Photodynamic Therapy for Gastrointestinal Tumors J. H . P. WILSON, R. VAN HILLEGERSBERG, J. W. 0. VAN DEN BERG, W. J. KORT& 0.T. TERPSTRA Dept. of Internal Medicine and Laboratory for Experimental Surgery, Erasmus University, Rotterdam, The Netherlands

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Wilson JHP, van Hillegersberg R, van den Berg JWO, Kort WJ, Terpstra OT. Photodynamic therapy for gastrointestinal tumors. Scand J Gastroenterol 1991, 26 Suppl 188, 20-25 Photodynamic therapy is based on the administration of a compound that is preferentially accumulated by a tumor and which causes tumor destruction after exposure to light of a specific wavelength. The photosensitizers most commonly used in treating tumors of the gastrointestinal tract are porphyrins-hematoporphyrin derivative and dihematoporphyrin ether. These compounds have been used with success to produce reduction in tumor size of esophageal, gastric, and colorectal cancers. In some instances long-lasting complete remissions have been observed after photodynamic therapy. New developments include photosensitizers that react to light of a longer wavelength, which is able to penetrate tissue to a greater depth, the use of 5aminolevulinic acid, which is preferentially converted to porphyrin in malignant cells, and combination of photodynamic therapy with thermic laser, radiotherapy, or chemotherapy. Key words: Carcinoma; photodynamic therapy; photosensitizers

1. H . P . Wilson, Dept. of Internal Medicine, Erasmus University, Rotterdam, The Netherlands

Photodynamic therapy (PDT) has received much attention in the past 2 decades as a means of treating malignant tumors (1-5). PDT is based on the use of photosensitizers, substances that can produce tissue destruction on absorbing light of an appropriate wavelength. Some tumors have the ability to accumulate a photosensitizing agent to a greater extent than the surrounding tissue, which means that exposure to strong light causes selective damage to the tumor. The source of the light is in most instances a laser, as not only is the wavelength of the light sharply defined but alssso the light bundle of a laser shows little divergence. In recent years PDT has been applied clinically with various degrees of success to urinary tract, skin, upper respiratory tract, and gastrointestinal tumors. Although several thousand patients have been treated by PDT throughout the world, this form of treatment is still regarded as experimental by most authorities, and a clear positioning of

PDT among other forms of cancer therapy has not yet been made. PHOTOSENSITIZERS Photosensitizing compounds that have proved useful in PDT share several characteristics. They tend to be concentrated in malignant tissue to a greater extent than in normal tissue. They have characteristic absorption spectra for light and, on exposure to light of an appropriate wavelength, are raised to a higher energy level (triplet state). This energy can then be transferred to oxygen in the surroundings, causing the formation of highly reactive singlet oxygen. The singlet oxygen reacts in turn with amino acids, unsaturated fatty acids, and nucleic acids to cause damage to macromolecules, with resulting damage to cell function and structure. The efficiency of a photosensitizer in PDT

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Photodynamic Therapy

depends on 1) its ability to be concentrated by a tissue; 2) the penetration of light into the tissue; 3) the quantum yield of generation ofthe triplet state of the photosensitizer; 4) the presence of oxygen in the surrounding tissue; 5) the quantum yield of generation of singlet oxygen; and 6) the intracellular localization of the photosensitizer. The penetration of light into a tissue depends on the wavelength of the light and the nature of the tissue. An example is shown in Fig. 1, which is derived from a study of human liver and hepatic tumors by Nakamura et al. (6). As can be seen, red light (wavelength, 630 nm) penetrates all tissues to a greater depth than violet light (wavelength, 410nm), and there are quite marked differences in penetration between normal liver, cirrhotic liver, and tumors. The photosensitizers mainly used are hematoporphyrin derivative (Hpd), a mixture of different porphyrins, and dihematoporphyrin ether (DHE), a purified form of Hpd marketed as Photofrin 11" (Photomedica Inc., Raritan, N.J., USA). These modified porphyrins accumulate and are retained by many types of tumors. The accumulation has been ascribed to several mechanisms (Table I), of which the abnormal permeability of the tumor vasculature and the increased

Table I. Mechanisms responsible for porphyrin in 1. Increased permeabilityof tumor capillaries. 2. Increased number of low-density lipoprotein receptorson tumor cells. 3. Decreasedlymphaticdrainage, 4. Uptake of porphyrin - . . aggregates _ _ - by tumor macrophages. 5. Passive diffusion facilitated by low tumor pH. 6. Binding to exposed collagen and elastin. 7 , Binding toglutathione S-transferases. 8. Decreaiedconversion tohemeowing todecreased ferrochelataseactivity.

number of low-density lipoprotein (LDL) receptors (the porphyrins are transported by the lipoproteins) of malignant cells are probably the most important. Although Hpd and DHE have proved to be effective photosensitizers both experimentally and clinically, they are not ideal as they tend to be unstable in solution and the absorption peak used for PDT is a minor peak at approximately 630 nm, a wavelength that only penetrates to a depth of a few millimeters. Newer photosensitizers include the chlorins (7, €9,verdins (9), rhodamine-123 (10) and phthalocyanines (11,12). These have been shown to be effective in tumors in experimental animals, but little clinical work has been done. Theoretic

mm 3


21.5 1-

w normal Ilver




metart. ca

Fig. 1. Light penetration in human liver and hepatic tumors removed by surgical resection. Mean depth at which the optical power is reduced to 37% is shown for light of three wavelengths. Reproduced with permission from Nakamura et al. (6).

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J . H . P.Wilsonetal.

advantages include a greater stability during storage, absorption of light of longer wavelengths that are able to penetrate tissue to a greater depth than the light used with Hpd, and, in some instances, longer retention of the photosensitizer in the tissue. Tumor destruction during PDT can be due to direct tumor-cell inactivation or to damage to the endothelial cells resulting in ischemia. Evidence has been provided for both mechanisms (13), although the endothelial damage seems to be the more important effect, and endothelial cells are very sensitive to PDT (14). The endothelial damage is associated with thromboxane release, and indomethacin (which blocks thromboxane production) inhibits PDT-induced vascular stasis and tumor necrosis (15). In addition to release of thromboxane and prostaglandin EZ(16), PDT is associated with increased production of tumor necrosis factor, interleukin-lp, and interleukin 2, which suggests that PDT may elicit a local macrophage and immunologic response (17,lS). APPLICATIONS OF PHOTODYNAMIC THERAPY IN GASTROENTEROLOGY Most reports on PDT concern treatment of head and neck tumors, lung cancer, subcutaneous metastases of breast cancer, and bladder carcinomas. Small series of patients with esophageal, gastric, and colon carcinomas treated with PDT have been reported, and there have been isolated case reports of PDT in cholangiocarcinoma. Carcinoma of the esophagus McGaughan et al. started using PDT to treat patients with obstructing esophageal carcinomas in 1982 and have summarized their findings in a recent article (19). In general, PDT has been found to be reasonably useful in relieving obstructive symptoms, and some instances of prolonged complete remissions have been reported (19-22) (Table 11). Complications are relatively infrequent and include photosensitivity (which can be severe if the patient does not follow instructions to remain out of direct sunlight for up to 8 weeks (23,24)), stenosis, and, very occasionally, perforation (Table 111). PDT is not

Table 11. Results of photodynamic therapy of esophageal carcinoma No. of patients Center (Ref.) Columbus (19) Melbourne (21) Nantes (20) Tokyo (22)





28 15 24 17

2 2 11 14

21 13 8 2

3 0 5 1

CR = complete response with no identifiable tumor after treatment; PR = partial response with reduction in volume of 50%or more; and NR = non-responder (less than 50% reduction in tumor volume). In Tokyo mainly small tumors were treated, and in Nantes the figures are given for squamous cell carcinoma only.

more harmful for respiratory and acid-base functions than YAG laser or other common endoscopic procedures (25). In general, the smaller the tumor, the greater the chance of achieving a complete response. It is also possible that the tumor type influences the success rate (26). At present two phase-111 trials of PDT are being conducted in the USA and Canada. One is a comparison of PDT with Nd : YAG laser therapy of obstructing tumors (27). Once these large multicenter studies have been completed, it should be possible to obtain a clearer impression of the place of PDT in the management of the patient with late-stage esophageal carcinoma. The good results with small tumors suggest that it could be of value in treating small tumors in patients who are inoperable for other reasons. Colorectal cancer PDT with Hpd and with a flexible optic fibre inserted into the tumor by colonoscopy has been used by Barr et al. (28) to treat 10 patients with colorectal cancer who were unsuitable to undergo resection. Two patients with small tumors were tumor-free 20 and 28 months after PDT. In one patient with advanced tumor, the procedure was complicated by a hemorrhage. In colorectal cancer PDT may be most suitable for small tumors or to treat tumor remnants after other forms of treatment (29). After PDT there appears to be little damage to collagen, and the mechanical strength of the colonic wall is not weakened, even with transmural necrosis. This

Photodynamic Therapy


Table 111. Complications of photodynamic therapy for esophageal carcinoma Center

Melbourne (21) Columbus (19) Fever Pain Mediastinitis

Pleuritis Hyperpigmentation Photosensitivity Scand J Gastroenterol Downloaded from by Freie Universitaet Berlin on 05/01/15 For personal use only.



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contrasts with thermal laser damage of the colon, which weakens the colonic wall and may cause perforation (30). Photosensitizers also have potential as diagnostic aids. The porphyrin photosensitizers have a characteristic red fluorescence in ultraviolet light, and this has been used to detect ‘early’ carcinomas. Unfortunately, the tumor selectivity for squamous cell tumors is poor in those parts of the digestive tract with squamous cell epithelium (31).

Other tumors PDT has been used effectively in a small number of cases of Kaposi’s sarcoma of the mouth. This suggests that PDT might be suitable to treat Kaposi lesions in the rest of the gastrointestinal tract (31). Liver tumors To be effective in tumor therapy, more photosensitizer should accumulate in the tumor than in the surrounding tissue. Unfortunately, normal liver accumulates DHE efficiently, and higher levels have been found in the liver than in the malignant tissue (33,34). This means that DHE is not a suitable photosensitizer for PDT of liver cancer. As an alternative approach, we have considered the possibility of using the varying capacity of tissues to synthesize porphyrins, as a means of photosensitization. In various malignant and regenerating tissues a higher activity of porphobilinogen deaminase (PBGD) and a lower activity of ferrochelatase than normal tissues has been demonstrated (35,36). If one could increase the amount of porphobilinogen (PBG) available


Nantes (20) ? ? ? ?

6/24 2124 4/24 0124

in the cell, the increased PBGD activity and the decreased activity of ferrochelatase would result in accumulation of porphyrins in the tumor to a greater extent than in surrounding normal hepatic tissue. We have used a tumor model in the rat liver to investigate this proposition. As PBG does not cross cell membranes, its precursor S-aminolevulinic acid (ALA) was administered, and the porphyrin concentration in tumor and liver tissue was determined subsequently. During ALA administration the rate-limiting enzyme in the heme synthetic pathway is PBGD. Treatment with ALA resulted in a selective accumulation of porphyrins in malignant tissue in the liver. After 11 days of ALA the porphyrin concentration ratio between tumor and liver was 4:1. The main product found after ALA treatment was protoporphyrin. This substance has good photosensitizing properties, as evident from the severe cutaneous phototoxicity in erythropoietic protoporphyria. Moreover, destruction of malignant cells in vitro or skin tumors after local administration of ALA or protoporphyrin and subsequent exposure to photoactivating light has been demonstrated (37). As porphyrin accumulation is restricted to the tumor, PDT would act specifically on the tumor, causing minimal damage to the adjacent tissue. Another important application of ALA administration could be the early detection of malignant tissue, utilizing the fluorescence properties of protoporphyrin during illumination with ultraviolet light. A recent study reports good correlation between the location of the red fluorescence and the phototoxic damage to specific structures in mouse skin after intraperitoneal


J . H.P. Wilson et al.

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administration of ALA and subsequent illumination (38). Further studies on this approach to the diagnosis and treatment of liver tumors are now in progress.

Future developments Apart from the development of new photosensitizers mentioned above, recent research has focused on the possible benefits of combining treatments. This has taken the form of using multiple photosensitizers (39) or combination with thermic laser treatment (40), with radiotherapy (41), or with chemotherapy (42). The potential advantages of PDT-tumor specificity, minimal ‘collateral damage’ to normal tissue, and the possibility of repeated treatments-mean that this form of therapy will continue to receive much attention from gastroenterologists during the coming years. ACKNOWLEDGEMENTS

R. van Hillegersberg was supported by a grant from The Netherlands Digestive Disease Foundation. REFERENCES

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esophageal and endobronchial tumors under general and local anesthesia. Effects on arterial blood gas levels. Chest 1990, 98, 1374-1378 Perry RR, Matthews W, Mitchell JB, Russo A, Evans S, Pass HI. Sensitivity of different human lung cancer histologies to photodynamic therapy. Cancer Res 1990, 50,4272-4276 Dougherty TJ. Introduction. In: Bock G , Harnett S, eds. Photosensitizing compounds: their chemistry, biology and clinical use. Ciba Foundation Symposium 146. John Wiley & Sons, Chichester, 1989, 1-3 Barr H, Krasner N, Boulos PB, Chatlani P, Bown SG. Photodynamic therapy for colorectal cancer: a quantitative pilot study. Br J Surg 1990,77,93-96 Krasner N . Laser therapy in the management of benign and malignant tumours in the colon and rectum. Int J Colorectal Dis 1989, 4, 2-5 Barr H, Bown SG, Krasner N, Boulos PB. Photodynamic therapy for colorectal disease. Int J Colorectal Dis 1989, 4, 15-19 Monnier P, Savary M, Fontolliet C, et al. Photodetection and photodynamic therapy of early squamous cell carcinomas of the pharynx, oesophagus and tracheo-bronchial tree. Lasers Med Sci 1990, 5, 149-168 Schweitzer VG, Visscher D. Photodynamic therapy for treatment of AIDS-related oral Kaposi’s sarcoma. Otolaryngol Head Neck Surg 1990, 102, 639-649 Bugelski PJ, Porter CW, Dougherty TJ. Autoradiographic distribution of hematoporphyrin derivative in normal and tumor tissue of the mouse. Cancer Res 1981, 41, 46044612 Bellnier DA, Ho YK, Pandey RK, Missert JR, Dougherty TJ. Distribution and elimination of Photofrin I1 in mice. Photochem Photobiol 1989, 59, 221-228


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Photodynamic therapy for gastrointestinal tumors.

Photodynamic therapy is based on the administration of a compound that is preferentially accumulated by a tumor and which causes tumor destruction aft...
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