Urologic oncology: extraordinary opportunities for discovery

Urologic Oncology 6 (2001) 185–188

Review article

Urologic oncology: extraordinary opportunities for discovery New initiatives in radiation oncology C. Norman Coleman, M.D.* Radiation Oncology Sciences Program, ROB, Bldg. 10, B3B69, National Cancer Institute, NIH, Bethesda, MD 20892, USA Received 15 February 2001; accepted 13 March 2001

Abstract The discussion and debate over the “best” treatment for clinically localized prostate cancer will be an iterative process based on a combination of opinions and data. Success is a measure of both cancer control and quality of life such that in a disease with a long natural history, one must be very cautious about over-interpreting short- or medium-term results. As with many treatment approaches in the rapidly evolving world of medicine, outcomes improve over time so that retrospective studies are useful but of limited value due to changes in patient selection and therapeutic technique. Overly aggressive multimodality approaches will produce excellent short-term results such as PSA biochemical NED (bNED), yet these may be more costly in terms of toxicity and expense than necessary compared to uni-modality therapy. © 2001 Elsevier Science Inc. All rights reserved. Keywords: Radiation oncology; Molecular therapeutics; Urologic oncology; Radiation biology

1. Introduction This article represents a general approach toward improving efficacy and reducing toxicity of radiation oncology in the molecular era. 2. Discussion The extraordinary opportunities for radiation oncology include technological and biological advances. Technology includes improved imaging, both anatomical and functional, and improved treatment-delivery with external beam and brachytherapy. Building upon the platform of technological improvements will be a biological advance. Radiation therapy might be best considered in a paradigm of “focussed biology” in which radiation can create molecular and biochemical “perturbations” in tumors and normal tissues that can be subject to molecular treatment. Radiation oncology will be an essential component in the NCI initiatives of cancer imaging, defining signatures of cancer cells and molecular targets of prevention and treatment. This first Symposium on Urologic Oncology: extraordinary opportunities for discovery comes at an appropriate time * Corresponding author. Tel.: 1-301-496-5457; Fax: 1-301-4805439. E-mail: [email protected] (C.N. Coleman).

in that the human genome is nearing sequencing and the new techniques of proteomics are on the horizon so that the business end of the genes—their gene products—can be better understood. In this brief presentation, the purpose was not to discuss the pros and cons of surgery vs. radiation oncology vs. multi-modality therapy but to consider new opportunities. A few of the important contemporary issues well know to those in urologic oncology practice are in Table 1. Prostate cancer is a biological entity for which treatment is based on a combination of technological and biological approaches [1]. The primary and most effective biological therapy used for localized or advanced prostate cancer is anti-androgen therapy although, as covered elsewhere in this symposium, there are novel approaches toward androgen resistance tumor cells as well as new vaccine studies that might augment local therapy. The logic of the similarity in treatment outcomes obtained by a range of well-applied technical therapies for localized prostate cancer should be apparent. Disease that is truly confined to the gland can be treated with a high level of success by a range of local modalities including surgery, external beam radiation and brachytherapy. Other localized modalities such as cryotherapy and focussed ultrasound, while having interesting early results, must stand up to the test of time before they are used in a non-study setting. Disease beyond the gland may still be amenable to aggressive localized therapy, although there is a continued long-term hazard of progression that contin-

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Table 1 New and not-so-new initiatives for clinical results Reporting clinical results with efficacy and toxicity data Recognition that projection results much beyond the median followup is inaccurate with an indolent disease like prostate cancer Appreciation that there is patient selection in published clinical series Appreciation for the dilemma faced by patients in decision-making when doctors and policy-makers cannot agree

ues after 5 years even for some patients with apparently organ confined disease [2]. Disease beyond the local-regional tissue at the time of presentation requires systemic therapy at some point in time, either as part of the primary treatment or at the time of relapse. For a disease with a long natural history, the use of toxic or prolong up-front treatment must be balanced against quality of life in a patient population with a median age at diagnosis in the 1960s and 1970s. Due to the anatomic location in the posterior part of the gland and/or the unpredictable biology, even the most favorable subsets of patients have a 25–30% risk of extracapsular disease at presentation [3]. While inadequate technological approaches can increase the risk of not-controlling the cancer, the success of even the best local/regional therapy is limited by the biological propensity of prostate cancer to invade the surrounding tissue and to metastasize. 2.1. Extraordinary opportunities All of the above is fairly obvious and the debate over the “best” local therapy is beyond the scope of this article. It is an ongoing and sometimes contentious issue at clinically oriented oncology meetings. While current radiation oncology is increasingly sophisticated, the more complex techniques require a substantial investment in equipment and personnel which, in turn, necessitates expert physics and radiation therapist support. Table 2 summarizes some of the opportunities for radiation oncology based on functional and molecular imaging, improvements in dose delivery that allow for dose escalation [4,5] and understanding of prognostic factors.

Table 2 Areas of potential advancement in radiation oncology for prostate cancer treatment in 2001-2002 Technical- delivery of radiation 3D conformal; intensity modulate radiation brachytherapy- techniques; dose-rate real-time MR brachytherapy (MRT) Molecular/functional imaging and outcome correlation MRS Combined modality appropriate use of mono-therapy vs. excessive use of combined modality therapy Biological prognostic factors for failure Appreciation of radiation as “focused biology” Novel radiation modifiers radioprotectors for rectal injury

The theme of “Extraordinary Opportunities” of this meeting is similar in concept to that of the overall NCI as included in the Bypass budget for 2002 “The Nation’s Investment in Cancer Research” [6]. Radiation oncology’s participation will be based, in part, on a new paradigm that radiation is not merely a “dose” as measured by a dosimeter or illustrated by an isodose curve on a treatment plan, but rather, radiation produces an enormous array of molecular and biochemical perturbations within tumors and normal tissues. Some of these, such as DNA damage, can directly produce death. Others will produce changes that will impact the cellular phenotype and may impact the cell’s decision to undergo growth arrest, cell division, apoptosis, or production of stress related molecules. Recent data from Amundson demonstrated stress gene induction by a dose as low as 2cGy [7], and an eightfold sustained increase by a dose of 50cGy, which is just one-fourth of a standard fraction. Thus, the concept of “focussed biology” is a better concept than dose as “dose” to one tissue or tumor type will produce a different spectrum of molecular changes than in another type. The molecular perturbations created by radiation will depend on the physical factors of the radiation, such as energy, particle vs. x-ray, rate of delivery and heterogeneity of distribution at the centimeter down to subnanometer level. The changes will depend on the tissues within the field, recognizing that tumors contain a large proportion of non-cancerous cells [8]. The efficacy of cancer therapy is described as the therapeutic index, which is the ratio of efficacy to toxicity, therefore, normal tissue toxicity is a critical aspect of radiation oncology. Protecting normal tissues is done with imTable 3 Non-DNA targets (exclusive of targets within DNA and attached molecules) Cell membranes — receptors Cell membrane — apoptosis induction (e.g., ceramide) Signal transduction intermediates Kinases and phosphatases — “activation status” DNA damage recognition and response pathways DNA repair pathways RNA stability, splicing, translation (ribosomes) Transcriptional apparatus Apoptosis pathways Cell cycle checkpoints Protein stability/degradation — proteosome Other organelles — mitochondria, others? Cell-cell communication (bystander effect) Cell membrane molecules — immunologic targets Immunologic — MHC expression/antigen presentation Extracellular factors growth factors inflammatory cells inflammatory moleculers immunologic perturbation, physiological abnormalities Inducible, transiently expressed phenotypes redox regulated (R-S-S-R’) protein tertiary structure protein:protein interaction oxidative stress/ ischemia-reperfusion Etc.

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Fig. 1. This is a frequently updated cartoon illustrating the concept of radiation oncology being focussed biol-

proved technology and with radiation protectors, for example, amifostine [9]. For brevity (this was a 15 min presentation) the concepts of radiation oncology as focussed biology will be presented in a few tables and illustrations. Clearly DNA is a major target, and this includes DNA itself and the DNA damage recognition and response [10] pathways which including such proteins as Ataxia telangiectasis (ATM), Nijmegen breakage syndrome (NBS1), Li-Fraumeni syndrome (p53, CHK2), familial breast and ovarian cancer (BRCA1), and so forth. There are, however, also hosts of non-DNA targets. In considering target definition, the concept of the cDNA microarray is to study gene expression, for example comparing normal tissue to tumor or a tissue before vs. after radiation. Presumably, the effect of the changes in gene expression is reflected in the resultant protein.

However, it is worth emphasizing that many of the targets are not necessarily definable by the DNA expression profiles or by studying the cellular genotype. For example, a normal gene may be silenced by various mechanisms; proteins often function as a part of a large complex so that the presence of a protein may not mean it is functional. Furthermore, protein function depends on the presence or absence of phosphate groups or other attached smaller molecules and, relevant to the abnormal tumor microenvironment which has been a long-standing interest to radiation biologists, protein function may change based on redox state with altered conformation. Table 3 lists some of the non-DNA targets. Figure 1 is a frequently updated cartoon illustrating the concept of radiation oncology being focussed biology [11]. Energy deposition by the beam causes biological changes in

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a wide variety of molecules in the cancer cells and in normal tissues within the tumor. As illustrated, the future of radiation oncology will link technology and biology. The technological advances include intensity modulated radiation therapy (IMRT), which produces a heterogeneous dose within the target. A more challenging concept is that of “nano-IMRT” which is meant to imply that at the nano- to pico-meter scale, radiation is indeed a molecular perturbation and this is where radiation is essentially molecular biology. This is also the dimension for multi-modality therapy with radiation-induced molecular perturbations plus molecular therapeutics. At the NCI Radiation Oncology Sciences Program (ROSP) intramural program we will build on the concept of molecular imaging and therapeutics which will combine imaging, molecular profiling and therapy followed by further imaging and molecular profiling over time. The molecular therapeutics will consist of agents that target DNA and the malignant phenotype, as is being studied for chemoprevention and chemotherapeutic agents but also, ultimately, agents that target the molecular perturbations created by the radiation. Indeed, radiation may be used to kill cells directly, to stimulate targets and, for the new cytostatic agents, radiation may be used as the killing agent following administration of an agent that suppresses cancer growth, e.g., antiangiogenesis agents. On the other side of the equation, there is an interest in understanding the mechanisms of radiation late-effect [12] that, too, may be amenable to therapeutic intervention, possibly months or years following treatment. 3. Conclusion The future of radiation oncology for prostate tumors and cancer in general will be based on advances in imaging, technical delivery and the understanding of the molecular “perturbations” created by radiation. Molecular therapeutics will target DNA and the cancer phenotype that results from the DNA mutations. In addition, radiation may be used to create targets and to provide cell killing in conjunction with agents that by themselves are merely cytostatic in that they have an impact on the cancer but do not necessarily lead to death of the cancer cells without additional help. The paradigm of radiation oncology as “focussed biology” provides the field with a wide range of opportunities for research to complement technological development and places it

squarely within the molecular revolution. A partnership among urologic oncologists, radiation oncologists, and basic science researchers will lead to the elucidation of prostate biology so that the most effective and least toxic treatment can be administered, potentially with “on-the-fly” modification based on molecular imaging and profiling during a course of therapy. It is anticipated that the Urologic Oncology Meetings in the future will include both the “surgery vs. radiation therapy debate” but even more exciting, the “what does the biology tell us sessions” that will be based on a strong partnership among laboratory and translational scientist trying to understand and exploit the profound new knowledge now upon us. This Meeting and others like it will produce new paradigms of dynamic interdisciplinary collaboration.

References [1] Coleman CN, Kaplan ID. Prostate cancer. Technology versus biology. Cancer 1993;72:305–9. [2] Amling CL, Blute ML, Bergstralh EK, Seay TM, Slezak J, Zincke H. Long-term hazard of progression after radical prostatectomy for clinically localized prostate cancer: continued risk of biochemical failure after 5 years. J Urol 2000;164:101–5. [3] Partin AW, Kattan MW, Subong EN, et al. Combination of prostatespecific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 1997;277(18):1445–51. [4] Yu KK, Scheidler J, Hricak H, et al. Prostate cancer: prediction of extracapsular extension with endorectal MR imaging and three-dimensional proton MR spectroscopic imaging. Radiology 1999;213:481–8. [5] Pollack A, Zagars GK, Smith LG, et al. Preliminary results of a randomized radiotherapy dose-escalation study comparing 70 Gy with 78 Gy for prostate cancer. J Clin Oncol 2000;18:3904–11. [6] The National Cancer Institute “The Nation’s Investment in Cancer Res.: A plan and Budget Proposal for Fiscal Year 2002”. NIH Publication No. 00–4373, October 2000. [7] Amundson SA, Do KT, Fornace Jr. AJ. Induction of stress genes by low doses of gamma rays. Radiat Res 1999;152:225–31. [8] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100: 57–70. [9] Brizel DM, Wasserman TH, Henke M, et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 2000;18:3339–45. [10] Wang JYJ. New link in a web of human genes. Nature 2000;405:404–5. [11] Coleman CN. International Conference on Translational Research. Conference Summary. Ann Oncol 2001. In press. [12] 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;17:3283–90.