Trifluridine/tipiracil versus placebo for third or later lines of treatment in metastatic gastric cancer: an exploratory subgroup analysis from the TAGS study.

BACKGROUND: Metastatic gastric cancer and cancer of the esophagogastric junction (GC/EGJ) is an aggressive disease with poor prognosis. In the TAGS study, trifluridine/tipiracil (FTD/TPI) improved overall survival (OS) compared with placebo in heavily pre-treated patients. This unplanned, exploratory subgroup analysis of the TAGS study aimed to clarify outcomes when FTD/TPI was used as third-line (3L) treatment and fourth- or later-line (4L+) treatment. PATIENTS AND METHODS: Patients were divided into a 3L group (126 and 64 in FTD/TPI and placebo arms, respectively) and 4L+ group (211 and 106 in FTD/TPI and placebo arms, respectively). Endpoints included OS, progression-free survival (PFS), time to Eastern Cooperative Oncology Group performance status (ECOG PS) deterioration to ≥2, and safety. RESULTS: Baseline characteristics were generally well balanced between FTD/TPI and placebo for 3L and 4L+ treatment. Median OS (mOS) for FTD/TPI versus placebo was: 6.8 versus 3.2 months {hazard ratio (HR) [95% confidence interval (CI)] = 0.68 (0.47-0.97), P = 0.0318} in the 3L group; and 5.2 versus 3.7 months [0.73 (0.55-0.95), P = 0.0192] in the 4L+ group. Median PFS for FTD/TPI versus placebo was 3.1 versus 1.9 months [0.54 (0.38-0.77), P = 0.0004] in the 3L group; and 1.9 versus 1.8 months [0.57 (0.44-0.74), P < 0.0001] in the 4L+ group. Time to deterioration of ECOG PS to ≥2 for FTD/TPI versus placebo was 4.8 versus 2.0 months [HR (95% CI) = 0.60 (0.42-0.86), P = 0.0049] in the 3L group; and 4.0 versus 2.5 months [0.75 (0.57-0.98), P = 0.0329] in the 4L+ group. The safety of FTD/TPI was consistent in all subgroups. CONCLUSIONS: This analysis confirms the efficacy and safety of FTD/TPI in patients with GC/EGJ in third and later lines with a survival benefit that seems slightly superior in 3L treatment. When FTD/TPI is taken in 3L as recommended in the international guidelines, physicians can expect to provide patients with an mOS of 6.8 months.

Review: Gastric cancer-Clinical aspects.

Gastric cancer (GC) was responsible for over 1 000 000 new cases in 2018 and an estimated 783 000 deaths, making it still the fifth most frequently diagnosed cancer and the third leading cause of cancer deaths in both sexes worldwide. Divergent trends for GC incidence were observed in the USA. Incidence rates, particularly for non-cardia GC, were stable or increasing among persons aged <50 years. In an analysis of data from a public hospital database in Hong Kong, treatment of Helicobacter pylori infection was associated with a lower risk of GC, particularly in older subjects who received treatment ≥10 years before. Based on the results of a 16-year endoscopy-based follow-up eradication trial, patients with incomplete-type intestinal metaplasia (IM) should receive endoscopic surveillance upon H. pylori eradication therapy. Updated guidelines on the endoscopic surveillance of preneoplastic conditions of the stomach (MAPS II) have been published. In the RAINFALL trial, the addition of ramucirumab to a backbone chemotherapy as a first-line regimen failed to improve overall survival (OS) of patients with metastatic disease. Also, pembrolizumab did not prolong OS when compared to paclitaxel in the second-line treatment of patients with advanced GC or esophagogastric junction (EGJ) cancer. Trifluridine/tipiracil improved OS by 2.1 months in the third or further treatment line of patients with advanced GC. In a systematic investigation conducted on Chinese patients with GC, CLDN18-ARHGAP26/6 fusion was associated with signet-ring cell content and was prognostic for a worse outcome and predictive for no benefit from oxaliplatin/fluoropyrimidine-based chemotherapy. Organoid cultures represent an appealing model that may be applied for therapy response testing in the near future.

Comparison of international guidelines on the accompanying therapy for advanced gastric cancer: reasons for the differences.

The purpose of this study was to determine if international guidelines differ in their recommendations concerning additive therapy for advanced, but potentially curable, gastric cancer. A systematic search of the English and German literature was conducted in the databases Medline, Cochrane Database, Embase, and PubMed. The search terms used were 'guidelines gastric cancer,' 'guidelines stomach cancer,' and 'Leitlinien Magenkarzinom.' Six different guidelines published after January 1, 2010, in which the tumors were classified according to the seventh edition of the TNM system (2010), were identified. Although the examined guidelines were based on the same study results, their recommendations concerning accompanying therapy for gastric cancer differ considerably. While perioperative chemotherapy is recommended in Germany, Great Britain, and large parts of Europe, postoperative adjuvant radiochemotherapy or perioperative chemotherapy is recommended in the USA and Canada. In Japan, postoperative adjuvant chemotherapy is recommended.The results of identical studies were interpreted differently in different countries. Since considerable effort is required for each country to separately test relevant studies for their validity and suitability, an international cooperation could simplify the creation of a common basis for guidelines and contribute to improved comparability of international guidelines.

Transthoracic vs transhiatal surgery for cancer of the esophagogastric junction: a meta-analysis.

AIM: To compare the efficacy and safety of the transthoracic and transhiatal approaches for cancer of the esophagogastric junction. METHODS: An electronic and manual search of the literature was conducted in PubMed, EmBase and the Cochrane Library for articles published between March 1998 and January 2013. The pooled data included the following parameters: duration of surgical time, blood loss, dissected lymph nodes, hospital stay time, anastomotic leakage, pulmonary complications, cardiovascular complications, 30-d hospital mortality, and long-term survival. Sensitivity analysis was performed by excluding single studies. RESULTS: Eight studies including 1155 patients with cancer of the esophagogastric junction, with 639 patients in the transthoracic group and 516 in the transhiatal group, were pooled for this study. There were no significant differences between two groups concerning surgical time, blood loss, anastomotic leakage, or cardiovascular complications. Dissected lymph nodes also showed no significant differences between two groups in randomized controlled trials (RCTs) and non-RCTs. However, we did observe a shorter hospital stay (WMD = 1.92, 95%CI: 1.63-2.22, P < 0.00001), lower 30-d hospital mortality (OR = 3.21, 95%CI: 1.13-9.12, P = 0.03), and decreased pulmonary complications (OR = 2.95, 95%CI: 1.95-4.45, P < 0.00001) in the transhiatal group. For overall survival, a potential survival benefit was achieved for type III tumors with the transhiatal approach. CONCLUSION: The transhiatal approach for cancers of the esophagogastric junction, especially types III, should be recommended, and its long-term outcome benefits should be further evaluated.

Can perioperative chemotherapy for advanced gastric cancer be recommended on the basis of current research? A critical analysis.

PURPOSE: According to current guidelines, perioperative chemotherapy is an integral part of the treatment strategy for advanced gastric cancer. Randomized controlled studies have been conducted in order to determine whether perioperative chemotherapy leads to improved R0 resection rates, fewer recurrences, and prolonged survival. The aim of our project was to critically appraise three major studies to establish whether perioperative chemotherapy for advanced, potentially resectable gastric cancer can be recommended on the basis of their findings. MATERIALS AND METHODS: We analyzed the validity of the three most important studies (MAGIC, ACCORD, and EORTC) using a standardized questionnaire. Each study was evaluated for the study design, patient selection, randomization, changes in protocol, participating clinics, preoperative staging, chemotherapy, homogeneity of subjects, surgical quality, analysis of the results, and recruitment period. RESULTS: All three studies had serious shortcomings with respect to patient selection, homogeneity of subjects, changes in protocol, surgical quality, and analysis of the results. The protocols of the MAGIC and ACCORD-studies were changed during the study period because of insufficient recruitment, such that carcinomas of the lower esophagus and the stomach were examined collectively. In neither the MAGIC study nor the ACCORD study did patients undergo adequate lymphadenectomy, and only about half of the patients in the chemotherapy group could undergo the treatment specified in the protocol. The EORTC study had insufficient statistical power. CONCLUSIONS: We concluded that none of the three studies was sufficiently robust to justify an unrestrained recommendation for perioperative chemotherapy in cases of advanced gastric cancer.

Neoadjuvant Therapy of Gastric Cancer: A Decisive Step Forward.

BACKGROUND: Although its incidence has been steadily decreasing in Western countries, gastric cancer remains a leading cause of cancer deaths worldwide. The detection rate of early-stage cancers is improving; nevertheless, the majority of cases is still diagnosed at later stages with a poor prognosis. Furthermore, the results that can be achieved with surgery have reached a plateau of effectiveness. SUMMARY: Neoadjuvant chemotherapy was successfully introduced first in patients with non-curatively resectable disease. In the last decade, neoadjuvant chemotherapy has also been established in potentially curatively resectable cases and has become the state-of-the-art treatment. Esophagogastric junction (EGJ) tumors are not optimally treated with chemotherapy alone, and combined radiochemotherapy (RCT) seems to yield superior outcomes. KEY MESSAGE: The use of neoadjuvant therapy has been successfully established in patients with curatively resectable disease. Neoadjuvant chemotherapy is now a cornerstone in the treatment of gastric cancer and cancer of the EGJ, although further work is needed in order to define the optimal combination regimen. PRACTICAL IMPLICATIONS: Neoadjuvant chemotherapy is currently the gold standard for the treatment of gastric cancer and cancer of the EGJ. Several independent studies have shown the benefits of using combination regimens that included cisplatin and 5-fluorouracil, though recently the use of the EOX (epirubicin, oxaliplatin and capecitabine) regimen has been widely accepted in this setting. Tumors of the EGJ benefit from neoadjuvant treatment with combined RCT. It should be noted that the optimal neoadjuvant regimen in EGJ tumors has not yet been defined, and the survival advantage of neoadjuvant RCT over neoadjuvant chemotherapy remains to be established in this patient population.