.9 months; HR = 2.73; 95% CI, 1.29-5.75; p < 0.01), respectively, after adjustment for identified prognostic variables. Patients with a ctDNA decrease ≤75% between baseline and C3 versus a ctDNA decrease >75% had a worse objective response rate (p = 0.007), shorter PFS (2.2 vs. 7.4 months, HR = 1.90; 95% CI, 1.03-3.51; p = 0.04) and OS (6.6 vs 16.0 months; HR = 2.18; 95% CI, 1.09-4.37; p = 0.03).

An early decrease in ctDNA concentration is a strong predictor of the therapeutic efficacy of ICI plus chemotherapy in advanced gastric/GEJ adenocarcinoma. Clinical Trial Information NCT03959293 (DURIGAST).

Conversion surgery (CS) following systemic chemotherapy (SCT) has been suggested as a promising strategy for improving prognosis of patients with advanced gastric carcinoma (GC). The evidence, however, comes mostly from small-scale studies. Moreover, controversy exists over the criteria for selecting patients for SCT. We retrospectively analyzed 123 patients treated between 2007 and 2023. Thirty-one underwent CS, 44 received primary radical surgery (R0) with adjuvant chemotherapy (ACT), and 48 received surgical or palliative treatment. Survival rates and predictors of successful conversion were assessed. Median survival for R0 + ACT (30.4 months, 95%CI: 20.9-45.0) was non-significantly higher than SCT + R0 (19.4 months, 95%CI: 10.3-40.1; P = 0.2353). Successful downstaging after SCT was observed in 54.8% of CS patients. This group of SCT responders had significantly lower laboratory markers CEA, NLR and PLR (P-value of 0.019; 0.036 and 0.029, respectively). Both successful and failed conversion groups had significantly longer survival than group with palliative treatment (16.0 months, 95%CI: 8.4-19.1 vs. 7.4 months, 95%CI: 5.3-9.9; P = 0.0003). Multivariable analysis confirmed significantly lowered hazard and prolonged overall survival in CS vs. palliative treatments after adjusting for age and stage differences (P = 0.0014). Conversion therapy improves short-term survival and offers potential for long-term survival in select stage IV GC patients.

Gastric cancer is the fifth most common cancer globally and is associated with significant morbidity and mortality. Despite its alarming prevalence, limited comparative evidence exists on its treatment efficacy and prognosis across diverse China populations.

To address this, our study used a large-scale dataset from the National Cancer Information Database, including data from 220,304 patients from 53 leading hospitals across 27 provinces in China.

From 2017 to 2023, early-stage (Stages I-II) gastric cancer diagnoses increased to 35.63% of all cancer cases. Our study evaluated the neoadjuvant treatment strategies, adjuvant post-operative therapy, first- and second-line management for progressive stages, alongside current gastric cancer treatment guidelines in China. Notably, immunotherapy accounted for 16.17% and 23.28% of first- and second-line treatments for late-stage gastric cancers, and 14.56% and 5.00% for neoadjuvant and adjuvant therapies, respectively. Analysis of survival rates revealed that the 1-, 2-, 3-, 4-, and 5-year survival rates were 74.07%, 54.89%, 44.21%, 37.97%, and 33.53%, respectively. The 5-year survival rates across stages I-IV were 85.07%, 49.34%, 35.56%, and 13.15%, respectively.

These findings offer critical insights into the current state of gastric cancer treatment in China and can inform future initiatives to improve therapeutic outcomes for patients with gastric cancer.

Tumor microenvironment (TME) plays a pivotal role in progression and low responsiveness to chemotherapy of gastric cancer (GC). The cascade of events that culminate with a sustained and chronic activation of inflammatory pathways underlies gastric tumorigenesis. Infiltrating immune cells enrolling in crosstalk with cancer cells that regulate inflammatory and immune status, generating an immunosuppressive TME that influences the response to therapy. Here we discuss the role of TME and the activation of inflammatory pathways to comprehend strategies to improve drug response. Furthermore, we provides systematic insight the role of TME cytotypes and related signatures reinforcing the critical roles of TAMs and Tregs, in promoting GC chemoresistance and tumor progression.

Cancer is a systemic manifestation of aberrant cell cycle activity and dysregulated cell growth. Genetic mutations can determine tumor onset by either augmenting cell division rates or restraining normal controls such as cell cycle arrest or apoptosis. As a result, tumor cells not only undergo uncontrolled cell division but also become compromised in their ability to exit the cell cycle accurately. Regulation of cell cycle progression is enabled by specific surveillance mechanisms known as cell cycle checkpoints, and aberrations in these signaling pathways often culminate in cancer. For instance, DNA damage checkpoints, which preclude the generation and augmentation of DNA damage in the G1, S, and G2 cell cycle phases, are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Notably, tumors have evolved to become dependent on checkpoints for their survival. For example, checkpoint pathways such as the DNA replication stress checkpoint and the mitotic checkpoint rarely undergo mutations and remain intact because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation leading to cell death. In this review, we initially focus on cell cycle control pathways and specific functions of checkpoint signaling involved in normal and cancer cells and then proceed to examine how cell cycle control and checkpoint mechanisms can provide new therapeutic windows that can be exploited for cancer therapy. SIGNIFICANCE STATEMENT: DNA damage checkpoints are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Conversely, DNA replication stress and mitotic checkpoints rarely undergo mutations because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation, leading to cancer cell death. This review focuses on the checkpoint signaling mechanisms involved in cancer cells and how an emerging understanding of these pathways can provide new therapeutic opportunities for cancer therapy.

Recent advancements in biomarker-driven therapies have significantly transformed the treatment paradigm for unresectable metastatic gastric cancer (mGC). These innovations, however, have introduced not only issues related to accessibility but also complexities for treating physicians, particularly general oncologists, in selecting the most appropriate treatment for each patient and deciding on the best sequencing strategy. This manuscript presents an algorithm developed by the Brazilian Group of Gastrointestinal Tumours, designed to provide straightforward guidance in the management of unresectable mGC. This algorithm, grounded in evidence for fit patients, aims to streamline therapeutic decision-making in clinical practice, assuming the absence of access and resource constraints.

Gastrointestinal (GI) malignancies remain the culprit behind a substantial portion of cancer-related mortality worldwide, and outcomes for patients with advanced or metastatic GI cancers remain poor despite continued efforts to improve care. In 2024, the ongoing clinical trials to optimize and improve GI cancer care showcased progress in molecular diagnostics, systemic therapies, and localized treatment approaches, providing hope for continued progress toward improved patient outcomes.

This review summarizes selected updates in GI cancer care from the 2024 ASCO and ESMO Annual Meetings, including both positive and negative trials that, while not universally practice-changing, contribute to shaping GI cancer care, clinical management, or address key questions in the field. The selected trials cover early detection and diagnostic advances, perioperative management, metastatic disease management, and immune checkpoint inhibitor (ICI)'s emerging role in GI cancer.

Various clinical trials in perioperative management and their results continue to reshape or strengthen the current treatment paradigms. The use of ICIs for microsatellite instability-high colorectal cancer (CRC) presented a notable advancement with the potential to improve patient outcomes. Localized treatments such as thermal ablation appear to benefit some patients with CRC and liver metastases.

The collection of trial results presented at the 2024 ASCO and ESMO Annual Meetings denote the ongoing efforts of the medical and scientific community for optimizing GI cancer care. The ongoing efforts of the GI cancer research and patient community provide hope for continued progress toward improved patient outcomes and new standards of care.

Biweekly irinotecan plus cisplatin combination therapy (BIRIP) and irinotecan monotherapy (IRI) are both expectable second-line chemotherapy (SLC) options for treating advanced gastric cancer (AGC). Although many patients receiving SLC have undergone gastrectomy, the impact of gastrectomy on SLC remains unclear, and the impact of gastrectomy may vary from regimen to regimen.

A total of 290 eligible patients registered in two randomized phase III trials evaluating BIRIP (IRI, 60 mg/m2; CDDP, 30 mg/m2, q2w) or IRI (150 mg/m2, q2w) for patients with AGC was classified into the prior gastrectomy subgroup (PGG) or the no gastrectomy subgroup (NGG). We performed a subgroup analysis to evaluate the impact of gastrectomy on second-line BIRIP and IRI.

The BIRIP demonstrated significantly longer OS (11.1 vs. 6.8 months; HR 0.64; P = 0.026) and PFS (3.7 vs. 2.3 months; HR 0.54; P = 0.003) than the IRI, as well as better ORR (23.5% vs. 7.1%, P = 0.046) and DCR (74.5% vs. 47.6%, P = 0.010) in NGG. Although in PGG, the BIRIP failed to demonstrate differences in OS (13.8 vs. 13.8 months; HR 0.94; P = 0.722), PFS (4.9 vs. 4.5 months; HR 0.82; P = 0.194), ORR (18.3% vs. 20.5%) and DCR (70.4% vs. 65.1%). The incidence of grade 3 or worse adverse events did not differ except for a high incidence of anemia in the BIRIP group in PGG.

BIRIP was an effective treatment option that may improve survival outcomes among patients with AGC without previous gastrectomy.

UMIN000025367.

The FLOT4 trial demonstrated superior survival of perioperative chemotherapy with 5-fluorouracil, oxaliplatin, and docetaxel (FLOT) compared to anthracycline triplets for resectable gastric cancer. These results were presented at the American Society of Clinical Oncology (ASCO) congress in June 2017 and published in April 2019. However, adoption of novel treatments in clinical practice often encounters delays. This study assesses the patterns of perioperative chemotherapy utilization and FLOT uptake in clinical practice within the Netherlands.

A retrospective cohort study was conducted with resectable gastric cancer patients (cT1-4a,XcNallcM0) between 2015-2020 from the Netherlands Cancer Registry. Descriptive statistics, Cochran-Armitage tests, Fisher's exact or unpaired T-tests, and Jonckheere-Terpstra tests were used to analyze chemotherapy trends and FLOT uptake across hospitals.

Among 3290 included patients, 42.9 % received neoadjuvant treatment. In 2015, 43.6 % of patients received perioperative chemotherapy versus 43.5 % in 2020 (p = 0.63). 40 out of 62 hospitals (64.5 %) adopted FLOT between the ASCO presentation and the full publication. FLOT increased from 42.9 % before publication to 86.8 % after publication (p < 0.0001), while anthracycline triplet use decreased to 0.9 % (p < 0.0001). Higher hospital volume was associated with fewer days to adoption (p = 0.04) but not with adoption of FLOT before publication (p = 0.14).

Timing of FLOT adoption varied among Dutch hospitals, leading to unequal patient access to effective treatments. Establishing (inter)national guidelines on provisional treatment adjustment pending publication is crucial to reduce variation in access. Moreover, rapid publication of final trial results is imperative to reduce variation in practice and ensure fair patient treatment.

Conversion therapy is a treatment strategy that shifts from palliative systemic therapy to curative surgical treatment for primary and/or metastatic stage IV gastric cancer (GC). To address its clinical statements, the Korean Gastric Cancer Association aims to present a consensus on conversion therapy among experts attending KINGCA WEEK 2024. The KINGCA Scientific Committee and Development Working Group for Korean Practice Guidelines prepared preformulated topics and 9 clinical statements for conversion therapy. The Delphi method was applied to a panel of 17 experts for consensus and opinions. The final comments were announced after the statement presentation and discussed during the consensus meeting session of KINGCA WEEK 2024. Most experts agreed that conversion therapy provides a survival benefit for selected patients who respond to systemic therapy and undergo R0 resection (88.3%). Patients with limited metastases were considered good candidates (94.2%). The optimal timing was based on the response to systemic therapy (70.6%). The regimen was recommended to be individualized (100%) and the duration to be at least 6 months (88.3%). A minimally invasive approach (82.3%) and D2 lymph node dissection (82.4%) were considered for surgery. However, resection for metastases with a complete clinical response after systemic therapy was not advocated (41.2%). All experts agreed on the need for large-scale randomized-controlled trials for further evidence (100%). Recent advancements in treatment may facilitate radical surgery for patients with stage IV GC. Further evidence is warranted to establish the safety and efficacy of conversion therapy.

Doublet platinum or taxane-based therapies are the current standard backbone of treatment for advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Previously used anthracycline-based triplet regimens are no longer used routinely due to toxicity and lack of superior efficacy. We hypothesized that the addition of nab-paclitaxel to FOLFOX (FOLFOX-A) would induce higher efficacy and better tolerability.

Eligible patients with chemotherapy-naïve advanced unresectable HER2-negative gastric or GEJ adenocarcinoma were enrolled in this phase II single-arm trial of FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 mg/m2 over 46-48 hours) + nab-paclitaxel (150 mg/m2) every 14 days of a 28-day cycle. Evaluable disease according to RECIST v1.1 for solid tumors was required. The primary endpoint was the objective response rate. Simon's optimal 2-stage design was used to test 5% versus 20% response rate with 90% power and 10% one-sided type I error rate.

The study enrolled 39 patients. Median age was 63 (range 20-80) years, 30 (77%) were male, 34 (94%) were White, and 21 (57%) had gastric tumors. The median number of cycles completed was 4.5 (range: 0-36), and 25 patients required dose reductions or discontinuation of at least one component due to toxicity. Of the 38 patients evaluable for response, 15 (42.9%) had complete/partial response (CR/PR) as the best response, and 13 (37.1%) had stable disease. progression-free survival (PFS) and OS data were available for 38 patients, with a median follow-up duration of 27 months (range: 18.2-51.9 months for censored patients). Median PFS was 6.6 months (95% CI: 5.6-12.9), with 31.0% (95% CI: 18.4%-52.4%) 12-month PFS rate. The median OS was 10.5 months (95% CI: 8.8-20.7), 12-month OS rate was 44.7% (95% CI: 31.4%-63.7%). Treatment-related grade 3-4 toxicities included peripheral sensory neuropathy and anemia (18.4% each), neutropenia (15.8%), and diarrhea and lymphopenia (7.9% each).

FOLFOX-A has a significant response rate, expected toxicities, and should be considered for future investigation in combination with immunotherapy given the recent approvals.

Paclitaxel plus ramucirumab is recommended as a second-line treatment regimen in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer. We aimed to assess whether switch maintenance or early second-line therapy with paclitaxel plus ramucirumab improved outcomes compared with continuation of oxaliplatin and fluoropyrimidine doublet chemotherapy as a first-line strategy.

ARMANI was a multicentre, open-label, randomised, phase 3 trial done in 31 hospitals in Italy. We enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and locally advanced unresectable or metastatic HER2-negative gastric or gastro-oesophageal junction cancer, who had disease control after 3 months of FOLFOX (leucovorin, fluorouracil, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin). Patients were randomly assigned (1:1) to either paclitaxel 80 mg/m2 on days 1, 8, and 15 plus ramucirumab at 8 mg/kg on days 1 and 15 every 28 days intravenously (switch maintenance group) or continuation of oxaliplatin-based doublet chemotherapy (FOLFOX or CAPOX) for an additional 12 weeks, followed by fluoropyrimidine monotherapy maintenance (control group). Randomisation was stratified by previous gastrectomy (no vs yes), peritoneal carcinomatosis (yes vs no), and primary tumour location (gastro-oesophageal junction vs gastric). Treatment group allocation was done using a web-based system with a minimisation algorithm implementing a random component. The primary endpoint was progression-free survival, analysed on an intention-to-treat basis. The safety population included patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov, NCT02934464, and is complete.

Between Jan 1, 2017, and Oct 2, 2023, 280 patients were randomly assigned to receive paclitaxel plus ramucirumab (switch maintenance group; n=144) or to continue FOLFOX or CAPOX (control group; n=136). All patients were White. 180 (64%) of 280 patients were male and 100 (36%) were female. At a median follow-up of 43·7 months (IQR 24·0-57·9), 253 (90%) of 280 patients had a progression-free survival event: 131 (91%) of 144 patients in the switch maintenance group and 122 (90%) of 136 patients in the control group. Median progression-free survival was 6·6 months (95% CI 5·9-7·8) in the switch maintenance group and 3·5 months (2·8-4·2) in the control group (HR 0·61, 95% CI 0·48-0·79; p=0·0002). The assumption of proportional hazards was violated; in an analysis of 24-month restricted mean survival time, restricted mean progression-free survival was 8·8 months (95% CI 7·7-9·9) in the switch maintenance group and 6·1 months (5·0-7·2) in the control group (p=0·0010). The most frequent grade 3-4 treatment-related adverse events were neutropenia (37 [26%] patients in the switch maintenance group vs 13 [10%] patients in the control group), peripheral neuropathy (eight [6%] vs nine [7%]) and arterial hypertension (nine [6%] vs none). Serious adverse events occurred in 28 (20%) of 141 patients in the experimental group and 15 (11%) of 135 patients in the control group; these events were treatment-related in two (1%) patients in the switch maintenance group (pulmonary embolism) and two (1%) patients in the control group (mucositis and anaemia). No treatment-related deaths occurred.

Paclitaxel and ramucirumab switch maintenance could be a potential treatment strategy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer who are not eligible for immunotherapy or targeted agents.

Partly funded by Eli Lilly.

Gastric cancer with liver metastases (GCLM) is a challenging condition that significantly reduces long-term survival rates, but recent advancements in surgical techniques have shown promise. This study aims to comprehensively evaluate the impact of surgical resection on survival rates in GCLM patients.

We conducted a population-based analysis utilizing the SEER database for patients diagnosed with GCLM between 2010 and 2015. Overall survival (OS) was compared between patients who underwent cancer-directed surgery (CDS) and those who did not. The overlap weighting method based on lasso regression with penalty factors was employed to minimize selection bias. Survival outcomes were compared using Kaplan-Meier curves and Cox proportional hazards models, with subgroup analyses to further explore the effects of surgery among patients.

A total of 3694 patients with GCLM were identified. Of those, 354 (9.58%) patients underwent CDS. After propensity score adjustment, The median OS was significantly higher in the surgical resection group (12 months, 95% confidence interval (CI) 11-16) compared to the nonresection group (6 months, 95% CI: 5-6). Cox regression analysis revealed a substantial improvement in OS for the surgical resection group, with a hazard ratio (HR) of 0.562 (95% CI: 0.482-0.656), including patients with adverse conditions.

The analysis demonstrated a clear association between surgical resection and enhanced OS in GCLM patients. Nevertheless, further research endeavors should be undertaken to identify specific prognostic factors that aid in the selection of optimal candidates for surgical resection.

The efficacy of tislelizumab plus chemotherapy in improving progression-free survival (PFS) and overall survival (OS) in unresectable gastric or gastroesophageal junction cancer (GC/GEJC) has recently been emphasized. This study compared the cost-effectiveness of tislelizumab plus chemotherapy versus placebo plus chemotherapy for the United States (US) and Chinese populations.

Using data from the RATIONALE-305 phase 3 trial, a Markov model was developed to analyze quality-adjusted life years (QALYs), incremental cost-effectiveness ratios (ICERs), incremental net health benefits (INHBs), and incremental net monetary benefits (INMBs). The health state utilities and direct medical costs were obtained from the relevant literature and local cost databases. The model uncertainty was evaluated using sensitivity analyses.

In the base-case analysis, the addition of tislelizumab to chemotherapy yielded an ICER of $37,768.48 per QALY in China, slightly below the willingness-to-pay (WTP) threshold of $38,042.49 per QALY, showing marginal cost-effectiveness with an INHB of 0.05 QALYs and an INMB of $1,852.49. Subgroup analyses revealed ICERs of $23,853.52 for patients with a PD-L1 TAP score ≥ 5% (TAP ≥ 5%). In the US, the ICER was $502,786.22 per QALY in the intent-to-treat (ITT) and $321,395.28 per QALY in the TAP ≥ 5% subgroup, exceeding the US WTP threshold of $150,000.00.

In China, tislelizumab plus chemotherapy is a cost-effective first-line therapy for unresectable GC/GEJC in both ITT and TAP ≥ 5% subgroups. In the US, tislelizumab plus chemotherapy is not cost-effective.

One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design.

Older patients with gastroesophageal (GE) cancer are at increased risk of low treatment tolerability and poor outcome. Dose reduced chemotherapy has been shown to improve tolerability without compromising efficacy in advanced GE cancer. However, the impact of reduced dose preoperative chemotherapy in the curative setting of older patients is unknown. The primary aim of this study was to investigate if dose reduction during preoperative chemotherapy impacts survival in older patients aged≥70 years with resectable GE cancer.

This cohort study included consecutive patients referred to perioperative chemotherapy treated from November 2016 until October 2021. The primary endpoint was overall survival (OS) estimated by Kaplan-Meier analysis. The log-rank test was used to compare survival rates. A multivariate analysis was made to control for potentially interacting covariates.

A total of 548 patients (age ≥ 70, 179; age < 70, 369) were included. Fewer older compared to younger patients had Eastern Cooperative Oncology Group Performance Status 0 at baseline (50 % vs 63 %, p = 0.007). Preoperative chemotherapy was more often initiated at reduced dose in older patients compared to younger (37 % vs 14 %, p < 0.001). Older patients who did not receive a reduce dose in the second or subsequent cycles of preoperative chemotherapy were less likely to complete preoperative chemotherapy when compared to the younger patients (75 % vs 85 %, p = 0.03). Dose reduction in the second or subsequent preoperative chemotherapy cycles was associated with significantly better OS for the older patient population (HR = 0.54, 95 % CI: 1.2-2.9, p = 0.006) but not for the younger (HR = 0.97, 95 % CI: 0.75-1.4, p = 0.83). Dose reduction in the second or subsequent preoperative chemotherapy cycles was associated with lower mortality risk in the multivariate analysis for the older patients (HR = 0.56, 95 % CI: 0.33-0.97, p = 0.04).

Dose reduction in the second or subsequent preoperative chemotherapy cycles seems safe and feasible in older patients without compromising survival and may result in a benefit in OS. This finding should be validated in an independent cohort or a randomized trial.

Gastric cancer (GC) is the fifth most common cancer worldwide with a varied geographic distribution and an aggressive behavior. In Spain, the incidence is lower and GC represents the tenth most frequent tumor and the seventh cause of cancer mortality. Molecular biology knowledge allowed to better profile patients for a personalized therapeutic approach. In the localized setting, the multidisciplinary team discussion is fundamental for planning the therapeutic approach. Endoscopic resection in very early stage, perioperative chemotherapy in locally advanced tumors, and chemoradiation + surgery + adjuvant immunotherapy for the GEJ are current standards. For the metastatic setting, biomarker profiling including Her2, PD-L1, MSS status is needed. Chemotherapy in combination with checkpoint inhibitors had improved the outcomes for patients with PD-L1 expression. Her2 positive patients should receive antiHer2 therapy added to chemotherapy. We describe the different evidences and recommendations based on the literature.

This review highlights advances and recent changes in the treatment paradigm for advanced esophageal adenocarcinoma (EAC) and gastroesophageal junction adenocarcinoma (GEJAC).

Chemotherapy remains the backbone of treatment for advanced EAC/GEJAC. New targets/agents include immunotherapy, HER-2, claudin18.2, and FGFR2b, with various mechanisms (CAR-T, bispecific mAB, ADCs) altering the treatment landscape against these targets. The approaches to these targets may act together, in sequence, and even synergistically to improve outcomes. Herein, we review the state of the field, including highlighting ongoing clinical trials and additional emerging agents and approaches.

Immune checkpoint inhibitors (ICIs) have transformed advanced gastric cancer treatment, yet patient responses vary, highlighting the need for effective biomarkers. Common markers, such as programmed cell death ligand-1 (PD-L1), microsatellite instability/mismatch repair (MSI/MMR), tumor mutational burden, tumor-infiltrating lymphocytes, and Epstein-Barr virus, face sampling challenges and high costs. This study seeks practical, minimally invasive biomarkers to enhance patient selection and improve outcomes.

This multicenter retrospective study analyzed 617 patients with advanced gastric or gastroesophageal junction cancer treated with programmed cell death protein-1 (PD-1)/PD-L1 inhibitors from January 2019 to March 2023. Clinical data and peripheral blood marker data were collected before and after treatment. The primary endpoints were overall survival (OS) and progression-free survival (PFS); the secondary endpoints included the objective response rate (ORR) and disease control rate (DCR). Least absolute shrinkage and selection operator (LASSO)-Cox and LASSO logistic regression analyses identified independent factors for OS, PFS, and ORR. Predictive nomograms were validated using receiver operating characteristic (ROC) curves, areas under the curve (AUCs), C-indices, and calibration curves, with clinical utility assessed via decision curve analysis (DCA), net reclassification improvement (NRI), and integrated discrimination improvement (IDI).

OS-related factors included treatment line, T stage, ascites, pretreatment indirect bilirubin (pre-IBIL), posttreatment CA125, CA199, CA724, and the PLR. PFS-related factors included treatment lines, T stage, metastatic sites, pre-IBIL, posttreatment globulin (GLOB), CA125, and CA199 changes. ORR-related factors included treatment line, T stage, N stage, liver metastasis, pretreatment red cell distribution width-to-platelet ratio (RPR), CA125, and CA724 changes. The nomograms showed strong predictive performance and clinical utility.

Early treatment, lower T stage, the absence of ascites, and lower pre-IBIL, post-CA125, CA199, CA724, and PLR correlate with better OS. Factors for improved PFS include early treatment, lower T stage, fewer metastatic sites, and lower pre-IBIL, post-GLOB, and post-CA125 levels. Nomogram models can help identify patients who may benefit from immunotherapy, providing valuable clinical guidance.

This study compares first-line pembrolizumab plus chemotherapy with chemotherapy alone for patients with HER2-negative advanced gastric cancer (GC) and gastroesophageal junction cancer (GEJC) in China.

A Markov state-transition model was developed based on the phase 3 randomized KEYNOTE-859 clinical trial data. The health state utility values and direct medical costs were derived from the KEYNOTE-859 clinical trial, the relevant literature, and local charges. The measured outcomes included quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER). Probabilistic and one-way sensitivity analyses (OWSA) were performed to assess the uncertainty of the model.

In the base analysis, the incremental effectiveness and cost of pembrolizumab plus chemotherapy versus chemotherapy alone were 0.22 QALYs and $16,627.31, respectively, resulting in an ICER of $76,936.60/QALY, which is higher than the willingness-to-pay threshold in China ($35,864.61/QALY). Subgroup analyses revealed that the ICERs of pembrolizumab plus chemotherapy versus chemotherapy alone were $72,762.68 and $34,813.70 in the populations with PD-L1 CPS of 1 or higher (CPS ≥ 1) and PD-L1 CPS ≥ 10 (CPS ≥ 10), respectively.

As first-line therapy for patients with locally advanced or metastatic HER2-negative GC/GEJC in China, pembrolizumab plus chemotherapy is less cost-effective than chemotherapy alone, however, in the CPS ≥ 10 subgroup is more.

To explore the feasibility of modified docetaxel, cisplatin, and capecitabine (mDCX) chemotherapy with a lower dose of docetaxel than previously reported for stage III resectable gastric cancer patients with a high risk of recurrence or for stage IV gastric cancer patients aiming for conversion surgery.

Patients with stage III resectable HER2-negative gastric cancer with large type 3 or type 4 tumors or extensive lymph node metastasis (bulky N or cN3) and those who had stage IV HER2-negative gastric cancer with distant metastasis were enrolled to receive 30 mg/m2 docetaxel and 60 mg/m2 cisplatin on day 1, followed by 2000 mg/m2 capecitabine per day for 2 weeks every 3 weeks.

Five patients with stage III gastric cancer with a high risk of recurrence received three courses of mDCX, and four patients with stage IV gastric cancer received three or four courses of mDCX. In terms of grade 3 or worse adverse events, leukopenia was observed in one (11%) patient, neutropenia in two (22%) patients, anemia in one (11%) patient, anorexia in two (22%) patients and nausea in two (22%) patients. All six patients with measurable lesions achieved a partial response. All nine patients underwent subsequent surgeries. The histological responses of the nine patients revealed grade 3 in one (11%) patient, grade 2 in five (56%) patients, and grade 1a in three (33%) patients. Three of the nine patients survived without recurrence, and two of them survived for more than four years.

mDCX seems to be feasible and may be helpful as neoadjuvant chemotherapy for patients at high risk of recurrence or as chemotherapy for patients who are likely to undergo conversion surgery.

Fibroblast activation protein (FAP) is abundantly expressed in the stroma of most human solid tumors. Clinical-stage radiolabeled FAP ligands are increasingly used as tools for the detection of various cancer lesions. To unleash the full therapeutic potential of FAP-targeting agents, ligands need to remain at the tumor site for several days after administration. We recently described the discovery of OncoFAP, a high-affinity small organic ligand of FAP with a rapid accumulation in tumors and low uptake in healthy tissues in cancer patients. Trimerization of OncoFAP provided a derivative (named TriOncoFAP, or OncoFAP-23) with improved FAP affinity. In this work, we evaluated the tissue biodistribution profile and the therapeutic performance of OncoFAP-23 in tumor-bearing mice. Methods: OncoFAP-23 was radiolabeled with the theranostic radionuclide 177Lu. Preclinical experiments were conducted on mice bearing SK-RC-52.hFAP (BALB/c nude mice) or CT-26.hFAP (BALB/c mice) tumors. 177Lu-OncoFAP and 177Lu-FAP-2286 were included in the biodistribution study as controls. Toxicologic evaluation was performed on Wistar rats and CD1 mice by injecting high doses of OncoFAP-23 or its cold-labeled counterpart, respectively. Results: 177Lu-OncoFAP-23 emerged for its best-in-class biodistribution profile, high and prolonged tumor uptake (i.e., ∼16 percentage injected dose/g at 96 h), and low accumulation in healthy organs, which correlates well with its potent single-agent anticancer activity at low levels of administered radioactivity. Combination treatment with the tumor-targeted interleukin 2 (L19-IL2, a clinical-stage immunocytokine) further expands the therapeutic window of 177Lu-OncoFAP-23 by potentiating its in vivo antitumor activity. Proteomics studies revealed a potent tumor-directed immune response on treatment with the combination. OncoFAP-23 and natLu-OncoFAP-23 exhibited a favorable toxicologic profile, without showing any side effects or signs of toxicity. Conclusion: OncoFAP-23 presents enhanced tumor uptake and tumor retention and low accumulation in healthy organs, findings that correspond to a strongly improved in vivo antitumor efficacy. The data presented in this work support the clinical development of 177Lu-OncoFAP-23 for the treatment of FAP-positive solid tumors.

Preoperative chemotherapy with 5-fluorouracil and cisplatin (FP) followed by surgery has been considered a standard treatment for patients with stage II/III esophageal squamous cell carcinoma (ESCC) based on the results of a phase III trial (JCOG9907) in Japan. Subsequently, the phase III NExT trial (JCOG1109) revealed the survival benefit of the neoadjuvant DCF regimen, which adds docetaxel to FP, and it became a standard treatment. However, the long-term results and prognostic factors of neoadjuvant DCF therapy in the real world are unknown.

We retrospectively investigated 50 patients with ESCC treated with neoadjuvant DCF therapy from July 2012 to December 2017 at The University of Tokyo Hospital.

Median overall survival (OS) and progression-free survival (PFS) were 32.3 [95% confidence interval (CI) 21.0-NA] and 10.0 months (95% CI 6.3-15.6), respectively. Median OS [not reached (95% CI 31.5-NA) vs. 21.4 months (95% CI 13.5-33.0); p = 0.028] and PFS [83.3 months (95% CI 6.4-NA) vs. 7.4 months (95% CI 6.0-12.8] were significantly longer in patients with an objective response than in non-responders. Of 44 surgical cases, median PFS tended to be longer in pathological lymph node metastasis-negative patients. Conversely, survival did not differ according to cStage (II/III vs. IV) or the average relative dose intensity (ARDI, ≥ 85% vs. < 85%).

The response to neoadjuvant DCF therapy could predict patient prognosis. Additionally, pN+ tended to increase the recurrence risk, whereas cStage and ARDI did not influence survival.

Overall survival (OS) is the most meaningful endpoint in clinical trials. However, owing to their limitations, surrogate endpoints are commonly used and validation studies are required to assess their reliability. Analysis of phase III randomized controlled trials (RCTs) of advanced gastroesophageal cancer (AGC) with > 100 patients, correlation coefficients (r), and determination coefficients (R²) between OS and surrogates were evaluated through meta-analyses. Progression-free survival (PFS), time to progression (TTP), and objective response rate (ORR) were examined to determine their correlations with OS. Analysis of 65 phase III RCTs (29,766 subjects) showed a moderate correlation between PFS/TTP and OS (r = 0.77, R² = 0.59), while ORR correlation was low (r = 0.56, R² = 0.31). Excluding immunotherapy trials improved the PFS/TTP and OS correlations (r = 0.83, R² = 0.70). These findings suggest the potential use of PFS/TTP in AGC phase III investigations, disregarding the use of ORR as a surrogate endpoint.

We aimed to summarize survival data from RCTs in patients with GO adenocarcinoma; estimate and explain worst-, typical-, and best-case-scenarios of survival time; and determine if simple multiples of median overall survival (mOS) could estimate these percentiles.

We systematically searched RCTs of systemic therapies for GO adenocarcinoma published 2000-2022. The following key percentiles were extracted from overall survival curves: 90th (worst-case), 75th (lower-typical), 25th (upper-typical), and 10th (best-case). We tested if these percentiles could be estimated by simple multiples of mOS: 0.25 of the median for the 90th percentile, 0.5 for the 75th, 2 for the 25th, and 3 for the 10th.

We identified 44 trials (22,447 participants). For first line chemotherapy and immunotherapy combined (CI) trials (n = 3) worst-to-best case survival time ranged from 4 months to not reached, compared to 3-30 months for other trials (n = 27) and 1-23 months for subsequent lines (n = 14). Simple multiples of mOS accurately estimated the following survival percentiles: 90th (n = 3/3 trials), 75th (n = 3/3), and 25th (n = 2/3) in first line CI trials. In other first line trials, the mOS accurately estimated the 90th survival percentile in n = 22/27 trials, 75th percentile in n = 26/27, 25th percentile in 27/27 trials, and 10th percentile in 22/27 trials. Simple multiples of the mOS accurately predicted the 90th, 75th, 25th, and 10th survival percentiles in the majority of trials of second and subsequent lines apart from chemotherapy and immunotherapy only trials.

We provide realistic, evidence-based prognostic information as scenarios for survival time which can inform clinical decision-making. Simple multiples of the mOS accurately estimated the percentiles for most groups.

Zolbetuximab (ZOL) is a groundbreaking monoclonal antibody targeting CLDN 18.2, a cancer cell surface protein. It is a first-in-class therapy for gastric and gastroesophageal junction adenocarcinoma. However, there is currently any immunoassay available for bioanalysis of ZOL, hindering its pharmacokinetic studies, therapeutic monitoring, and safety profile refinement. To address this gap, this study presents the development and validation of a novel highly sensitive inner filter effect-based fluorescence immunoassay (IFE-FIA) with quantum dots (QDs) as a probe. This assay enables the quantitative determination of ZOL in plasma samples. The assay involved non-competitive capturing of ZOL from the samples using a specific antigen (CLDN 18.2 protein) immobilized on assay plate microwells. A horseradish peroxidase (HRP)-labelled anti-human IgG was used to measure the immune complex. The assay's detection system relies on the formation of a light-absorbing colored product through an HRP-catalyzed oxidative reaction with the substrate 3,3',5,5'-tetramethylbenzidine. This light absorption efficiently quenched the fluorescence of QDs via the IFE. The measured fluorescence signals corresponded to the concentrations of ZOL in the samples. The conditions of the IFE-FIA and its detection system were refined, and the optimum procedures were established. Following the guidelines of immunoassay validation for bioanalysis, the assay was validated, and all the validation criteria were acceptable. The assay demonstrates high sensitivity, accurately quantifying ZOL at concentrations as low as 10 ng/mL in plasma samples, with acceptable precision. Importantly, it avoids interferences from endogenous substances and plasma matrix. The recoveries in spiked human plasma ranged from 96.8 % to 104.5 %, with relative standard deviations of 4.1 %-6.5 %. The proposed IFE-FIA represents a valuable tool for quantifying ZOL in clinical settings, enabling assessment of its pharmacokinetics, therapeutic drug monitoring, and safety profile refinement.

Locoregional gastric cancer is a still serious problem and perioperative treatments may improve the success of management. Different regimens were examined. The present study purposed to compare the efficacy of fluorouracil-leucovorin-oxaliplatin-docetaxel (FLOT) and docetaxel-cisplatin-fluorouracil (DCF) regimens.

A retrospective multicenter study assessed the patients with locoregional gastric cancer. There are 240 patients (137 DCF, 103 FLOT). Survival rates were compared.

Demographic features were similar between the two groups, but the time period was different. The FLOT group had 7.8% pathological complete response, while the DCF group did not. Disease-free survival was longer in the FLOT than in the DCF group (median not reached - 13.94 months, respectively). Median overall survival was similar (30.9 vs. 37.8 months), but median follow-up affected the analysis. Survival for 36 months was 63% for the FLOT group and 40% for the DCF group (log-rank; p = 0.015).

FLOT regimen was superior to DCF regimen for response and survival rates. DCF is a historical approach. Long-term follow-up period is needed for FLOT treatment.

Neoadjuvant therapy is the standard treatment for patients with locally advanced oesophageal squamous cell carcinoma (OSCC). However, the prognosis remains poor and more intensive neoadjuvant treatment might be needed to improve patient outcomes. We therefore aimed to compare the efficacy and safety of neoadjuvant doublet chemotherapy, triplet chemotherapy, and doublet chemotherapy plus radiotherapy in patients with previously untreated locally advanced OSCC.

In this randomised, open-label, phase 3 trial, patients aged 20-75 years with previously untreated locally advanced OSCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 44 centres across Japan. Patients were randomly assigned (1:1:1) centrally via a web-based system to receive neoadjuvant doublet chemotherapy (two courses of fluorouracil [800 mg/m2 per day intravenously on days 1-5] and cisplatin [80 mg/m2 per day on day 1] separated by an interval of 3 weeks [NeoCF]), triplet chemotherapy (three courses of fluorouracil [750 mg/m2 per day on days 1-5], cisplatin [70 mg/m2 per day on day 1], and docetaxel [70 mg/m2 per day on day 1] repeated every 3 weeks [NeoCF+D]), or doublet chemotherapy (two courses of fluorouracil [1000 mg/m2 per day on days 1-4] and cisplatin [75 mg/m2 per day on day 1] separated by an interval of 4 weeks) plus 41·4 Gy radiotherapy [NeoCF+RT]) followed by oesophagectomy with regional lymph node dissection. Randomisation was stratified by T stage and institution. Participants, investigators, and those assessing outcomes were not masked to group assignment. The primary endpoint was overall survival, analysed by intention to treat. Analysis of safety included all patients who received at least one course of chemotherapy, and analysis of surgical complications included those who also underwent surgery. This study is registered with the Japan Registry of Clinical Trials, jRCTs031180202, and the trial is complete.

A total of 601 patients (529 male individuals and 72 female individuals) were randomly assigned between Dec 5, 2012, and July 20, 2018, with 199 patients in the NeoCF group, 202 patients in the NeoCF+D group, and 200 patients in the NeoCF+RT group. Compared with the NeoCF group, during a median follow-up period of 50·7 months (IQR 23·8-70·7), the 3-year overall survival rate was significantly higher in the NeoCF+D group (72·1% [95% CI 65·4-77·8] vs 62·6% [55·5-68·9]; hazard ratio [HR] 0·68, 95% CI 0·50-0·92; p=0·006) but not in the NeoCF+RT group (68·3% [61·3-74·3]; HR 0·84, 0·63-1·12; p=0·12). Grade 3 or higher febrile neutropenia occurred in two (1%) of 193 patients in the NeoCF group, 32 (16%) of 196 patients in the NeoCF+D group, and nine (5%) of 191 patients in the NeoCF+RT group. Treatment-related adverse events leading to termination of neoadjuvant therapy were more common in the NeoCF+D group (18 [9%] of 202 participants) than in the NeoCF+RT group (12 [6%] of 200) and NeoCF group (eight [4%] of 199). There were three (2%) treatment-related deaths during neoadjuvant therapy in the NeoCF group, four (2%) deaths in the NeoCF+D group, and two (1%) deaths in the NeoCF+RT group. Grade 2 or higher postoperative pneumonia, anastomotic leak, and recurrent laryngeal nerve paralysis were reported in 19 (10%), 19 (10%), and 28 (15%) of 185 patients, respectively, in the NeoCF group; 18 (10%), 16 (9%), and 19 (10%) of 183 patients, respectively, in the NeoCF+D group; and 23 (13%), 23 (13%), and 17 (10%) of 178 patients, respectively, in the NeoCF+RT group. The in-hospital deaths following surgery included three deaths in the NeoCF group, two deaths in the NeoCF+D group, and one in the NeoCF+RT group.

Neoadjuvant triplet chemotherapy followed by oesophagectomy resulted in a statistically significant overall survival benefit compared with doublet chemotherapy and might be the new standard of care for locally advanced OSCC who are in good condition in Japan. Neoadjuvant doublet chemotherapy plus radiotherapy did not show significant improvement of survival compared with doublet chemotherapy.

Japan Agency for Medical Research and Development and National Cancer Center Research and Development Fund.

This study aimed to assess the efficacy and safety of FOLFIRI and paclitaxel in patients with advanced gastric cancer (AGC) who were previously treated with first-line modified docetaxel, cisplatin, 5-fluorouracil (mDCF), or 5-fluorouracil, oxaliplatin, docetaxel (FLOT).

Patients who received a triplet regimen in the first line setting and were treated with FOLFIRI or paclitaxel in the second-line treatment were included.

The study included 198 patients, with 115 receiving FOLFIRI and 83 receiving paclitaxel. The median age was 58 (range = 24-69). The median progression-free survival (mPFS) was 5.2 [95% confidence interval (CI) = 4.4-5.5] months in the FOLFIRI arm, and 4.1 (95% CI = 3.3-4.6) months in the paclitaxel arm (p = .007). The median overall survival (mOS) was 9.4 (95% CI = 7.4-10.5) months in the FOLFIRI arm and 7.2 (95% CI = 5.6-8.3) months in the paclitaxel arm (p = .008). Grade 3-4 neuropathy was higher in patients receiving paclitaxel compared to those receiving FOLFIRI (p = .04). Grade 3-4 diarrhea was 8% in the FOLFIRI arm and 2.4% in the paclitaxel arm (p = .02).

Beyond progression with docetaxel-based triplet chemotherapy, FOLFIRI may be preferred as a second-line treatment over paclitaxel due to its longer mPFS and mOS.

We evaluated whether the addition of docetaxel (D) to a combination comprising 5-fluorouracil/leucovorin (5-FU/LV) or capecitabine (C) plus oxaliplatin (O) (DOF/DOX) improved overall survival (OS) compared with 6 months of 5-fluorouracil (5-FU) or capecitabine in combination with oxaliplatin (FOLFOX/CAPOX) alone in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas (G/GEJ).

This study was an investigator-initiated, open-label, multi-institutional, randomized phase III trial in adult patients with HER2-negative advanced G/GEJs. The primary endpoint of the study was a comparison of median OS by Kaplan-Meier method. Next-generation sequencing was performed on tissue.

Of the 324 patients randomly assigned between July 2020 and November 2022, 305 patients were evaluable for analysis (FOLFOX/CAPOX: 156; DOF/DOX: 149). With a median follow-up time of 19.2 months (95% Confidence Interval [CI] = 16.5 months to 21.9 months) for the entire cohort, the median OS was 10.1 months (95% CI = 9.2 to 10.9) for FOLFOX/CAPOX and 8.9 months (95% CI = 7.3 to 10.5) for DOF/DOX, and this difference was not statistically significant (P = .70). An increased proportion of grade 3 or grade 4 neutropenia (21% vs 3%; P < .001) and grade 2/3 neuropathy (17% vs 7%; P = .005) was seen in patients receiving DOF/DOX. Genomic profiling revealed a low incidence of microsatellite instability (1%) and a high incidence of BRCA1 (8.4%) and BRCA2 (7.5%) somatic alterations.

FOLFOX or CAPOX chemotherapy for 6 months remains one of the standards of care in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas, with no additional survival benefit seen with the addition of docetaxel. Genomic profiling of patients revealed a higher than previously known incidence of somatic BRCA alterations, which requires further evaluation.CTRI (Clinical Trial Registry of India: CTRI/2020/03/023944).