Salvage systemic therapy for advanced gastric and oesophago-gastric junction adenocarcinoma.
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ABSTRACT:
SUBMITTER: Tomita Y
PROVIDER: S-EPMC8094513 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background18-Fluorodeoxyglucose-PET (18F-FDG-PET) can be used for early response assessment in patients with locally advanced adenocarcinomas of the oesophagogastric junction (AEG) undergoing neoadjuvant chemotherapy. It has been recently shown in the MUNICON trials that response-guided treatment algorithms based on early changes of the FDG tumor uptake detected by PET are feasible and that they can be implemented into clinical practice. Only 40%-50% of the patients respond metabolically to therapy. As metabolic non-response is known to be associated with a dismal prognosis, metabolic non-responders are increasingly treated with alternative neoadjuvant chemotherapies or chemoradiation in order to improve their clinical outcome. We plan to investigate whether PET can be used as response assessment during radiochemotherapy given as salvage treatment in early metabolic non-responders to standard chemotherapy.Methods/designThe HICON trial is a prospective, non-randomized, explorative imaging study evaluating the value of PET as a predictor of histopathological response in metabolic non-responders. Patients with resectable AEG type I and II according to Siewerts classification, staged cT3/4 and/or cN+ and cM0 by endoscopic ultrasound, spiral CT or MRI and FDG-PET are eligible. Tumors must be potentially R0 resectable and must have a sufficient FDG-baseline uptake. Only metabolic non-responders, showing a < 35% decrease of SUV two weeks after the start of neoadjuvant chemotherapy are eligible for the study and are taken to intensified taxane-based RCT (chemoradiotherapy (45 Gy) before surgery. 18FDG-PET scans will be performed before ( = Baseline) and after 14 days of standard neoadjuvant therapy as well as after the first cycle of salvage docetaxel/cisplatin chemotherapy (PET 1) and at the end of radiochemotherapy (PET2). Tracer uptake will be assessed semiquantitatively using standardized uptake values (SUV). The percentage difference ΔSUV = 100 (SUV Baseline - SUV PET1)/SUV Baseline will be calculated and assessed as an early predictor of histopathological response. In a secondary analysis, the association between the difference SUV PET1 - SUV PET2 and histopathological response will be evaluated.DiscussionThe aim of this study is to investigate the potential of sequential 18FDG-PET in predicting histopathological response in AEG tumors to salvage neoadjuvant radiochemotherapy in patients who do not show metabolic response to standard neoadjuvant chemotherapy.
| S-EPMC3149600 | biostudies-literature
Project description:BackgroundPerioperative chemotherapy is a recommended treatment approach for localised oesophago-gastric junction adenocarcinoma, but not all patients respond to neoadjuvant chemotherapy. Early identification of non-responders and treatment adaptation in the preoperative period could improve outcomes. GastroPET is a national, multicentre phase II trial evaluating a 18FDG-PET/CT-guided preoperative treatment strategy with the R0 resection rate as a primary endpoint. Here, we report on the accuracy of the methodology, the feasibility of the study design and patient safety data after enrolment of the first 63 patients.MethodsPatients with locally advanced oesophago-gastric junction adenocarcinoma (Siewert I - III) stage Ib-IIIc underwent baseline 18FDG-PET/CT scanning and re-evaluation after 14 days of oxaliplatinum-5FU-(docetaxel) chemotherapy. Responders were defined by a ⩾ 35% decrease in tumour FDG standardised uptake value (SUV)average from baseline. Responders continued with the same chemotherapy for 2 to 3 months prior to surgery. PET-non-responders switched to preoperative chemoradiotherapy [weekly carboplatin and paclitaxel with concurrent radiotherapy (45 Gy in 25 fractions)]. Here, we aim to confirm the feasibility of FDG-PET-based response assessment in a multicenter setting and to compare local versus central reading. In addition, we report on the feasibility of the study conduct and patient safety data.ResultsA total of 64 patients received baseline and sequential 14-day 18FDG-PET/CT scanning. And, 63 were allocated to the respective treatment arm according to PET-response [35 (56%) responders and 28 (44%) non-responders]. The concordance of local versus central reading of SUV changes was 100%. Until the date of this analysis, 47 patients (28 responders and 19 non-responders) completed surgery. Postoperative complications of grade ⩾ 3 (Common Terminology Criteria for Adverse Events, CTCAE Version 5.0) were reported in five responders (18%; 95% CI: 7.9-36%) and two non-responders (11%; 95% CI: 2.9-31%), with no statistical difference (p = 0.685). One patient in each arm died after surgery, leading to a postoperative in-hospital mortality rate of 4.3% (2/47 patients; 95% CI: 1.2-14%).ConclusionLocal and central FDG-SUV quantification and PET-response assessment showed high concordance. This confirms the accuracy of a PET-response-guided treatment algorithm for locally advanced oesophago-gastric junction cancer in a multicenter setting. Preoperative treatment adaptation revealed feasible and safe for patients.
| S-EPMC8753528 | biostudies-literature
Project description:Pembrolizumab is a monoclonal antibody directed against PD-1 that is US FDA approved for treatment of advanced PD-L1 positive gastric and gastroesophageal junction adenocarcinoma in patients who have progressed on at least two prior lines of chemotherapy. This article summarizes the clinical evidence regarding safety, tolerability and efficacy of pembrolizumab in this setting. In addition, this article describes the investigational use of pembrolizumab as first- and second-line therapy and in combination with other treatments. Finally, this review compares other checkpoint inhibitors to pembrolizumab for the treatment of this disease, and explores predictive biomarkers of response to PD-1 blockade.
| S-EPMC5827797 | biostudies-literature
Project description:Ramucirumab, a fully humanized monoclonal antibody directed against vascular endothelial growth factor receptor 2, is the first targeted agent to have demonstrated an improvement in survival, as a single agent or in combination, in a molecularly unselected population in gastro-oesophageal cancer. Now that second-line treatment is routinely considered for patients with advanced gastro-oesophageal cancer, ramucirumab, with its favourable toxicity profile compared with cytotoxic treatment, provides a valuable additional treatment option.
| S-EPMC4622287 | biostudies-literature
Project description:BackgroundThis study aimed to identify microRNAs (miRs) as circulating biomarkers of resistance to first-line trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients.MethodsA high-throughput 1015 Exiqon miRCURY LNA™ microRNA inhibitor library screen was performed in trastuzumab-treated HER2-positive NCI-N87 and HER2-negative FLO-1 oesophago-gastric cancer cell lines. NanoString nCounter® miR analysis was performed in NCI-N87, FLO-1, and MAGIC trial (ISRCTN93793971) formalin-fixed paraffin-embedded (FFPE) oesophago-gastric cancer patient samples. MiR-148a-3p copies in plasma samples were quantified using digital droplet polymerase chain reaction (ddPCR) from HER2-positive oesophago-gastric cancer patients treated with standard-of-care trastuzumab-based therapy within the FOrMAT (NCT02112357) and PLATFORM (NCT02678182) clinical trials. The primary endpoints were overall survival (OS) for plasma miR-148a-3p HIGH (>median) versus LOW (≤median). The secondary endpoints were progression-free survival (PFS) and 3-month progression-free rates (PFRs) miR-148a-3p HIGH versus LOW. PLATFORM sensitivity analysis normalised miR-148a-3p (NmiR-148a-3p).ResultsThe inhibition of miR-148a-3p reduced NCI-N87 relative cell viability (<0.6) and expression was high (>242) in NCI-N87 and HER2-positive MAGIC trial patients (n=5). Normalised-miR-148a-3p (NmiR-148a-3p) LOW versus HIGH demonstrated a statistically significant difference in 3-month PFRs (n=23; OR, 0.11 [0.02-0.78]; p=0.027; aOR, 0.03 [0.001-0.71], p=0.029) but no difference in OS or PFS. There was no statistically significant relationship between miR-148-3p LOW versus HIGH for OS (PLATFORM, n=62; hazard ratio [HR], 0.98 [0.57-1.66]; p=0.933; FOrMAT, n=8; HR, 0.54 [0.13-2.31]; p=0.322), PFS (n=62; HR, 1.08 [0.65-1.81]; p=0.759; FOrMAT, n=8; HR, 1.26 [0.31-5.07]; p=0.714), or PFRs (PLATFORM, n=31; odds ratio [OR], 0.67 [0.2-2.8]; p=0.577).ConclusionNormalised miR-148a-3p may be a relevant biomarker for trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients.
| S-EPMC10718572 | biostudies-literature
Project description:BackgroundDegradation of the extracellular matrix is fundamental to tumour development, invasion and metastasis. Several protease families have been implicated in the development of a broad range of tumour types, including oesophago-gastric (OG) adenocarcinoma. The aim of this study was to analyse the expression levels of all core members of the cancer degradome in OG adenocarcinoma and to investigate the relationship between expression levels and tumour/patient variables associated with poor prognosis.MethodsComprehensive expression profiling of the protease families (matrix metalloproteinases (MMPs), members of the ADAM metalloproteinase-disintegrin family (ADAMs)), their inhibitors (tissue inhibitors of metalloproteinase), and molecules involved in the c-Met signalling pathway, was performed using quantitative real-time reverse transcription polymerase chain reaction in a cohort of matched malignant and benign peri-tumoural OG tissue (n=25 patients). Data were analysed with respect to clinico-pathological variables (tumour stage and grade, age, sex and pre-operative plasma C-reactive protein level).ResultsGene expression of MMP1, 3, 7, 9, 10, 11, 12, 16 and 24 was upregulated by factors >4-fold in OG adenocarcinoma samples compared with matched benign tissue (P<0.01). Expression of ADAM8 and ADAM15 correlated significantly with tumour stage (P=0.048 and P=0.044), and ADAM12 expression correlated with tumour grade (P=0.011).ConclusionThis study represents the first comprehensive quantitative analysis of the expression of proteases and their inhibitors in human OG adenocarcinoma. These findings implicate elevated ADAM8, 12 and 15 mRNA expression as potential prognostic molecular markers.
| S-EPMC3389427 | biostudies-literature
Project description:Tumors of the upper gastrointestinal tract are increasing in incidence; yet, approaches to the treatment of advanced gastric and/or gastroesophageal junction cancer vary widely, with no internationally agreed first-line regimens. Recent clinical trials have shown that second-line treatment is now possible for selected patients with advanced disease, and current data suggest that the combination of ramucirumab plus paclitaxel may become a standard of care in the second-line setting for metastatic gastric cancer. Several prognostic factors have been identified for overall survival in the second-line setting; this emphasizes the need for careful sequencing of all treatments to ensure that individual patients receive optimum care. This article reviews published data on the treatment of advanced gastric cancer, with a particular emphasis on second-line chemotherapy, and suggests treatment sequences based on current understanding.
| S-EPMC5224844 | biostudies-literature
Project description:To investigate the safety and efficacy of the neoadjuvant chemoradiotherapy (NCRT) followed by neoadjuvant consolidation chemotherapy (NCCT) and surgery for locally advanced gastric cancer (GC) or gastroesophageal junction (GEJ) adenocarcinoma. Patients diagnosed as locally advanced GC or Siewert II/III GEJ adenocarcinoma with clinical stage T3-4 and/or N positive were prospectively enrolled. Patients underwent NCRT (45 Gy/25 fractions) with concurrent S-1, followed by NCCT (4 to 6 cycles of the SOX regimen) 2 to 4 weeks after NCRT. Gastric cancer radical resection with D2 lymph node dissection was performed 4 to 6 weeks after the total neoadjuvant therapy. The study was conducted from November 2019 to January 2023, enrolling a total of 46 patients. During the NCRT, all patients completed the treatment without dose reduction or delay. During the NCCT, 32 patients (69.6%) completed at least 4 cycles of chemotherapy. Grade 3 or higher adverse events in NCRT (5 cases) were non-hematological. During the course of NCCT, a notable occurrence of hematological toxicities was observed, with grade 3 or higher leukopenia (9.7%) and thrombocytopenia (12.2%) being experienced. A total of 28 patients (60.9%) underwent surgery, achieving R0 resection in all cases. A significant proportion of cases (71.4%) exhibited pathological downstaging to ypT0-2, while 10 patients (35.7%) demonstrated a pathologic complete response (pCR). The total neoadjuvant therapy comprising NCRT followed by NCCT and surgery demonstrates a low severe adverse reactions and promising efficacy, which could be considered as a viable treatment for locally advanced GC or GEJ adenocarcinoma.Trial registration: Clinicaltrials.gov (registration number: NCT04062058); the full date of first trial registration was 20/08/2019.
| S-EPMC10980744 | biostudies-literature
Project description:Recently, the global incidence of gastric/gastroesophageal junction (G/GEJ) cancer has remained high. China is also a large country with a high gastric cancer (GC) incidence rate, where the cases of GC account for 40% of all cases worldwide. More than 90% of GEJ cancers are the adenocarcinoma pathological type. Patients with early-stage G/GEJ adenocarcinoma may have a better prognosis after surgery. In contrast, patients with advanced metastatic G/GEJ adenocarcinoma usually choose comprehensive treatment based on systemic pharmacotherapy, but the subsequent long-term survival is not optimistic. The discovery of various biomarkers, especially microsatellite instability (MSI), programmed cell death-ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), tumor mutational burden (TMB) and Epstein-Barr virus (EBV), has led to the identification of an increasing number of targeted populations and has greatly improved the clinical efficacy of treatments for G/GEJ adenocarcinoma. The ToGA trial added trastuzumab to standard chemotherapy, showed improved survival of patients with HER2-positive advanced G/GEJ adenocarcinoma and brought these patients into a new era of HER2-targeted therapy. Moreover, many HER2-targeted agents have been developed and studied in patients with advanced HER2-positive G/GEJ adenocarcinoma who have demonstrated excellent clinical outcomes. However, many patients experience disease progression with HER2-targeted therapy; hence, new anti-HER2 drugs keep being developed, significantly reducing HER2 resistance. This paper reviews HER2-targeted drugs for advanced metastatic G/GEJ adenocarcinoma, potential resistance mechanisms and future directions.
| S-EPMC9524015 | biostudies-literature
Project description:BackgroundPLAnning Treatment For Oesophago-gastric Cancer: a Randomised Maintenance Therapy Trial (PLATFORM) is an adaptive phase II study assessing the role of maintenance therapies in advanced oesophago-gastric (OG) adenocarcinoma. We evaluated the role of the anti-programmed death-ligand 1 (PD-L1) inhibitor durvalumab in these patients.Patients and methodsPatients with human epidermal growth factor receptor 2-negative locally advanced or metastatic OG adenocarcinoma with disease control or response to 18 weeks of platinum-based first-line chemotherapy were randomised to active surveillance or maintenance durvalumab. The primary endpoint was progression-free survival (PFS). Safety was assessed in all patients who had commenced surveillance visits or received at least one dose of durvalumab. Exploratory survival analyses according to PD-L1 Combined Positive Score (CPS) and immune (biomarker-positive) or angiogenesis dominant (biomarker-negative) tumour microenvironment (TME) phenotypes were conducted.ResultsBetween March 2015 and April 2020, 205 patients were randomised to surveillance (n = 100) and durvalumab (n = 105). No significant differences were seen in PFS [hazard ratio (HR) 0.84, P = 0.13] and overall survival (OS; HR 0.98, P = 0.45) between surveillance and durvalumab. Five patients randomised to durvalumab demonstrated incremental radiological responses compared with none with surveillance. Treatment-related adverse events occurred in 77 (76.2%) durvalumab-assigned patients. A favourable effect in OS with durvalumab over surveillance in CPS ≥5 and immune biomarker-positive patients was observed compared with CPS <5 and biomarker-negative subgroups, respectively: CPS ≥5 versus <5: HR 0.63, 95% confidence interval (CI) 0.32-1.22 versus HR 0.93, 95% CI 0.44-1.96; biomarker-positive versus negative: HR 0.60, 95% CI 0.29-1.23 versus HR 0.84, 95% CI 0.42-1.65.ConclusionMaintenance durvalumab does not improve PFS in patients with OG adenocarcinoma who respond to first-line chemotherapy but induced incremental radiological responses in a subset of patients. TME characterisation could refine patient selection for anti-PD-L1 therapy above PD-L1 CPS alone.
| S-EPMC11298822 | biostudies-literature