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Challenges for photodynamic therapy in the treatment of gastrointestinal tumours T. Patrice D&partement LASER, H&pita1 Lahmec,

BP 1005, F-44035 Nantes (France)

When Giulio Jori asked me to write a short paper for the “News and Views” section of the Journal of Photochemistry and Photobiology, B: Biology, the first thing I did was to obtain a computer listing of the very latest papers concerning photodynamic therapy (PDT). I was surprised to discover that, some 10 years after the initial work of Dougherty et al. [ 1 ] and 20. years after that of Gregorie et al. [2] and Lipson et al. [3], only seven out of the 58 papers concerning PDT published between July 1988 and July 1989 (Medline data bank) were devoted to clinical studies. This scarcity of clinical data certainly points to the main challenge for PDT and particularly for gastroenterology. I would like to discuss this challenge and consider the ways research could help clinicians develop PDT as efficiently as possible. PDT is a new method of treating cancer. It is not just another application of technology, but may be considered as a completely new concept. Yet, despite the important experimental work already carried out, this concept is based essentially on hypotheses. One reason is that no experimental results can be directly applied to the human being. This is particularly critical since the choice of the PDT target for tumour control still remains unclear. At least three different targets could be involved: endothelium of the tumour neovasculature [ 41, membrane receptors for growth factors [ 51 or immune determinants and, of course, the tumour cell itself [6]. This lack of certitude is one of the reasons why few clinical experiments have been carried out. PDT is intended for treatment of patients. In the absence of rigorous, large-scale clinical trials, there will be no future for PDT. At least two pharmaceutical companies are involved in PDT research at the present time, which is of considerable importance for the worldwide clinicaI development of this technique. These companies will guarantee the accuracy of the phase III clinical trials that should be starting now. These trials will determine the role of PDT by random comparison of results obtained after PDT and conventional treatment. If these studies are not encouraging, I fear that further and unpredictable delays will occur and perhaps even compromise the future of PDT. This is why these studies must be multicentre, international and homogeneous in patient selection. Inclusion of gastrointestinal tumours in the clinical indications for PDT requires that the effect of the technique on the tumour be predictable. It is difhcult to propose PDT to our staff when we do not know what amount of sensitizer is present in tumour tissues or at what depth light will penetrate

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through tissues in a particular patient. In radiotherapy, which can be considered to a certain extent as a model for PDT, it is possible to determine before treatment the exact delivered dose per unit of volume of turnour tissue. The development of PDT also requires the elaboration of predictive tools complementary to the new sensitizers. These systems must have the capability of determining the sensitizer concentration in tissues and be safe, inexpensive and reliable. They will also be needed to analyse and integrate the optical properties for each tumour. These conditions will certainly give rise to some technical problems. Precise pharmacokinetic analysis will be particularly necessary for drugs (sensitizers) claimed to have relative selective retention by cancer tissues. Moreover, the optimization of drug delivery in phase lV clinical trials will require such tools for rapid determination of the procedure providing the highest drug peak in the tumour and an indication of when this peak occurs. Unpredictable specific sensitivity will also be a factor, but can be considered as an aspect of the development of the clinician’s experience. PDT is a local treatment to be included in combined therapeutic approaches intended to treat not only the tumour itself but the cancer disease. Such therapeutic associations will influence each other, so that care must be taken to define a logical sequence. Moreover, it is possible that some tumours will respond only to some sensitizers and be resistant to others. The laser dose delivered may also have considerable importance. Several workers have suggested that laser dose fractionation would be more efficient than a single laser dose. Furthermore, a tumour may not be monoclonal, but may be made up of several cancer cell populations. In a study currently being carried out in collaboration with D. Cortese (Rochester, MN, U.S.A.) and F. Cardin (Padua, Italy), we have demonstrated that cell sensitivity to haematoporphyrin derivative (HPD) PDT in human cancers varies widely from one cell population to another within a single tumour. For all these reasons, the role of PDT in sophisticated therapeutic schemes must be carefully evaluated, and experiments to study the effects of such combined protocols need to be performed to determine the best therapeutic associations. The relatively better selectivity of drug uptake or retention by cancer tissues and the improved repair of normal tissues after PDT are certainly the main advantages of this technique compared with conventional treatments. These advantages are of particular interest in therapy for small (or early) carcinomas not easy to treat effectively when surgical excision is difficult or impossible. In these cases, tumours are often well differentiated and poorly vascularized, so that chemotherapy or radiotherapy are of little use. To increase the number of PDT-treated patients, selectivity must be improved through the discovery of new sensitizers with better retention in tumours or selective protectors for normal tissues. In gastroenterology, as in other medical fields, we are hopefully at the beginning of a new era for PDT. This technique will be used routinely in a few years, provided that clinical trials are performed carefully and precise answers to clinical problems obtained. If this is not done, PDT will undoubtedly still have a solid future since the basic concept should survive and be of

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considerable use. However, in that case the benefits will be greatly delayed, something that none of us wishes to see.

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T. J. Dougherty, J. E. Kaufman, A. Goldfarb, K. R. Weishaupt, D. G. Boyle and A. Mittleman, Photoradiation therapy for the treatment of malignant tumors, Cancer Res., 38 (1978) 2628-2635. H. B. Gregorie, E. 0. Horger, J. L. Ward, J. F. Green, T. Richards, H. C. Robertson and T. B. Stevenson, Hematoporphyrin derivative fluorescence in malignant neoplasms, Ann. Surg., 167 (1968) 820-828. R. L. Lipson, E. J. Baldes and A. D. Olsen, The use of a derivative of hematoporphyrin in tumor detection, J. Natl. Cancer Inst., 26 (1961) 1-12. S. H. Selman, M. Kreimer-Bimbaum, J. E. Klaunig, P. J. Goldblatt, R. W. Keck and S. L. B&ton, Blood flow in transplantable bladder tumors treated with hematoporphyrin derivative, Cancer Res., 44 (1984) 1924-1927. R. J. Lanzafame, D. W. Rogers, J. 0. Naim, H. R. Herrera and J. R. Hinshaw, Effect of hematoporphyrin derivative 2 on estrogen receptors in experimental mammary tumors, Lasers Surg. Med., 7 (1987) 280-282. T. Patrice, M. T. Foultier, S. Yactayo, M. C. Douet, F. Maloisel and L. Lebodic, Endoscopic photodynamic therapy with haematoporphyrin derivative in gastroenterology, J. Photochem. Photobiol. B: Biol., 6 (1990) 157-165.

Challenges for photodynamic therapy in the treatment of gastrointestinal tumours.

372 Challenges for photodynamic therapy in the treatment of gastrointestinal tumours T. Patrice D&partement LASER, H&pita1 Lahmec, BP 1005, F-44035...
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