Preclinical Data on Efficacy of 10 Drug-Radiation Combinations: Evaluations, Concerns, and Recommendations.

BACKGROUND: Clinical testing of new therapeutic interventions requires comprehensive, high-quality preclinical data. Concerns regarding quality of preclinical data have been raised in recent reports. This report examines the data on the interaction of 10 drugs with radiation and provides recommendations for improving the quality, reproducibility, and utility of future studies. The drugs were AZD6244, bortezomib, 17-DMAG, erlotinib, gefitinib, lapatinib, oxaliplatin/Lipoxal, sunitinib (Pfizer, Corporate headquarters, New York, NY), thalidomide, and vorinostat. METHODS: In vitro and in vivo data were tabulated from 125 published papers, including methods, radiation and drug doses, schedules of administration, assays, measures of interaction, presentation and interpretation of data, dosimetry, and conclusions. RESULTS: In many instances, the studies contained inadequate or unclear information that would hamper efforts to replicate or intercompare the studies, and that weakened the evidence for designing and conducting clinical trials. The published reports on these drugs showed mixed results on enhancement of radiation response, except for sunitinib, which was ineffective. CONCLUSIONS: There is a need for improved experimental design, execution, and reporting of preclinical testing of agents that are candidates for clinical use in combination with radiation. A checklist is provided for authors and reviewers to ensure that preclinical studies of drug-radiation combinations meet standards of design, execution, and interpretation, and report necessary information to ensure high quality and reproducibility of studies. Improved design, execution, common measures of enhancement, and consistent interpretation of preclinical studies of drug-radiation interactions will provide rational guidance for prioritizing drugs for clinical radiotherapy trials and for the design of such trials.

Radiation-induced brain damage, impact of Michael Robbins' work and the need for predictive biomarkers.

PURPOSE: To review the literature on radiation-induced normal tissue injury in the context of treatment of primary and metastatic brain tumors with a focus on Michael Robbins' work on mechanisms of injury and approaches to mitigation, and also to identify other potential opportunities to improve treatment outcome and quality of life (QOL). BACKGROUND: Brain tumors remain a significant challenge for patients, their families, the physicians treating them, and researchers seeking more effective treatments. Current treatment of brain tumors involves combinations of radiotherapy with surgery, chemotherapy, and molecularly targeted agents. As patient survival improves with advances in treatment there is an increasing concern for the cognitive deficits that may become apparent months or years after treatment some of which are related to radiation-induced brain damage. One area of Michael Robbins' research was unraveling the mechanisms of radiation-induced cognitive deficits, which formed the basis for the development of some mitigators of radiation injury. Extrapolating from this, new opportunities to identify and develop putative predictive biomarkers of radiation-induced brain damage can be explored. CONCLUSIONS: Predictive biomarkers of radiation-induced brain injury may enable stratifying patients for customization of treatment and thus aid in improving the QOL and possibly prolonging survival. Here we discuss the challenges involved in leveraging recent advances in radiation-specific biomarker research and translating them to radiotherapy, which for the foreseeable future is likely to remain a cornerstone of the treatment of brain tumors.

Lessons learned from radiation oncology clinical trials.

A workshop entitled "Lessons Learned from Radiation Oncology Trials" was held on December 7-8, 2011, in Bethesda, MD, to present and discuss some of the recently conducted radiation oncology clinical trials with a focus on those that failed to refute the null hypothesis. The objectives of this workshop were to summarize and examine the questions that these trials provoked, to assess the quality and limitations of the preclinical data that supported the hypotheses underlying these trials, and to consider possible solutions to these challenges for the design of future clinical trials. Several themes emerged from the discussions: (i) opportunities to learn from null-hypothesis trials through tissue and imaging studies; (ii) value of preclinical data supporting the design of combinatorial therapies; (iii) significance of validated biomarkers; (iv) necessity of quality assurance in radiotherapy delivery; (v) conduct of sufficiently powered studies to address the central hypotheses; and (vi) importance of publishing results of the trials regardless of the outcome. The fact that well-designed hypothesis-driven clinical trials produce null or negative results is expected given the limitations of trial design and complexities of cancer biology. It is important to understand the reasons underlying such null results, however, to effectively merge the technologic innovations with the rapidly evolving biology for maximal patient benefit through the design of future clinical trials.

Normal tissue protection for improving radiotherapy: Where are the Gaps?

Any tumor could be controlled by radiation therapy if sufficient dose were delivered to all tumor cells. Although technological advances in physical treatment delivery have been developed to allow more radiation dose conformity, normal tissues are invariably included in any radiation field within the tumor volume and also as part of the exit and entrance doses relevant for particle therapy. Mechanisms of normal tissue injury and related biomarkers are now being investigated, facilitating the discovery and development of a next generation of radiation protectors and mitigators. Bringing recent research advances stimulated by development of radiation countermeasures for mass casualties, to clinical cancer care requires understanding the impact of protectors and mitigators on tumor response. These may include treatments that modify cellular damage and death processes, inflammation, alteration of normal flora, wound healing, tissue regeneration and others, specifically to counter cancer site-specific adverse effects to improve outcome of radiation therapy. Such advances in knowledge of tissue and organ biology, mechanisms of injury, development of predictive biomarkers and mechanisms of radioprotection have re-energized the field of normal tissue protection and mitigation. Since various factors, including organ sensitivity to radiation, cellular turnover rate, and differences in mechanisms of injury manifestation and damage response vary among tissues, successful development of radioprotectors/mitigators/treatments may require multiple approaches to address cancer site specific needs. In this review, we discuss examples of important adverse effects of radiotherapy (acute and intermediate to late occurring, when it is delivered either alone or in conjunction with chemotherapy, and important limitations in the current approaches of using radioprotectors and/or mitigators for improving radiation therapy. Also, we are providing general concepts for drug development for improving radiation therapy.

Models for evaluating agents intended for the prophylaxis, mitigation and treatment of radiation injuries. Report of an NCI Workshop, December 3-4, 2003.

To develop approaches to prophylaxis/protection, mitigation and treatment of radiation injuries, appropriate models are needed that integrate the complex events that occur in the radiation-exposed organism. While the spectrum of agents in clinical use or preclinical development is limited, new research findings promise improvements in survival after whole-body irradiation and reductions in the risk of adverse effects of radiotherapy. Approaches include agents that act on the initial radiochemical events, agents that prevent or reduce progression of radiation damage, and agents that facilitate recovery from radiation injuries. While the mechanisms of action for most of the agents with known efficacy are yet to be fully determined, many seem to be operating at the tissue, organ or whole animal level as well as the cellular level. Thus research on prophylaxis/protection, mitigation and treatment of radiation injuries will require studies in whole animal models. Discovery, development and delivery of effective radiation modulators will also require collaboration among researchers in diverse fields such as radiation biology, inflammation, physiology, toxicology, immunology, tissue injury, drug development and radiation oncology. Additional investment in training more scientists in radiation biology and in the research portfolio addressing radiological and nuclear terrorism would benefit the general population in case of a radiological terrorism event or a large-scale accidental event as well as benefit patients treated with radiation.

Education and training for radiation scientists: radiation research program and American Society of Therapeutic Radiology and Oncology Workshop, Bethesda, Maryland, May 12-14, 2003.

Current and potential shortfalls in the number of radiation scientists stand in sharp contrast to the emerging scientific opportunities and the need for new knowledge to address issues of cancer survivorship and radiological and nuclear terrorism. In response to these challenges, workshops organized by the Radiation Research Program (RRP), National Cancer Institute (NCI) (Radiat. Res. 157, 204-223, 2002; Radiat. Res. 159, 812-834, 2003), and National Institute of Allergy and Infectious Diseases (NIAID) (Nature, 421, 787, 2003) have engaged experts from a range of federal agencies, academia and industry. This workshop, Education and Training for Radiation Scientists, addressed the need to establish a sustainable pool of expertise and talent for a wide range of activities and careers related to radiation biology, oncology and epidemiology. Although fundamental radiation chemistry and physics are also critical to radiation sciences, this workshop did not address workforce needs in these areas. The recommendations include: (1) Establish a National Council of Radiation Sciences to develop a strategy for increasing the number of radiation scientists. The strategy includes NIH training grants, interagency cooperation, interinstitutional collaboration among universities, and active involvement of all stakeholders. (2) Create new and expanded training programs with sustained funding. These may take the form of regional Centers of Excellence for Radiation Sciences. (3) Continue and broaden educational efforts of the American Society for Therapeutic Radiology and Oncology (ASTRO), the American Association for Cancer Research (AACR), the Radiological Society of North America (RSNA), and the Radiation Research Society (RRS). (4) Foster education and training in the radiation sciences for the range of career opportunities including radiation oncology, radiation biology, radiation epidemiology, radiation safety, health/government policy, and industrial research. (5) Educate other scientists and the general public on the quantitative, basic, molecular, translational and applied aspects of radiation sciences.

Effects of radiation on normal tissue: consequences and mechanisms.

The use of radiation therapy to treat cancer inevitably involves exposure of normal tissues. As a result, patients may experience symptoms associated with damage to normal tissue during the course of therapy for a few weeks after therapy or months or years later. Symptoms may be due to cell death or wound healing initiated within irradiated tissue, and may be precipitated by exposure to further injury or trauma. Many factors contribute to risk and severity of normal tissue reactions; these factors are site specific and vary with time after treatment. Treatments that reduce the risk or severity of damage to normal tissue or that facilitate the healing of radiation injury are being developed. These could greatly improve the quality of life of patients treated for cancer.

Molecular and cellular biology of moderate-dose (1-10 Gy) radiation and potential mechanisms of radiation protection: report of a workshop at Bethesda, Maryland, December 17-18, 2001.

Exposures to doses of radiation of 1-10 Gy, defined in this workshop as moderate-dose radiation, may occur during the course of radiation therapy or as the result of radiation accidents or nuclear/radiological terrorism alone or in conjunction with bioterrorism. The resulting radiation injuries would be due to a series of molecular, cellular, tissue and whole-animal processes. To address the status of research on these issues, a broad-based workshop was convened. The specific recommendations were: (1) RESEARCH: Identify the key molecular, cellular and tissue pathways that lead from the initial molecular lesions to immediate and delayed injury. The latter is a chronic progressive process for which postexposure treatment may be possible. (2) Technology: Develop high-throughput technology for studying gene, protein and other biochemical expression after radiation exposure, and cytogenetic markers of radiation exposure employing rapid and accurate techniques for analyzing multiple samples. (3) Treatment strategies: Identify additional biological targets and develop effective treatments for radiation injury. (4) Ensuring sufficient expertise: Recruit and train investigators from such fields as radiation biology, cancer biology, molecular biology, cellular biology and wound healing, and encourage collaboration on interdisciplinary research on the mechanisms and treatment of radiation injury. Communicate knowledge of the effects of radiation exposure to the general public and to investigators, policy makers and agencies involved in response to nuclear accidents/events and protection/treatment of the general public.

Modifying normal tissue damage postirradiation. Report of a workshop sponsored by the Radiation Research Program, National Cancer Institute, Bethesda, Maryland, September 6-8, 2000.

Late effects that develop in normal tissues adjacent to the tumor site in the months to years after radiotherapy can reduce the quality of life of cancer survivors. They can be dose-limiting and debilitating or life-threatening. There is now evidence that some late effects may be preventable or partially reversible. A workshop, "Modifying Normal Tissue Damage Postirradiation", was sponsored by the Radiation Research Program of the National Cancer Institute to identify the current status of and research needs and opportunities in this area. Mechanistic, genetic and physiological studies of the development of late effects are needed and will provide a rational basis for development of treatments. Interdisciplinary teams will be needed to carry out this research, including pathologists, physiologists, geneticists, molecular biologists, experts in functional imaging, wound healing, burn injury, molecular biology, and medical oncology, in addition to radiation biologists, physicists and oncologists. The participants emphasized the need for developing and choosing appropriate models, and for radiation dose-response studies to determine whether interventions remain effective at the radiation doses used clinically. Both preclinical and clinical studies require long-term follow-up, and easier-to-use, more objective clinical scoring systems must be developed and standardized. New developments in biomedical imaging should provide useful tools in all these endeavors. The ultimate goals are to improve the quality of life and efficacy of treatment for cancer patients treated with radiotherapy.