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Current therapeutic landscape for advanced gastroesophageal cancers.

ABSTRACT: Treatment of advanced gastroesophageal cancers remains challenging for clinicians, patients, and caregivers alike. Despite considerable research, the therapeutic armamentarium is restricted and hardly personalized. In the first-line setting, trastuzumab with a fluoropyrimidine and platinum agent is the standard-of-care in patients with HER2-positive tumor. For the others, a platinum-based doublet (preferably with oxaliplatin) is recommended. Three-drug cytotoxic regimens should be reserved for exceptional cases where patients have good performance status. Triple combinations produce higher toxicity and provide marginal advantage. In the second line setting, the combination of paclitaxel and ramucirumab is preferred over all others. Currently, nothing is approved in the 3rd or later line. Nivolumab has resulted in an improved benefit in an Asian trial. Early trials of TAS-102, STAT3 inhibitors, anti-claudin 18.2 and other immune checkpoint inhibitors (alone or in combination) are ongoing. However, development of reproducible biomarkers for patient enrichment is critical for future progress.

SUBMITTER: Lopez A

PROVIDER: S-EPMC5890037 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Current therapeutic landscape for advanced gastroesophageal cancers.

Lopez Anthony A Harada Kazuto K Mizrak Kaya Dilsa D Ajani Jaffer A JA

Annals of translational medicine 20180201 4

Treatment of advanced gastroesophageal cancers remains challenging for clinicians, patients, and caregivers alike. Despite considerable research, the therapeutic armamentarium is restricted and hardly personalized. In the first-line setting, trastuzumab with a fluoropyrimidine and platinum agent is the standard-of-care in patients with HER2-positive tumor. For the others, a platinum-based doublet (preferably with oxaliplatin) is recommended. Three-drug cytotoxic regimens should be reserved for e ...[more]

PMID: 29666801

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Project description:Gastroesophageal cancer (GEC) remains a challenging problem in oncology. Anatomically, GEC is comprised of distal gastric adenocarcinoma (GC), classically associated with Helicobacter Pylori, while proximal esophagogastric adenocarcinoma (EGJ AC) has increased significantly in incidence over the past years. Despite contrasting etiologies, histologies, and molecular phenotypes of distal and proximal GEC, in many cases perioperative (and metastatic) treatment strategies converge to similar approaches. For patients undergoing curative intent surgery, advances in perioperative chemotherapy and/or chemoradiotherapy, either before and/or after surgery, have demonstrated improved survivals compared to surgery alone. This review focuses on how the 'boundary' of the Z-line and/or the anatomical distinction of 'proximal' (EGJ) vs. 'distal' (GC) cancer has led to diverse inclusion/exclusion criteria for clinical trial enrollment, embodying various combinations of chemotherapy and radiation before and/or after surgery. Supporting evidence of each of these approaches consequently has led to a number of varying practices by geographical region and Institution/Physician, based on differing experience, preference, and clinical circumstance. Adequate direct comparison of these approaches is lacking currently, but data from a number of concerted efforts should be available in the next years to further direct best standards of care. Introduction of biologically targeted agents, namely anti-angiogenics and anti-HER family therapeutics are being evaluated to determine whether further therapeutic gains can be realized over classic cytotoxic chemotherapy alone (with/without radiotherapy). To date, novel molecularly targeted agents have yet to demonstrate benefit in this setting. In the following comprehensive review we will address the intricacies of perioperative treatment of locally advanced GEC, with focus on clinical trials supporting the diverse set of perioperative multidisciplinary approaches.

Project description:ImportanceStandard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have an approximate 40% objective response rate (ORR). The combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) has been efficacious as first-line therapy for other gastrointestinal cancers, such as pancreatic and colon cancers.ObjectiveTo evaluate the clinical activity and safety of FOLFIRINOX as first-line treatment for patients with advanced gastroesophageal adenocarcinoma.Design, setting, and participantsThis is an open-label, single-arm phase 2 study of first-line FOLFIRINOX in patients with advanced gastroesophageal adenocarcinoma. Estimated sample size included 41 patients with ERBB2-negative disease with 90% power to detect an ORR of 60% or greater with α of .10. No enrollment goal was planned for ERBB2-positive patients, but they were allowed to receive trastuzumab in combination with FOLFIRINOX.InterventionsStarting doses were fluorouracil, 400 mg/m2 bolus, followed by 2400 mg/m2 over 46 hours; leucovorin, 400 mg/m2; irinotecan, 180 mg/m2; and oxaliplatin, 85 mg/m2. Trastuzumab was administered as a 6 mg/kg loading dose, followed by 4 mg/kg every 14 days in patients with ERBB2-positive disease.Main outcomes and measuresThe primary end point was ORR by the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included safety profile, progression-free survival (PFS), overall survival (OS), and duration of response.ResultsFrom November 2013 to May 2018, 67 patients were enrolled (median [range] age, 59.0 [34-78] years; including 56 [84%] men), and 26 of 67 (39%) had ERBB2-positive disease. Median follow-up was 17.4 months. The ORR was 61%(95% CI, 44.5%-75.8%) (25 of 41) in the ERBB2-negative group and 85% (95% CI, 65.1%-95.6%) (22 of 26) in the ERBB2-positive group, including 1 patient with complete response. For ERBB2-negative patients, median PFS was 8.4 months and median OS was 15.5 months; for ERBB2-positive patients, median PFS was 13.8 months and median OS was 19.6 months. Fifty-six patients (84%) had dose modifications or treatment delays. The most common toxic effects were neutropenia (91%, n = 61), diarrhea (63%, n = 42), peripheral sensory neuropathy (61%, n = 41), and nausea (48%, n = 32), with no unexpected toxic effects.Conclusions and relevanceThe FOLFIRINOX regimen with or without trastuzumab was associated with improved ORR and PFS in patients with advanced gastroesophageal adenocarcinoma in the first-line setting. This regimen may be a reasonable therapeutic option for patients with preserved performance status.Trial registrationClinicalTrials.gov Identifier: NCT01928290.

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Current therapeutic landscape for advanced gastroesophageal cancers.

Publications

Current therapeutic landscape for advanced gastroesophageal cancers.

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