Search

Background: Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma., Methods: In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6-12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete., Findings: Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63-75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3-4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT., Interpretation: SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results., Funding: Galera Therapeutics., Competing Interests: Declaration of interests CMT reports grant or contracts with US National Institutes of Health (NIH and CPRIT), licenses with Xerient Pharmaceuticals for licensed or individual patent for radioprotection of the upper gastrointestinal tract, and consulting fees with Phebry. JMF reports consultant and advisory board roles for Viewray, and payment for presentations for Boston Scientific. TAA reports an unfunded study steering committee role for Galera Therapeutics (Galera). MP reports research support to their institution from Merck and Varian, royalties to serve as section editor for cholangiocarcinoma, consulting fees from Voxelmetric and Syntactx, a speakers honorarium for Oakstone CME, advisory board participation for Varian, and an unpaid ASTRO Education Committee role. BC reports royalties from Springer, honoraria for Varian-Educational and Oakstone, and a leadership or fiduciary role with the National Comprehensive Cancer Network. MSB reports funding from Galera, institution grants or contracts from Nanobiotix, Silenseed, Trisalis, Artidis, SUC2, CPRIT, AstraZeneca, Merck, Siemens Medical, and Boston Scientific (Augmenix) and consulting fees from Oncosil and Strapax. SP reports consulting or advisory roles for Zymeworks, Ipsen, Novartis, Janssen, Boehringer Ingelheim, and AskGene Pharma, and institutional research funding from Mirati Therapeutics, Lilly, Xencor, Novartis, Rgenix, Bristol-Myers Squibb, Astellas Pharma, Framewave, 4D Pharma, Boehringer Ingelheim, NGM Biopharmaceuticals, Janssen, Arcus Biosciences, Elicio Therapeutics, Bionte, Ipsen, Zymeworks, Pfizer, ImmunoMET, Immuneering, and Amal Therapeutics. C-WDT reports an institution-sponsored research agreement with Sirtex, and individual and institutional honoraria from PanTher. DWK reports grants or contracts from Bold Therapeutics, and payment or honoraria from AstraZeneca. JC reports travel expense money from Galera. EJK reports research grants and contracts from NIH, US Department of Defense, Cancer Prevention and Research Institute of Texas, and Artidis, royalties or licenses from Taylor and Francis, and Kallisio, consulting fees from Kallisio, AstraZeneca, RenovoRx, MD Anderson Physician Network, MJH Life Sciences, and Quantum Aurea Capital, honoraria from Northwestern University and Amplity, a patent pending for 3D oral stents, scientific and medical advisory board roles for Cholangiocarcinoma Foundation, and stock or stock options with Quantum Aurea Capital. PD reports consulting fees from the American Society for Radiation Oncology, payment or honoraria from American Society for Clinical Oncology, Conveners, Physicians Education Resource, Imedex, and Bayer. RAW reports royalties from McGraw-Hill. GOS reports a research agreement with Artios Pharma. RSST reports institutional funding from Galera and NIH National Cancer Institute (NCI). YY reports personal fees from AbbVie, Amgen, Bexion Pharmaceuticals, BeyondSpring Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Bristol Myers Squibb, Century Therapeutics, Enliven Therapeutics, Repare Therapeutics, Servier Pharmaceuticals, Starpax Pharmaceuticals, and Vertex Pharmaceuticals during the conduct of the study. PFT reports research funding from NIH NCI. RAB is an employee and officer of, reports receiving compensation from, and holds equity in the sponsor, Galera, residual royalties resulting from the acquisition of Confluence from Aclaris Therapeutics, stock or stock options with Galera, Euclises, Aclaris Therapeutics, and Novocure, and patents for methods for treatment of diseases, (US Pat 10,493,081, 2019 issued to Galera); a patent methods for treatment of diseases (US Pat 9,149,483, 2015 issued to Galera). JH was an employee and officer of, reports receiving compensation from, and holds equity in the sponsor, Galera. JMH reports research funding to their institution and support for attending a meeting from Canopy Cancer Collective, royalties or licenses from Springer, stock or stock options with Histosonics, and consulting fees from Histosonics and Boston Scientific. SEH is an employee of MyCareGorithm and has her own limited liability company, Beyond the White Coat. She has received travel assistance from ViewRay, stock options from Rittenhouse, and her institution received research funding from ViewRay and Galera. LEC, JAJ, VB, MM, GM, NR, EBL, MHGK, SB, and SM declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Adenocarcinoma of the anal canal is an uncommon malignancy, making it challenging to perform randomized controlled clinical trials to define best practices in care. For patients with localized disease, there remains a lack of consensus regarding the optimal management, with some physicians advocating for trimodality therapy (similar to the locally advanced rectal adenocarcinoma paradigm) and others advocating for definitive radiation therapy with concurrent chemotherapy (similar to the management of anal squamous cell carcinoma). The objective of this clinical review is to describe the management and outcomes of patients with anal adenocarcinoma to help inform treatment recommendations.

Background & Aims: We aimed to investigate the clinical utility of circulating tumor cell DNA (ctDNA) and exosome DNA (exoDNA) in pancreatic cancer., Methods: We collected liquid biopsy samples from 194 patients undergoing treatment for localized or metastatic pancreatic adenocarcinoma from April 7, 2015, through October 13, 2017 (425 blood samples collected before [baseline] and during therapy). Additional liquid biopsy samples were collected from 37 disease control individuals. Droplet digital polymerase chain reaction was used to determine KRAS mutant allele fraction (MAF) from ctDNA and exoDNA purified from plasma. For the longitudinal analysis, we analyzed exoDNA and ctDNA in 123 serial blood samples from 34 patients. We performed analysis including Cox regression, Fisher exact test, and Bayesian inference to associate KRAS MAFs in exoDNA and ctDNA with prognostic and predictive outcomes., Results: In the 34 patients with potentially resectable tumors, an increase in exoDNA level after neoadjuvant therapy was significantly associated with disease progression (P = .003), whereas ctDNA did not show correlations with outcomes. Concordance rates of KRAS mutations present in surgically resected tissue and detected in liquid biopsy samples were greater than 95%. On univariate analysis, patients with metastases and detectable ctDNA at baseline status had significantly shorter times of progression-free survival (PFS) (hazard ratio [HR] for death, 1.8; 95% CI, 1.1-3.0; P = .019), and overall survival (OS) (HR, 2.8; 95% CI, 1.4-5.7; P = .0045) compared with patients without detectable ctDNA. On multivariate analysis, MAFs ≥5% in exoDNA were a significant predictor of PFS (HR, 2.28; 95% CI, 1.18-4.40; P = .014) and OS (HR, 3.46; 95% CI, 1.40-8.50; P = .007). A multianalyte approach showed detection of both ctDNA and exoDNA MAFs ≥5% at baseline status to be a significant predictor of OS (HR, 7.73, 95% CI, 2.61-22.91, P = .00002) on multivariate analysis. In the longitudinal analysis, an MAF peak above 1% in exoDNA was significantly associated with radiologic progression (P = .0003)., Conclusions: In a prospective cohort of pancreatic cancer patients, we show how longitudinal monitoring using liquid biopsy samples through exoDNA and ctDNA provides both predictive and prognostic information relevant to therapeutic stratification., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with variable presentations and natural histories of disease. We hypothesized that different morphologic characteristics of PDAC tumors on diagnostic computed tomography (CT) scans would reflect their underlying biology., Experimental Design: We developed a quantitative method to categorize the PDAC morphology on pretherapy CT scans from multiple datasets of patients with resectable and metastatic disease and correlated these patterns with clinical/pathologic measurements. We modeled macroscopic lesion growth computationally to test the effects of stroma on morphologic patterns, hypothesizing that the balance of proliferation and local migration rates of the cancer cells would determine tumor morphology., Results: In localized and metastatic PDAC, quantifying the change in enhancement on CT scans at the interface between tumor and parenchyma (delta) demonstrated that patients with conspicuous (high-delta) tumors had significantly less stroma, higher likelihood of multiple common pathway mutations, more mesenchymal features, higher likelihood of early distant metastasis, and shorter survival times compared with those with inconspicuous (low-delta) tumors. Pathologic measurements of stromal and mesenchymal features of the tumors supported the mathematical model's underlying theory for PDAC growth., Conclusions: At baseline diagnosis, a visually striking and quantifiable CT imaging feature reflects the molecular and pathological heterogeneity of PDAC, and may be used to stratify patients into distinct subtypes. Moreover, growth patterns of PDAC may be described using physical principles, enabling new insights into diagnosis and treatment of this deadly disease., (©2018 American Association for Cancer Research.)

Purpose: To determine how the respiratory phase impacts dose to normal organs during stereotactic body radiation therapy (SBRT) for pancreatic cancer., Methods and Materials: Eighteen consecutive patients with locally advanced, unresectable pancreatic adenocarcinoma treated with SBRT were included in this study. On the treatment planning 4-dimensional computed tomography (CT) scan, the planning target volume (PTV), defined as the gross tumor volume plus 3-mm margin, the duodenum, and the stomach were contoured on the end-expiration (CTexp) and end-inspiration (CTinsp) phases for each patient. A separate treatment plan was constructed for both phases with the dose prescription of 33 Gy in 5 fractions with 95% coverage of the PTV by the 100% isodose line. The dose-volume histogram (DVH) endpoints, volume of duodenum that received 20 Gy (V20), V25, and V30 and maximum dose to 5 cc of contoured organ (D5cc), D1cc, and D0.1cc, were evaluated., Results: Dosimetric parameters for the duodenum, including V25, V30, D1cc, and D0.1cc improved by planning on the CTexp compared to those on the CTinsp. There was a statistically significant overlap of the PTV with the duodenum but not the stomach during the CTinsp compared to the CTexp (0.38 ± 0.17 cc vs 0.01 ± 0.01 cc, P=.048). A larger expansion of the PTV, in accordance with a Danish phase 2 trial, showed even more overlapping volume of duodenum on the CTinsp compared to that on the CTexp (5.5 ± 0.9 cc vs 3.0 ± 0.8 cc, P=.0003) but no statistical difference for any stomach dosimetric DVH parameter., Conclusions: Dose to the duodenum was higher when treating on the inspiratory than on the expiratory phase. These data suggest that expiratory gating may be preferable to inspiratory breath-hold and free breathing strategies for minimizing risk of toxicity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated‐dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. Methods: We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas‐directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional‐dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. Results: Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas‐directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80–0.91; p < 0.001) with longer OS versus CDR. Discussion and Conclusions: Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real‐world results additionally provide an estimate of effect size of EDR for future prospective trials. [ABSTRACT FROM AUTHOR]