187 Reversing fibrosis

Symposia

Our laboratory investigates enteroprotective strategies that directly target molecular and cellular aspects of radiation enteropathy. Ongoing projects are aimed at A) minimizing epithelial barrier breakdown; B) modulating local inflammatory processes; C) preventing radiation-induced endothelial dysfunction; and D) interrupting pathways of extraceltular matrix deposition. Future goals are to develop and optimize methods for targeted delivery of radiation response modifiers, techniques for modulating tissue-specific radiation effects, novel predictive assays, and diagnostic tests to monitor toxicity below the threshold of clinical detection. Development of prophylactic or therapeutic measures that minimize intestinal radiation toxicity will provide opportunities for increasing cancer cure rates and improving the quality of life among cancer survivors. 187

Reversing fibrosis S. De/anian J.L. Lefaix Hdpital Saint-Louis, Department of Radiotherapy, Paris, France Fibro-atrophic process is a severe irreversible late effect on tissues induced by high dose irradiation. This RIF process is notoriously difficult to manage. Corticosteroids have only reduced the associate acute inflammatory signs. We published succesful results for the rediction of superficial RIF by superoxide dismutase (SOD) and a combination of pentoxifylline and tocopherol. 42 distinct palpabel zones of superficial RIF were treated with Liposomal Cu/Zn SOD with 6 injections of 5 mg in 3 weeks. The significant mean surface regression was 57 + 26% at 2 months. Lip SOD was the first agent shown to be effective in reducing RIF, however, this drug was not available. The same SOD treatment was delivered in 10 pigs with an uniform well-characterized RIF to the outer side of the thigh after acute localized irradiation. Significant shrinking of the fibrotic block were noted in all treated animals until autopsy at 12 weeks, with 73± 9% mean surface regression. Histopathological observations showed completely normal muscle and subcutaneous tissues surrounding the residual scar. Mechanisms implicated in RIF reversibility have been investigated by in vitro studies in primary cultures of human and pig fibroblasts. SOD modulation induced a fibroblastic phenotype reversion with an increase endogeneous Mn SOD activity and a decrease of TIMP and TGF beta gene expression. 50 symptomatic,RIF areas involving the skin and underlying tissues, were treated orally by a combination of PTX (800 mg/d) + Vit. E (1000 mg/d) for at least 6 months. Mean RIF surface regressioin and SOMA score were improved significantly at 6 months respectively with -53% and -35%, and at 12 months -66%, -48%. We did not attempt the maximum effect. The same PTX-Vlt. E treatment was delivered in the porcine model, versus PTX alone or placebo during 6 months. Significant shrinking of this block was noted in the PTX-Vit. E treated pigs with 70% ean surface regression and no response in both other groups. Histologic examination showed completely normal muscle tissue surrounding the residual scar. The tissular and cellular immunolocalization of TGF beta-1 diminished only in the residual fibrotic scar of the PTX-Vit. E treated pigs. Radiation-induced fibrosis is reversible in clinic with SOD as with combined PTX-Vit. E. Experimental and in vitro studies confirmed and demonstrated this reversibility and helped mechanisms understanding.

C L I N I C A L T R I A L S IN D E V E L O P I N G C O U N T R I E S 188

Needs and pitfalls of cooperation between developing countries and cancer research organizations J.C. Horiot Director Regiona/ Cancer Institute G.F. Lec/erc, Dijon, France EORTC Past-President Is Cancer Research a priority for developing countries? Certainly not the first priority since in most of these countries, cancer is a relatively neglected disease compared to others of higher incidence. Can Cancer Research be a priority when basic public health issues such as a clean water supply, adequate diet, major infections and parasitosis, are not under control? Can Cancer Research be a priority when basic requirements for multidisciplinary medical competence, diagnostic/therapeutic equipment and hospital facilities are not equally accessible to the population? Major and rapid progress in the diagnosis and treatment of cancer is occurring in industrialized countries. The gap between these countries and the rest of the world is ]ikely to increase exponentially. There are huge differences in access to knowledge, training, experience, and time to transfer results of research to standard practice. Hence, international cooperation is mandatory to aim at providing equal access to state of art cancer diag-

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nosis and treatment modalities including radiation therapy, to harmonize the fall out of research on new drugs and novel therapies. There would be a real hazard in opposing the priority to meet local needs to the apparently less urgent objective to develop international cooperation for cancer research. In fact these two aspects are complementary, providing a comprehensive approach is undertaken worldwide, aiming at harmonizing access to knowledge and progress, developing a dialogue between scientists, healthcare professionals and politicians, internationally as well as within each country. Designing anti-cancer strategies to meet local needs and developing concomitant clinical research raises several challenges, one of which is how to distribute insufficient resources without further increasing the gap between industrialized and developing countries. A possible answer lies in two parallel pathways: - Strengthening the Education and Training of cancer specialists and nursing staff from developing countries. - Developing joint Cancer Research projects primarily dedicated to meet local needs. Although these two aspects have strong interactions, we shall now focus on research in developing countries and on the role of international cooperation. The main pitfall of research in developing countries lies in the risk of importing/exporting the research objectives and priorities of industrialized countries, without taking local needs into account. The knowledge of regional epidemiology reveals the pattern of prevailing cancers and often discloses the causative environmental, toxic addiction, lifestyles and alimentary factors. A number of basic and translational research topics can be hence individualized to specific studies of molecular pathways from normal cells to cancer cells, early diagnosis of pre-cancereus conditions, and the use of novel therapies including vaccines and gene therapy. Targeting genetic abnormalities responsible for locally prevalent cancer types and sites will allow more specific treatment approaches that are likely to be less toxic, and should ultimately be more cost effective than the presently used destructive strategies (surgery, radiotherapy and cytotoxic chemotherapy). The late diagnosis of some of the major cancers in developing countries (for example cervix, lung, head and neck...) is so common that the best chance for changing this observation in the next two decades will undoubtedly be given by prevention programs, systematic screening and identification of populations at risk. An earlier diagnosis usually gives a better chance for a cure with the presently available treatment modalities that unfortunately are not available to the largest part of the world population. Within a hopefully not so distant future, the development of novel therapies will probably result in the ability to stop or modify the cancer molecular pathways at the pre-clinical disease stage. This presentation should not give the impression that "conventional" clinical research is not amenable to a cooperation between developing countries and cancer research organizations. It is, however a fact, that there are substantial difficulties in planning the participation of (even) major hospitals from developing countries in research trials undertaken in Europe and North America. If modern communication tools have lead to spectacular changes in transferring and securing information, the extension of European or North American criteria for staff, equipment and quality assurance, to developing countries, is rather unrealistic. The development of specific cancer research programs and networks for developing countries, in close cooperation with international Cancer Research Organizations is probably the answer to this dilemma. The INCTR (International Network for Cancer Treatment and Research), a joint venture of NCI, UICC, WHO, the Belgian Pasteur Institute is an excellent model of this emerging strategy. The wealth of developing countries lies in the huge number of cancer patients eligible for research and in the improved cost/efficiency ratio to conduct mega-trials on basic questions within a very short time. The interaction between doctors and scientists, politicians and industry representatives, is the cornerstone to materialize and accelerate cancer research ventures designed to lessen the suffering and limit the number of lives lost in developing countries. Let's act together for making the XXI century one of drastic progress in sharing resources and knowledge. If successful, the outcome will eventually benefit the whole of humanity. 189

Unique trial opportunities A. Lee Pamela Youde Nethersole Eastern Hosp, Dept. of Clinical Oncology, Hong Kong, China By the year 2020, the projected population in developing countries will be 5 fold (6.6 versus 1.3 billions), and the total number of cancer deaths will be 3 fold (9 versus 3 millions), that of developed countries. In addition to the huge case numbers, the pattern of prevalent cancers is markedly dif-