For survival studies, pooling hazard ratios (HRs) across multiple clinical trials through meta-analysis is commonly performed to achieve widely accepted and robust conclusions. However, clinical trials sometimes do not report HRs.

We developed a new, simple approach to estimate HRs by reconstructing life tables from Kaplan-Meier (KM) curves, particularly for small clinical trials. First, we extracted the time points and survival rates from the published KM curves. Then, we reconstructed the life table by reverse derivation of its parameters, using time points and survival rates extracted from the KM curves. Finally, we replotted the KM curves using the Kaplan-Meier method and estimated the HRs via the Cox regression method by SPSS software, using the survival data from the reconstructed life table.

The estimated HRs of 3 examples were 0.510 (95% CI 0.272-0.958, P = 0.036), 2.472 (95% CI 1.548-3.949, P < 0.001), and 0.591 (95% CI 0.291-1.199, P = 0.145), compared with the original HRs of 0.51 (95% CI 0.27-0.96, P = 0.04), 2.33 (95% CI 1.45-3.73, P < 0.001), and 0.62 (95% CI 0.31-1.26, P = 0.18), respectively.

This simple approach allows for the estimate of HRs from published KM curves in small survival studies without reported HRs, facilitating their inclusion in meta-analyses. This increases the overall sample size and enhances the reliability of synthesized clinical evidence.

Several options have been evaluated in metastatic gastro-oesophageal adenocarcinomas (mGA) after failure of first-line fluoropyrimidine and platinum-based chemotherapy. Regorafenib (REGO), a receptor tyrosine kinase inhibitor, has shown promising activity as second- and third-line treatment of mGA.

PRODIGE58-UCGI35-REGIRI was a comparative, prospective, phase II, open-label study evaluating the safety and efficacy of REGO [160 mg/day on day 2 (D2)-D8/D16-D22] plus irinotecan (IRI: 180 mg/m2 intravenously on D1/D15 every 28 days) versus IRI alone in patients with mGA (gastric or gastro-oesophageal junction/tumour Siewert II and III) after failure of first-line fluoropyrimidine and platinum-based chemotherapy. Primary endpoint was overall survival (OS).

Forty-four patients were included in the REGIRI arm and 45 in the IRI arm, primary tumours (67.4%) were mainly localised in the gastro-oesophageal junction, and 60.7% patients had synchronous metastases. With a median follow-up of 19.4 months [95% confidence interval (CI) 16.8-29.9 months], median OS was 6.3 months (95% CI 5.2-7.1 months) versus 8.2 months (95% CI 5.2-9.7 months) in the REGIRI versus IRI arms (hazard ratio 1.11, 95% CI 0.70-1.74, P = 0.66). Median progression-free survival was 2.2 months versus 1.9 months, objective response rate 15.9% versus 13.3%, and disease control rate 45.5% versus 33.3%. Grade 3 treatment-related adverse events (AEs) were reported for 52.3% of patients in the REGIRI arm versus 23.3% in the IRI arm with four toxic deaths (two homozygous UGT1A1∗28 patients died from sepsis and thrombotic microangiopathy, and two heterozygous UGT1A1∗1/∗28 patients from diarrhoea and pulmonary embolism), versus one (UGT1A1∗1 wild-type patient died from primary tumour perforation). Main grade ≥3 AEs were diarrhoea (18.2% versus 7.0%), hypertension (9.1% versus 0.0%), asthenia (6.8% versus 0.0%), febrile neutropenia (6.8% versus 0.0%), neutropenia (6.8% versus 11.6%), and weight decrease (6.8% versus 0.0%).

The study was stopped early because of limited efficacy and increased toxicities in the REGIRI arm, possibly due to drug interactions. No optimal sub-population that could benefit from a REGIRI regimen exposure was identified.

Larotrectinib is the first-in-class, highly selective TRK inhibitor with demonstrated efficacy in various TRK fusion solid tumours. We report the efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal (GI) cancer.

Patients with TRK fusion GI cancer from NAVIGATE (NCT02576431) were included. Response was independent review committee (IRC)-assessed per RECIST v1.1.

As of July 2023, 44 patients were enrolled. Tumour types included colorectal (CRC; n = 26), pancreatic (n = 7), cholangiocarcinoma (n = 4), gastric (n = 3), and one each of appendiceal, duodenal, oesophageal and hepatic cancers. Of the 26 patients with CRC, 16 (62 %) had known microsatellite instability-high (MSI-H) status. For the 43 IRC-eligible patients, overall response rate was 28 % (95 % confidence interval [CI] 15-44) for all patients and 44 % (95 % CI 24-65) for those with CRC. In patients overall and in those with CRC, median duration of response was 27 months (95 % CI 6-not estimable [NE]) and 27 months (95 % CI 6-NE), median progression-free survival was 6 months (95 % CI 5-9) and 7 months (95 % CI 6-NE), and median overall survival was 13 months (95 % CI 7-29) and 29 months (95 % CI 7-NE), respectively. Grade 3/4 treatment-related adverse events (TRAEs) occurred in seven (16 %) patients. There were no deaths due to TRAEs.

Larotrectinib demonstrated long durability, extended survival and manageable safety in patients with TRK fusion GI cancer, including those with MSI-H CRC. This supports the wider adoption of next-generation sequencing testing for NTRK gene fusions in patients with GI 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).

to analyze the most robust research and recommendations that have informed the potential superiority of treatments with anticancer drugs over any type of supportive care for advanced esophageal cancer (EC).

We conducted a critical historical review. First, we identified randomized clinical trials (RCTs) from a previous scoping review conducted by our research group, ASTAC, updating the search strategy. Second, we searched for the most important and recognized international clinical practice guidelines (CPGs) in advanced EC. Finally, we performed a systematic document analysis to compare whether the recommendations proposed in the CPGs were supported by the previously identified relevant evidence.

We identified and assessed 15 RCTs and 11 CPGs from ESMO (eight), ASCO (two), and NICE (one) published over the last 40 years. There is a clear mismatch between these guidelines' recommendations and the available RCTs regarding the efficacy of anticancer drugs compared to best supportive care (BSC).

There is a lack of consistent evidence to support the treatment of advanced EC patients with anticancer drugs, and a notable mismatch exists between the available evidence and the recommendations made by relevant CPGs. As a result, these guidelines may be biased in favoring the use of anticancer drugs over supportive care and in consequence it is advisable to be very prudent when proposing systemic treatments to patients with advanced EC. Further rigorous and independent research is needed to better evaluate the true benefits of anticancer treatments in advanced EC and to update the CPGs accordingly.

Esophageal cancer (EC) continues to be a significant global health concern, with two main subtypes: esophageal squamous cell carcinoma and esophageal adenocarcinoma. Prevention and changes in etiology, improvements in early detection, and refinements in the treatment have led to remarkable progress in the outcomes of EC patients in the past two decades. This seminar provides an in-depth analysis of advances in the epidemiology, disease biology, screening, diagnosis, and treatment landscape of esophageal cancer, focusing on the ongoing debate surrounding multimodality therapy. Despite significant advancements, EC remains a deadly disease, underscoring the need for continued research into early detection methods, understanding the molecular mechanisms, and developing effective treatments.

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.

Nivolumab-based therapies are efficacious with acceptable safety in patients with gastric cancer (GC) and gastroesophageal junction cancer (GEJC). Novel nivolumab-based combination immunotherapies may offer enhanced efficacy in these indications. FRACTION-GC was a signal-seeking, randomized, open-label, phase II adaptive-design trial assessing efficacy and safety of nivolumab in combination with ipilimumab [cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody], relatlimab (lymphocyte-activation gene 3 antibody), or IDO1i (BMS986205, an indoleamine-2,3-dioxygenase-1 inhibitor) in patients with unresectable, advanced/metastatic GC/GEJC.

Previously treated patients with GC/GEJC were randomized to receive nivolumab + ipilimumab, nivolumab + relatlimab, or nivolumab + IDO1i across two tracks: anti-programmed death-(ligand) 1/anti-CTLA-4-naïve (track 1) and -experienced (track 2). Primary endpoints were objective response rate (ORR) by investigator per RECIST v1.1, duration of response, and progression-free survival (PFS) rate at 24 weeks. Secondary endpoint was safety.

Eighty-one patients in track 1 and 81 in track 2 received one combination therapy. With a median follow-up of 50.2 months, ORR [95% confidence interval (CI)] by investigator for nivolumab + ipilimumab, nivolumab + relatlimab, and nivolumab + IDO1i in track 1 was 4% (0.1% to 21.9%), 5% (0.1% to 24.9%), and 13% (4.4% to 28.1%), and for track 2 was 9% (1.1% to 28.0%), 6% (0.7% to 18.7%), and 0% (0% to 15.4%), respectively. PFS rate at 24 weeks (95% CI) was 24% (11% to 39%) for nivolumab + IDO1i track 1, 17% (16% to 32%) for nivolumab + relatlimab track 2, and not estimable for other treatment arms. Grade 3/4 treatment-related adverse events were reported in 22%, 5%, and 18% of patients receiving nivolumab + ipilimumab, nivolumab + relatlimab, and nivolumab + IDO1i in track 1 and in 35%, 11%, and 18% of patients in track 2, respectively. No treatment-related deaths were reported.

While ORR did not meet prespecified expansion criteria in any treatment arm, the safety profile of the combinations was manageable. FRACTION-GC represents a novel adaptive protocol for testing multiple combination immunotherapies.

Gastric cancer is the fourth most common malignancy in Korea and remains the fifth and seventh leading cause of cancer death in males and females, respectively. Although the survival rates for gastric cancer have improved, unresectable or metastatic gastric cancer still has an abysmal prognosis, and the five-year survival rate for patients with stage IV gastric cancer is approximately 6.6% in Korea. The treatment of patients with unresectable or metastatic gastric cancer is based on chemotherapy. A combination of fluoropyrimidine and platinum is the most widely used first-line treatment for gastric cancer worldwide. In recent decades, a better understanding of cancer biology has led to targeted therapies becoming the treatment paradigm for many cancers, including gastric cancer. In addition, immunotherapies have also been reported to improve survival in several cancers, particularly in patients with unresectable or metastatic gastric cancer who have failed multiple lines of chemotherapy. This review evaluates landmark studies on chemotherapy for unresectable or metastatic gastric cancer, including targeted therapies and immunotherapies.

Gastric cancer is one of the most common cancers in both Korea and worldwide. Since 2004, the Korean Practice Guidelines for Gastric Cancer have been regularly updated, with the 4th edition published in 2022. The 4th edition was the result of a collaborative work by an interdisciplinary team, including experts in gastric surgery, gastroenterology, endoscopy, medical oncology, abdominal radiology, pathology, nuclear medicine, radiation oncology, and guideline development methodology. The current guideline is the 5th version, an updated version of the 4th edition. In this guideline, 6 key questions (KQs) were updated or proposed after a collaborative review by the working group, and 7 statements were developed, or revised, or discussed based on a systematic review using the MEDLINE, Embase, Cochrane Library, and KoreaMed database. Over the past 2 years, there have been significant changes in systemic treatment, leading to major updates and revisions focused on this area. Additionally, minor modifications have been made in other sections, incorporating recent research findings. The level of evidence and grading of recommendations were categorized according to the Grading of Recommendations, Assessment, Development and Evaluation system. Key factors for recommendation included the level of evidence, benefit, harm, and clinical applicability. The working group reviewed and discussed the recommendations to reach a consensus. The structure of this guideline remains similar to the 2022 version. Earlier sections cover general considerations, such as screening, diagnosis, and staging of endoscopy, pathology, radiology, and nuclear medicine. In the latter sections, statements are provided for each KQ based on clinical evidence, with flowcharts supporting these statements through meta-analysis and references. This multidisciplinary, evidence-based gastric cancer guideline aims to support clinicians in providing optimal care for gastric cancer patients.

Differences in demographics, medical expertise, and patient healthcare resources across countries have led to significant variations in guidelines. In light of these differences, in this review, we aimed to explore and compare the most recent updates to gastric cancer treatment from five guidelines that are available in English. These English-version guidelines, which have been recently published and updated for journal publication, include those published in South Korea in 2024, Japan in 2021, China in 2023, the United States in 2024, and Europe in 2024. The South Korean and Japanese guidelines provide a higher proportion of content to endoscopic and surgical treatments, reflecting their focus on minimally invasive techniques, function-preserving surgeries, and systemic therapy. The Chinese guidelines provide recommendations addressing not only surgical approaches but also perioperative chemotherapy and palliative systemic therapy. Meanwhile, in the United States and European guidelines, a higher proportion of the content is dedicated to perioperative and palliative systemic therapy, aligning with their approaches to advanced-stage disease management. All guidelines address surgical and systemic chemotherapy treatments; however, the proportion and emphasis of content vary based on the patient distribution and treatment approaches specific to each country. With emerging research findings on gastric cancer treatment worldwide, the national guidelines are being progressively revised and updated. Understanding the commonalities and differences among national guidelines, along with the underlying evidence, can provide valuable insights into the treatment of gastric cancer.

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.

With relatively few direct comparisons among treatment options for previously treated advanced gastric cancer or gastroesophageal junction (GEJ) cancer, network meta-analysis (NMA) may inform evidence-based decision-making. Ramucirumab plus paclitaxel (RAM + PTX) is a preferred regimen in guideline recommendations. NMA of key outcomes may further characterize the relative clinical value of RAM + PTX.

A systematic literature review of randomized controlled trials of adult patients with previously treated advanced gastric/GEJ cancer informed a NMA which compared overall survival, progression-free survival, and discontinuations due to adverse events. Comparisons were reported relative to placebo/best supportive care (BSC) when possible, otherwise relative to RAM + PTX.

The base-case NMA focused on second-line treatment only, from 19 of 28 studies identified. For overall survival, seven of 16 regimens were favorable relative to placebo/BSC, with RAM + PTX as the most favorable. For progression-free survival, five of 14 regimens were unfavorable relative to RAM + PTX. For discontinuations due to adverse events, two of 13 regimens were similar to placebo/BSC: ramucirumab monotherapy and fluorouracil; relative to RAM-PTX, all regimens were similar except ramucirumab monotherapy which was favorable and irinotecan + cisplatin which was unfavorable.

This NMA of trials of previously treated gastric/GEJ cancer suggests that RAM + PTX has one of the more favorable clinical profiles.

Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs), possess immunomodulatory properties and have shown promising outcomes when combined with anti-PD-1 antibodies. The OASIS phase II trial (NCT04503967) is designed to determine the clinical activity and safety of nivolumab (anti-PD-1) and anlotinib hydrochloride (a multi-targets TKI) as second-line or above therapy in patients with advanced gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC). From December 2020 to September 2022, 45 patients with GAC and 3 with ESCC were enrolled in this study. The pre-specified endpoints were reached, with the primary endpoint of overall response rate achieving 29.2%. For secondary objectives, disease control rate was 64.6%; median progression-free survival was 4.0 months; and median overall survival was 11.1 months with a manageable toxicity profile. The exploratory analyses unveiled that the balance of gut bacteria and the presence of a pre-existing immune signature characterized by a high percentage of CD68+PD-L1+ PD-1+ macrophages and low pretreatment variant allele frequencies (VAF), as well as low expression of certain cytokines were significantly associated with improved clinical outcomes in patients with GAC.

Recent advances in the development of biomarker-directed therapy and immunotherapy, for advanced and metastatic gastric cancers, have the potential to improve survival and quality of life. Much attention has been directed towards second- and later-line treatments, and the landscape here is evolving rapidly. However, uncertainty in relative effectiveness, high costs and uncertainty in cost effectiveness represent challenges for decision makers.

To identify economic evaluations for the second-line or later-line treatment of advanced and metastatic gastric cancer. Also, to assess key criteria (including model assumptions, inputs and outcomes), reporting completeness and methodological quality to inform future cost-effectiveness evaluations.

A systematic literature search (from database inception to 5 March 2023) of EconLit via EBSCOhost, Cochrane Library (restricted to National Health Service [NHS] Economic Evaluation Database and Health Technology Assessment [HTA] Database), Embase, MEDLINE and of grey literature was conducted. This aimed to identify systemic treatments that align with National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) Clinical Practice Guidelines. Data were collected on key criteria and on reporting completeness and methodological quality. A narrative synthesis focussed on cost-effectiveness and cost-of-illness studies. Outcomes of interest included total and incremental costs and outcomes (life-years and quality-adjusted life-years), ratios of incremental costs per unit outcome and other summary cost and outcome measures. Also, for cost-effectiveness studies, reporting completeness and the methodological quality were assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and the Philips Checklist, respectively.

A total of 19 eligible economic evaluations were identified (cost-effectiveness studies [n = 15] and cost-of-illness studies [n = 4]). There was a general lack of consistency in the methodological approaches taken across studies. In the main, the cost-effectiveness studies indicated that the intervention under consideration was more effective and more costly than the comparator(s). However, most interventions were not cost effective. No studies were fully compliant with reporting-completeness and methodological-quality requirements. Given the lack of consistency in the approaches taken across cost-of-illness studies, outcomes could not be directly compared.

To our knowledge, this is the first published systematic literature review that has qualitatively synthesised economic evaluations for advanced and metastatic gastric cancer. There were differences in the approaches taken across the cost-effectiveness studies and the cost-of-illness studies. The conclusions of most of the cost-effectiveness studies were consistent despite identified differences in approaches. In the main, the interventions under consideration were not cost effective, presenting challenges to sustainability and affordability. We highlight a requirement for cost-effectiveness evaluations and for second-line or later-line treatments of advanced and metastatic gastric cancer that consider all relevant comparators and that are compliant with reporting-completeness and methodological-quality requirements. By addressing the methodological gaps identified here, future healthcare decision-making, within the context of this rapidly changing treatment landscape, would be better informed.

CRD42023405951.

Background: Osteosarcomas are rare malignancies (<1% of all cancers) that produce an osteoid matrix. Osteosarcomas are the second most frequent type of primary bone tumor after multiple myeloma and the most prevalent primary bone tumor in children. The spectrum of imaging findings of these malignancies varies significantly, reflecting different histological subtypes. For instance, conventional osteosarcoma typically presents with a mixed radiological pattern (lytic and bone mineralization) or with a completely eburneous one; aggressive periosteal reactions such as sunburst, Codman triangle, and soft-tissue components are frequently displayed. On the other hand, telangiectatic osteosarcoma usually presents as a purely lytic lesion with multiple fluid-fluid levels on MRI fluid-sensitive sequences. Other typical and atypical radiological patterns of presentation in other subtypes of osteosarcomas are described in this review. In addition to the characteristics associated with osteosarcoma subtyping, this review article also focuses on imaging features that have been associated with patient outcomes, namely response to chemotherapy and event-free and overall survivals. This includes simple semantic radiological features (such as tumor dimensions, anatomical location with difficulty of radical surgery, occurrence of pathological fractures, and presence of distant metastases), but also quantitative imaging parameters from diffusion-weighted imaging, dynamic contrast-enhanced MRI, and 18F-FDG positron emission tomography and radiomics approaches. Other particular features are described in the text. Overall, this comprehensive literature review aims to be a practical tool for oncologists, pathologists, surgeons, and radiologists involved in these patients' care.

Nonresectable gastric cancer develops rapidly; thus, monitoring disease progression especially in patients receiving nivolumab as late-line therapy is important. Biomarkers may facilitate the evaluation of nivolumab treatment response. Herein, we assessed the utility of serum-based inflammatory indicators for evaluating tumor response to nivolumab.

This multicenter retrospective cohort study included 111 patients treated with nivolumab monotherapy for nonresectable advanced or recurrent gastric cancer from October 2017 to October 2021. We measured changes in the C-reactive protein (CRP)-to-albumin ratio (CAR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) in serum from baseline to after the fourth administration of nivolumab. Furthermore, we calculated the area under the receiver operating characteristic curves (AUC ROCs) for CAR, PLR, and NLR to identify the optimal cutoff values for treatment response. We also investigated the relationship between clinicopathologic factors and disease control (complete response, partial response, and stable disease) using the chi-squared test.

The overall response rate (complete and partial response) was 11.7%, and the disease control rate was 44.1%. The median overall survival (OS) was 14.0 (95% CI 10.7‒19.2) months, and the median progression-free survival (PFS) was 4.1 (95% CI 3.0‒5.9) months. The AUC ROCs for CAR, PLR, and NLR before nivolumab monotherapy for patients with progressive disease (PD) were 0.574 (95% CI, 0.461‒0.687), 0.528 (95% CI, 0.418‒0.637), and 0.511 (95% CI, 0.401‒0.620), respectively. The values for changes in CAR, PLR, and NLR were 0.766 (95% CI, 0.666‒0.865), 0.707 (95% CI, 0.607‒0.807), and 0.660 (95% CI 0.556‒0.765), respectively. The cutoff values for the treatment response were 3.0, 1.3, and 1.4 for CAR, PLR, and NLR, respectively. The PFS and OS were significantly longer when the treatment response values for changes in CAR, PLR, and NLR were below these cutoff values (CAR: OS, p < 0.0001 and PFS, p < 0.0001; PLR: OS, p = 0.0289 and PFS, p = 0.0302; and NLR: OS, p = 0.0077 and PFS, p = 0.0044).

Measurement of the changes in CAR, PLR, and NLR could provide a simple, prompt, noninvasive method to evaluate response to nivolumab monotherapy.

This study is registered with number K2023006.

Esophageal cancer is the seventh most common malignancy worldwide, with over 470 000 new cases diagnosed each year. Two distinct histological subtypes predominate, and should be considered biologically separate disease entities.1 These subtypes are esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). Outcomes remain poor regardless of subtype, with most patients presenting with late stage disease.2 Novel strategies to improve early detection of the respective precursor lesions, squamous dysplasia, and Barrett's esophagus offer the potential to improve outcomes. The introduction of a limited number of biologic agents, as well as immune checkpoint inhibitors, is resulting in improvements in the systemic treatment of locally advanced and metastatic esophageal cancer. These developments, coupled with improvements in minimally invasive surgical and endoscopic treatment approaches, as well as adaptive and precision radiotherapy technologies, offer the potential to improve outcomes still further. This review summarizes the latest advances in the diagnosis and management of esophageal cancer, and the developments in understanding of the biology of this disease.

Efficacy of second-line chemotherapy in advanced gastric or gastrooesphageal junction (GEJ) adenocarcinoma remains limited.

To determine the efficacy of 1 or 2 immune checkpoint inhibitors combined with FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) in the treatment of advanced gastric/GEJ adenocarcinoma.

The PRODIGE 59-FFCD 1707-DURIGAST trial is a randomized, multicenter, noncomparative, phase 2 trial, conducted from August 27, 2020, and June 4, 2021, at 37 centers in France that included patients with advanced gastric/GEJ adenocarcinoma who had disease progression after platinum-based first-line chemotherapy.

Patients were randomized to receive FOLFIRI plus durvalumab (anti-programmed cell death 1 [PD-L1]) (FD arm) or FOLFIRI plus durvalumab and tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4 [CTLA-4]) (FDT arm). The efficacy analyses used a clinical cutoff date of January 9, 2023.

The primary end point was progression-free survival (PFS) at 4 months according to RECIST 1.1 criteria evaluated by investigators.

Overall, between August 27, 2020, and June 4, 2021, 96 patients were randomized (48 in each arm). The median age was 59.7 years, 28 patients (30.4%) were women and 49 (53.3%) had GEJ tumors. Four month PFS was 44.7% (90% CI, 32.3-57.7) and 55.6% (90% CI, 42.3-68.3) in the FD and FDT arms, respectively. The primary end point was not met. Median PFS was 3.8 and 5.4 months, objective response rates were 34.7% and 37.7%, and median overall survival was 13.2 and 9.5 months in the FD and FDT arms, respectively. Disease control beyond 1 year was 14.9% in the FD arm and 24.4% in the FDT arm. Grade 3 to 4 treatment-related adverse events were observed in 22 (47.8%) patients in each arm. A combined positive score (CPS) PD-L1 of 5 or higher was observed in 18 tumors (34.0%) and a tumor proportion score (TPS) PD-L1 of 1% or higher in 13 tumors (24.5%). Median PFS according to CPS PD-L1 was similar (3.6 months for PD-L1 CPS ≥5 vs 5.4 months for PD-L1 CPS <5) by contrast for TPS PD-L1 (6.0 months for PD-L1 TPS ≥1% vs 3.8 months for PD-L1 TPS <1%).

Combination of immune checkpoint inhibitors with FOLFIRI in second-line treatment for advanced gastric/GEJ adenocarcinoma showed an acceptable safety profile but antitumor activity only in a subgroup of patients.

ClinicalTrials.gov Identifier: NCT03959293.

Gastric cancer has the highest incidence and mortality in Eastern Asia. The efficacy and safety of ramucirumab (RAM) monotherapy or in combination with paclitaxel (PTX) for patients with unresectable advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (G/GEA) have been established in clinical trials. To assess the effectiveness and safety of RAM or RAM-based therapy as a second-line treatment in real-world clinical practice in Eastern Asia and to pave the way for future research, a systematic literature review (SLR) was conducted.

Studies published between January 2014 and December 2021 were identified in PubMed, Embase, Cochrane Library, CNKI, Wanfang, and CBM databases.

This SLR included 23 studies from Japan and South Korea, of which 22 were retrospective and 11 were full-text articles. Most studies investigated RAM + PTX (range of median overall survival [mOS] 7.4-12.2 months; median progression-free survival [mPFS] 3.35-7.0 months). Data were limited for RAM, RAM + albumin-bound paclitaxel, and RAM + taxane. RAM + PTX was associated with longer survival (mOS 9.3-12.2 months vs. 5.2-9.7 months; mPFS 4.1-5.1 months vs. 3.0-4.1 months) than PTX. Patients with prior anti-programmed cell death 1 (anti-PD-1) exposure experienced longer mPFS (4.8 vs. 3.4 months) from RAM + taxane than those without prior anti-PD-1 exposure. Few patients (3.3-6.3%) discontinued RAM or RAM-based therapy because of adverse events (AEs). Hematological toxicities were most frequently occurring AEs and no new safety signals were identified compared to clinical trials.

RAM + PTX as a second-line treatment is effective and associated with an acceptable toxicity profile in patients with advanced or metastatic G/GEA in real-world settings of Japan and South Korea. More studies are recommended to further evaluate effectiveness and safety of RAM or RAM-based therapy, especially after anti-PD-1 therapy, in a wider Eastern Asian population.

INPLASY registration number INPLASY2022120023.

The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib showed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumors in a phase I study.

This open-label, multi-cohort study in China enrolled patients with advanced solid tumors who had failed or were intolerable to standard treatment into tumor-specific cohorts. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every three weeks). Results for three cohorts (gastric/gastroesophageal junction [GC/GEJ] adenocarcinoma, esophageal squamous cell carcinoma [ESCC], and biliary tract carcinoma [BTC]) are reported here. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation criteria in Solid Tumors version 1.1.

Between December 17, 2019, and January 29, 2021, 60 patients were enrolled (GC/GEJ, n = 20; ESCC, n = 20; BTC, n = 20). At data cutoff (February 28, 2023), ORRs were 31.6%, 30.0%, and 11.1%, respectively. Median progression-free survival was 4.1, 2.7, and 2.9 months, respectively. Median overall survival was 13.7, 10.4, and 7.0 months, respectively. Overall, grade ≥  3 treatment-related adverse events occurred in 28 (46.7%) patients.

Surufatinib plus toripalimab showed promising antitumor activity and a tolerable safety profile in immunotherapy-naïve patients with GC/GEJ adenocarcinoma, ESCC, or BTC. These findings warrant further study in larger randomized trials comparing surufatinib plus toripalimab with standard therapies in these tumors.

gov NCT04169672.

Paclitaxel is commonly used as a second-line therapy for advanced gastric cancer (AGC). The decision to proceed with second-line chemotherapy and select an appropriate regimen is critical for vulnerable patients with AGC progressing after first-line chemotherapy. However, no predictive biomarkers exist to identify patients with AGC who would benefit from paclitaxel-based chemotherapy.

This study included 288 patients with AGC receiving second-line paclitaxel-based chemotherapy between 2017 and 2022 as part of the K-MASTER project, a nationwide government-funded precision medicine initiative. The data included clinical (age [young-onset vs. others], sex, histology [intestinal vs. diffuse type], prior trastuzumab use, duration of first-line chemotherapy), and genomic factors (pathogenic or likely pathogenic variants). Data were randomly divided into training and validation sets (0.8:0.2). Four machine learning (ML) methods, namely random forest (RF), logistic regression (LR), artificial neural network (ANN), and ANN with genetic embedding (ANN with GE), were used to develop the prediction model and validated in the validation sets.

The median patient age was 64 years (range 25-91), and 65.6% of those were male. A total of 288 patients were divided into the training (n = 230) and validation (n = 58) sets. No significant differences existed in baseline characteristics between the training and validation sets. In the training set, the areas under the ROC curves (AUROC) for predicting better progression-free survival (PFS) with paclitaxel-based chemotherapy were 0.499, 0.679, 0.618, and 0.732 in the RF, LR, ANN, and ANN with GE models, respectively. The ANN with the GE model that achieved the highest AUROC recorded accuracy, sensitivity, specificity, and F1-score performance of 0.458, 0.912, 0.724, and 0.579, respectively. In the validation set, the ANN with GE model predicted that paclitaxel-sensitive patients had significantly longer PFS (median PFS 7.59 vs. 2.07 months, P = 0.020) and overall survival (OS) (median OS 14.70 vs. 7.50 months, P = 0.008). The LR model predicted that paclitaxel-sensitive patients showed a trend for longer PFS (median PFS 6.48 vs. 2.33 months, P = 0.078) and OS (median OS 12.20 vs. 8.61 months, P = 0.099).

These ML models, integrated with clinical and genomic factors, offer the possibility to help identify patients with AGC who may benefit from paclitaxel chemotherapy.

Gastric cancer is one of the most frequent and deadly tumours worldwide. However, the evidence that currently exists for the treatment of older adults is limited and is derived mainly from clinical trials in which older patients are poorly represented. In this article, a group of experts selected from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (SEOM), the Spanish Group for the Treatment of Digestive Tumours (TTD), and the Spanish Multidisciplinary Group on Digestive Cancer (GEMCAD) reviews the existing scientific evidence for older patients (≥65 years old) with gastric cancer and establishes a series of recommendations that allow optimization of management during all phases of the disease. Geriatric assessment (GA) and a multidisciplinary approach should be fundamental parts of the process. In early stages, endoscopic submucosal resection or laparoscopic gastrectomy is recommended depending on the stage. In locally advanced stage, the tolerability of triplet regimens has been established; however, as in the metastatic stage, platinum- and fluoropyrimidine-based regimens with the possibility of lower dose intensity are recommended resulting in similar efficacy. Likewise, the administration of trastuzumab, ramucirumab and immunotherapy for unresectable metastatic or locally advanced disease is safe. Supportive treatment acquires special importance in a population with different life expectancies than at a younger age. It is essential to consider the general state of the patient and the psychosocial dimension.

Trifluridine-tipiracil has shown a survival benefit compared with placebo in patients with chemorefractory metastatic esophago-gastric adenocarcinoma. We aimed to compare the efficacy of trifluridine-tipiracil plus bevacizumab vs trifluridine-tipiracil monotherapy in pre-treated patients with metastatic esophago-gastric adenocarcinoma.

This investigator-initiated, open-label, randomized trial enrolled patients with metastatic esophago-gastric adenocarcinoma. The main inclusion criteria were patients with pre-treated metastatic esophago-gastric adenocarcinoma, and WHO performance status 0 or 1. Participants were randomly assigned (1:1) to receive oral trifluridine-tipiracil (35 mg/m2 twice daily on days 1-5 and 8-12 every 28 days) alone or combined with bevacizumab (5 mg/kg on days 1 and 15) until progression, unacceptable toxicity, or patient decision to withdraw. Randomisation was stratified by sex and treatment line. The primary endpoint was investigator-evaluated progression-free survival. All analyses were based on intention to treat. This trial is registered with EudraCT, 2018-004845-18.

From Oct 1, 2019, to Sept 30, 2021, 103 patients were enrolled and randomly assigned to trifluridine-tipiracil (n = 53) or trifluridine-tipiracil plus bevacizumab (n = 50). The clinical cut-off date was March 1st, 2023, after a median follow-up of 36.6 months. Median progression-free survival was 3.1 months (95% CI 2.0-4.3) in the trifluridine-tipiracil group vs 3.9 months (3.0-6.3) in the trifluridine-tipiracil plus bevacizumab group (hazard ratio 0.68, 95% CI 0.46-1.02; p = 0.058). The most frequent grade 3 or worse adverse event was neutropenia, observed in 26 (49%) patients in the trifluridine-tipiracil group vs 23 patients (46%) in the trifluridine-tipiracil plus bevacizumab group. At least one hospitalization was observed in 21 patients (40%) in the trifluridine-tipiracil group and 22 patients (44%) in the trifluridine-tipiracil plus bevacizumab group. No deaths were deemed treatment related.

In patients with pre-treated metastatic esophago-gastric cancer, trifluridine-tipiracil plus bevacizumab, compared to trifluridine-tipiracil monotherapy, did not significantly prolong progression-free survival. The combination of trifluridine-tipiracil with bevacizumab was well tolerated without increase in severe neutropenia and no new safety signals.

Servier, Roche.

Currently, there is no recommended standard third-line chemotherapy for metastatic gastric cancer.

In this study, we aimed to evaluate irinotecan's efficacy and safety in treating metastatic gastric cancer after the failure of first- and second-line chemotherapy.

Prospective single-arm, two-center, phase II trial.

Patients were aged 18-70 years, with histologically confirmed gastric adenocarcinoma and an Eastern Cooperative Oncology Group performance status of 0-1, progressed during or within 3 months following the last administration of second-line chemotherapy and had no other severe hematologic, cardiac, pulmonary, hepatic, or renal functional abnormalities or immunodeficiency diseases. Eligible patients received 28-day cycles of irinotecan (180 mg/m2 intravenously, days 1 and 15) and were assessed according to the RECIST 1.1 criteria every two cycles. Patients who discontinued treatment for any reason were followed up every 2 months until death. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity.

A total of 98 eligible patients were enrolled in this study. In the intention-to-treat population, the median OS was 7.17 months, the median PFS was 3.47 months, and the ORR and DCR were 4.08% and 47.96%, respectively. In the per-protocol population, the median OS was 7.77 months, the median PFS was 3.47 months, and the ORR and DCR were 4.82% and 50.60%, respectively. The incidence of grade 3 or 4 hematological and non-hematological toxicities was 19.4%, and none of the patients died owing to adverse events. Cox regression analysis revealed neutropenia and baseline thrombocyte levels were independently correlated with PFS and OS.

Irinotecan monotherapy is an efficient, well-tolerated, and economical third-line treatment for patients with metastatic gastric cancer as a third-line treatment.

ClinicalTrials.gov identifier: NCT02662959.

Adding immune checkpoint inhibitors to chemotherapy has been associated with improved outcomes in metastatic esophagogastric adenocarcinoma, but treatment combinations and optimal patient selection need to be established.

To investigate the efficacy and tolerability of the programmed cell death ligand 1 (PDL-1) inhibitor avelumab with paclitaxel plus ramucirumab.

This multicenter, single-group, phase 2 nonrandomized controlled trial was conducted among patients with second-line metastatic esophagogastric adenocarcinoma. Patients pretreated with platinum plus fluoropyrimidine between April 2019 and November 2020 across 10 German centers (median follow-up, 27.4 months [95% CI 22.0-32.9 months]) were included. Data analysis was performed from January to December 2022.

Patients received ramucirumab at 8 mg/kg on days 1 and 15, avelumab at 10 mg/kg on days 1 and 15, and paclitaxel at 80 mg/m2 on days 1, 8, and 15 every 4 weeks.

The prespecified primary end point was overall survival (OS) rate at 6 months, with the experimental therapy considered insufficiently active with an OS rate of 50% or less and a promising candidate with an OS rate of 65% or greater.

Of 60 enrolled patients, 59 patients (median [range] age, 64 [18-81] years; 47 males [70.7%]) were evaluable, including 30 patients with metastatic adenocarcinoma of the stomach and 29 patients with gastroesophageal junction. All patients were pretreated with platinum plus fluoropyrimidine, and 40 patients (67.8%) had received prior taxanes; 24 of 56 evaluable patients (42.9%) had a PDL-1 combined positive score (CPS) of 5 or greater, centrally assessed. The OS rate at 6 months was 71.2% (95% CI, 61.5%-83.7%). The median OS in the intention-to-treat population (59 patients) was 10.6 months (95% CI, 8.4-12.8 months) overall. Among patients assessable by central pathology, median OS was 9.4 months (95% CI, 7.2-11.7 months) in 32 patients with a PDL-1 CPS less than 5 and 14.0 months (95% CI, 6.0-22.1 months) in 24 patients with a PDL-1 CPS of 5 or greater (P = .25). Treatment was generally well tolerated, without unexpected toxicities. Patients with higher vs lower than median T cell repertoire richness showed an increased median OS of 20.4 months (95% CI, 7.7-33.0 months) compared with 8.3 months (95% CI, 3.7-12.9 months; hazard ratio, 0.43; 95% CI, 0.23-0.81; P = .008). Patients with lower vs higher than median cell-free DNA burden had a median OS of 19.2 months (95% CI, 8.9-29.6 months) compared with 7.3 months (95% CI, 3.2-11.4 months; hazard ratio, 0.30; 95% CI, 0.16-0.59; P < .001).

In this study, the combination of avelumab with paclitaxel plus ramucirumab showed favorable efficacy and tolerability in the second-line treatment for metastatic esophagogastric adenocarcinoma. A PDL-1 CPS score of 5 or greater, cell-free DNA level less than the median, and T cell repertoire richness greater than the median were associated with increased median OS.

ClinicalTrials.gov Identifier: NCT03966118.

The updated edition of the German, Austrian and Swiss Guidelines for Systemic Treatment of Gastric Cancer was completed in August 2023, incorporating new evidence that emerged after publication of the previous edition. It consists of a text-based "Diagnosis" part and a "Therapy" part including recommendations and treatment algorithms. The treatment part includes a comprehensive description regarding perioperative and palliative systemic therapy for gastric cancer and summarizes recommended standard of care for surgery and endoscopic resection. The guidelines are based on a literature search and evaluation by a multidisciplinary panel of experts nominated by the hematology and oncology scientific societies of the three involved countries.