Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of... Show moreGastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment (TME) in early disease remain largely unknown. We hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with nonmetastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n = 21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by four cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well tolerated. There were grade 3 immune-related adverse events in two of 20 patients (10%) but no grade 4 or 5 immune-related adverse events, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent anti-programmed cell death ligand 1 (PD-L1) and the subsequent combination with chemotherapy on the TME. Twenty of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. A major pathologic response (<= 10% residual viable tumor) was observed in 14 of 20 (70%, 95% confidence interval 46-88%) patients, including 9 (45%, 95% confidence interval 23-68%) pathologic complete responses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and five of six nonresponders had died as a result of recurrence. Notably, baseline anti-programmed cell death protein 1 (PD-1)+CD8+ T cell infiltration was significantly higher in responders versus nonresponders, and comparison of TME alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy showed an increased immune activation on single-agent PD-1/L1 axis blockade. On the basis of these data, monotherapy anti-PD-L1 before its combination with chemotherapy warrants further exploration and validation in a larger cohort of patients with nonmetastatic G/GEJ cancer. ClinicalTrials.gov registration: NCT03448835.A neoadjuvant treatment regimen of anti-PD-L1 monotherapy followed by anti-PD-L1 plus chemotherapy was well tolerated and led to a major pathologic response rate of 70% in patients with resectable gastric or gastroesophageal junction adenocarcinoma. Show less
Purpose: To accurately quantify esophageal tumor position variability and to optimize image guided correction strategies.Material and Methods: Esophageal cancer patients receiving chemoradiotherapy... Show morePurpose: To accurately quantify esophageal tumor position variability and to optimize image guided correction strategies.Material and Methods: Esophageal cancer patients receiving chemoradiotherapy (41.4-50.4 Gy in 23-28 fractions combined with carboplatin plus paclitaxel) were included in a prospective cohort study (NCT02139488). Gold fiducial markers were inserted into the esophageal tumors during diagnostic endoscopic ultrasound. Four-dimensional (4D) planning computed tomography (CT) and daily 4D cone beam (CB) CT scans were acquired. Each CBCT was registered to the planning CT using different regions of interest (bone; 3D), and carina, diaphragm, clinical target volume (CTV), and fiducial markers (4D) for alignment and using the fiducial markers as the true tumor position. Subsequently, a planning target volume (PTV) margin accounting for residual uncertainties, including the average respiratory motion, was calculated for each of these registrations.Results: Fifty-six patients with tumors located in the proximal (n=1), mid (n=7), or distal esophagus (n=25) or at the gastroesophageal junction (n=23) were included. The average peak-to-peak respiratory tumor motion was 0.20, 0.92, and 0.34 cm on the planning CT in left-right (LR), cranial-caudal (CC), and anterior-posterior (AP) directions, respectively. The required PTV margin with average motion amplitude, depending on the correction strategy used for image guidance, ranged from 0.8 cm to 1.0 cm, 1.1 cm to 1.6 cm, and 0.7 cm to 0.9 cm in LR, CC, and AP direction, respectively. A registration based on the CTV resulted in the smallest PTV margins (0.8, 1.1, and 0.7 cm in LR, CC, and AP direction, respectively). For bone registration the calculated PTV margins were 1.0, 1.3, and 0.7 cm in LR, CC, and AP directions, respectively. The registration based on the diaphragm increased PTV margins.Conclusions: Substantial and anisotropic position variability of esophageal tumors was observed during radiation therapy, and nonuniform margins should be considered. Cranial-caudal PTV margins need to be larger than those commonly used. Target positioning during image-guided radiotherapy could be improved with a CTV registration-based correction strategy. (C) 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. Show less
