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International conference on translational research and preclinical strategies in radio-oncology (ICTR)—conference summary
Int. J. Radiation Oncology Biol. Phys., Vol. 49, No. 2, pp. 301–309, 2001 Copyright © 2001 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/01/$–see front matter
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ICTR 2000
Keynote Lecture
INTERNATIONAL CONFERENCE ON TRANSLATIONAL RESEARCH AND PRECLINICAL STRATEGIES IN RADIO-ONCOLOGY (ICTR)—CONFERENCE SUMMARY C. NORMAN COLEMAN, M.D. Radiation Oncology Sciences Program, Division of Clinical Sciences, Division of Cancer Diagnosis and Treatment, National Cancer Institute, National Institute of Health, Bethesda, MD “After all, science is essentially international, and it is only through lack of the historical sense that national qualities have been attributed to it.” Marie Curie, “Intellectual Co-operation”
INTRODUCTION
izing Radiation Oncology in Y2K,” with the following five questions to be addressed:
Formulating the Conference Summary for the “First International Conference on Translational Research and Preclinical Strategies in Radio-Oncology” (ICTR 2000) presented a challenge. This novel conference had as its theme “Individualizing Cancer Treatment.” Ably spearheaded by Dr. Jacques Bernier, the conference was an action-packed 3 days, with keynote and named lectures, workshops, meetthe-professor sessions, symposia, proffered papers, forums, oral poster presentations, and debates. Overall, there were approximately 300 different abstracts/presentations, often presented in 3– 4 parallel sessions. The days were indeed very full, with excellent scientific interaction among the speakers and attendees. For those who will consider the challenge of being a “conference summarizer” in this or other meetings, Table 1 includes an offering of “10 Basic Commandments for Conference Summarizers.” The international nature of science is well stated in the above quotation of Madame Curie. The meeting was indeed eclectic in its participants and topics. The venue of the meeting was conducive to collegial interaction among the multinational cadre of medical physicists, biologists, mathematicians, and radiation and medical oncologists who are not usually all at the same meeting. The success of this first effort led the Organizing Committee to vote to hold the second ICTR in Lugano in 2003. All aspects of radiation-oncology–related science and technology are undergoing exciting changes. The task of conference summary for this new thematic conference is akin to my new position as the Director of the Radiation Oncology Sciences Program (ROSP) at the National Cancer Institute in that it is important to look at the field as an entity. Thus, the structure of this summary is “Conceptual-
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What currently comprises the fields of “radiation oncology” and “radiation research?” How do we present our research and development to the “outside world?” What are the potential opportunities for improved treatment and new fundamental knowledge and how do we relate them to each other? How do we establish priorities and create a balanced portfolio of research and development? How do we stimulate our colleagues and trainees to pursue new knowledge and consequently better outcomes for patients?
CANCER IS A BIOLOGIC ENTITY Cancer is both genetic, due to abnormal gene structure, and epigenetic, as it is the function of the molecules that determines cell function. A normal protein may function abnormally depending on the biochemical state of the cell. Ultimately, a multiplicity of abnormal biochemical pathways leads to uncontrolled and sustained growth for localized tumors, invasion for regional tumors, and metastases for advanced cancers (1). Given the biologic nature of cancer, how can a technically based specialty have a working “model” in common to all translational radiation oncology scientists so that we appreciate that we are all indeed facing the same problem? Borrowing from the “Power of 10” concept often seen at science museums in which one takes a view of earth from outside the Milky Way galaxy and zooms in by log10 step sizes until one enters a cell, Fig. 1 is a schematic of the field
Reprint requests to: Dr. C. Norman Coleman, ROB, Bldg 10, B3B69, National Institute of Health, Bethesda, MD 20892. E-mail: ccoleman@ mail.nih.gov
Presented at ICTR 2000, Lugano, Switzerland, March 5– 8, 2000. Accepted for publication 31 August 2000. 301
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Table 1. 10 “Basic Commandments” of meeting summaries 1. Must read all of the abstracts before the meeting. 2. Must miss a substantial majority of the actual presentations due to simultaneous sessions, so must guess what was actually said. 3. Must attend the entire meeting, even if it is in a location as scenic as Lugano. 4. Must maintain moderation in what one ingests, particularly the final evening, although the definition of “moderation” evolves rapidly as the meeting progresses. 5. Must prepare the bulk of the talk and slides before the meeting and therefore depend on the abstracts being at least vaguely representative of the presentation at the meeting. 6. Must be comprehensive but not too detailed. A 45-min summary for 300 presentations, results in an average of 10 sec per presentation. 7. Must mention enough people’s work without too much individual attribution for fear of neglecting and/or insulting colleagues. 8. Must be optimistic yet realistic. This may vary depending on when you are to be reimbursed. 9. Must finish on time so that those who stay to the end of the conference can catch their plane/train/bus/boat/car ride. 10. Must be stimulating and entertaining to reward those who hung on till the end. Bonus Commandment should one succeed with most or all of the first 10: Must write up a comprehensive paper within 2 weeks.
of radiation oncology (2). Defined are four domains denoted macro-, normo-, micro-, and nano-, with the latter implying subnano to picometer dimensions. Thus, the field of clinical/ translational radiation oncology is a single entity that is viewed by various investigators with vantage points that differ by approximately 10 orders of magnitude. The research topics in this conference are somewhat arbitrarily placed within one of the domains, emphasizing the continuity and inter-relatedness of the various disciplines, as summarized in the Fig. 1 legend. Each of the four environments will be summarized with two tables, one for “Issues and Problems” and another for “New Opportunities.” The content of the tables will not be reiterated within the text. Scientific findings that emerged from this meeting will be discussed in the text, generally without specific attribution to avoid this becoming an exhaustive review article. The “New Opportunities” will be a compilation of concepts that emerged from this and other meetings and my personal opinion. These do not represent any “institutional” policy or priority list, and it is likely that some important items have been inadvertently omitted. MACRO-ENVIRONMENT Table 2a includes Macro-environment: issues and problems. The presentations at ICRT can be subdivided into a few categories. Dose optimization: Intensity-modulated radiation therapy (IMRT) is feasible for cancers of the central nervous system, head and neck, lung, and prostate. Imaging is crucial,
Fig. 1. The range and domains of radiation oncology sciences research.The Macro-environment is the normal tissue surrounding the patient. Research is involved in avoiding normal tissue injury through dose-optimization, external beam radiation techniques, the use of brachytherapy, and the employment of models of normal tissue complication probability (NTCP) and tumor control probability (TCP). The Normo-environment refers to that which we see and measure in the clinic. It includes routine evaluations that assess the patients’ general health and tumor status, predictive assays of treatment outcome and response, clinical trials with tumor response assessment and pharmacokinetic studies.The Microenvironment focuses on the cellular environment of the tumor but also includes the normal cellular component of a tumor—stromal, epithelial, vascular, immunologic, and inflammatory cells. It includes the physiologic perturbations within a tumor, hypoxia being one of longstanding interest. It includes other cellular targets, such as organelles, and larger sized therapeutics, such as antibodies, gene therapy vectors, and adoptive immunotherapy.The Nano-to-pico environment includes molecular targets and the many biochemical and molecular processes that occur within the cancer cell before, during, and after perturbation with radiation. This is the environment of molecular pharmacology and track structure. It is where physics, chemistry, and biology unify. It is also where molecular therapeutics are targeted using approaches ranging from targeting a specific molecular structure (as defined by structural biology) to generating an enormous number of compounds and sorting out which are “active” in impacting a biologic process (combinatorial chemistry). Figure reprinted with permission from Ref. 2.
as the treatment volume (including size of margins) depends on the imaging and uncertainties in defining the tumor. Technologic advances have been made in developing mini-
ICTR— conference summary
Table 2. Macro-environment a. Issues and problems Normal tissue 䡠 Identifying tumor & normal tissue 䡠 Localizing target reproducibly: inter- and intra-observer variability 䡠 Hitting target on a daily basis without too much collateral damage 䡠 Will the precision of IMRT compromise accuracy? 䡠 Integral dose—radiation must go somewhere. What is the impact of low dose per day radiation on normal tissue? Is there low dose hypersensitivity? 䡠 Particle therapy—what proof is required before it is used as standard treatment? Are randomized trials necessary? Should this technology be in specialized centers only and should it involve true multi-institutional resource sharing? b. New opportunities Normal tissue 䡠 Functional imaging—MRI, MRS, SPECT, PET, EPR, etc. 䡠 Real-time imaging during therapy with appropriate treatment modification 䡠 CT–tomotherapy 䡠 Ultrasound imaging during treatment 䡠 Portal imaging 䡠 Brachytherapy—MRT, ultrasound with real-time dose calculation 䡠 Immobilizing patient and tumor—precision relocatable devices for stereotactic radiosurgery and radiotherapy 䡠 Intensity modulation of photons, electrons, and heavier particles; unlimited number of fields possible (need to be optimized and “realistic” for daily use) 䡠 Protecting normal tissue 䡠 chemical radioprotector, 䡠 growth factors 䡠 altering death response (e.g., inhibiting p53 [pifithrinalpha] (3)) 䡠 Reversing late effects—months and years later, e.g, pentoxyfyline ⫹ tocopherol (4)
multileaf collimators and in respiratory and cardiac gating. Fractionation is both feasible and important with stereotactic radiosurgery. Technology development must be somewhat practical with the need to balance infinitely complex approaches with those that are “acceptable” for daily practice, that is, how many fields should be used for a particular treatment. For very expensive technology, resource sharing is appropriate and necessary as demonstrated by the successful multinational EORTC proton project. Brachytherapy is both conformal and intensity-modulated radiation therapy by virtue of being able to place seeds in a range of patterns. Dose heterogeneity is also important in toxicity. Prostate brachytherapy is probable the best studied site. At this meeting, the importance of adequate technique was discussed as well as the potential of the addition of gene therapy to brachytherapy. Mathematical modeling is necessary to calculating TCP (tumor control probability) and NTCP (normal tissue complication probability). In addition to the current “target volumes (TVs)” gross (GTV), clinical (CTV), and planning (PTV), the concept of biologic target volume (BTV) was
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presented by Cliff Ling. Unfortunately, at present, when a treatment plan is developed along with dose–volume histograms (DVHs), it is not readily apparent which is the worst or best plan. Normal tissue studies indicate that late radiation injury is a dynamic process, in essence, a chronic “active” process. Fibroblasts that have been irradiated have a stable increase in collagen production. Radiation late effects are not simply stochastic but appear to involve the genotype and phenotype of the patient’s cellular response. Included in normal tissue issues is the role of radiation therapy in inducing secondary malignancies in patients with hereditary cancer predisposition. These cells (for example, BrCA1 and 2 and AT) may be more radiosensitive, but it is unknown if radiation will be more mutagenic in these patients. For all tissues irradiated with low doses, what is the impact of the low-dose radiation hypersensitivity now being defined mechanistically? What is the impact of the increased volume of normal tissue that will receive some irradiation with the multifield IMRT techniques? Added to the radioprotector armamentarium are growth factors that can increase the number of mucosal cells, such as rhKGF. Table 2b includes Macro-environment: new opportunities. Functional imaging is being developed to help discern tumor from normal tissue and distinguish between more and less critical normal tissues (e.g., functional centers within the brain). Real-time imaging during therapy— external beam and brachytherapy—will help reduce uncertainty and normal tissue volume. Completely novel concepts in radiation protection include inhibiting processes that lead to cell death, such as inhibition of p53 function to abrogate toxicity of therapy (3). Critical to normal tissue protection is whether or not cells that are protected will have an increased number of chromosomal abnormalities. Intriguing reports indicating that late normal tissue injury may be partly reversible (4) have challenged the dogma of the irreversibility of late radiation fibrosis and may open up remarkable new interventions into radiation injury as well as the possibility of further dose escalation. Some distance down the road may be the use of stem cells or organotypic cell transplant to restore organ function after cancer therapy-related injury. NORMO-ENVIRONMENT Table 3a includes the Normo-environment: issues and problems. This includes the range of laboratory studies that are conducted to stage, prognosticate outcome, predict treatment response, and assess immunologic, biochemical, and physiologic parameters of the patient. Pharmacologic and pharmacokinetic analyses are often done to assure that the optimal dose of a drug is delivered. A laudable goal has been to establish predictive assays of tumor and normal tissue response to radiation therapy. These have included cell kinetics, apoptosis index, assessment of individual genes, such as p53, and others. As summarized in the meeting by Lester Peters, these have not as yet demonstrated utility for predicting response for an individual patient. Studies that have demonstrated differences
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Table 3. Normo-environment a. Issues and problems Clinical and laboratory evaluation 䡠 Markers—staging and prognosis 䡠 prognostic factors need to be predictive for individual patients 䡠 Markers of response—is there different information derived from rate of response and absolute value of a parameter 䡠 Immunologic status and the impact on patient outcome 䡠 Circulating and sub-microscopic deposits of tumor cells are now detectable with PCR, immunohistochemistry (IHC). What do these mean? 䡠 Overall medical condition in an aging population Pharmacology: Issues and problems 䡠 Drug administration and schedule 䡠 drug is usually optimized for chemotherapy and not radiation therapy 䡠 Pharmacogenetics—predicting toxicity especially for the very susceptible patient b. New opportunities Clinical and laboratory evaluation 䡠 Markers of response—intermediate end-points for response, relapse, survival provide a short-track to results 䡠 Immunologic augmentation—vaccine, adoptive therapy; how to integrate radiation to augment and not impair immune response and/or immunotherapy 䡠 Circulating tumor cells or microscopic disease in lymph nodes—what do they mean and how should they impact local/regional treatment? Will this be a novel role for systemic radiation therapy? 䡠 Patient’s overall medical condition—radiation oncologists must be good general clinicians and active in general patient care. Pharmacology 䡠 Drug administration—schedule and toxicity with RT require different approach than using drugs by themselves—mechanisms may differ; schedule of administration likely to be different than with drug alone. 䡠 Radiation oncologists must be active in radiation modifier administration.
among groups of patients for one parameter or other and a correlation of outcome for a patient group are useful in guiding future mechanistic research as they may help define an area of investigation. However, a predictive assay should be applicable to individual patients because a group average may only separate a few “outliers” from the whole population and, therefore, be of limited value in treatment selection. The Normo-environment: new opportunities in Table 3b include the development of intermediate markers of response. For example, might a comet assay from a tumor biopsy following the first treatment or change in PET or MRI scan early in a course of therapy indicate the likelihood of successful radiation for that particular patient? Intermediate markers would also accelerate the rate of generation of new knowledge. Immunologic therapies involve radiation therapy, often as part of immunosuppression for transplantation but also as part of the therapeutic regimen to treat local tumor masses. Can radiation enhance the immunologic response, as reported in this meeting? When should radia-
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tion be given in conjunction with adoptive immunotherapy so as not to eliminate the reinfused lymphocytes? Very sensitive assays for detecting microscopic disease can find rare cancer cells in lymph nodes, bone marrow, surgical margins, and peripheral blood. Not all patients with microscopic disease so detected will relapse, so that local treatment is not necessarily contraindicated as one might incorrectly conclude for a patient with PCR detected cells in a lymph node or marrow. With an aging population more cancer patients will have comorbid illnesses that might impact the outcome of cancer treatment. The radiation oncologist should have sufficient general medical skills to help manage such problems during treatment and to be able to discern co-morbid disease from radiation side effects. For an increasing number of disease sites, radiation treatments are accompanied by systemic agents. Because the use of a drug as a radiation modifier may be substantially different than the use of the drug as a chemotherapeutic agent there must be a sufficiently large cadre of radiation oncologists skilled in drug administration and management to help the radiation modifier field develop optimally. MICROENVIRONMENT The Microenvironment is the one that we generally think of when we consider the tumor. Table 4a includes Microenvironment: issues and problems, all of which are familiar to radiation biologists. This environment involves tumor cell interaction with the stroma, immune and inflammatory cells, and vasculature. The environment is not only abnormal and heterogeneous but it changes constantly. This impacts cellular stress, drug and nutrient distribution, and genetic instability by adding an epigenetic component. Among the microenvironmental topics in this meeting hypoxia and angiogenesis had numerous presentations. The cellular response to hypoxia is driven in part by the transcription factor HIF-1␣. In murine systems, the structure of the tumor vasculature was an effect of the tumor cell. Techniques to image and detect hypoxia are progressing, and potential antihypoxia strategies included new nitroimidazole sensitizers, hypoxic cytotoxic agents and carbogen, the latter producing substantial changes in tumor oxygenation. The use of anti-angiogenesis agents with radiation is a promising area of investigation, one that represents the paradigm of using a “cytostatic” agent with a cytotoxic one. There was a provocative paper in a mouse model in which irradiation of the primary tumor led to growth of the metastases, as seen in the models with surgical excision. There are numerous research opportunities related to the Microenvironment included in Table 4b. New techniques, such as cDNA microarrays, are bringing forth an enormous amount of data that must somehow be brought together with clever bioinformatics approaches. Seeking patterns in gene expression using the cDNA microchips is the modern scientific version of “fish and chips.” Clearly, the ability to
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Table 4. Micro-environment
Table 5. Nano-to-pico environment
a. Issues and problems Tumor and its interaction with normal tissue and stroma: 䡠 Identifying tumor from normal tissue 䡠 Abnormal physiology; stress response and epigenetic changes 䡠 Normal tissue and stromal component—cytokines, GFs, cell–cell contact 䡠 Immunologic response 䡠 Inflammatory processes 䡠 Interstitial pressure—a barrier to therapy? 䡠 Drug distribution—depends on size, charge, solubility 䡠 Heterogeneity—very complex and hard to replicate in the lab 䡠 Instability—genetic, environmental. Inherent cellular genetic instability is also subject to dynamic changes (e.g., ischemia-reperfusion) b. New opportunities 䡠 Laser-capture microscopy—analyze heterogeneity 䡠 cDNA microarray—molecular phenotype and identification of families of genes and genes that modify the impact of mutated genes 䡠 Protein function depends on conformation such that a normal gene product may function abnormally in the tumor microenvironment 䡠 Tumor progression may be result of combination of tumor and stromal cell factors 䡠 Normal tissues within the tumor may become therapeutic target (e.g., endothelial cells) 䡠 Immunologic response—adoptive immunotherapy, enhancing immunogenecity with co-stimulatory molecules and factors and possibly with radiation to increase antigen expression. 䡠 Heterogeneity of radiation dose-intensity within tumor— intensity-modulated radiotherapy, brachytherapy, radiolabeled molecules (antibodies, ligands, peptides) 䡠 Inflammatory processes and inflammatory molecules and their role in: 䡠 Tumor resistance to therapy 䡠 Late effects; these may be a continuous/continual “chronic active” process 䡠 Interstitial space analysis—microdialysis, pharmacokinetics 䡠 Drug/nutrient distribution—target abnormal tumor physiology with hypoxia activation of drugs and genes 䡠 Instability—genetic, environmental 䡠 Need to understand selection pressure based on environment. Successful treatment or prevention strategies may require abrogating the tumor cell’s ability to evolve a more malignant phenotype
a. Issues and problems Where the real action is 䡠 Subcellular dosimetry—heterogeneity at nano-level where dense ionizations occur 䡠 Multiple molecular targets beyond DNA 䡠 Molecular pharmacology—cell is highly compartmentalized 䡠 For effective cancer treatment both drug and RT-induced radical or other biochemical perturbation—must be at right concentration, right place at the right time. b. New opportunities 䡠 Subcellular dosimetry—understanding of molecular dosimetry, tracks and impact of dense ionizations on non-DNA processes 䡠 Fractionation effects—low dose hypersensitivity, adaptive response and bystander effect—what are impacts on normal tissue and tumors. 䡠 Molecular targets beyond DNA (molecular targets—see Figs. 2 and 3) 䡠 New drug discovery 䡠 Designer molecules synthesized using specific target and structural biology 䡠 Combinatorial molecules can create many molecules and then one sorts out activity 䡠 Imaging—functional and molecular of tumor and normal tissue 䡠 PET, MR, EPR, etc., e.g., image oxygen 䡠 Nanotechnology⫺biomolecular sensors/probes, e.g., image biochemical processes 䡠 Targeting radioisotopes—select isotope (␣, , or ␥) by desired path length 䡠 Ultimate planning of biology plus physics Nano Inverse planning 䡠 Radiation oncology more than technology, we need to convey the concept of “focussed biology” to colleagues.
study many genes at once will provide information far beyond the previous era when so many effects were attributed to a single gene (for example, p53). Families of genes and modifier genes will begin to emerge. Nonetheless, the cDNA arrays do not tell about protein structure and function, which will require approaches to proteomics and likely “good old-fashioned” biochemistry. NANO-ENVIRONMENT The Nano-pico-environment (Table 5a) is a continuum of the Microenvironment. It is, indeed, where the action is—
where physics, chemistry, and biology merge. The effect of radiation is ultimately biologic perturbation. For a dose of 1 Gy, which kills less than one-half the cells, many biochemical perturbations occur (5), and stress genes are activated at doses as low as 2 cGy (6). Radiation track structure indicates that there is dense ionization at the end of the track so that, while radiation is not limited in its “pharmacologic” distribution at the microlevel, i.e., it has no tissue barriers, there is heterogeneity of dose at the nanometer level within the cell (5). A very recent report indicated that DNA damage by low-energy electrons at energies below that required for DNA strand break (3–20 eV), may be due to molecular resonances; therefore, direct strand break by the electron may not be necessary (7, 8). Figure 2 illustrates the concept of “complementary” radiation oncology, that is, a cell may be killed directly by sufficient DNA damage or, as on the right hand side of the figure, cellular homeostasis may be altered such that the cell within the radiation beam is set up for cell killing by the radiation. In essence, radiation physics is focused biology with the action at the nano- to picometer level. The opportunities for the nano-to-pico environment are included in Table 5b. Combinatorial chemistry has the potential to produce an enormous number of molecules that will be in
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Fig. 2. Complementary concepts in radiation cell killing. The “classic” concept, and one that is most important, is that radiation causes direct DNA damage that is fatal (left side). Additional targets for radiation modification may be to alter cellular homeostasis so that the cell is set up for killing by the radiation (right side). In essence, the mechanisms in the right hand side complement the DNA damage, a form of radiation “complementary” therapy which serves as an “alternative” to classic radiation therapy. Adapted from Ref. 2.
search of a target. This approach complements the more traditional concept of designing a molecule for a specific target based on structure–activity relationship. In the future, we will understand radiation biology at the nano- level and may well have nanotechnology devices to assess biochemical processes and radiation perturbation within the cell. Ultimately, physics and biology will meet with nano-inverse planning or “nanoIMRT.” Figure 3 includes an update illustration of radiation biol-
ogy. It includes not only the biologic aspects but the intensity-modulated radiation, which can be produced by external beam, brachytherapy, and radioactive molecules, and the “abscopal” effects such as cytokine release by radiation and possibly anti-angiogenesis molecules that might be impacted by the eradication of the local tumor. The next few years should bring us much new information, some new knowledge, and likely some very innovative therapies to enhance the efficacy of radiation therapy.
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Fig. 3. Radiation oncology sciences—Focused Biology. This is an updated figure including the many targets for modifying the radiation response. In addition to the biologic targets within the tumor, this figure includes the concept of intensity-modulated radiation therapy with the radiation being deliverable by external beam, brachytherapy, or radiolabeled molecules (antibody, ligands, peptides, etc.). Also included is the so-called abscopal effect of radiation and the tumor, in that tumor-derived products may produce systemic symptoms, conceivably immune alteration, and, in mice, anti-angiogenic molecules that encourage dormancy in metastases. Figure updated from Ref 2.
DISCUSSION So, where do we go from here, and what will be discussed at ICTR 2003? Biologic research will require molecular approaches, but the more “classic” radiation biology will remain relevant in the study of new therapies, normal tissue effects, and drug–radiation interaction. There will be a convergence of physics and biology in understanding the cellular and
molecular effects of radiation. Biomolecular sensors will be under development, possibly in unique collaborations with groups involved in nanotechnology (e.g., NASA). As we develop new technology, we must remember that technology is for the benefit of the patient. As individuals and institutions increase collaboration with industry, oversight bodies and universities must maintain the highest ethical standards to avoid the appearance and/or reality of
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Table 6. The unifying force of radiation oncology: 10-dimensional “string-along theory” 1. Radiation is focused biology 2. Target size varies by 109–1012 from macro to nano (? to pico) 3. DNA damage is the critical lesion. 4. Altered cellular homeostasis can “encourage” death from RT 䡠 nonlethal perturbation becomes lethal following RT 5. Inverse planning—applies to physics and biology 䡠 We should endeavor to deliver what we need to deliver to kill the tumor, not what we can deliver. Nano-IMRT will require biology, physics, and chemistry 6. Normal tissue effects include immunologic approaches and inflammatory cells 䡠 Using the immune system with antibodies—cold and hot 䡠 Understanding the impact of radiation therapy on tumor immunogenicity. 䡠 Inflammatory and stromal cells can impact tumor progression and therapeutic response 7. Molecular targets—numerous novel targets are being identified. 8. The new approaches to drug development include combinatorial chemistry which, along with the more traditional approaches, will produce innumerable new structures. 䡠 For new molecular therapies RT may be ideal for establishing Proof of Principle and may allow a much lower and less toxic dose of drug. 䡠 Cytostatic agents will require a cytotoxic event—either radiation or other drugs. 9. Biotechnology will make us all enlightened empiricists with proper analytical tools. 䡠 Informatics—mathematical models are a major part of radiation oncology’s heritage! 10. Collaboration among disciplines and laboratories is essential Adapted with a kilo of poetic license from the concept of a 10-dimensional universe (Ref. 9). IMRT ⫽ intensity-modulated radiotherapy.
conflict of interest. The damage due to the loss of confidence in the integrity of medical research has a profound impact on patient participation, research support, excessive regulation (punishing the innocent), and, most importantly, the rate of progress in cancer care. Cost containment and the wise use of technology is far better than excessive proliferation in a competitive healthcare environment. Furthermore, as new technology can do more and more, we must determine what is an “acceptable” level of technology for the community practitioner to be considered appropriately up to date. To that end, I offer the 5Ps of Proper Professional Practice, analogous to the 4Rs of radiation therapy. The 5Ps are: Proof of Principle Prior to Pecuniary Proliferation! As a specialty, we radiation oncologists must maintain a firm commitment to education and training of our residents and those already in practice, so that they develop and maintain the necessary skill set for the molecular era. A reasonable subset of radiation oncology residents should be highly skilled in bench research to enhance the laboratory– clinical interaction. This may
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require an additional 3– 4 years of training for this subset of residents. Once trained, it is necessary that departments and hospitals allow for adequate time away from the “billable units” so that our academic leaders can develop first rate research programs. How should research, development, and training be paid for? It is a partnership among the physicians, healthcare system, industry, and government. Patient advocacy groups make strong allies in our communication with the politicians and the average citizen. Our radiation oncology community needs a balanced portfolio of research and development, avoiding internecine battles. In an attempt to be responsive to Commandment 10 (“Must be stimulating and entertaining”), I have put together, for fun, Table 6. The amateur cosmology buffs have likely heard of string theory, which is a model for the unifying theory of the forces of the universe. Superstring theory postulates a 10- or 11-dimensional universe. Because radiation oncology (Fig. 1) spans about 10 orders of magnitude, but is obviously not as profound as the entire universe, Table 6 is the unifying force of radiation oncology—in a 10-dimensional string-along theory. A THOUGHTFUL FUTURE Radiation oncology has made enormous advances in technology and biology. The three named awards at this meeting were in honor of Dr. Ged Adams, a chemist and biologist, who had pioneered the radiosensitizer field; Dr. Gilbert Fletcher, a consummate clinical oncologist and teacher; and Dr. Emanuel van der Scheuren, the prototype of the physician–scientist. They represent the spectrum of talent needed to build and sustain the translational bridge between the clinic and the laboratory and the inspirational leadership that medicine requires to train and motivate young people to work toward new knowledge and improved treatment. ICTR 2000 is an outstanding example of the interdisciplinary nature of radiation oncology and will serve as an important benchmark as to the state of translational radiation oncology as we enter the 21st century. ICTR 2003 will be a most interesting next step. Cancer is a biologic entity. As we understand better the organization of a cell and the many processes involved in cellular division, growth, differentiation, and function, it is clear that the cell is not arranged linearly but more akin to a complex nerve net. Indeed, in a sense it can “think.” Dr. Henry S. Kaplan, perhaps the most influential physician– scientist in our field, understood what we as physicians and scientists need to do so that we may unravel the mysteries of cancer and develop effective and nontoxic means to prevent and cure it. Undoubtedly, he would have been pleased by the efforts and enthusiasm displayed by the clinicians, physicists, biologists, and mathematicians at ICRT 2000. We did endeavor to rise to his challenge, paraphrased as follows: “If you want to cure Hodgkin’s Disease, you must think like a Hodgkin’s cell.”
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REFERENCES 1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70. 2. Coleman CN, Mitchell JB. Radiation modifiers. In: Chabner BA, Meyers CA, Longo D, editors. Cancer chemotherapy and biotherapy: Principles and practice. Philadelphia: JB Lippincott; 2001 In press. 3. Komarov PG, Komarova EA, Kondratov RV, et al. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 1999;285:1733–1737. 4. Delanian S, Balla-Mekias S, Lefaix JL. Striking regression of chronic radiotherapy damage in a clinical trial of combined pentoxifylline and tocopherol. J Clin Oncol 1999;17:3283– 3290.
5. Nikjoo H, Uehara S, Wilson WE, et al. Track structure in radiation biology: theory and applications. Int J Radiat Oncol Biol Phys 1998;73:355–364. 6. Amundson SA, Do KT, Fornace AJ Jr. Induction of stress genes by low doses of gamma rays. Radiat Res 1999;152:225– 231. 7. Boudaiffa B, Cloutier P, Hunting D, et al. Resonant formation of DNA strand breaks by low-energy (3 to 20 eV) electrons. Science 2000;287:1658 –1660. 8. Michael BD, O’Niell P. A sting in the tail of electron tracks. Science 2000;287:1603–1604. 9. Kaku M. Hyperspace. New York: Oxford University Press; 1994.
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ICTR 2000
Keynote Lecture
INTERNATIONAL CONFERENCE ON TRANSLATIONAL RESEARCH AND PRECLINICAL STRATEGIES IN RADIO-ONCOLOGY (ICTR)—CONFERENCE SUMMARY C. NORMAN COLEMAN, M.D. Radiation Oncology Sciences Program, Division of Clinical Sciences, Division of Cancer Diagnosis and Treatment, National Cancer Institute, National Institute of Health, Bethesda, MD “After all, science is essentially international, and it is only through lack of the historical sense that national qualities have been attributed to it.” Marie Curie, “Intellectual Co-operation”
INTRODUCTION
izing Radiation Oncology in Y2K,” with the following five questions to be addressed:
Formulating the Conference Summary for the “First International Conference on Translational Research and Preclinical Strategies in Radio-Oncology” (ICTR 2000) presented a challenge. This novel conference had as its theme “Individualizing Cancer Treatment.” Ably spearheaded by Dr. Jacques Bernier, the conference was an action-packed 3 days, with keynote and named lectures, workshops, meetthe-professor sessions, symposia, proffered papers, forums, oral poster presentations, and debates. Overall, there were approximately 300 different abstracts/presentations, often presented in 3– 4 parallel sessions. The days were indeed very full, with excellent scientific interaction among the speakers and attendees. For those who will consider the challenge of being a “conference summarizer” in this or other meetings, Table 1 includes an offering of “10 Basic Commandments for Conference Summarizers.” The international nature of science is well stated in the above quotation of Madame Curie. The meeting was indeed eclectic in its participants and topics. The venue of the meeting was conducive to collegial interaction among the multinational cadre of medical physicists, biologists, mathematicians, and radiation and medical oncologists who are not usually all at the same meeting. The success of this first effort led the Organizing Committee to vote to hold the second ICTR in Lugano in 2003. All aspects of radiation-oncology–related science and technology are undergoing exciting changes. The task of conference summary for this new thematic conference is akin to my new position as the Director of the Radiation Oncology Sciences Program (ROSP) at the National Cancer Institute in that it is important to look at the field as an entity. Thus, the structure of this summary is “Conceptual-
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What currently comprises the fields of “radiation oncology” and “radiation research?” How do we present our research and development to the “outside world?” What are the potential opportunities for improved treatment and new fundamental knowledge and how do we relate them to each other? How do we establish priorities and create a balanced portfolio of research and development? How do we stimulate our colleagues and trainees to pursue new knowledge and consequently better outcomes for patients?
CANCER IS A BIOLOGIC ENTITY Cancer is both genetic, due to abnormal gene structure, and epigenetic, as it is the function of the molecules that determines cell function. A normal protein may function abnormally depending on the biochemical state of the cell. Ultimately, a multiplicity of abnormal biochemical pathways leads to uncontrolled and sustained growth for localized tumors, invasion for regional tumors, and metastases for advanced cancers (1). Given the biologic nature of cancer, how can a technically based specialty have a working “model” in common to all translational radiation oncology scientists so that we appreciate that we are all indeed facing the same problem? Borrowing from the “Power of 10” concept often seen at science museums in which one takes a view of earth from outside the Milky Way galaxy and zooms in by log10 step sizes until one enters a cell, Fig. 1 is a schematic of the field
Reprint requests to: Dr. C. Norman Coleman, ROB, Bldg 10, B3B69, National Institute of Health, Bethesda, MD 20892. E-mail: ccoleman@ mail.nih.gov
Presented at ICTR 2000, Lugano, Switzerland, March 5– 8, 2000. Accepted for publication 31 August 2000. 301
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Table 1. 10 “Basic Commandments” of meeting summaries 1. Must read all of the abstracts before the meeting. 2. Must miss a substantial majority of the actual presentations due to simultaneous sessions, so must guess what was actually said. 3. Must attend the entire meeting, even if it is in a location as scenic as Lugano. 4. Must maintain moderation in what one ingests, particularly the final evening, although the definition of “moderation” evolves rapidly as the meeting progresses. 5. Must prepare the bulk of the talk and slides before the meeting and therefore depend on the abstracts being at least vaguely representative of the presentation at the meeting. 6. Must be comprehensive but not too detailed. A 45-min summary for 300 presentations, results in an average of 10 sec per presentation. 7. Must mention enough people’s work without too much individual attribution for fear of neglecting and/or insulting colleagues. 8. Must be optimistic yet realistic. This may vary depending on when you are to be reimbursed. 9. Must finish on time so that those who stay to the end of the conference can catch their plane/train/bus/boat/car ride. 10. Must be stimulating and entertaining to reward those who hung on till the end. Bonus Commandment should one succeed with most or all of the first 10: Must write up a comprehensive paper within 2 weeks.
of radiation oncology (2). Defined are four domains denoted macro-, normo-, micro-, and nano-, with the latter implying subnano to picometer dimensions. Thus, the field of clinical/ translational radiation oncology is a single entity that is viewed by various investigators with vantage points that differ by approximately 10 orders of magnitude. The research topics in this conference are somewhat arbitrarily placed within one of the domains, emphasizing the continuity and inter-relatedness of the various disciplines, as summarized in the Fig. 1 legend. Each of the four environments will be summarized with two tables, one for “Issues and Problems” and another for “New Opportunities.” The content of the tables will not be reiterated within the text. Scientific findings that emerged from this meeting will be discussed in the text, generally without specific attribution to avoid this becoming an exhaustive review article. The “New Opportunities” will be a compilation of concepts that emerged from this and other meetings and my personal opinion. These do not represent any “institutional” policy or priority list, and it is likely that some important items have been inadvertently omitted. MACRO-ENVIRONMENT Table 2a includes Macro-environment: issues and problems. The presentations at ICRT can be subdivided into a few categories. Dose optimization: Intensity-modulated radiation therapy (IMRT) is feasible for cancers of the central nervous system, head and neck, lung, and prostate. Imaging is crucial,
Fig. 1. The range and domains of radiation oncology sciences research.The Macro-environment is the normal tissue surrounding the patient. Research is involved in avoiding normal tissue injury through dose-optimization, external beam radiation techniques, the use of brachytherapy, and the employment of models of normal tissue complication probability (NTCP) and tumor control probability (TCP). The Normo-environment refers to that which we see and measure in the clinic. It includes routine evaluations that assess the patients’ general health and tumor status, predictive assays of treatment outcome and response, clinical trials with tumor response assessment and pharmacokinetic studies.The Microenvironment focuses on the cellular environment of the tumor but also includes the normal cellular component of a tumor—stromal, epithelial, vascular, immunologic, and inflammatory cells. It includes the physiologic perturbations within a tumor, hypoxia being one of longstanding interest. It includes other cellular targets, such as organelles, and larger sized therapeutics, such as antibodies, gene therapy vectors, and adoptive immunotherapy.The Nano-to-pico environment includes molecular targets and the many biochemical and molecular processes that occur within the cancer cell before, during, and after perturbation with radiation. This is the environment of molecular pharmacology and track structure. It is where physics, chemistry, and biology unify. It is also where molecular therapeutics are targeted using approaches ranging from targeting a specific molecular structure (as defined by structural biology) to generating an enormous number of compounds and sorting out which are “active” in impacting a biologic process (combinatorial chemistry). Figure reprinted with permission from Ref. 2.
as the treatment volume (including size of margins) depends on the imaging and uncertainties in defining the tumor. Technologic advances have been made in developing mini-
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Table 2. Macro-environment a. Issues and problems Normal tissue 䡠 Identifying tumor & normal tissue 䡠 Localizing target reproducibly: inter- and intra-observer variability 䡠 Hitting target on a daily basis without too much collateral damage 䡠 Will the precision of IMRT compromise accuracy? 䡠 Integral dose—radiation must go somewhere. What is the impact of low dose per day radiation on normal tissue? Is there low dose hypersensitivity? 䡠 Particle therapy—what proof is required before it is used as standard treatment? Are randomized trials necessary? Should this technology be in specialized centers only and should it involve true multi-institutional resource sharing? b. New opportunities Normal tissue 䡠 Functional imaging—MRI, MRS, SPECT, PET, EPR, etc. 䡠 Real-time imaging during therapy with appropriate treatment modification 䡠 CT–tomotherapy 䡠 Ultrasound imaging during treatment 䡠 Portal imaging 䡠 Brachytherapy—MRT, ultrasound with real-time dose calculation 䡠 Immobilizing patient and tumor—precision relocatable devices for stereotactic radiosurgery and radiotherapy 䡠 Intensity modulation of photons, electrons, and heavier particles; unlimited number of fields possible (need to be optimized and “realistic” for daily use) 䡠 Protecting normal tissue 䡠 chemical radioprotector, 䡠 growth factors 䡠 altering death response (e.g., inhibiting p53 [pifithrinalpha] (3)) 䡠 Reversing late effects—months and years later, e.g, pentoxyfyline ⫹ tocopherol (4)
multileaf collimators and in respiratory and cardiac gating. Fractionation is both feasible and important with stereotactic radiosurgery. Technology development must be somewhat practical with the need to balance infinitely complex approaches with those that are “acceptable” for daily practice, that is, how many fields should be used for a particular treatment. For very expensive technology, resource sharing is appropriate and necessary as demonstrated by the successful multinational EORTC proton project. Brachytherapy is both conformal and intensity-modulated radiation therapy by virtue of being able to place seeds in a range of patterns. Dose heterogeneity is also important in toxicity. Prostate brachytherapy is probable the best studied site. At this meeting, the importance of adequate technique was discussed as well as the potential of the addition of gene therapy to brachytherapy. Mathematical modeling is necessary to calculating TCP (tumor control probability) and NTCP (normal tissue complication probability). In addition to the current “target volumes (TVs)” gross (GTV), clinical (CTV), and planning (PTV), the concept of biologic target volume (BTV) was
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presented by Cliff Ling. Unfortunately, at present, when a treatment plan is developed along with dose–volume histograms (DVHs), it is not readily apparent which is the worst or best plan. Normal tissue studies indicate that late radiation injury is a dynamic process, in essence, a chronic “active” process. Fibroblasts that have been irradiated have a stable increase in collagen production. Radiation late effects are not simply stochastic but appear to involve the genotype and phenotype of the patient’s cellular response. Included in normal tissue issues is the role of radiation therapy in inducing secondary malignancies in patients with hereditary cancer predisposition. These cells (for example, BrCA1 and 2 and AT) may be more radiosensitive, but it is unknown if radiation will be more mutagenic in these patients. For all tissues irradiated with low doses, what is the impact of the low-dose radiation hypersensitivity now being defined mechanistically? What is the impact of the increased volume of normal tissue that will receive some irradiation with the multifield IMRT techniques? Added to the radioprotector armamentarium are growth factors that can increase the number of mucosal cells, such as rhKGF. Table 2b includes Macro-environment: new opportunities. Functional imaging is being developed to help discern tumor from normal tissue and distinguish between more and less critical normal tissues (e.g., functional centers within the brain). Real-time imaging during therapy— external beam and brachytherapy—will help reduce uncertainty and normal tissue volume. Completely novel concepts in radiation protection include inhibiting processes that lead to cell death, such as inhibition of p53 function to abrogate toxicity of therapy (3). Critical to normal tissue protection is whether or not cells that are protected will have an increased number of chromosomal abnormalities. Intriguing reports indicating that late normal tissue injury may be partly reversible (4) have challenged the dogma of the irreversibility of late radiation fibrosis and may open up remarkable new interventions into radiation injury as well as the possibility of further dose escalation. Some distance down the road may be the use of stem cells or organotypic cell transplant to restore organ function after cancer therapy-related injury. NORMO-ENVIRONMENT Table 3a includes the Normo-environment: issues and problems. This includes the range of laboratory studies that are conducted to stage, prognosticate outcome, predict treatment response, and assess immunologic, biochemical, and physiologic parameters of the patient. Pharmacologic and pharmacokinetic analyses are often done to assure that the optimal dose of a drug is delivered. A laudable goal has been to establish predictive assays of tumor and normal tissue response to radiation therapy. These have included cell kinetics, apoptosis index, assessment of individual genes, such as p53, and others. As summarized in the meeting by Lester Peters, these have not as yet demonstrated utility for predicting response for an individual patient. Studies that have demonstrated differences
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Table 3. Normo-environment a. Issues and problems Clinical and laboratory evaluation 䡠 Markers—staging and prognosis 䡠 prognostic factors need to be predictive for individual patients 䡠 Markers of response—is there different information derived from rate of response and absolute value of a parameter 䡠 Immunologic status and the impact on patient outcome 䡠 Circulating and sub-microscopic deposits of tumor cells are now detectable with PCR, immunohistochemistry (IHC). What do these mean? 䡠 Overall medical condition in an aging population Pharmacology: Issues and problems 䡠 Drug administration and schedule 䡠 drug is usually optimized for chemotherapy and not radiation therapy 䡠 Pharmacogenetics—predicting toxicity especially for the very susceptible patient b. New opportunities Clinical and laboratory evaluation 䡠 Markers of response—intermediate end-points for response, relapse, survival provide a short-track to results 䡠 Immunologic augmentation—vaccine, adoptive therapy; how to integrate radiation to augment and not impair immune response and/or immunotherapy 䡠 Circulating tumor cells or microscopic disease in lymph nodes—what do they mean and how should they impact local/regional treatment? Will this be a novel role for systemic radiation therapy? 䡠 Patient’s overall medical condition—radiation oncologists must be good general clinicians and active in general patient care. Pharmacology 䡠 Drug administration—schedule and toxicity with RT require different approach than using drugs by themselves—mechanisms may differ; schedule of administration likely to be different than with drug alone. 䡠 Radiation oncologists must be active in radiation modifier administration.
among groups of patients for one parameter or other and a correlation of outcome for a patient group are useful in guiding future mechanistic research as they may help define an area of investigation. However, a predictive assay should be applicable to individual patients because a group average may only separate a few “outliers” from the whole population and, therefore, be of limited value in treatment selection. The Normo-environment: new opportunities in Table 3b include the development of intermediate markers of response. For example, might a comet assay from a tumor biopsy following the first treatment or change in PET or MRI scan early in a course of therapy indicate the likelihood of successful radiation for that particular patient? Intermediate markers would also accelerate the rate of generation of new knowledge. Immunologic therapies involve radiation therapy, often as part of immunosuppression for transplantation but also as part of the therapeutic regimen to treat local tumor masses. Can radiation enhance the immunologic response, as reported in this meeting? When should radia-
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tion be given in conjunction with adoptive immunotherapy so as not to eliminate the reinfused lymphocytes? Very sensitive assays for detecting microscopic disease can find rare cancer cells in lymph nodes, bone marrow, surgical margins, and peripheral blood. Not all patients with microscopic disease so detected will relapse, so that local treatment is not necessarily contraindicated as one might incorrectly conclude for a patient with PCR detected cells in a lymph node or marrow. With an aging population more cancer patients will have comorbid illnesses that might impact the outcome of cancer treatment. The radiation oncologist should have sufficient general medical skills to help manage such problems during treatment and to be able to discern co-morbid disease from radiation side effects. For an increasing number of disease sites, radiation treatments are accompanied by systemic agents. Because the use of a drug as a radiation modifier may be substantially different than the use of the drug as a chemotherapeutic agent there must be a sufficiently large cadre of radiation oncologists skilled in drug administration and management to help the radiation modifier field develop optimally. MICROENVIRONMENT The Microenvironment is the one that we generally think of when we consider the tumor. Table 4a includes Microenvironment: issues and problems, all of which are familiar to radiation biologists. This environment involves tumor cell interaction with the stroma, immune and inflammatory cells, and vasculature. The environment is not only abnormal and heterogeneous but it changes constantly. This impacts cellular stress, drug and nutrient distribution, and genetic instability by adding an epigenetic component. Among the microenvironmental topics in this meeting hypoxia and angiogenesis had numerous presentations. The cellular response to hypoxia is driven in part by the transcription factor HIF-1␣. In murine systems, the structure of the tumor vasculature was an effect of the tumor cell. Techniques to image and detect hypoxia are progressing, and potential antihypoxia strategies included new nitroimidazole sensitizers, hypoxic cytotoxic agents and carbogen, the latter producing substantial changes in tumor oxygenation. The use of anti-angiogenesis agents with radiation is a promising area of investigation, one that represents the paradigm of using a “cytostatic” agent with a cytotoxic one. There was a provocative paper in a mouse model in which irradiation of the primary tumor led to growth of the metastases, as seen in the models with surgical excision. There are numerous research opportunities related to the Microenvironment included in Table 4b. New techniques, such as cDNA microarrays, are bringing forth an enormous amount of data that must somehow be brought together with clever bioinformatics approaches. Seeking patterns in gene expression using the cDNA microchips is the modern scientific version of “fish and chips.” Clearly, the ability to
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Table 4. Micro-environment
Table 5. Nano-to-pico environment
a. Issues and problems Tumor and its interaction with normal tissue and stroma: 䡠 Identifying tumor from normal tissue 䡠 Abnormal physiology; stress response and epigenetic changes 䡠 Normal tissue and stromal component—cytokines, GFs, cell–cell contact 䡠 Immunologic response 䡠 Inflammatory processes 䡠 Interstitial pressure—a barrier to therapy? 䡠 Drug distribution—depends on size, charge, solubility 䡠 Heterogeneity—very complex and hard to replicate in the lab 䡠 Instability—genetic, environmental. Inherent cellular genetic instability is also subject to dynamic changes (e.g., ischemia-reperfusion) b. New opportunities 䡠 Laser-capture microscopy—analyze heterogeneity 䡠 cDNA microarray—molecular phenotype and identification of families of genes and genes that modify the impact of mutated genes 䡠 Protein function depends on conformation such that a normal gene product may function abnormally in the tumor microenvironment 䡠 Tumor progression may be result of combination of tumor and stromal cell factors 䡠 Normal tissues within the tumor may become therapeutic target (e.g., endothelial cells) 䡠 Immunologic response—adoptive immunotherapy, enhancing immunogenecity with co-stimulatory molecules and factors and possibly with radiation to increase antigen expression. 䡠 Heterogeneity of radiation dose-intensity within tumor— intensity-modulated radiotherapy, brachytherapy, radiolabeled molecules (antibodies, ligands, peptides) 䡠 Inflammatory processes and inflammatory molecules and their role in: 䡠 Tumor resistance to therapy 䡠 Late effects; these may be a continuous/continual “chronic active” process 䡠 Interstitial space analysis—microdialysis, pharmacokinetics 䡠 Drug/nutrient distribution—target abnormal tumor physiology with hypoxia activation of drugs and genes 䡠 Instability—genetic, environmental 䡠 Need to understand selection pressure based on environment. Successful treatment or prevention strategies may require abrogating the tumor cell’s ability to evolve a more malignant phenotype
a. Issues and problems Where the real action is 䡠 Subcellular dosimetry—heterogeneity at nano-level where dense ionizations occur 䡠 Multiple molecular targets beyond DNA 䡠 Molecular pharmacology—cell is highly compartmentalized 䡠 For effective cancer treatment both drug and RT-induced radical or other biochemical perturbation—must be at right concentration, right place at the right time. b. New opportunities 䡠 Subcellular dosimetry—understanding of molecular dosimetry, tracks and impact of dense ionizations on non-DNA processes 䡠 Fractionation effects—low dose hypersensitivity, adaptive response and bystander effect—what are impacts on normal tissue and tumors. 䡠 Molecular targets beyond DNA (molecular targets—see Figs. 2 and 3) 䡠 New drug discovery 䡠 Designer molecules synthesized using specific target and structural biology 䡠 Combinatorial molecules can create many molecules and then one sorts out activity 䡠 Imaging—functional and molecular of tumor and normal tissue 䡠 PET, MR, EPR, etc., e.g., image oxygen 䡠 Nanotechnology⫺biomolecular sensors/probes, e.g., image biochemical processes 䡠 Targeting radioisotopes—select isotope (␣, , or ␥) by desired path length 䡠 Ultimate planning of biology plus physics Nano Inverse planning 䡠 Radiation oncology more than technology, we need to convey the concept of “focussed biology” to colleagues.
study many genes at once will provide information far beyond the previous era when so many effects were attributed to a single gene (for example, p53). Families of genes and modifier genes will begin to emerge. Nonetheless, the cDNA arrays do not tell about protein structure and function, which will require approaches to proteomics and likely “good old-fashioned” biochemistry. NANO-ENVIRONMENT The Nano-pico-environment (Table 5a) is a continuum of the Microenvironment. It is, indeed, where the action is—
where physics, chemistry, and biology merge. The effect of radiation is ultimately biologic perturbation. For a dose of 1 Gy, which kills less than one-half the cells, many biochemical perturbations occur (5), and stress genes are activated at doses as low as 2 cGy (6). Radiation track structure indicates that there is dense ionization at the end of the track so that, while radiation is not limited in its “pharmacologic” distribution at the microlevel, i.e., it has no tissue barriers, there is heterogeneity of dose at the nanometer level within the cell (5). A very recent report indicated that DNA damage by low-energy electrons at energies below that required for DNA strand break (3–20 eV), may be due to molecular resonances; therefore, direct strand break by the electron may not be necessary (7, 8). Figure 2 illustrates the concept of “complementary” radiation oncology, that is, a cell may be killed directly by sufficient DNA damage or, as on the right hand side of the figure, cellular homeostasis may be altered such that the cell within the radiation beam is set up for cell killing by the radiation. In essence, radiation physics is focused biology with the action at the nano- to picometer level. The opportunities for the nano-to-pico environment are included in Table 5b. Combinatorial chemistry has the potential to produce an enormous number of molecules that will be in
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Fig. 2. Complementary concepts in radiation cell killing. The “classic” concept, and one that is most important, is that radiation causes direct DNA damage that is fatal (left side). Additional targets for radiation modification may be to alter cellular homeostasis so that the cell is set up for killing by the radiation (right side). In essence, the mechanisms in the right hand side complement the DNA damage, a form of radiation “complementary” therapy which serves as an “alternative” to classic radiation therapy. Adapted from Ref. 2.
search of a target. This approach complements the more traditional concept of designing a molecule for a specific target based on structure–activity relationship. In the future, we will understand radiation biology at the nano- level and may well have nanotechnology devices to assess biochemical processes and radiation perturbation within the cell. Ultimately, physics and biology will meet with nano-inverse planning or “nanoIMRT.” Figure 3 includes an update illustration of radiation biol-
ogy. It includes not only the biologic aspects but the intensity-modulated radiation, which can be produced by external beam, brachytherapy, and radioactive molecules, and the “abscopal” effects such as cytokine release by radiation and possibly anti-angiogenesis molecules that might be impacted by the eradication of the local tumor. The next few years should bring us much new information, some new knowledge, and likely some very innovative therapies to enhance the efficacy of radiation therapy.
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Fig. 3. Radiation oncology sciences—Focused Biology. This is an updated figure including the many targets for modifying the radiation response. In addition to the biologic targets within the tumor, this figure includes the concept of intensity-modulated radiation therapy with the radiation being deliverable by external beam, brachytherapy, or radiolabeled molecules (antibody, ligands, peptides, etc.). Also included is the so-called abscopal effect of radiation and the tumor, in that tumor-derived products may produce systemic symptoms, conceivably immune alteration, and, in mice, anti-angiogenic molecules that encourage dormancy in metastases. Figure updated from Ref 2.
DISCUSSION So, where do we go from here, and what will be discussed at ICTR 2003? Biologic research will require molecular approaches, but the more “classic” radiation biology will remain relevant in the study of new therapies, normal tissue effects, and drug–radiation interaction. There will be a convergence of physics and biology in understanding the cellular and
molecular effects of radiation. Biomolecular sensors will be under development, possibly in unique collaborations with groups involved in nanotechnology (e.g., NASA). As we develop new technology, we must remember that technology is for the benefit of the patient. As individuals and institutions increase collaboration with industry, oversight bodies and universities must maintain the highest ethical standards to avoid the appearance and/or reality of
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Table 6. The unifying force of radiation oncology: 10-dimensional “string-along theory” 1. Radiation is focused biology 2. Target size varies by 109–1012 from macro to nano (? to pico) 3. DNA damage is the critical lesion. 4. Altered cellular homeostasis can “encourage” death from RT 䡠 nonlethal perturbation becomes lethal following RT 5. Inverse planning—applies to physics and biology 䡠 We should endeavor to deliver what we need to deliver to kill the tumor, not what we can deliver. Nano-IMRT will require biology, physics, and chemistry 6. Normal tissue effects include immunologic approaches and inflammatory cells 䡠 Using the immune system with antibodies—cold and hot 䡠 Understanding the impact of radiation therapy on tumor immunogenicity. 䡠 Inflammatory and stromal cells can impact tumor progression and therapeutic response 7. Molecular targets—numerous novel targets are being identified. 8. The new approaches to drug development include combinatorial chemistry which, along with the more traditional approaches, will produce innumerable new structures. 䡠 For new molecular therapies RT may be ideal for establishing Proof of Principle and may allow a much lower and less toxic dose of drug. 䡠 Cytostatic agents will require a cytotoxic event—either radiation or other drugs. 9. Biotechnology will make us all enlightened empiricists with proper analytical tools. 䡠 Informatics—mathematical models are a major part of radiation oncology’s heritage! 10. Collaboration among disciplines and laboratories is essential Adapted with a kilo of poetic license from the concept of a 10-dimensional universe (Ref. 9). IMRT ⫽ intensity-modulated radiotherapy.
conflict of interest. The damage due to the loss of confidence in the integrity of medical research has a profound impact on patient participation, research support, excessive regulation (punishing the innocent), and, most importantly, the rate of progress in cancer care. Cost containment and the wise use of technology is far better than excessive proliferation in a competitive healthcare environment. Furthermore, as new technology can do more and more, we must determine what is an “acceptable” level of technology for the community practitioner to be considered appropriately up to date. To that end, I offer the 5Ps of Proper Professional Practice, analogous to the 4Rs of radiation therapy. The 5Ps are: Proof of Principle Prior to Pecuniary Proliferation! As a specialty, we radiation oncologists must maintain a firm commitment to education and training of our residents and those already in practice, so that they develop and maintain the necessary skill set for the molecular era. A reasonable subset of radiation oncology residents should be highly skilled in bench research to enhance the laboratory– clinical interaction. This may
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require an additional 3– 4 years of training for this subset of residents. Once trained, it is necessary that departments and hospitals allow for adequate time away from the “billable units” so that our academic leaders can develop first rate research programs. How should research, development, and training be paid for? It is a partnership among the physicians, healthcare system, industry, and government. Patient advocacy groups make strong allies in our communication with the politicians and the average citizen. Our radiation oncology community needs a balanced portfolio of research and development, avoiding internecine battles. In an attempt to be responsive to Commandment 10 (“Must be stimulating and entertaining”), I have put together, for fun, Table 6. The amateur cosmology buffs have likely heard of string theory, which is a model for the unifying theory of the forces of the universe. Superstring theory postulates a 10- or 11-dimensional universe. Because radiation oncology (Fig. 1) spans about 10 orders of magnitude, but is obviously not as profound as the entire universe, Table 6 is the unifying force of radiation oncology—in a 10-dimensional string-along theory. A THOUGHTFUL FUTURE Radiation oncology has made enormous advances in technology and biology. The three named awards at this meeting were in honor of Dr. Ged Adams, a chemist and biologist, who had pioneered the radiosensitizer field; Dr. Gilbert Fletcher, a consummate clinical oncologist and teacher; and Dr. Emanuel van der Scheuren, the prototype of the physician–scientist. They represent the spectrum of talent needed to build and sustain the translational bridge between the clinic and the laboratory and the inspirational leadership that medicine requires to train and motivate young people to work toward new knowledge and improved treatment. ICTR 2000 is an outstanding example of the interdisciplinary nature of radiation oncology and will serve as an important benchmark as to the state of translational radiation oncology as we enter the 21st century. ICTR 2003 will be a most interesting next step. Cancer is a biologic entity. As we understand better the organization of a cell and the many processes involved in cellular division, growth, differentiation, and function, it is clear that the cell is not arranged linearly but more akin to a complex nerve net. Indeed, in a sense it can “think.” Dr. Henry S. Kaplan, perhaps the most influential physician– scientist in our field, understood what we as physicians and scientists need to do so that we may unravel the mysteries of cancer and develop effective and nontoxic means to prevent and cure it. Undoubtedly, he would have been pleased by the efforts and enthusiasm displayed by the clinicians, physicists, biologists, and mathematicians at ICRT 2000. We did endeavor to rise to his challenge, paraphrased as follows: “If you want to cure Hodgkin’s Disease, you must think like a Hodgkin’s cell.”
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