The therapeutic properties of light have been known for thousands of years, but it was only in the last century that photodynamic therapy (PDT) was developed. At present, PDT is being tested in the clinic for use in oncology--to treat cancers of the head and neck, brain, lung, pancreas, intraperitoneal cavity, breast, prostate and skin. How does PDT work, and how can it be used to treat cancer and other diseases?

Photodynamic therapy for cancer

Keywords: Photomedicine group Reference LPAS-ARTICLE-1998-003View record in Web of Science Record created on 2007-07-20, modified on 2016-08-08

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1751-1097.1998.tb02521.x

In Vivo Fluorescence Spectroscopy and Imaging for Oncological Applications

BACKGROUND
Photodynamic therapy (PDT) for cancer patients has developed into an important new clinical treatment modality in the past 25 years PDT involves administration of a tumor-localizing photosensitizer or photosensitizer prodrug (5-aminolevulinic acid [ALA], a precursor in the heme biosynthetic pathway) and the subsequent activation of the photosensitizer by light Although several photosensitizers other than ALA-derived protoporphyrin IX (PpIX) have been used in clinical PDT, ALA-based PDT has been the most active area of clinical PDT research during the past 5 years Studies have shown that a higher accumulation of ALA-derived PpIX in rapidly proliferating cells may provide a biologic rationale for clinical use of ALA-based PDT and diagnosis However, no review updating the clinical data has appeared so far

METHODS
A review of recently published data on clinical ALA-based PDT and diagnosis was conducted

RESULTS
Several individual studies in which patients with primary nonmelanoma cutaneous tumors received topical ALA-based PDT have reported promising results, including outstanding cosmetic results However, the modality with present protocols does not, in general, appear to be superior to conventional therapies with respect to initial complete response rates and long term recurrence rates, particularly in the treatment of nodular skin tumors Topical ALA-PDT does have the following advantages over conventional treatments: it is noninvasive; it produces excellent cosmetic results; it is well tolerated by patients; it can be used to treat multiple superficial lesions in short treatment sessions; it can be applied to patients who refuse surgery or have pacemakers and bleeding tendency; it can be used to treat lesions in specific locations, such as the oral mucosa or the genital area; it can be used as a palliative treatment; and it can be applied repeatedly without cumulative toxicity Topical ALA-PDT also has potential as a treatment for nonneoplastic skin diseases Systemic administration of ALA does not seem to be severely toxic, but the advantage of using this approach for PDT of superficial lesions of internal hollow organs is still uncertain The ALA-derived porphyrin fluorescence technique would be useful in the diagnosis of superficial lesions of internal hollow organs

CONCLUSIONS
Promising results of ALA-based clinical PDT and diagnosis have been obtained The modality has advantages over conventional treatments However, some improvements need to be made, such as optimization of parameters of ALA-based PDT and diagnosis; increased tumor selectivity of ALA-derived PpIX; better understanding of light distribution in tissue; improvement of light dosimetry procedure; and development of simpler, cheaper, and more efficient light delivery systems Cancer 1997; 79:2282-308 © 1997 American Cancer Society

5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges.

http://bmlaser.physics.ecu.edu/literature/2004%2005_Photosensitizers%20in%20clinical%20PDT.pdf?origin=publication_detail

Photosensitizers in clinical PDT.

Background: Few pancreatic cancers are suitable for surgery and few respond to chemoradiation. Photodynamic therapy produces local necrosis of tissue with light after prior administration of a photosensitising agent, and in experimental studies can be tolerated by the pancreas and surrounding normal tissue.

Aims: To undertake a phase I study of photodynamic therapy for cancer of the pancreas.

Patients: Sixteen patients with inoperable adenocarcinomas (2.5–6 cm in diameter) localised to the region of the head of the pancreas were studied. All presented with obstructive jaundice which was relieved by biliary stenting prior to further treatment.

Methods: Patients were photosensitised with 0.15 mg/kg meso-tetrahydroxyphenyl chlorin intravenously. Three days later, light was delivered to the cancer percutaneously using fibres positioned under computerised tomographic guidance. Three had subsequent chemotherapy.

Results: All patients had substantial tumour necrosis on scans after treatment. Fourteen of 16 left hospital within 10 days. Eleven had a Karnofsky performance status of 100 prior to treatment. In 10 it returned to 100 at one month. Two patients with tumour involving the gastroduodenal artery had significant gastrointestinal bleeds (controlled without surgery). Three patients developed duodenal obstruction during follow up that may have been related to treatment. There was no treatment related mortality. The median survival time after photodynamic therapy was 9.5 months (range 4–30). Seven of 16 patients (44%) were alive one year after photodynamic therapy.

Conclusions: Photodynamic therapy can produce necrosis in pancreatic cancers with an acceptable morbidity although care is required for tumours invading the duodenal wall or involving the gastroduodenal artery. Further studies are indicated to assess its influence on the course of the disease, alone or in combination with chemoradiation.

https://gut.bmj.com/content/gutjnl/50/4/549.full.pdf

Photodynamic therapy for cancer of the pancreas

Photodynamic therapy (PDT) produces localized necrosis with light after prior administration of a photosensitizing drug. As PDT lesions in the gastrointestinal tract heal well, the technique is suitable for repeated endoscopic use. In this study we used PDT to treat benign and malignant gastrointestinal tumors in esophagus, duodenum and rectum in 22 patients, who refused or were not suitable for surgery. Patients were sensitized with 0.15 mg/kg of body weight with mesotetrahydroxyphenylchlorin i.v. m-THPc (2 patients), with 2.0 mg/kg Photofrin i.v. (4 patients) or 60 mg/kg 5-aminolevulinic acid orally ALA (which is converted in vivo to active derivate protoporphyrin IX-PRIX) in fractionated doses (16 patients). Laser treatment was performed 2 days after Photofrin, 2 and 4 days after mTHPc and 4 hours after ALA, using a metal vapour laser (628 nm, 50-150 J/cm2 for ALA and Photofrin, 650 nm and 10-15 J/cm2 for mTHPc). Using ALA, the necrosis was only superficial (up to 1.8 mm depth). Four patients treated with Photofrin showed deeper necrosis, in one case of 8 mm colon cancer complete response, in three cases 1-1.5 cm adenomatous polyps involving the ampulla Vateri 50% longer term reduction in size-seen endoscopically. Two patients with rectal villous adenomas treated with mTHPc showed 60-80% reduction in size (observed endoscopically) within few days after PDT, with better effects for treatment carried out 4 rather than 2 days after the sensitization. In all patients the healing was without any complications. Photofrin and mTHPc work better, but cause cutaneous photosensitivity lasting 12 and 5 weeks, respectively. Better results with ALA are possible when using higher drug doses or modified light dosimetry. PDT is a promising treatment for small localized tumors in patients unsuitable for surgery, but further work is required to optimize the treatment conditions.

Photodynamic therapy for gastrointestinal tumors using three photosensitizers--ALA induced PPIX, Photofrin and MTHPC. A pilot study

5-Aminolaevulinic acid (ALA) is a promising agent for photodynamic therapy (PDT) sensitization as it can be given orally and only causes skin photosensitivity for 1-2 days. In fluorescence and photodynamic studies 26 patients with benign and malignant gastrointestinal tumors were given 30-60 mg ALA orally (single or divided doses) and biopsies were taken of tumor and normal tissue at 1-24 hours for fluorescence microscopy. With 30 mg/kg, highest protoporphyrin IX (PPIX) levels were seen in esophagus, duodenum and less in colon, but without tumor selectivity. Better tumor selectivity was seen in colon after 60 mg/kg (5 :1). Six patients had transient rises in transaminases and five mild nausea. Sixteen patients were later treated (after further ALA) with red light (628 nm, bare or diffuser fibre, 50-100 J at 50 mW at each site). All but two showed subsequent necrosis, but only 0.5-1.5 mm of depth. PDT with ALA is simple, safe and promising for tumors in the gastrointestinal tract. Modification of treatment parameters may make it suitable for larger lesions.

Sensitization and photodynamic therapy (PDT) of gastrointestinal tumors with 5-aminolaevulinic acid (ALA) induced protoporphyrin IX (PPIX). A pilot study.

Photodynamic therapy (PDT) has the potential to destroy small tumours with safe healing of adjacent normal tissue. This study looks at the effects of PDT on the normal pancreas and adjacent tissues in hamsters using the photosensitiser meso-tetrahydroxyphenylchlorin (mTHPC). Pharmacokinetic studies used fluorescence microscopy on sections of pancreas, stomach and duodenum 1 h to 6 days after mTHPC. Highest levels of sensitiser were seen in the gastric and duodenal mucosa and in the acinar pancreas after 2-4 days. For PDT, light at 652 nm was delivered by placing a 0.2 mm diameter bare-ended fibre against the tissue. An energy of 50 J was used 2 or 4 days after 0.1 or 0.3 mg kg-1 mTHPC and animals killed 1 to 7 days later. Maximum necrosis was seen 3 days after PDT with lesions up to 4 mm in pancreas, 4.5 mm in duodenum and 2.5 mm in stomach. By fractionating the light dose, the lesion size could be increased by 30%. The main complication was free or sealed duodenal perforation (avoided by shielding the duodenum). Partial, reversible bile duct obstruction was seen occasionally. There was no macroscopic damage to the bile ducts or major blood vessels. Apart from the duodenum, all lesions healed safely. In this animal model, only the duodenum was at risk of serious, irreversible damage. Treatment is likely to be safer in the much thicker human duodenum. mTHPC is a powerful photosensitiser and suitable for further study for tumours in the region of the pancreas although care is required near the duodenum.

Distribution and photodynamic effects of meso-tetrahydroxyphenylchlorin (mTHPC) in the pancreas and adjacent tissues in the Syrian golden hamster

Five aminolaevulinic acid (ALA) is a promising agent for PDT sensitization as it can be given orally and only causes skin photosensitivity for 1 - 2 days. In fluorescence and photodynamic studies 26 patients with benign and malignant gastrointestinal tumors (M 17, F 9; mean age 79) were given 30 - 60 mg ALA orally (single or divided doses) and biopsies taken of tumor and normal tissue at 1 - 24 hours for fluorescence microscopy. With 30 mg/kg, highest protoporphyrin IX (PPIX) levels were seen in oesophagus, duodenum and less in colon, but without tumor selectivity. Better tumor selectivity was seen in the colon after 60 mg/kg (5:1). Six patients had transient rises in transaminases and five mild nausea. Sixteen patients were later treated (after further ALA) with red light (628 nm, bare fiber or diffuser, 50 - 100 J at 50 mW at each site). All but two showed subsequent necrosis, but only 0.5 - 1.5 mm depth. PDT with ALA is simple, safe, and promising for tumors in the GI tract. Modification of treatment parameters may make it suitable for larger lesions.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Sensitization and photodynamic therapy of esophageal,duodenal, and colonic tumors with 5-aminolaevulinic acid (ALA) induced protoporphyrin IX (PPIX)

Experimental study has been carried out using metatetrahydroxyphenylchlorin (m-THPC) in female Syrian golden hamsters. For quantitative fluorescence study, using a CCD camera, the dose of 1.0 mg/kg bodyweight of mTHPC was given intracaval and animals were sacrificed 1 and 4 hours and 1, 2, 3, 4, 5, 6 days afterwards and specimens from the pancreas, stomach, duodenum, gallbladder, aorta and vena cava were examined. A sensitizing dose of 0.3 mg/kg and 0.1 mg/kg respectively was given for PDT, which followed after 2 and 4 days and animals were sacrificed after 1, 2, 3, 4 and 7 days. The treated areas included the pancreas, antral part of the stomach, duodenum and wedge of lesser omentum. In the treated pancreas necrosis up to 3 - 4 mm, marked ulceration in treated duodenum up to 3 - 4.5 mm and in the stomach up to 2 - 2.5 mm in diameter were observed. No macroscopic and histological signs of necrosis were seen in bile duct and major blood vessels. Sealed duodenal perforation occurred in all treated animals with 0.3 mg/kg sensitizing dose and was not observed in 0.1 mg/kg dose with protected duodenum during PDT. Using breaks during PDT (3 X 1; 3 X 3 minutes, respectively) approximately 30% increase of pancreatic necrosis has been observed. In this model, only the duodenum is at risk of irreversible damage. The risk to normal organs in this region is similar to that of photofrin and sulphonated aluminum phtalocyanine. mTHPC is a promising photosensitizer for tumors in the region of the pancreas, although care is required in the region of the duodenum.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Distribution and photodynamic effect of meta-tetrahydroxyphenylchlorin (mTHPC) in the pancreas and adjacent tissues in Syrian golden hamsters

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