C. Norman Coleman, M.D., Associate Director

The Radiation Research Program (RRP) establishes priorities, allocates resources, and evaluates the effectiveness of clinically related radiation research conducted by NCI grantees. The RRP coordinates its activities with other radiation research programs at NCI, NIH, other federal agencies, and national and international research organizations, and provides a focal point at NIH for extramural investigators concerned with clinically related radiation research.

GRANTS

Signal Transduction Pathways and Radiation Effects
Many molecularly targeted agents that become available in the next few years will likely have to be used with conventional therapies for maximal effect. Gleevec, a drug first made available to patients with Chronic Myeloid Leukemia (CML) in May 2001, may be the exception. Gleevec is highly selective for tumor cells and by itself can produce complete remissions, perhaps even cures. Many molecularly targeted agents show significant responses that may not differ from those seen with conventional chemotherapeutic agents, so both must be carefully selected and combined to produce a synergistic effect. Central to the development of such drugs is defining the signal transduction pathways involved.

It is now possible to sketch a common pathway or pathways that affect the radiation sensitivity of solid tumors. McKenna et al. have made progress outlining the components of a pathway that has a significant effect on the survival of cells of human solid tumors after exposure to ionizing radiation. This pathway contains the elements EGFR, Ras, PI3 kinase, and AKT. The data suggest that influencing signaling through this pathway can lead to a phenotype of altered sensitivity. Loss of the PTEN oncogene, which acts as a negative regulator of PI3K signaling, may also affect radiation sensitivity by influencing signaling through this pathway. Downstream components of this pathway must be more fully elucidated. AKT has three isoforms and multiple potential downstream targets that are not easily categorized, although several involve cell survival mechanisms. Testa and Bellacosa have pointed out that, as a general mechanism, phosphorylation events downstream of AKT often affect nuclear translocation of factors involved either in the regulation of cell cycle progression or apoptosis.

Studies initiated by the McKenna group at the University of Pennsylvania have led to two clinical trials. Data from a series of head and neck cancer patients strongly support the hypothesis that phosphorylation of AKT is a good marker for a resistant phenotype. These data are now being explored in lung and breast patients. In the next funding period, the researchers hope to more firmly establish the validity of this pathway and determine the circumstances under which it is active and regulates cell survival. They will determine the most significant downstream pathway components and investigate how best to manipulate the pathway to alter the radiation sensitivity of human tumor cells.

Kinetochores and the Spindle and Mitotic Checkpoint Pathway
Studying the structure and function of human chromosomal structures called kinetochores has led to surprising and unexpected connections with DNA damage, and the realization that kinetochore assembly is a critical event defining the G2 cell-cycle phase.

The kinetochore was thought to be responsible for establishing mechanical connections with spindle microtubules and to possess checkpoint functions that prevented cells with unaligned chromosomes from exiting mitosis. Muschel and colleagues at the University of Pennsylvania identified CENP-E, the first molecular motor shown to specifically associate with kinetochores. She also demonstrated critical steps in CENP-E-mediated kinetochore microtubule attachments. Her CENP-E studies also showed how unattached chromosomes activate the checkpoint to prevent mitotic exit. CENP-E was found to form a complex with the hBUBR1 checkpoint kinase. She discovered that hBUBR1 function is complex because it can act downstream of the kinetochore by directly inhibiting the ubiquitin ligase activity of the Anaphase Promoting Complex (APC) to block exit from mitosis. This inhibitory activity is mediated not by BUBR1 alone but in association with the other checkpoint proteins. This work provided a new paradigm for understanding how checkpoint proteins inhibit the APC.

Muschel also identified two new checkpoint proteins associated with kinetochores. hZW10 and hROD are human orthologs of Drosophila genes that are essential for chromosome segregation. As was shown for the Drosophila genes, she demonstrated that hZW10 and hROD were necessary for kinetochores to recruit the microtubule motor dynein there. She discovered that hZW10 and hROD are also required for the spindle checkpoint, despite the fact that neither gene is conserved in yeast, where many spindle checkpoint genes were first identified. This evolutionary divergence reflected the increased complexity of metazoan kinetochores because dynein is not known to associate with kinetochores in yeast. She postulated that hZW10 and hROD might specifically monitor dynein-mediated kinetochore microtubule interactions.

These studies have created new opportunities to examine kinetochore assembly. EM studies showed that the trilaminar kinetochore is only visible during mitosis, suggesting that this macromolecular complex must be assembled during each cell cycle. She found that many proteins exhibit a strict temporal localization pattern to kinetochores that occurs between late G2 and the onset of mitosis. This temporal pattern might reflect the order of assembly. It may also reflect a functional dependence in which assembly of one component is critical for completing subsequent steps. Muschel's overall hypothesis is that kinetochore assembly may be a major event that defines the G2 cell-cycle phase. If true, analysis of the mechanism that temporally regulates kinetochore assembly will help link cell-cycle determinants with their targets. Preliminary data show that kinetochore assembly is monitored by a G2 checkpoint. A detailed analysis of Cenp-F found that its complex distribution pattern might define distinct G2 substages. Cenp-F appears to define a critical step in the kinetochore assembly pathway, and blocking the assembly of Cenp-F onto kinetochores prevents the subsequent assembly of Cenp-F, Mad1, and Mad2 onto kinetochores. Cenp-F-defective cells are delayed in G2 for about 3 hours before resuming the progression into aberrant mitosis. Furthermore, when HeLa cells are exposed to ionizing radiation or etoposide chemotherapy, they arrest at a discrete phase in G2 where Cenp-F has not assembled onto kinetochores. These observations prompted the researchers to investigate the mechanism that regulates the cell-cycle-dependent localization of Cenp-F onto kinetochores, whether the mechanism is sensitive to the DNA-damage-induced G2 checkpoint, and what mechanisms might monitor the assembly of Cenp-F onto kinetochores.

Electron Paramagnetic Resonance Imaging
Using in vivo electron paramagnetic resonance (EPR) spectroscopy and imaging (EPRI), it has been shown that tumor tissues are highly reducing and hypoxic compared to normal tissues. Using low-frequency (1.2 GHz) in vivo EP spectroscopy and imaging techniques with a nitroxide redox probe, Dr. Priya Kuppusamy spatially resolved redox data from normal and tumor tissues of RIF-I tumor-bearing mice, and examined the role of intracellular glutathione on the tissue redox state. L-buthionine-S,R-sulfoxirnine (BSO), an inhibitor of glutathione synthesis, was used to deplete tissue glutathione levels. Results showed the existence of significant heterogeneity of redox status in the tumor tissue compared to normal tissue. Tumor tissues showed at least 4-fold higher concentrations of GSH levels than did normal tissues in the tumor-bearing mice. BSO treatment also showed a differential depletion of GSH and reducing equivalents in the tumor tissue. Thus, it appears that tumor redox status is an important parameter that may be related to tumor growth and therapy.

Dr. Kuppusamy also noninvasively monitored tumor oxygenation and redox status during hyperoxygenation treatment with carbogen breathing in a murine tumor model. The study was performed using implanted lithium phthalocyanine (LiPc) microcrystals as an oximetry probe and 3-carbamoylproxyl (3-CP) as a redox probe in RIP-I tumors implanted in the hind leg of C3H mice. Repetitive measurements of pO2 from the same tumors as a function of tumor growth (8-24 mm size) showed that the tumors were hypoxic and that tumor pO2 values decreased with tumor growth. Carbogen breathing mostly showed an increase in tumor oxygenation, although there were variations in the magnitude of change among tumors. Pharmacokinetic studies with 3-CP showed a significant decrease in overall tumor-reduction status in carbogen-breathing mice. Spatially resolved (imaging) pharmacokinetic data over the tumor volume were obtained to visualize the distribution of redox status in the tumor. Redox images of the tumor in air-breathing mice showed significant heterogeneity in the magnitude and spatial distribution of reducing equivalents. On carbogen-breathing the tissue, reduction status decreased considerably with a concomitant decrease in the heterogeneity of redox status distribution. These results suggest that carbogen breathing considerably enhances tissue oxygenation and significantly decreases redox status in RIF-l tumor, and that changes in the magnitude and distribution of redox status in tumor volume during carbogen breathing correlates to increased tissue oxygenation.

Dr. Kuppusamy also investigated the efficacy of a macromolecular intravascular nitroxide, polynitroxyl-albumin (PNA), as a tumor radiosensitizer. PNA is compartmentalized in blood vessels and prevents vasoconstriction without altering mean arterial pressure. He hypothesized that PNA is capable of opening previously closed tumor vascular beds, presumably in the hypoxic core. This increased flow in blood vessels would enhance radiosensitivity by augmenting oxygen delivery by red cells. The vascular volume of a tumor versus that of normal tissue was measured by in vivo EPR spectroscopy in a RIP-l murine tumor. Two bolus infusions of PNA were administered intravenously, and nitroxide pharmacokinetics was followed at the tumor site. Tumor tissue pO2 was simultaneously measured using a LiPc oximetry probe. The data showed a small but stable increase of tumor vascular volume following first infusion; after 60 min. and a second PNA dose, tumor blood vessels opened to about what would be normal for muscle; and the volume increased steadily over time, indicating that PNA continued to penetrate tumor tissue. Increased vascular volume also correlated with enhanced tumor pO2. Thus, PNA appears to be a potential sensitizer for tumor radiotherapy.

References 1. IIangovan G, Li H, Zweier JL, Kuppusamy P. Electrochemical preparation and EPR studies of lithium phthalocyanine. Part 3: Measurements of oxygen concentration in tissues and biochemical reactions. Journal of Physical Chemistry B 2001;105:5323-30. 2. He G, Samouilov A, Kuppusamy P, Zweier J. In vivo imaging of the distribution and metabolism of nitroxide radicals in human skin. Journal of Magnetic Resonance 2001;148:155-64. 3. Krishna MC, Devasahayam N, Cook JA, Subramanian S, Kuppusamy P, Mitchell JB. Electron paramagnetic resonance for small animal imaging applications. Institute of Laboratory Animal Resources Journal 2001;42:209-18. 4. Kuppusamy P, Li H, Dangovan G, et al. Noninvasive imaging of redox status in tumor: Effect of tissue glutathione levels in a RIP-I tumor model. Cancer Research 2002;62:307-12. 5. IIangovan G, Manivanpan A, Li H, Yanagi H, Zweier JL, Kuppusamy P. A new naphthalocyanine-based EPR oximetry and imaging probe for biological applications. Free Radical Biology and Medicine 2002;32:139-47. 6. He G, Deng Y, Li H, Kuppusamy P, Zweier JL. EPR/NMR co-imaging for anatomic registration of whole-body free radical images. Magnetic Resonance in Medicine 2002;47;571-8. 7. Kuppusamy P, Krishna MC. EPR imaging of tissue redox status. Current Topics in Biophysics 2003 (in press). 8. Ilangovan G, Li H, Zweier JL, Krishna MC, Mitchell JB, Kuppusamy P. In vivo measurement of regional oxygenation and imaging of redox status in RIP-I murine tumor: Effect of carbogen-breathing. Magnetic Resonance in Medicine 2003 (in press). 9. Yamada K, Kuppusamy P, Irie A, et al. In vivo EPR imaging of spatiotemporal changes of nitroxide in tumor-bearing mice. Acta Radiologica 2003 (in press).

Vascular Radioresistance
Melanoma and the brain tumor glioblastoma multiforme are resistant to radiotherapy. Blood vessels in these tumors are also more radioresistant than those in more sensitive tumors. Dr. Dennis Hallahan of Vanderbilt University postulated that vascular radioresistance may cause the poor radiation response of these tumors. The growth factor VEGF initiates important signaling pathways in vascular endothelial cells that direct endothelial cell proliferation, migration, and differentiation. Elevated VEGF levels are found in treatment-resistant tumors, compared to levels in more sensitive tumors. Dr. Hallahan found that agents that block various points along VEGF-signaling pathways can enhance radiation-induced cell killing in cultured endothelial cells, decrease vascular density in tumors growing in window chambers in mice, and increase the radiation-induced growth delay in radioresistant tumors in mice. Enhanced growth delay was found even when radiation treatment was given in multiple fractions, as it is in the clinic. These studies support Dr. Hallahan's hypothesis that targeting vasculature of radioresistant tumors by blocking the VEGF pathway enhances tumor response to radiotherapy, and suggest that this approach might be successful in the clinic.

References 1. Geng L, Donnelly E, McMahon G, et al. Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Research 2001;61:2413-9. 2. Edwards E, Geng L, Tan J, Onishko H, Donnelly E, Hallahan DE. Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation. Cancer Research 2002;62:4671-7.

Astatine-211 Radiotherapy
Michael Zalutsky, Ph.D., and his team at Duke University are developing more effective approaches for labeling monoclonal antibodies with the alpha-particle-emitting nuclide Astatine-211 (211-At). The clinical impact of labeled monoclonal antibodies is hampered by the loss of the label from monoclonal antibodies in vivo and uptake of radioactivity in normal tissues. His research focused on monoclonal antibodies reactive with epidermal growth factor variant III (EGFRvIII) because this mutant receptor is present in high concentrations on gliomas, breast carcinomas, and other tumors, and because it is not found on normal tissues, including those expressing wild type EGFR. Anti-EGFRvIII 211-At is internalized and rapidly processed, resulting in rapid loss of the label from tumor cells when monoclonal antibodies are labeled by conventional methods. His team tried to optimize labeling methods for internalizing monoclonal antibodies to enhance tumor retention and tumor-to-normal-tissue ratios and improve their clinical potential as diagnostic and therapeutic agents. A phase I trial of 211-At-labeled chimeric 81C6 antitenascin monoclonal antibody in patients with surgically created glioma resection cavities demonstrated for the first time that clinical evaluation of 211-At-labeled therapeutics is feasible. In 17 recurrent glioma patients studied to date, excellent retention of 211-At in the tumor resection cavity and minimal leakage into the blood was observed in two patients with recurrent glioblastoma multiforme surviving for three years after treatment with 211-At-labeled chimeric 81C6. Different labeling strategies were used to increase up to 5-fold the retention of radioiodine activity in tumor cells and xenografts, but resulted in higher kidney activities. Ongoing work is directed at developing a reagent suitable for 211-At labeling, optimizing the promising positively charged templates and performing catabolism studies in animal models to determine efficacy before translation.

Pathophysiology of Solid Tumors
The physiology of solid tumors is central to their growth, progression, metastasis, detection, and treatment. For example, angiogenesis and the resulting vascular network are essential for supplying nutriments and removing metabolic products during tumor growth. The success of tumor detection using various agents, including contrast agents and monoclonal antibodies, requires their selective uptake by the tumor. The efficacy of all nonsurgical cancer treatment methods depends substantially on tumor blood flow and the metabolic microenvironment of cells, including molecular transport and intrinsic cellular parameters. For example, response to radiation therapy depends in part on local oxygen tension that is governed by oxygen consumption rates and local blood flow. In chemotherapy, immunotherapy, gene therapy, and photodynamic therapy, treatment effectiveness depends on the localization in tumors of adequate quantities of an appropriate therapeutic agent. This must be balanced with the goal of limiting accumulation of these agents to a tolerable level in sensitive normal tissues. Whether or not a therapeutic agent reaches its target cells depends on blood perfusion and molecular transport in the tumor. Even then, the target cell may be resistant to the agent. Tumor cell sensitivity to most drugs or radiation is a function of their inherent characteristics and their proliferation kinetics and phase in the cell cycle. Such kinetics are modified by the tissue's nutritional and metabolic microenvironment. Better understanding of tumor pathophysiology is therefore needed to improve cancer detection and treatment methods and to develop new methods that overcome or exploit unique vascular and interstitial barriers in a solid tumor's microenvironment. Research at Massachusetts General Hospital under the direction of Dr. Rakesh Jain, with support from an NCI grant, is addressing many such problems and generating interesting results.

The discovery that host cells contribute to the production of pro- and anti-angiogenic therapies changed the thinking about anti-angiogenic therapies. The discovery that about 15% of tumor blood vessels are mosaic in nature explains why several conventional chemotherapeutics act as anti-angiogenic agents. The discovery that the host-tumor interaction governs production of the extracellular matrix provides a novel target for modulating the interstitial matrix so therapeutics can be delivered more effectively. The finding that entrapment of activated lymphocytes by lung can be significantly reduced by lowering their rigidity with thiologlycolic acid offers new hope for delivering genetically engineered immune cells to tumors.

TARGETED INITIATIVES

Cancer Disparities Research
In September 2002, Cooperative Planning Grants for Cancer Disparities Research Partnership (CDRP) were awarded to Rapid City Regional Hospital in South Dakota and Mercy Health Center in Texas. These grants provide resources for cooperative planning, development, and conduct of radiation oncology clinical research trials in institutions nationwide that care for a disproportionate number of medically underserved, low-income, ethnic, and minority populations, but that have not traditionally been involved in NCI-sponsored research. The grant offers a unique opportunity to use radiation oncology to help reduce the significant negative consequences of cancer-related health disparities. A major component of the CDRP program is the development and maintenance of mentor partnerships between institutions new to radiation clinical trials and experienced research institutions.

Rapid City Regional Hospital (RCRH) in Rapid City, SD, has a total reach of about 100,000 Native Americans from surrounding reservations. For this grant, RCRH will concentrate on the Pine Ridge, Cheyenne River, and Rosebud reservations. The Pine Ridge Reservation is in the poorest county in the United States and has some of the highest cancer mortality rates. RCRH is the primary provider of radiation oncology care for the Native American population in this region. Dr. Daniel Petereit, the RCRH principal investigator, plans to partner with the University of Wisconsin Comprehensive Cancer Center and the Mayo Clinic Comprehensive Cancer Center.

Mercy Health Center (MHC) in Laredo, TX, serves a community that is 95% Hispanic and in which more than 35% of residents live in poverty. Laredo has one of the highest poverty rates in the nation, with one in three families living at or below the poverty level. MHC also serves 40-60 colonias (unincorporated areas with substantial substandard housing). Most colonias have no running water, electricity, or telephone service. Dr. Yadvindera Bains, MHC principal investigator, plans to partner with the University of Texas Health Science Center and M.D. Anderson Cancer Center.

Both institutions are developing infrastructure for the Cancer Disparities Research Partnership Program.

Advanced Technology Quality Assurance Center
The mission of the Advanced Technology Quality Assurance Center (ATC) is to facilitate the conduct of NCI-sponsored advanced technology radiation therapy clinical trials while maintaining patient confidentiality. This effort includes support in radiation therapy clinical trial quality assurance, image and radiation therapy digital data management, and developmental efforts in these areas. The ATC is using advanced medical informatics to facilitate education, collaboration, and peer review, and providing an environment in which clinical investigators can receive, share, and analyze volumetric treatment planning volume digital data. The ultimate ATC goal is to improve standards of care in cancer management by improving the quality of clinical trials medicine.

This quality assurance resource was used in protocol RTOG (Radiation Therapy Oncology Group) 94-06 and is being extended to other RTOG protocols for lung and brain cancer. The scientific question addressed by RTOG 94-06 is whether strict quality assurance can allow high-dose radiation therapy to be given by conformal techniques for early-stage prostate cancer.

A total of 288 cases of patients with prostate cancer were analyzed for bowel and bladder toxicity. Acute toxicity was low; most patients had no toxicity or had grade-1 toxicity, very few had grade-3 toxicity, and none had grade-4 or -5 toxicity. Toxicity was correlated with the amount of rectum or bladder receiving high-dose radiation.

Tolerance to high-dose 3-dimensional conformal radiotherapy (3D CRT) was better than expected in this dose-escalation trial for Stage T1,2 prostate cancer compared to low-dose RTOG historical experience. With strict quality-assurance standards and review, 3D CRT can be safely studied in a cooperative group setting. There appears to be a dose-volume relationship with respect to the development of acute and late bladder toxicities. A prospective randomized trial will determine whether this treatment approach can improve efficacy. Meanwhile, the innovated image/clinical database resulting from this trial will be an important resource in the study of late effects and tumor control. This resource has also been used to assess the tolerance of lung cancer to radiation therapy and to perform quality assurance for an RTOG phase II clinical trial for high-dose CRT in non-small-cell lung cancer.

The economic and social impact of reducing radiation-related complications is obvious from a quality-of-life perspective. Unrelated reports in the literature suggest that high-dose conformal radiation may also improve long-term, disease-free outcome in early prostate cancer.

References 1. Purdy JA, Harms WB, Michalski J, Bosch WR. Initial experience with quality assurance of multi-institutional 3D radiotherapy clinical trials. A brief report. Strahlentherapie Onkologie 1998;174(Suppl 2):40-42. 2. Michalski JM, Purdy JA, Winter K, et al. Preliminary report of toxicity following 3D radiation therapy for prostate cancer on 3DOG/RTOG 9406. International Journal of Radiation Oncology, Biology, Physics 2000;46:391-402. 3. Michalski JM, Winter K, Purdy JA, et al. Trade-off to low-grade toxicity with conformal radiation therapy for prostate cancer on Radiation Therapy Oncology Group 9406. Seminars in Radiation Oncology 2002;12(1 Suppl 1):75-80. 4. Graham MV, Purdy JA, Emami B, et al. Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC) International Journal of Radiation Oncology, Biology, Physics 1999;45:323-329.

WORKSHOPS/MEETINGS

Potential Mechanisms of Radiation Protection
Normal tissue response and injury after exposure to ionizing radiation are of great importance to cancer patients; those subjected to military, accidental, or intentional exposure; and nuclear power industry workers. In these situations, exposure is likely to include the moderate-radiation dose range (1-10 Gy). An interdisciplinary workshop was convened in December 2001 by a coalition of government agencies (NCI, Department of Defense/Armed Forces Radiobiology Research Institute, and Department of Energy) and the Radiation Research Society to survey consequences of human exposure to 1-10 Gy, and discuss ways to improve radiation injury diagnosis, triage, prevention, and treatment now and in the next 5 years. The following recommendations describe basic, preclinical, and clinical research programs that would benefit radiation accident and terrorism preparedness and clinical radiation oncology. Workshop participants discussed how these recommendations could be implemented. Suggestions included asking relevant federal agencies to review their research portfolios on normal tissue radiation injury, undertaking targeted research on radiation toxicology and biodosimetry, and convening a follow-up workshop on drug development that includes participants from the pharmaceutical industry and the Food and Drug Administration. Finally, the group identified research opportunities and required resources, and recommended an action plan. Workshop participants made the following recommendations:

Determine genetic and epigenetic mechanisms that govern individual susceptibility to radiation, including normal tissue injuries and carcinogenesis.

Develop and characterize genetic, protein, chromosomal, and tissue biomarkers for exposure in the range of 1-10 Gy.

Develop systems for analyzing gene and protein expression in irradiated normal tissues.

Identify physiologic and molecular targets for prophylaxis and treatment of radiation injuries.

Define functional effects of ionizing irradiation on stem and parenchymal cells of tissues and organs that develop acute or chronic radiation injuries.

Investigate the role of oxidative stress in the cellular and tissue response to ionizing irradiation and the role of antioxidants for radiation injury prophylaxis and treatment.

Develop strategies for radiation injury prophylaxis and treatment based on optimizing current approaches and discovering new molecular, cellular, and tissue targets.

Support long-term animal studies to determine the consequences of radiation-induced parenchymal cell dysfunction, including studies of strategies for radiation injury prophylaxis and treatment.

Conduct epidemiologic studies of late normal-tissue toxicity in people exposed to ionizing radiation in cancer treatment and accidental or intentional exposures.

Develop high-throughput assays based on molecular targets to identify novel protectors of normal-tissue injury.

Develop detection technology for rapid analysis of molecular biomarkers of ionizing radiation exposure for large numbers of samples.

Facilitate cooperation and collaboration among industry, government agencies, and academic communities for developing, testing, and producing new agents for radiation injury prophylaxis and treatment.

Increase the pool of researchers with expertise in normal-tissue and animal radiation biology, and increase the pool of experts in health physics, radiation protection, and dosimetry.

Recruit individuals with expertise in cellular biology, molecular biology, physiology, and wound healing into the normal-tissue radiobiology field.

Include training in the diagnosis, prophylaxis, and treatment of late normal-tissue effects of ionizing radiation in the education of oncologists.

Support and expand national capabilities for medical radiologic response.

References 1. Moulder JE. Report on an interagency workshop on the radiobiology of nuclear terrorism. Radiation Research 2002;158:118-24. 2. Moulder JE. Radiobiology of nuclear terrorism: Report on an interagency workshop. 17-18 Dec 2001, Bethesda, MD. International Journal of Radiation Oncology, Biology, Physics 2002;54:327-8. 3. Coleman CN, Tofilon P, Stone H, Wong R. Molecular and Cellular Biology of Moderate Dose (1-10 Sv) Radiation and Potential Mechanisms of Radiation Protection (draft report). 17-18 Dec 2001, Bethesda, MD.

Monte Carlo Techniques in Radiation Dosimetry
In recent years, a great deal of effort has gone into developing and using dose-calculation algorithms for radiotherapy treatment planning. To evaluate the status of the use of Monte Carlo algorithms, NCI, in association with Oak Ridge National Laboratory, organized a 2001 workshop on Issues Limiting the Clinical Use of Monte Carlo Dose Calculation Algorithms. The objective was to identify research topics that would help implement the use of Monte Carlo dose-calculation algorithms in the clinical setting. Though this area of investigation is not new, it may now be appropriate to assess this approach to radiation dose calculations for the following reasons: computer hardware improvements make many Monte Carlo methods fast enough to be clinically useful, there is a need for more accurate dose calculations due to the increasing sophistication of treatment methods and assessments, and several Monte Carlo calculation algorithms are available for research or clinical use.

Goals of the meeting were to identify issues that might limit Monte Carlo use, determine their status, determine which might be most appropriate for research or developmental assistance, and, if support is required, determine where the support could be most productively used. Specific Monte Carlo codes and their advantages or disadvantages were not addressed; the goal was to examine scientific and clinical issues.

Three topics focused the discussion. The first reviewed the status of various aspects of Monte Carlo algorithms, the second concentrated on clinical issues, and the third addressed algorithm verification and validation requirements, methods, and studies. There were brief discussions on the use of Monte Carlo dose-calculation algorithms for brachytherapy and internal emitters. Recommendations included validation of Monte Carlo algorithms, study of the potential clinical impact of Monte Carlo, further Monte Carlo research areas, and continuing education.

It is crucial to educate physicists and physicians on the methods and clinical implications of Monte Carlo algorithms and their implementation. This should include symposia, training, and guidance materials from vendors and societies. Without these efforts, some may accept the potential superior accuracy of Monte Carlo as fact, when accuracy may be worse than existing computations in clinics that do not properly implement the method.

Optimizing Radiotherapy
The availability of sophisticated radiotherapy delivery systems--known as Intensity-Modulated Radiation Therapy (IMRT)--promise enormous benefits to patients. Such systems allow the fluence pattern across radiation beams to vary substantially. The intricacy and variety of choices they offer for beam angles, fluence maps, and segmentation, however, make effective computer-aided planning tools essential.

The Operations Research (OR) community has long investigated such mathematical optimization technologies and is interested in addressing complex planning problems. To bring the OR and radiation oncology communities together to discuss this research area and potential collaborations, an NCI/NSF-sponsored workshop on Operations Research Applied to Radiation Therapy was held in February 2002 for radiation oncology physicians, radiation oncology physicists, and OR community members.

Recommendations included research on multiple aspects of IMRT algorithm optimization improvements, an optimized treatment planning test library, reducing uncertainty in outcome predictors, flexibility in the planning interface, and quality assurance of planning solutions.