Contribution of capecitabine for therapy of patients with gastroesophageal cancer: an update of recent phase III results

Putao Cen, Eric D Tetzlaff, Jaffer A AjaniDepartment of Gastrointestinal Medical Oncology in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center, Houston, TX, USABackground: Capecitabine, an orally administered fluoropyrimidines, is widely used in the treatment of multiple malignancies. It has been extensively evaluated in patients with gastroesophageal carcinoma. Since recent reviews have discussed phase I/II trials (Cancer 107:221–231, 2006; Drugs 67:601–610, 2007), we focus on the impact of the results of the most current phase III trials using capectiabine in the treatment of advanced gastroesophageal cancers, primarily in the first-line setting.Methods: To find published phase III trials, Medline was searched for English-language clinical trials published from 1996 through June 2007 along with relevant abstracts presented at the American Society of Clinical Oncology, and meetings of the European Cancer Conference and European Society of Medical Oncology. Only representative trials were chosen for this manuscript.Results: The most frequently investigated combinations are capecitabine with taxanes, platinols, and camptothecins. Recent results of a large phase III trial (REAL-2) in untreated patients with gastroesophageal cancer suggest that capecitabine is a non-inferior substitute for intravenous 5-fluorouracil. These results of REAL-2 trial are substantiated by a smaller phase III trial. Previous analysis of multiple trials had suggested that capecitabine, when combined in doses lower than 1250 mg/m2 twice daily, consistently resulted in lower frequency of Grade 3 or 4 toxic effects.Conclusions: Capecitabine provides much needed convenience to patients with gastroesophageal cancer. The recent data derived from two phase III trials confirm that capecitabine is a suitable substitute for intravenous 5-fluorouracil in patients whose swallowing is not greatly affected. Capecitabine remains a subject of further investigations in this group of patients with interest.Keywords: capecitabine, gastroesophageal cancer, oral fluoropyrimidine

Polymorphisms of TGFB1 and VEGF genes and survival of patients with gastric cancer

<p>Abstract</p> <p>Background</p> <p>Some <it>TGFB1 </it>and <it>VEGF </it>polymorphisms are believed to be functional. Given that these genes are involved in tumor growth and progression including angiogenesis, dissemination, and invasiveness, we hypothesized that these polymorphisms would be associated with survival in patients with gastric cancer.</p> <p>Methods</p> <p>We genotyped <it>TGFB1 </it>-509 C>T, +1869 T>C, and +915 G>C and <it>VEGF </it>-1498T>C, -634G>C, and +936C>T in 167 patients with gastric cancer. Using the Kaplan and Meier method, log-rank tests, and Cox proportional hazard models, we evaluated associations among <it>TGFB1 </it>and <it>VEGF </it>variants with overall, 1-year, and 2-year survival rates.</p> <p>Results</p> <p>Although there were no significant differences in overall survival rates among all polymorphisms tested, patients with <it>TGFB1</it>+915CG and CC genotypes had a poorer 2-year survival (adjusted hazard ratio (HR), 3.06; 95% confidence interval (CI), 1.09–8.62; <it>P </it>= 0.034) than patients with the GG genotype had. In addition, patients heterozygous for <it>VEGF </it>-634CG also had a poorer 1-year survival (adjusted HR, 2.08; 95% CI, 1.03–4.22; <it>P </it>= 0.042) than patients with the -634GG genotype.</p> <p>Conclusion</p> <p>Our study suggested that <it>TGFB1</it>+915CG/CC and <it>VEGF </it>-634CG genotypes may be associated with short-term survival in gastric cancer patients. However, larger studies are needed to verify these findings.</p

Tislelizumab versus chemotherapy as second-line treatment for European and North American patients with advanced or metastatic esophageal squamous cell carcinoma: a subgroup analysis of the randomized phase III RATIONALE-302 study

Esophageal squamous cell carcinoma; TislelizumabCarcinoma de células escamosas de esófago; TislelizumabCarcinoma de cèl·lules escamoses d'esòfag; TislelizumabBackground The phase III RATIONALE-302 study evaluated tislelizumab, an anti-programmed cell death protein 1 antibody, as second-line (2L) treatment for advanced/metastatic esophageal squamous cell carcinoma (ESCC). This prespecified exploratory analysis investigated outcomes in patients from Europe and North America (Europe/North America subgroup). Patients and methods Patients with tumor progression during/after first-line systemic treatment were randomized 1 : 1 to open-label tislelizumab or investigator’s choice of chemotherapy (paclitaxel, docetaxel, or irinotecan). Results The Europe/North America subgroup comprised 108 patients (tislelizumab: n = 55; chemotherapy: n = 53). Overall survival (OS) was prolonged with tislelizumab versus chemotherapy (median: 11.2 versus 6.3 months), with a hazard ratio (HR) of 0.55 [95% confidence interval (CI) 0.35-0.87]; HR was similar irrespective of programmed death-ligand 1 score [≥10%: 0.47 (95% CI 0.18-1.21); <10%: 0.55 (95% CI 0.30-1.01)]. Median progression-free survival was 2.3 versus 2.7 months with tislelizumab versus chemotherapy [HR: 0.97 (95% CI 0.64-1.47)]. Overall response rate was greater with tislelizumab (20.0%) versus chemotherapy (11.3%), with more durable response (median duration of response: 5.1 versus 2.1 months). Tislelizumab had a favorable safety profile versus chemotherapy, with fewer patients experiencing ≥grade 3 treatment-related adverse events (13.0% versus 51.0%). Those on tislelizumab experienced less deterioration in health-related quality of life, physical functioning, and/or disease- and treatment-related symptoms (i.e. fatigue, pain, and eating problems) as compared to those on chemotherapy, per the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and QLQ-OES18 scores. Conclusions As a 2L therapy for advanced/metastatic ESCC, tislelizumab improved OS and had a favorable safety profile as compared to chemotherapy in European/North American ESCC patients in the randomized phase III RATIONALE-302 study.This work was supported by BeiGene, Ltd. In collaboration with the academic authors, the sponsor participated in the study design, in the collection, analysis and interpretation of data, and in the writing of the report. The authors led the writing of the report, with professional medical writing assistance funded by the sponsor, and the authors were responsible for the decision to submit the article for publication

SRMS as a Novel Therapeutic Target in Gastric Cancer Peritoneal Metastases

https://openworks.mdanderson.org/sumexp21/1233/thumbnail.jp

Recent advances in the management of gastric adenocarcinoma patients [version 1; referees: 2 approved]

Gastric adenocarcinoma (GAC) is one of the most aggressive malignancies and has a dismal prognosis. Therefore, multimodality therapies to include surgery, chemotherapy, targeted therapy, immunotherapy, and radiation therapy are needed to provide advantage. For locally advanced GAC (>cT1B), the emerging strategies have included preoperative chemotherapy, postoperative adjuvant chemotherapy, and (occasionally) postoperative chemoradiation in various regions. Several novel therapies have been assessed in clinical trials, but only trastuzumab and ramucirumab (alone and in combination with paclitaxel) have shown overall survival advantage. Pembrolizumab has been approved by the US Food and Drug Administration on the basis of response rate only for patients with microsatellite instability (MSI-H) or if PD-L1 expression is positive (≥1% labeling index in tumor/immune cells in the presence of at least 100 tumor cells in the specimen). Nivolumab has been approved in Japan on the basis of a randomized trial showing significant survival advantage for patients who received nivolumab compared with placebo in the third or later lines of therapy. The cure rate of patients with localized GAC in the West is only about 40% and that for metastatic cancer is very poor (only 2–3%). At this stage, much more target discovery is needed through molecular profiling. Personalized therapy of patients with GAC remains a challenge

Evolution of checkpoint inhibitors for the treatment of metastatic gastric cancers: Current status and future perspectives

Abstract Background Standard treatment options for patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC) are associated with limited efficacy and some toxicity. Recently, immunotherapy with antibodies that inhibit the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interaction has emerged as a new treatment option. This manuscript reviews early-phase and late-phase trials of immunotherapy in advanced GC/GEJC. Methods Searches for studies of immunotherapy in GC/GEJC were performed using PubMed, ClinicalTrials.gov, and abstract databases for select annual congresses. Findings were interpreted based on expert opinion. Results Monotherapy with anti–PD-1/PD-L1 antibodies, including pembrolizumab, nivolumab, avelumab, durvalumab, and atezolizumab, has shown interesting objective response rates (ORRs; 7–26%) across varying GC/GEJC populations, with ORRs potentially higher in PD-L1 + vs PD-L1 − tumors. Safety profiles compare favorably with chemotherapy, with grade ≥3 treatment-related adverse events occurring in 5–17%. Based on a large phase 2 study, pembrolizumab was approved in the United States for third-line treatment of patients with PD-L1 + GC/GEJC. In a phase 3 trial, third-line or later nivolumab increased overall survival vs placebo in an Asian population, leading to regulatory approval in Japan, although other completed phase 3 trials did not show superiority for pembrolizumab or avelumab monotherapy vs chemotherapy. Other trials in advanced GC/GEJC are assessing various anti–PD-1/PD-L1–based strategies, including administration in first-line and later-line settings and as combination (with chemotherapy or agents targeting other immune checkpoint proteins, eg, CTLA-4, LAG-3, and IDO) or switch-maintenance regimens. Conclusions Anti–PD-1/PD-L1 antibodies have shown encouraging clinical activity in advanced GC/GEJC. Results from ongoing phase 3 trials are needed to further evaluate the potential roles of these agents within the continuum of care

HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology

-ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the as

HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma

CONTEXT: ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. OBJECTIVES: To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. DESIGN: The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. RESULTS: The panel is proposing 11 recommendations with strong agreement from the open-comment participants. RECOMMENDATIONS: The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. CONCLUSIONS: This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results

Galectin-3 synergizes with CD47 to Suppress Phagocytosis and T cell immunity in Peritoneal Metastases of Gastric Adenocarcinoma

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