Adjuvant chemoradiation in pancreatic cancer: impact of radiotherapy dose on survival.

BACKGROUND: To evaluate the impact of radiation dose on overall survival (OS) in patients treated with adjuvant chemoradiation (CRT) for pancreatic ductal adenocarcinoma (PDAC). METHODS: A multicenter retrospective analysis on 514 patients with PDAC (T1-4; N0-1; M0) treated with surgical resection with macroscopically negative margins (R0-1) followed by adjuvant CRT was performed. Patients were stratified into 4 groups based on radiotherapy doses (group 1: < 45 Gy, group 2: ≥ 45 and < 50 Gy, group 3: ≥ 50 and < 55 Gy, group 4: ≥ 55 Gy). Adjuvant chemotherapy was prescribed to 141 patients. Survival functions were plotted using the Kaplan-Meier method and compared through the log-rank test. RESULTS: Median follow-up was 35 months (range: 3-120 months). At univariate analysis, a worse OS was recorded in patients with higher preoperative Ca 19.9 levels (≥ 90 U/ml; p < 0.001), higher tumor grade (G3-4, p = 0.004), R1 resection (p = 0.004), higher pT stage (pT3-4, p = 0.002) and positive nodes (p < 0.001). Furthermore, patients receiving increasing doses of CRT showed a significantly improved OS. In groups 1, 2, 3, and 4, median OS was 13.0 months, 21.0 months, 22.0 months, and 28.0 months, respectively (p = 0.004). The significant impact of higher dose was confirmed by multivariate analysis. CONCLUSIONS: Increasing doses of CRT seems to favorably impact on OS in adjuvant setting. The conflicting results of randomized trials on adjuvant CRT in PDAC could be due to < 45 Gy dose generally used.

Prognostic Impact of Presurgical CA19-9 Level in Pancreatic Adenocarcinoma: A Pooled Analysis.

BACKGROUND: Presurgical carbohydrate antigen 19-9 (CA19-9) level predicts overall survival (OS) in resected pancreatic adenocarcinoma (PaC). The aim of this pooled analysis was to evaluate if presurgical CA19-9 level can also predict local control (LC) and distant metastasis-free survival (DMFS). METHODS: Seven hundred patients with PaC from eight institutions who underwent surgical resection ± adjuvant treatment between 2000 and 2014 were analyzed. Patients were divided based on four presurgical CA19-9 level cutoffs (5, 37, 100, 353 U/ml). Weibull regression model to identify independent predictors of OS on 404 patients with complete information was fitted. RESULTS: Median follow-up was 17 months (range: 2-225 months). Univariate analysis showed a better prognosis in pT1-2, pN0, diameter <30 mm, or grade 1 tumors and in patients undergoing R0 resection, distal pancreatectomy, or adjuvant chemotherapy and with lower CA19-9 levels. Five-year OS, LC, and DMFS were as follows: CA19-9 <5.0: 5.7%, 47.2%, 17.0%; CA19-9 5.1-37.0: 37.9%, 63.3%, 46.0%; CA19-9 37.1-100.0: 27.1%, 59.4%, 39.0%; CA19-9 100.1-353.0: 17.4%, 43.4%, 26.7%; CA19-9 >353.1: 10.9%, 50.2%, and 23.4%, respectively. At multivariate analysis, CA19-9 >100 and <353 level (P=.002), CA19-9 ≥353.1 (P<.001) level, G3 tumor (P=.002), and tumor diameter >30 mm (P<.001) correlated with worse OS. Patients treated with postoperative chemoradiation doses >50.0 Gy showed improved OS (P<.001). CONCLUSION: Presurgical CA19-9 predicts both OS and pattern of failure. Therefore, CA19-9 should be included in predictive models in order to customize treatments based on prognostic factors. Moreover, future studies should stratify patients according to presurgical CA19-9 level.

Cellular Therapies for Treatment of Radiation Injury: Report from a NIH/NIAID and IRSN Workshop.

In recent years, there has been increasing concern over the possibility of a radiological or nuclear incident occurring somewhere in the world. Intelligence agencies frequently report that terrorist groups and rogue nations are seeking to obtain radiological or nuclear weapons of mass destruction. In addition, there exists the real possibility that safety of nuclear power reactors could be compromised by natural (such as the tsunami and subsequent Fukushima accident in Japan in March, 2011) or accidental (Three Mile Island, 1979 and Chernobyl, 1986) events. Although progress has been made by governments around the world to prepare for these events, including the stockpiling of radiation countermeasures, there are still challenges concerning care of patients injured during a radiation incident. Because the deleterious and pathological effects of radiation are so broad, it is desirable to identify medical countermeasures that can have a beneficial impact on several tissues and organ systems. Cellular therapies have the potential to impact recovery and tissue/organ regeneration for both early and late complications of radiation exposure. These therapies, which could include stem or blood progenitor cells, mesenchymal stromal cells (MSCs) or cells derived from other tissues (e.g., endothelium or placenta), have shown great promise in treating other nonradiation injuries to and diseases of the bone marrow, skin, gastrointestinal tract, brain, lung and heart. To explore the potential use of these therapies in the treatment of victims after acute radiation exposure, the National Institute of Allergy and Infectious Diseases co-sponsored an international workshop in July, 2015 in Paris, France with the Institut de Radioprotection et de Sûreté Nucléaire. The workshop included discussions of data available from testing in preclinical models of radiation injury to different organs, logistics associated with the practical use of cellular therapies for a mass casualty incident, as well as international regulatory requirements for authorizing such drug products to be legally and readily used in such incidents. This report reviews the data presented, as well as key discussion points from the meeting.

UNITED STATES DEPARTMENT OF HEALTH AND HUMAN SERVICES BIODOSIMETRY AND RADIOLOGICAL/NUCLEAR MEDICAL COUNTERMEASURE PROGRAMS.

The United States Department of Health and Human Services (HHS) is fully committed to the development of medical countermeasures to address national security threats from chemical, biological, radiological, and nuclear agents. Through the Public Health Emergency Medical Countermeasures Enterprise, HHS has launched and managed a multi-agency, comprehensive effort to develop and operationalize medical countermeasures. Within HHS, development of medical countermeasures includes the National Institutes of Health (NIH), (led by the National Institute of Allergy and Infectious Diseases), the Office of the Assistant Secretary of Preparedness and Response/Biomedical Advanced Research and Development Authority (BARDA); with the Division of Medical Countermeasure Strategy and Requirements, the Centers for Disease Control and Prevention, and the Food and Drug Administration as primary partners in this endeavor. This paper describes various programs and coordinating efforts of BARDA and NIH for the development of medical countermeasures for radiological and nuclear threats.

Adjuvant Chemoradiation in Pancreatic Cancer: A Pooled Analysis in Elderly (≥75 years) Patients.

AIM: To determine the impact of postoperative chemoradiation (POCR) on overall survival (OS) after resection of pancreatic adenocarcinoma (PAC) in elderly (≥75 years) patients. MATERIALS AND METHODS: A multi-center retrospective review of 1248 patients who underwent complete resection with macroscopically negative margins (R0-1) for invasive PAC was performed. Exclusion criteria included age <75 years, metastatic or unresectable disease at surgery, macroscopic residual disease (R2), treatment with intraoperative radiotherapy (IORT) and postoperative death. RESULTS: A total of 98 patients were included in the analysis (males=39.8%, females=60.2%; R1 resections=33.7%; pN1=61.2%); 63 patients received POCR and 26 patients received adjuvant chemotherapy alone. The median follow-up was 25.6 months. The mean age for the entire cohort of patients was 78.1±2.9 (SD) years. No differences were observed between patients receiving or not receiving POCR in terms of age (p=0.081), tumor diameter (p=0.412), rate of R1 resection (p=0.331) and incidence of lymph node-positive disease (p=0.078). The only factor predicting an improved OS was POCR. The median OS was 69.0 months in patients treated by POCR and 23.0 months in patients treated without POCR (p=0.008). Even by Cox multivariate analysis, the only significant predictor of OS was POCR (hazard ratio=0.449; 95% confidence interval=0.212-0.950; p=0.036). CONCLUSION: The study represents the first comparative approach on POCR in elderly patients after resection of PAC. OS was higher in patients who received POCR. Further analyses are warranted to evaluate the toxicity rate/grade and the impact of POCR on patient quality of life.

Public health and medical preparedness for a nuclear detonation: the nuclear incident medical enterprise.

Resilience and the ability to mitigate the consequences of a nuclear incident are enhanced by (1) effective planning, preparation and training; (2) ongoing interaction, formal exercises, and evaluation among the sectors involved; (3) effective and timely response and communication; and (4) continuous improvements based on new science, technology, experience, and ideas. Public health and medical planning require a complex, multi-faceted systematic approach involving federal, state, local, tribal, and territorial governments; private sector organizations; academia; industry; international partners; and individual experts and volunteers. The approach developed by the U.S. Department of Health and Human Services Nuclear Incident Medical Enterprise (NIME) is the result of efforts from government and nongovernment experts. It is a "bottom-up" systematic approach built on the available and emerging science that considers physical infrastructure damage, the spectrum of injuries, a scarce resources setting, the need for decision making in the face of a rapidly evolving situation with limited information early on, timely communication, and the need for tools and just-in-time information for responders who will likely be unfamiliar with radiation medicine and uncertain and overwhelmed in the face of the large number of casualties and the presence of radioactivity. The components of NIME can be used to support planning for, response to, and recovery from the effects of a nuclear incident. Recognizing that it is a continuous work-in-progress, the current status of the public health and medical preparedness and response for a nuclear incident is provided.

Multi-institutional pooled analysis on adjuvant chemoradiation in pancreatic cancer.

PURPOSE: To determine the impact of chemoradiation therapy (CRT) on overall survival (OS) after resection of pancreatic adenocarcinoma. METHODS AND MATERIALS: A multicenter retrospective review of 955 consecutive patients who underwent complete resection with macroscopically negative margins (R0-1) for invasive carcinoma (T1-4; N0-1; M0) of the pancreas was performed. Exclusion criteria included metastatic or unresectable disease at surgery, macroscopic residual disease (R2), treatment with intraoperative radiation therapy (IORT), and a histological diagnosis of no ductal carcinoma, or postoperative death (within 60 days of surgery). In all, 623 patients received postoperative radiation therapy (RT), 575 patients received concurrent chemotherapy (CT), and 462 patients received adjuvant CT. RESULTS: Median follow-up was 21.0 months. Median OS after adjuvant CRT was 39.9 versus 24.8 months after no adjuvant CRT (P<.001) and 27.8 months after CT alone (P<.001). Five-year OS was 41.2% versus 24.8% with and without postoperative CRT, respectively. The positive impact of CRT was confirmed by multivariate analysis (hazard ratio [HR] = 0.72; confidence interval [CI], 0.60-0.87; P=.001). Adverse prognostic factors identified by multivariate analysis included the following: R1 resection (HR = 1.17; CI = 1.07-1.28; P<.001), higher pT stage (HR = 1.23; CI = 1.11-1.37; P<.001), positive lymph nodes (HR = 1.27; CI = 1.15-1.41; P<.001), and tumor diameter >20 mm (HR = 1.14; CI = 1.05-1.23; P=.002). Multivariate analysis also showed a better prognosis in patients treated in centers with >10 pancreatic resections per year (HR = 0.87; CI = 0.78-0.97; P=.014) CONCLUSION: This study represents the largest comparative study on adjuvant therapy in patients after resection of carcinoma of the pancreas. Overall survival was better in patients who received adjuvant CRT.

Building the strategic national stockpile through the NIAID Radiation Nuclear Countermeasures Program.

The possibility of a public health radiological or nuclear emergency in the United States remains a concern. Media attention focused on lost radioactive sources and international nuclear threats, as well as the potential for accidents in nuclear power facilities (e.g., Windscale, Three Mile Island, Chernobyl, and Fukushima) highlight the need to address this critical national security issue. To date, no drugs have been licensed to mitigate/treat the acute and long-term radiation injuries that would result in the event of large-scale, radiation, or nuclear public health emergency. However, recent evaluation of several candidate radiation medical countermeasures (MCMs) has provided initial proof-of-concept of efficacy. The goal of the Radiation Nuclear Countermeasures Program (RNCP) of the National Institute of Allergy and Infectious Diseases (National Institutes of Health) is to help ensure the government stockpiling of safe and efficacious MCMs to treat radiation injuries, including, but not limited to, hematopoietic, gastrointestinal, pulmonary, cutaneous, renal, cardiovascular, and central nervous systems. In addition to supporting research in these areas, the RNCP continues to fund research and development of decorporation agents targeting internal radionuclide contamination, and biodosimetry platforms (e.g., biomarkers and devices) to assess the levels of an individual's radiation exposure, capabilities that would be critical in a mass casualty scenario. New areas of research within the program include a focus on special populations, especially pediatric and geriatric civilians, as well as combination studies, in which drugs are tested within the context of expected medical care management (e.g., antibiotics and growth factors). Moving forward, challenges facing the RNCP, as well as the entire radiation research field, include further advancement and qualification of animal models, dose conversion from animal models to humans, biomarker identification, and formulation development. This paper provides a review of recent work and collaborations supported by the RNCP.

Perceived comfort level of medical students and residents in handling clinical ethics issues.

BACKGROUND: Studies have shown that medical students and residents believe that their ethics preparation has been inadequate for handling ethical conflicts. The objective of this study was to determine the self-perceived comfort level of medical students and residents in confronting clinical ethics issues. METHODS: Clinical medical students and residents at the University of Maryland School of Medicine completed a web-based survey between September 2009 and February 2010. The survey consisted of a demographic section, questions regarding the respondents' sense of comfort in handling a variety of clinical ethics issues, and a set of knowledge-type questions in ethics. RESULTS: Survey respondents included 129 medical students (response rate of 40.7%) and 207 residents (response rate of 52.7%). There were only a few clinical ethics issues with which more than 70% of the respondents felt comfortable in addressing. Only a slight majority (60.8%) felt prepared, in general, to handle clinical situations involving ethics issues, and only 44.1% and 53.2% agreed that medical school and residency training, respectively, helped prepare them to handle such issues. Prior ethics training was not associated with these responses, but there was an association between the level of training (medical students vs residents) and the comfort level with many of the clinical ethics issues. CONCLUSIONS: Medical educators should include ethics educational methods within the context of real-time exposure to medical ethics dilemmas experienced by physicians-in-training.

Medical planning and response for a nuclear detonation: a practical guide.

This article summarizes major points from a newly released guide published online by the Office of the Assistant Secretary for Preparedness and Response (ASPR). The article reviews basic principles about radiation and its measurement, short-term and long-term effects of radiation, and medical countermeasures as well as essential information about how to prepare for and respond to a nuclear detonation. A link is provided to the manual itself, which in turn is heavily referenced for readers who wish to have more detail.

Development and licensure of medical countermeasures to treat lung damage resulting from a radiological or nuclear incident.

Due to the ever-present threat of a radiological or nuclear accident or attack, the National Institute of Allergy and Infectious Diseases, Radiation Medical Countermeasures Program was initiated in 2004. Since that time, the Program has funded research to establish small and large animal models for radiation damage, as well as the development of approaches to mitigate/treat normal tissue damage following radiation exposure. Because some of these exposures may be high-dose, and yet heterogeneous, the expectation is that some victims will survive initial acute radiation syndromes (e.g. hematopoietic and gastrointestinal), but then suffer from potentially lethal lung complications. For this reason, efforts have concentrated on the development of animal models of lung irradiation damage that mimic expected exposure scenarios, as well as drugs to treat radiation-induced late lung sequelae including pneumonitis and fibrosis. Approaches targeting several pathways are under study, with the eventual goal of licensure by the United States Food and Drug Administration for government stockpiling. This Commentary outlines the status of countermeasure development in this area and provides information on the specifics of licensure requirements, as well as guidance and a discussion of challenges involved in developing and licensing drugs and treatments specific to a radiation lung damage indication.

Animal models and medical countermeasures development for radiation-induced lung damage: report from an NIAID Workshop.

Since 9/11, there have been concerns that terrorists may detonate a radiological or nuclear device in an American city. Aside from several decorporation and blocking agents for use against internal radionuclide contamination, there are currently no medications within the Strategic National Stockpile that are approved to treat the immediate or delayed complications resulting from accidental exposure to radiation. Although the majority of research attention has focused on developing countermeasures that target the bone marrow and gastrointestinal tract, since they represent the most acutely radiosensitive organs, individuals who survive early radiation syndromes will likely suffer late effects in the months that follow. Of particular concern are the delayed effects seen in the lung that play a major role in late mortality seen in radiation-exposed patients and accident victims. To address these concerns, the National Institute of Allergy and Infectious Diseases convened a workshop to discuss pulmonary model development, mechanisms of radiation-induced lung injury, targets for medical countermeasures development, and end points to evaluate treatment efficacy. Other topics covered included guidance on the challenges of developing and licensing drugs and treatments specific to a radiation lung damage indication. This report reviews the data presented, as well as key points from the ensuing discussion.

Analysis of local control in patients receiving IMRT for resected pancreatic cancers.

PURPOSE: Intensity-modulated radiotherapy (IMRT) is increasingly incorporated into therapy for pancreatic cancer. A concern regarding this technique is the potential for geographic miss and decreased local control. We analyzed patterns of first failure among patients treated with IMRT for resected pancreatic cancer. METHODS AND MATERIALS: Seventy-one patients who underwent resection and adjuvant chemoradiation for pancreas cancer are included in this report. IMRT was used for all to a median dose of 50.4 Gy. Concurrent chemotherapy was 5-FU-based in 72% of patients and gemcitabine-based in 28%. RESULTS: At median follow-up of 24 months, 49/71 patients (69%) had failed. The predominant failure pattern was distant metastases in 35/71 patients (49%). The most common site of metastases was the liver. Fourteen patients (19%) developed locoregional failure in the tumor bed alone in 5 patients, regional nodes in 4 patients, and concurrently with metastases in 5 patients. Median overall survival (OS) was 25 months. On univariate analysis, nodal status, margin status, postoperative CA 19-9 level, and weight loss during treatment were predictive for OS. On multivariate analysis, higher postoperative CA19-9 levels predicted for worse OS on a continuous basis (p < 0.01). A trend to worse OS was seen among patients with more weight loss during therapy (p = 0.06). Patients with positive nodes and positive margins also had significantly worse OS (HR for death 2.8, 95% CI 1.1-7.5; HR for death 2.6, 95% CI 1.1-6.2, respectively). Grade 3-4 nausea and vomiting was seen in 8% of patients. Late complication of small bowel obstruction occurred in 4 (6%) patients. CONCLUSIONS: This is the first comprehensive report of patterns of failure among patients treated with adjuvant IMRT for pancreas cancer. IMRT was not associated with an increase in local recurrences in our cohort. These data support the use of IMRT in the recently activated EORTC/US Intergroup/RTOG 0848 adjuvant pancreas trial.

Medical countermeasures for platelet regeneration after radiation exposure. Report of a workshop and guided discussion sponsored by the National Institute of Allergy and Infectious Diseases, Bethesda, MD, March 22­23, 2010.

The events of September 11, 2001 and their aftermath increased awareness of the need to develop medical countermeasures (MCMs) to treat potential health consequences of a radiation accident or deliberate attack. The medical effects of lethal exposures to ionizing radiation have been well described and affect multiple organ systems. To date, much of the research to develop treatments for mitigation of radiation-induced hematopoietic damage has focused on amelioration of radiation-induced neutropenia, which has long been considered to be the primary factor in determining survival after an unintentional radiation exposure. Consistent with historical data, recent studies have highlighted the role that radiation-induced thrombocytopenia plays in radiation mortality, yet development of MCMs to mitigate radiation damage to the megakaryocyte lineage has lagged behind anti-neutropenia approaches. To address this gap and to foster research in the area of platelet regeneration after radiation exposure, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored a workshop on March 22-23, 2010 to encourage collaborations between NIAID program awardees and companies developing pro-platelet approaches. NIAID also organized an informal, open discussion between academic investigators, product development contractors, and representatives from the U.S. Food and Drug Administration (FDA) and other relevant government agencies about drug development toward FDA licensure of products for an acute radiation syndrome indication. Specific emphasis was placed on the challenges of product licensure for radiation/nuclear MCMs using current FDA regulations (21 CFR Parts 314 and 601) and on the importance of animal efficacy model development, design of pivotal protocols, and standardization of irradiation and animal supportive care.

The NIAID Radiation Countermeasures Program business model.

The National Institute of Allergy and Infectious Diseases (NIAID) Radiation/Nuclear Medical Countermeasures Development Program has developed an integrated approach to providing the resources and expertise required for the research, discovery, and development of radiation/nuclear medical countermeasures (MCMs). These resources and services lower the opportunity costs and reduce the barriers to entry for companies interested in working in this area and accelerate translational progress by providing goal-oriented stewardship of promising projects. In many ways, the radiation countermeasures program functions as a "virtual pharmaceutical firm," coordinating the early and mid-stage development of a wide array of radiation/nuclear MCMs. This commentary describes the radiation countermeasures program and discusses a novel business model that has facilitated product development partnerships between the federal government and academic investigators and biopharmaceutical companies.

Rapid radiation dose assessment for radiological public health emergencies: roles of NIAID and BARDA.

A large-scale radiological incident would result in an immediate critical need to assess the radiation doses received by thousands of individuals to allow for prompt triage and appropriate medical treatment. Measuring absorbed doses of ionizing radiation will require a system architecture or a system of platforms that contains diverse, integrated diagnostic and dosimetric tools that are accurate and precise. For large-scale incidents, rapidity and ease of screening are essential. The National Institute of Allergy and Infectious Diseases of the National Institutes of Health is the focal point within the Department of Health and Human Services (HHS) for basic research and development of medical countermeasures for radiation injuries. The Biomedical Advanced Research and Development Authority within the HHS Office of the Assistant Secretary for Preparedness and Response coordinates and administers programs for the advanced development and acquisition of emergency medical countermeasures for the Strategic National Stockpile. Using a combination of funding mechanisms, including funds authorized by the Project BioShield Act of 2004 and those authorized by the Pandemic and All-Hazards Preparedness Act of 2006, HHS is enhancing the nation's preparedness by supporting the radiation dose assessment capabilities that will ensure effective and appropriate use of medical countermeasures in the aftermath of a radiological or nuclear incident.

Medical countermeasures against nuclear threats: radionuclide decorporation agents.

Exposure to radionuclides disseminated by a radiological dispersion device or deposited as fallout after a nuclear power plant accident or detonation of an improvised nuclear device could result in internal contamination of a significant number of individuals. Internalized radionuclides may cause both acute and chronic radiation injury and increase an individual's risk of developing cancer. This damage and risk can be mitigated by the use of decorporation agents that reduce internal contamination. Unfortunately, most effective agents decorporate only a limited range of radionuclides, and some are formulated in ways that would make administration in mass casualty situations challenging. There is a need for new radionuclide decorporation agents, reformulations of existing agents, and/or expansion of the labeled indications for existing treatments. Researchers developing novel or improved decorporation agents should also understand the regulatory pathway for these products. This workshop, the first in nearly half a century to focus exclusively on radionuclide decorporation, brought together researchers and scientific administrators from academia, government and industry as well as senior regulatory affairs officers and U.S. Food and Drug Administration personnel. Meeting participants reviewed recent progress in the development of decorporation agents and contemplated the future of the field.