Dig Dis 1992:10:53-60
Second Department of Surgery. Helsinki University Central Hospital, Helsinki. Finland
Keywords Photodynamic therapy Laser Photosensitizing agent Gastrointestinal tumors Cancer Therapy
Photodynamic Therapy of Gastrointestinal T umors: A Review
Abstract Photodynamic therapy (PDT) is a new modality of cancer treatment. It consists of intravenously injecting a patient with a photosensitizing agent and. when this agent has accumulated in tumor cells, decomposing it by exposure to red light pro duced by an argon dye laser. Toxic compounds produced in this reaction then destroy the malignant cells, while normal tissue is not significantly affected. Most clinical experience with PDT has been gained in the treatment of lung cancer, cancer of the urinary bladder and malignancies of the head and neck region. In gastroenterology, esophageal, gastric and colonic tumors have clinically been treated with PDT. This paper is to review the current use of PDT in the treatment of gastrointestinal tumors.
Introduction Photodynamic therapy (PDT) is a new mo dality of cancer treatment. It is based on the use of photosensitizing agents and laser light which interact producing singlet oxygen. This toxic compound destroys malignant tumors while healthy tissue remains intact.
Research on PDT was started in the early 1960s when Lipson et al. [1] published a paper demonstrating the photodynamic prop erties of a hematoporphyrin derivative (HpD). They suggested that PDT might be of use in the treatment of malignant tumors. Subsequently. Dougherty et al. [2-4] have published several studies on the biochemical
Pauli Puolakkainen. MD. PhD Oncogen 3005 First Avenue Seattle. WA 98121 (USA)
©1992 S. Karger AG. Basel 0257-2753/92/ 0 10 1— 0053S2.75/0
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Pauli Puolakkainen Tom Schroder
Principle and Characteristics of PDT In PDT. a patient is given an intravenous injection of a photosensitizing agent known to accumulate preferentially in tumor cells [2]. Initially, all tissues take up these agents to an equal extent after injection. During an equi librium period of 48-72 h, the compound is cleared from the normal tissue while retained in the malignant cells [2. 5-7], In addition to malignant cells, liver, spleen, kidneys and skin are also known to accumulate the agent [8]. The precise basis of this selective reten tion mechanism remains unclear in spite of intensive research [7], After 48-72 h. the tu mor containing the photosensitizing com pound is exposed to red light produced by an argon dye laser (wavelength 625-635 nm) or gold vapor laser (628 nm) [2, 9], Laser light can be delivered to the tumor, according to its location, either directly or through an endo scope [5]. The light intensity and light dose required depend on the size of the tumor and the depth of its infiltration. The light doses for maximal effect are still empirical: 50300J/cm2 appear sufficient for tumor de struction while lower doses ( 10-50 J/cm2) ap pear adequate for carcinoma in situ and dys plasia [10, 11]. Laser beam delivered to the tumor excites the photosensitizing agent to a higher energy level. This energy is released when the excited sensitizer reacts with oxygen present; the presence of oxygen is required for PDT. The oxygen molecule is then excited to singlet oxygen, which damages the blood ves
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sels in the tumor area and destroys the tumor, while normal tissue is not significantly af fected [3. 12, 13]. At the cellular level, pri mary sites of photodynamic activity are thought to be cellular and mitochondrial membranes, but nucleic acids and proteins are also damaged bv this photooxidation [14. 15]. The photosensitizing agents most com monly used are HpD and dihematoporphyrin ether (DHE or photofrin II). HpD is a hemo globin derivative [16], and DHE is a combi nation of esthers and ethers of purified HpD [17], Intravenous dosages have been 2.5-5 and 1.5-2.5 mg/kg for HpD and DHE, respec tively [4, 7, 18, 19], The advantages of HpD and DHE in clinical use are their suboptimal ability to accumulate in malignant tissue and their low toxicity to healthy tissue [2, 20], Currently. DHE is usually administered in human studies since it is the only Food and Drug Administration-approved photosensi tizing agent in the USA [7], Other photosensi tizing agents developed for PDT include evanins, carotenoids, chlorins and chloro phylls as well as cationic dyes like rhodantines [ 12,
21],
The effectiveness of PDT and the extent of malignant tissue destruction depend on the light absorbed at different depths and on the concentration of photosensitizing compound in the treated tissue [12], Clinically, only the light intensity can be routinely measured. There have been no general treatment recom mendations in PDT, for the doses used arc empirical and based on tests that cannot be applied to all patients in the same form [22]; there might be some improvement however by the development of a new endoluminal light delivery system [23]. The concept of a closed system for this light delivery system has for the first time allowed accurate dosime try to be applied to the entire length of a malignant stricture and ensures that a prede
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PDT of Gastrointestinal Tumors
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and cellular mechanisms of PDT, as well as experimental and clinical series which have partly led to the development of PDT as a modern, alternative method of cancer treat ment. The present paper reviews the method of PDT and its current and potential use in the treatment of gastrointestinal tumors.
mor bed [25]. This intraoperative PDT has been attempted mainly in neurosurgery [12]. PDT can also be utilized as an adjuvant to other standard forms of tumor therapy. Posi tive synergistic effects of PDT and hyperther mia as well as PDT and some cytotoxic drugs have been observed [26-29], Safety considerations of PDT include the necessity for all personnel and patients to use protective glasses with appropriate filters to laser light of 630 nm. Further, the use of com bustible gases in association with the anesthe sia should be avoided.
Clinical Applications of PDT Most clinical experience with PDT has been gained in the treatment of lung cancer, cancer of the urinary bladder and malignan cies in the head and neck region [22, 30]. On the whole, treatment results have been prom ising with regard to palliation [3, 19], Up to 90% of treated tumors have responded to PDT either by disappearing or diminishing in size, which has significantly eased the symp toms [19]. Phase III clinical trials employing photofrin II as photosensitizer are currently being organized in the United States and Can ada. Three different neoplastic conditions have been chosen: obstructive endobronchial and esophageal tumors and papillary tumors of the urinary bladder [21,31].
Treatment of Gastrointestinal Tumors by PDT In gastroenterology, clinical experience with PDT has been gained mainly in the treat ment of esophageal, gastric and colorectal ma lignant tumors. In addition to this, experi mental PDT research has been done on pan creatic, colon and liver tumors.
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termined light energy dose is absorbed by the tumor during PDT [23]. In PDT. the tumor destruction occurs gen erally very rapidly but the final effect of treat ment is usually not estimated until 4 weeks after treatment. The assessment of the amount of tumor destruction in clinical studies is often done by analyzing it as no response, partial response or complete response. The general advantages of PDT in the treatment of carcinomas include selective, fairly effective tumor destruction, the possi bility of repeated treatment if necessary, since no maximum dose exists, and the possibility of using other treatment methods simulta neously with PDT. because there are no harmful interactions [3. 5. 22, 24], Further, PDT can be given as outpatient treatment, and operative treatment of patients at high risk can be avoided. The main disadvantage of the method is photosensitization of the skin. Exposure to bright light should be avoided for 4-8 weeks after the treatment to avoid severe sunburns [5. 6. 24], Other reported side effects and dis advantages of PDT include nausea, vomiting, metallic taste, eye photosensitivity and liver toxicity as well as nonspecificity and rela tively poor effect on deep-seated tumors be cause of the limited depth of laser penetration [7], As laser equipments are expensive, clini cal applications are so far limited [24], Another problem is the lack of international standardization, which complicates compari son of treatment results and makes it difficult to establish optimal treatment methods [5]. On the basis of clinical experiences accu mulated so far. it appears that PDT is most effective in those malignant tumors that are localized and have a depth of less than about 1 cm. In case of bulky tumors. PDT can be successfully used for palliative purposes. PDT can also be applied in combination with sur gery to achieve better sterilization of the tu
The current palliative treatment of esopha geal cancer remains unsatisfactory. Radio therapy and chemotherapy are of limited val ue. and the swallowing ability enhanced by the dilatation or intubation with tube prosthe sis is temporary. Laser vaporization of the tumor has proven useful as a palliation. There have been many attempts to improve the effi cacy of laser treatment by PDT. McCaughan et al. [32] treated 16 patients with esophageal carcinoma; in every patient the tumor dimin ished in size and swallowing improved. In 1989, the same group reported on the effects of PDT in 40 patients with esophageal tumors [33]. At 1 month, the average minimal diame ter opening of 28 accessible tumors increased from 6 to 9 mm. The authors concluded that PDT was effective in achieving the ability to swallow, the most important factor in pallia tion of these patients. Complications in cluded six esophageal strictures, three tra cheoesophageal fistulas and four photosensi tivity reactions [33], Other reported compli cations have included substernal and epigas tric pain and expectoration of necrotic tissue. Similar results of the treatment of esophageal carcinoma have been reported also by other groups [34. 35]. Recently, Thomas et al. [36] reported on the effects of PDT in 15 patients with locally advanced esophageal cancer. In every patient, the tumor responded to thera py, and two complete remissions were achieved. The authors concluded that photo therapy is an effective alternative to other forms of palliation and may replace the use of surgery in selected cases of locally advanced esophageal cancer [36]. Tian et al. [37] treated 13 patients with esophageal carcinoma and concluded that PDT is an effective treatment method for patients refusing surgical treat ment and for those at high operative risk. Early or superficial esophageal cancer is defined as mucosal or submucosal involve
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ment only. In China and Japan, these esopha geal lesions have been treated at an earlier stage because of earlier tumor discovery by routine screening practises [34], Hayata et al. [34] reported four complete remissions in six treated lesions; disease-free follow-up lasted 19-41 months. Tajiri et al. [24] reported the PDT treatment of 6 patients with superficial esophageal cancer and 13 with early gastric cancer with no tumor recurrence during the follow-up period. Kato et al. [39] published recently a study on the PDT treatment of 66 patients with esophageal cancer (22 cases of early cancer). Complete response was achieved in 80% of patients with no recur rences. The long-term follow-up of those pa tients with early esophageal carcinoma having complete response has been encouraging [38]. Gastric Carcinoma
The use of PDT in treating gastric cancer is technically more complicated than that of esophagus owing to gastric folds, peristalsis and the shape of the stomach itself, all of which limit access to the tumor [38], In the study of Song et al. [5] on gastric cancer, only mild cure response was achieved in 10 of 23 patients and 7 did not respond at all. Hu et al. [40] treated 42 patients with various histo logic types of carcinoma of the gastric cardia. Adenocarcinoma and mucinous adenocarci noma responded well to PDT treatment, but all papillary' adenocarcinomas (2 patients) and squamous cell carcinomas (3 patients) were refractory. Further, the treatment was effective in patients with limited and superfi cial tumor infiltrations in the gastric wall but unsatisfactory in those with wider and deeper infiltrations [40], Hayata et al. [34] treated 16 patients with early gastric carcinoma, 4 of them had com plete response to PDT but 3 of these 4 had recurrences 5-27 months after treatment.
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Esophageal Carcinoma
Colorectal Carcinoma With regard to palliation, promising re sults of PDT have been obtained in the treat ment of colonic and rectal carcinomas [5], although the use of PDT for colorectal cancer has been limited, and the series of patients are small [38]. In a study of Herrera-Ornelas [41], 14 patients were treated. In some patients relieve of pain and obstructional symptoms was achieved [41]. Recently. Barr et al. [42] concluded that PDT is an evolving method of laser therapy with the potential for safe endo scopic treatment of colorectal cancers. In ex periments on rats, these workers demon strated the biological advantages of PDT compared with thermal methods of tissue de struction like electrocautery or pure laser treatment. PDT does not destroy colonic col lagen, as the thermal methods do, thus reduc ing markedly the risk of perforation [42. 43], Further, Barr et al. [44] have performed re cently an experimental study on the produc tion of selective necrosis in rat colon tumors by PDT. It was postulated that at low dosages of the photosensitizing agent, selective necro sis of the tumor can occur because the photo sensitizer is photodegraded in the normal co lon before a threshold photodynamic dose is reached, whereas in tumor containing twice as much photosensitizer, a photodynamic threshold can be achieved and necrosis pro duced [44], They have also reported a clinical
study of 10 patients with colorectal cancer treated with endoscopic PDT [45], Two pa tients with small lesions are tumor free 20 and 28 months after PDT. One treatment of ad vanced tumor was complicated by a hemodynamically significant secondary hemorrhage, the risk of which is a known disadvantage of PDT in large tumors [43]. In conclusion, PDT may be suitable for the treatment of small colorectal tumors, small anastomotic recur rences and conditions such as dysplasia and carcinoma in situ in chronic ulcerative colitis [43-45], but it seems likely that neodymium yttrium aluminum garnet laser treatment will remain the laser option of choice for ad vanced bulky tumors [46], However, further studies are mandatory in order to judge the precise role of PDT in clinical practice [43], Miscellaneous Gastrointestinal Tumors
Patrice et al. [47] used PDT to treat 27 nonoperable patients with various gastroin testinal tract tumors less than 40 mm in diam eter. Normalization of biopsy specimens were observed in 12 patients (6 squamous cell car cinomas and 6 adenocarcinomas). PDT was able to destroy significant volumes of the tumor, although subsequent biopsy speci mens proved negative in very few cases. Ac cordingly, the same group reported recently the treatment of 54 patients with nonoperable gastrointestinal neoplasms by PDT [48], Dur ing follow-up (average: 14.5 months), com plete local tumor destruction and negative histology were observed in 24 cases. The mean recurrence-free period varied from 13.8 to 17.4 months. Fifteen patients have re mained alive and disease free [48], In a study of 52 patients. 77% of the tumors of the upper gastrointestinal tract responded favorably to PDT treatment [49], As Patrice et al. [48] and Zera [38] summarized, PDT can be of great value in palliation in esophageal and colorec tal cancer, as a primary therapy in superficial
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Kato et al. [39] have reported recently the treatment of 133 cases of gastric cancer (in cluding 120 cases of early stage cancer). Com plete response was achieved in 100% of pa tients with a recurrence rate of 22.2% [39]. On the whole, the role of PDT in the treat ment, and even for palliation, of advanced gastric cancer seems to be limited [38], but it might be of value in cases of early or superfi cial gastric carcinoma when surgical treat ment is excluded.
tumors of the esophagus and stomach and perhaps as an adjuvant therapy in rectal can cer. Schröder et al. [50] have performed an experimental study of PDT in the treatment of pancreatic tumors. They found that suffi cient amounts of HpD accumulated in the tumors to achieve extensive necrosis in them without any visible effect on the healthy pan creatic tissue, but they warned against the potentially harmful effects on the surrounding tissues if PDT was used clinically. Similar results were reported also bv others [13. 51. 52]. The application of PDT to hepatocellular carcinoma has been difficult because the pho tosensitizing agent accumulates not only in cancer cells, but also in normal hcpatocytes. and. hence, laser irradiation causes necrosis of both diseased and healthy tissue [53]. How ever, normal healthy liver tissue was shielded from laser phototoxicity using indocyanine green as a protective agent [53]. Another way of making the PDT applicable also to liver could be the intra-arterial administration of the photosensitizer as shown by Nishiwaki et al. [54] in a recent experimental study. Dou glas et al. [55] have studied the effectiveness of PDT in the treatment of experimental liver métastasés. Yamashita et al. [56] have re ported recently the treatment of experimental hepatocellular carcinoma using pheophorbide-a as a photosensitizer and intestitial neo dymium yttrium aluminum garnet laser (Qswitch) irradiation. They concluded that this combination is useful in the treatment of deep-seated tumors [56].
possible with reduced costs of lasers and with the development of new laser types (argon ion laser, gold vapor laser). Moreover, in the fu ture it will be possible to achieve deeper tissue penetration and more exact targeting with the contact laser technique [57], The accumula tion of photosensitizing compounds in the tumor can still be further improved by com bining them with human serum albumin, with tumor-specific monoclonal antibodies or lipo proteins (LDL) or by applying them directly to the tumor [ 12, 21, 58-61 ]. Other possibili ties would be the discovery of new photosen sitizing agents with optimal specificity in tu mor accumulation, absorbance in the far visi ble red or near infrared range and no toxicity for normal tissues or the use of multiple pho tosensitizers and wavelengths in PDT [62], Such improvements would broaden the clini cal applications of PDT to gastroenterology and gastrointestinal tumors and permit treat ment of more advanced malignancies. Absten and Joffe [63] summarizing the current clinical uses of PDT pointed out that this method is still at a research stage but that it has proved useful in the treatment of sev eral types of malignancy. It is considered likely that PDT will be ultimately used as an adjuvant treatment and even as a primary treatment of some tumors.
Acknowledgement This work was supported by the Sigrid Juselius Foundation.
The clinical indications for PDT will prob ably widen as appropriate laser equipment becomes more readily available. This will be
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Future Aspects of PDT
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55 Douglas HO. Nava HR. Weishaupt KR: Intra-abdominal applications of hematoporphyrin photoradiation therapy. Adv Exp Med Biol 1983: 160:15-21. 56 Yamashita Y. Moriyasu F. Tamada T, et al: Evaluation of the efficacy of photodynamic therapy on experi mental hepatocellular carcinoma us ing local injection of photosensitizer. Nippon Gan Chiryo Gakkai Shi 1990;25:770-775. 57 Daikuzono N. Joffe SN: Artificial sapphire probe for contact photo coagulation and tissue vaporization with the Nd:YAG-laser. Med In strum 1985:19:173-178. 58 Oseroff AR. Ohuoha D. Hasan T. et al: Antibody-targeted photolysis: Se lective photodestruction of human T-cell leukemia cells using mono clonal antibody-chlorin e6 conju gates. Proc Natl Acad Sci USA 1986:83:8744-8748. 59 Kirschner RA. Unger M, Imper P: An introduction to dye lasers and photoradiation therapy. Surg Clin North Am 1984:64:939-940. 60 Amano T. Prout GR Jr. Lin CW: Intratumor injection as a more ef fective means of porphyrin adminis tration for photodynamic therapy. J Urol 1988:139:392-395. 61 Cohen S. Margalit R: Binding of porphyrin to human serum albu min. Structure-activity relation ships. Biochem J 1990:270:325330. 62 Nelson JS. Liaw LH. Lahlum RA. et al: Use of multiple photosensitizers and wavelengths during photody namic therapy: A new approach to enhance tumor eradication. J Natl Cancer Inst 1990:82:868-873. 63 Absten GT. Joffe SN: Lasers in Medicine - An introductory' guide. London, Chapman & Hall. 1985.
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Second Department of Surgery. Helsinki University Central Hospital, Helsinki. Finland
Keywords Photodynamic therapy Laser Photosensitizing agent Gastrointestinal tumors Cancer Therapy
Photodynamic Therapy of Gastrointestinal T umors: A Review
Abstract Photodynamic therapy (PDT) is a new modality of cancer treatment. It consists of intravenously injecting a patient with a photosensitizing agent and. when this agent has accumulated in tumor cells, decomposing it by exposure to red light pro duced by an argon dye laser. Toxic compounds produced in this reaction then destroy the malignant cells, while normal tissue is not significantly affected. Most clinical experience with PDT has been gained in the treatment of lung cancer, cancer of the urinary bladder and malignancies of the head and neck region. In gastroenterology, esophageal, gastric and colonic tumors have clinically been treated with PDT. This paper is to review the current use of PDT in the treatment of gastrointestinal tumors.
Introduction Photodynamic therapy (PDT) is a new mo dality of cancer treatment. It is based on the use of photosensitizing agents and laser light which interact producing singlet oxygen. This toxic compound destroys malignant tumors while healthy tissue remains intact.
Research on PDT was started in the early 1960s when Lipson et al. [1] published a paper demonstrating the photodynamic prop erties of a hematoporphyrin derivative (HpD). They suggested that PDT might be of use in the treatment of malignant tumors. Subsequently. Dougherty et al. [2-4] have published several studies on the biochemical
Pauli Puolakkainen. MD. PhD Oncogen 3005 First Avenue Seattle. WA 98121 (USA)
©1992 S. Karger AG. Basel 0257-2753/92/ 0 10 1— 0053S2.75/0
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Pauli Puolakkainen Tom Schroder
Principle and Characteristics of PDT In PDT. a patient is given an intravenous injection of a photosensitizing agent known to accumulate preferentially in tumor cells [2]. Initially, all tissues take up these agents to an equal extent after injection. During an equi librium period of 48-72 h, the compound is cleared from the normal tissue while retained in the malignant cells [2. 5-7], In addition to malignant cells, liver, spleen, kidneys and skin are also known to accumulate the agent [8]. The precise basis of this selective reten tion mechanism remains unclear in spite of intensive research [7], After 48-72 h. the tu mor containing the photosensitizing com pound is exposed to red light produced by an argon dye laser (wavelength 625-635 nm) or gold vapor laser (628 nm) [2, 9], Laser light can be delivered to the tumor, according to its location, either directly or through an endo scope [5]. The light intensity and light dose required depend on the size of the tumor and the depth of its infiltration. The light doses for maximal effect are still empirical: 50300J/cm2 appear sufficient for tumor de struction while lower doses ( 10-50 J/cm2) ap pear adequate for carcinoma in situ and dys plasia [10, 11]. Laser beam delivered to the tumor excites the photosensitizing agent to a higher energy level. This energy is released when the excited sensitizer reacts with oxygen present; the presence of oxygen is required for PDT. The oxygen molecule is then excited to singlet oxygen, which damages the blood ves
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sels in the tumor area and destroys the tumor, while normal tissue is not significantly af fected [3. 12, 13]. At the cellular level, pri mary sites of photodynamic activity are thought to be cellular and mitochondrial membranes, but nucleic acids and proteins are also damaged bv this photooxidation [14. 15]. The photosensitizing agents most com monly used are HpD and dihematoporphyrin ether (DHE or photofrin II). HpD is a hemo globin derivative [16], and DHE is a combi nation of esthers and ethers of purified HpD [17], Intravenous dosages have been 2.5-5 and 1.5-2.5 mg/kg for HpD and DHE, respec tively [4, 7, 18, 19], The advantages of HpD and DHE in clinical use are their suboptimal ability to accumulate in malignant tissue and their low toxicity to healthy tissue [2, 20], Currently. DHE is usually administered in human studies since it is the only Food and Drug Administration-approved photosensi tizing agent in the USA [7], Other photosensi tizing agents developed for PDT include evanins, carotenoids, chlorins and chloro phylls as well as cationic dyes like rhodantines [ 12,
21],
The effectiveness of PDT and the extent of malignant tissue destruction depend on the light absorbed at different depths and on the concentration of photosensitizing compound in the treated tissue [12], Clinically, only the light intensity can be routinely measured. There have been no general treatment recom mendations in PDT, for the doses used arc empirical and based on tests that cannot be applied to all patients in the same form [22]; there might be some improvement however by the development of a new endoluminal light delivery system [23]. The concept of a closed system for this light delivery system has for the first time allowed accurate dosime try to be applied to the entire length of a malignant stricture and ensures that a prede
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and cellular mechanisms of PDT, as well as experimental and clinical series which have partly led to the development of PDT as a modern, alternative method of cancer treat ment. The present paper reviews the method of PDT and its current and potential use in the treatment of gastrointestinal tumors.
mor bed [25]. This intraoperative PDT has been attempted mainly in neurosurgery [12]. PDT can also be utilized as an adjuvant to other standard forms of tumor therapy. Posi tive synergistic effects of PDT and hyperther mia as well as PDT and some cytotoxic drugs have been observed [26-29], Safety considerations of PDT include the necessity for all personnel and patients to use protective glasses with appropriate filters to laser light of 630 nm. Further, the use of com bustible gases in association with the anesthe sia should be avoided.
Clinical Applications of PDT Most clinical experience with PDT has been gained in the treatment of lung cancer, cancer of the urinary bladder and malignan cies in the head and neck region [22, 30]. On the whole, treatment results have been prom ising with regard to palliation [3, 19], Up to 90% of treated tumors have responded to PDT either by disappearing or diminishing in size, which has significantly eased the symp toms [19]. Phase III clinical trials employing photofrin II as photosensitizer are currently being organized in the United States and Can ada. Three different neoplastic conditions have been chosen: obstructive endobronchial and esophageal tumors and papillary tumors of the urinary bladder [21,31].
Treatment of Gastrointestinal Tumors by PDT In gastroenterology, clinical experience with PDT has been gained mainly in the treat ment of esophageal, gastric and colorectal ma lignant tumors. In addition to this, experi mental PDT research has been done on pan creatic, colon and liver tumors.
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termined light energy dose is absorbed by the tumor during PDT [23]. In PDT. the tumor destruction occurs gen erally very rapidly but the final effect of treat ment is usually not estimated until 4 weeks after treatment. The assessment of the amount of tumor destruction in clinical studies is often done by analyzing it as no response, partial response or complete response. The general advantages of PDT in the treatment of carcinomas include selective, fairly effective tumor destruction, the possi bility of repeated treatment if necessary, since no maximum dose exists, and the possibility of using other treatment methods simulta neously with PDT. because there are no harmful interactions [3. 5. 22, 24], Further, PDT can be given as outpatient treatment, and operative treatment of patients at high risk can be avoided. The main disadvantage of the method is photosensitization of the skin. Exposure to bright light should be avoided for 4-8 weeks after the treatment to avoid severe sunburns [5. 6. 24], Other reported side effects and dis advantages of PDT include nausea, vomiting, metallic taste, eye photosensitivity and liver toxicity as well as nonspecificity and rela tively poor effect on deep-seated tumors be cause of the limited depth of laser penetration [7], As laser equipments are expensive, clini cal applications are so far limited [24], Another problem is the lack of international standardization, which complicates compari son of treatment results and makes it difficult to establish optimal treatment methods [5]. On the basis of clinical experiences accu mulated so far. it appears that PDT is most effective in those malignant tumors that are localized and have a depth of less than about 1 cm. In case of bulky tumors. PDT can be successfully used for palliative purposes. PDT can also be applied in combination with sur gery to achieve better sterilization of the tu
The current palliative treatment of esopha geal cancer remains unsatisfactory. Radio therapy and chemotherapy are of limited val ue. and the swallowing ability enhanced by the dilatation or intubation with tube prosthe sis is temporary. Laser vaporization of the tumor has proven useful as a palliation. There have been many attempts to improve the effi cacy of laser treatment by PDT. McCaughan et al. [32] treated 16 patients with esophageal carcinoma; in every patient the tumor dimin ished in size and swallowing improved. In 1989, the same group reported on the effects of PDT in 40 patients with esophageal tumors [33]. At 1 month, the average minimal diame ter opening of 28 accessible tumors increased from 6 to 9 mm. The authors concluded that PDT was effective in achieving the ability to swallow, the most important factor in pallia tion of these patients. Complications in cluded six esophageal strictures, three tra cheoesophageal fistulas and four photosensi tivity reactions [33], Other reported compli cations have included substernal and epigas tric pain and expectoration of necrotic tissue. Similar results of the treatment of esophageal carcinoma have been reported also by other groups [34. 35]. Recently, Thomas et al. [36] reported on the effects of PDT in 15 patients with locally advanced esophageal cancer. In every patient, the tumor responded to thera py, and two complete remissions were achieved. The authors concluded that photo therapy is an effective alternative to other forms of palliation and may replace the use of surgery in selected cases of locally advanced esophageal cancer [36]. Tian et al. [37] treated 13 patients with esophageal carcinoma and concluded that PDT is an effective treatment method for patients refusing surgical treat ment and for those at high operative risk. Early or superficial esophageal cancer is defined as mucosal or submucosal involve
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ment only. In China and Japan, these esopha geal lesions have been treated at an earlier stage because of earlier tumor discovery by routine screening practises [34], Hayata et al. [34] reported four complete remissions in six treated lesions; disease-free follow-up lasted 19-41 months. Tajiri et al. [24] reported the PDT treatment of 6 patients with superficial esophageal cancer and 13 with early gastric cancer with no tumor recurrence during the follow-up period. Kato et al. [39] published recently a study on the PDT treatment of 66 patients with esophageal cancer (22 cases of early cancer). Complete response was achieved in 80% of patients with no recur rences. The long-term follow-up of those pa tients with early esophageal carcinoma having complete response has been encouraging [38]. Gastric Carcinoma
The use of PDT in treating gastric cancer is technically more complicated than that of esophagus owing to gastric folds, peristalsis and the shape of the stomach itself, all of which limit access to the tumor [38], In the study of Song et al. [5] on gastric cancer, only mild cure response was achieved in 10 of 23 patients and 7 did not respond at all. Hu et al. [40] treated 42 patients with various histo logic types of carcinoma of the gastric cardia. Adenocarcinoma and mucinous adenocarci noma responded well to PDT treatment, but all papillary' adenocarcinomas (2 patients) and squamous cell carcinomas (3 patients) were refractory. Further, the treatment was effective in patients with limited and superfi cial tumor infiltrations in the gastric wall but unsatisfactory in those with wider and deeper infiltrations [40], Hayata et al. [34] treated 16 patients with early gastric carcinoma, 4 of them had com plete response to PDT but 3 of these 4 had recurrences 5-27 months after treatment.
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Esophageal Carcinoma
Colorectal Carcinoma With regard to palliation, promising re sults of PDT have been obtained in the treat ment of colonic and rectal carcinomas [5], although the use of PDT for colorectal cancer has been limited, and the series of patients are small [38]. In a study of Herrera-Ornelas [41], 14 patients were treated. In some patients relieve of pain and obstructional symptoms was achieved [41]. Recently. Barr et al. [42] concluded that PDT is an evolving method of laser therapy with the potential for safe endo scopic treatment of colorectal cancers. In ex periments on rats, these workers demon strated the biological advantages of PDT compared with thermal methods of tissue de struction like electrocautery or pure laser treatment. PDT does not destroy colonic col lagen, as the thermal methods do, thus reduc ing markedly the risk of perforation [42. 43], Further, Barr et al. [44] have performed re cently an experimental study on the produc tion of selective necrosis in rat colon tumors by PDT. It was postulated that at low dosages of the photosensitizing agent, selective necro sis of the tumor can occur because the photo sensitizer is photodegraded in the normal co lon before a threshold photodynamic dose is reached, whereas in tumor containing twice as much photosensitizer, a photodynamic threshold can be achieved and necrosis pro duced [44], They have also reported a clinical
study of 10 patients with colorectal cancer treated with endoscopic PDT [45], Two pa tients with small lesions are tumor free 20 and 28 months after PDT. One treatment of ad vanced tumor was complicated by a hemodynamically significant secondary hemorrhage, the risk of which is a known disadvantage of PDT in large tumors [43]. In conclusion, PDT may be suitable for the treatment of small colorectal tumors, small anastomotic recur rences and conditions such as dysplasia and carcinoma in situ in chronic ulcerative colitis [43-45], but it seems likely that neodymium yttrium aluminum garnet laser treatment will remain the laser option of choice for ad vanced bulky tumors [46], However, further studies are mandatory in order to judge the precise role of PDT in clinical practice [43], Miscellaneous Gastrointestinal Tumors
Patrice et al. [47] used PDT to treat 27 nonoperable patients with various gastroin testinal tract tumors less than 40 mm in diam eter. Normalization of biopsy specimens were observed in 12 patients (6 squamous cell car cinomas and 6 adenocarcinomas). PDT was able to destroy significant volumes of the tumor, although subsequent biopsy speci mens proved negative in very few cases. Ac cordingly, the same group reported recently the treatment of 54 patients with nonoperable gastrointestinal neoplasms by PDT [48], Dur ing follow-up (average: 14.5 months), com plete local tumor destruction and negative histology were observed in 24 cases. The mean recurrence-free period varied from 13.8 to 17.4 months. Fifteen patients have re mained alive and disease free [48], In a study of 52 patients. 77% of the tumors of the upper gastrointestinal tract responded favorably to PDT treatment [49], As Patrice et al. [48] and Zera [38] summarized, PDT can be of great value in palliation in esophageal and colorec tal cancer, as a primary therapy in superficial
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Kato et al. [39] have reported recently the treatment of 133 cases of gastric cancer (in cluding 120 cases of early stage cancer). Com plete response was achieved in 100% of pa tients with a recurrence rate of 22.2% [39]. On the whole, the role of PDT in the treat ment, and even for palliation, of advanced gastric cancer seems to be limited [38], but it might be of value in cases of early or superfi cial gastric carcinoma when surgical treat ment is excluded.
tumors of the esophagus and stomach and perhaps as an adjuvant therapy in rectal can cer. Schröder et al. [50] have performed an experimental study of PDT in the treatment of pancreatic tumors. They found that suffi cient amounts of HpD accumulated in the tumors to achieve extensive necrosis in them without any visible effect on the healthy pan creatic tissue, but they warned against the potentially harmful effects on the surrounding tissues if PDT was used clinically. Similar results were reported also bv others [13. 51. 52]. The application of PDT to hepatocellular carcinoma has been difficult because the pho tosensitizing agent accumulates not only in cancer cells, but also in normal hcpatocytes. and. hence, laser irradiation causes necrosis of both diseased and healthy tissue [53]. How ever, normal healthy liver tissue was shielded from laser phototoxicity using indocyanine green as a protective agent [53]. Another way of making the PDT applicable also to liver could be the intra-arterial administration of the photosensitizer as shown by Nishiwaki et al. [54] in a recent experimental study. Dou glas et al. [55] have studied the effectiveness of PDT in the treatment of experimental liver métastasés. Yamashita et al. [56] have re ported recently the treatment of experimental hepatocellular carcinoma using pheophorbide-a as a photosensitizer and intestitial neo dymium yttrium aluminum garnet laser (Qswitch) irradiation. They concluded that this combination is useful in the treatment of deep-seated tumors [56].
possible with reduced costs of lasers and with the development of new laser types (argon ion laser, gold vapor laser). Moreover, in the fu ture it will be possible to achieve deeper tissue penetration and more exact targeting with the contact laser technique [57], The accumula tion of photosensitizing compounds in the tumor can still be further improved by com bining them with human serum albumin, with tumor-specific monoclonal antibodies or lipo proteins (LDL) or by applying them directly to the tumor [ 12, 21, 58-61 ]. Other possibili ties would be the discovery of new photosen sitizing agents with optimal specificity in tu mor accumulation, absorbance in the far visi ble red or near infrared range and no toxicity for normal tissues or the use of multiple pho tosensitizers and wavelengths in PDT [62], Such improvements would broaden the clini cal applications of PDT to gastroenterology and gastrointestinal tumors and permit treat ment of more advanced malignancies. Absten and Joffe [63] summarizing the current clinical uses of PDT pointed out that this method is still at a research stage but that it has proved useful in the treatment of sev eral types of malignancy. It is considered likely that PDT will be ultimately used as an adjuvant treatment and even as a primary treatment of some tumors.
Acknowledgement This work was supported by the Sigrid Juselius Foundation.
The clinical indications for PDT will prob ably widen as appropriate laser equipment becomes more readily available. This will be
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Future Aspects of PDT
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