a randomized, placebo-controlled phase II AIO trial with serum biomarker program

Background As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response. Methods This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively. Results Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70–1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50–1.34, one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A (P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were observed. Conclusions Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti- angiogenic RTK inhibitors are warranted. Trial registration This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland- Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009

Minimally Invasive Versus Open Ivor-Lewis Esophagectomy for Esophageal Cancer or Cancer of the Gastroesophageal Junction: Comparison of Postoperative Outcomes and Long-term Survival Using Propensity Score Matching Analysis.

BACKGROUND/AIM Esophagectomy is crucial for achieving long-term survival in patients with esophageal cancer, while being associated with a significant risk of complications. Aiming to reduce invasiveness and morbidity, total minimal-invasive esophagectomy (MIE) has been gradually implemented worldwide. The aim of the study was to compare MIE to open Ivor-Lewis esophagectomy (OE) for esophageal cancer or cancer of the gastroesophageal junction (GEJ), in terms of postoperative and oncological outcomes. PATIENTS AND METHODS Clinicopathological data of patients undergoing oncologic transthoracic esophagectomy (Ivor Lewis procedure) between 2010 and 2019 were assessed. Postoperative outcomes and long-term survival of patients undergoing OE were compared to those after MIE using 1:1 propensity score matching. RESULTS After excluding hybrid and robotic procedures, 90 patients who underwent MIE were compared with a matched cohort of 90 patients who underwent OE. MIE was associated with lower major postoperative morbidity (31% vs. 46%, p=0.046) and lower 90-day mortality (2% vs. 12%, p=0.010) compared to OE. MIE showed non-inferior 3-year overall (65% vs. 52%, p=0.019) and comparable disease-free survival rates (49% vs. 51%, p=0.851) in comparison to OE. CONCLUSION Our data suggest that MIE should be preferably performed in patients with esophageal cancer or cancer of the GEJ

A FDG-PET radiomics signature detects esophageal squamous cell carcinoma patients who do not benefit from chemoradiation

Detection of patients with esophageal squamous cell carcinoma (ESCC) who do not benefit from standard chemoradiation (CRT) is an important medical need. Radiomics using 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a promising approach. In this retrospective study of 184 patients with locally advanced ESCC. 152 patients from one center were grouped into a training cohort (n = 100) and an internal validation cohort (n = 52). External validation was performed with 32 patients treated at a second center. Primary endpoint was disease-free survival (DFS), secondary endpoints were overall survival (OS) and local control (LC). FDG-PET radiomics features were selected by Lasso-Cox regression analyses and a separate radiomics signature was calculated for each endpoint. In the training cohort radiomics signatures containing up to four PET derived features were able to identify non-responders in regard of all endpoints (DFS p < 0.001, LC p = 0.003, OS p = 0.001). After successful internal validation of the cutoff values generated by the training cohort for DFS (p = 0.025) and OS (p = 0.002), external validation using these cutoffs was successful for DFS (p = 0.002) but not for the other investigated endpoints. These results suggest that pre-treatment FDG-PET features may be useful to detect patients who do not respond to CRT and could benefit from alternative treatment

Biomarker analysis of the GATSBY study of trastuzumab emtansine versus a taxane in previously treated HER2-positive advanced gastric/gastroesophageal junction cancer

BACKGROUND: Prespecified exploratory biomarker analyses of the phase II/III GATSBY study (NCT01641939) assessed whether patient subgroups experienced a survival benefit from trastuzumab emtansine (T-DM1) versus taxane therapy, and to advance understanding of HER2-positive advanced gastric/gastroesophageal junction cancer (AGC) disease biology. METHODS: Adults with HER2-positive AGC whose disease progressed during/after first-line therapy were enrolled and randomized to receive T-DM1 [Stage 1: 3.6 mg/kg q3w, 2.4 mg/kg qw, or taxane (docetaxel/paclitaxel); Stage 2: 2.4 mg/kg qw or taxane]. Primary efficacy endpoint was overall survival (OS). Prespecified exploratory biomarkers included HER2, HER3, PTEN, PIK3CA mutation status, FcγR, and cMET. Tumor samples from patients who received 2.4 mg/kg T-DM1 (n = 228) or taxane (n = 117) were included. RESULTS: Median OS was longer in subgroups with HER2 immunohistochemistry (IHC) 3+ [9.5 versus 8.3 months for T-DM1 versus taxane; hazard ratio (HR) 0.99 (95% CI 0.68-1.43)] versus HER2 IHC 2+/in situ hybridization-positive [5.2 versus 9.2 months for T-DM1 versus taxane; HR 1.53 (95% CI 0.94-2.50)] tumors. Trends towards increased median OS were also observed in subgroups with > versus ≤ median HER2 mRNA expression, higher versus lower HER2 gene copy number, HER2 gene ratio and H score, and homogenous or nonfocal HER2 IHC staining. T-DM1 was not associated with superior OS versus taxane in any subgroup. CONCLUSIONS: Patients with previously treated HER2-positive AGC with higher HER2 expression experienced a better treatment effect from T-DM1 than those with lower HER2 expression and may derive comparable survival benefits from T-DM1 and taxane therapy. CLINICAL TRIALS REGISTRATION: NCT01641939 ( https://clinicaltrials.gov/ct2/show/NCT01641939 ).status: publishe