Stephen G. Bown

Photosensitisation and photodynamic therapy of oesophageal, duodenal, and colorectal tumours using 5 aminolaevulinic acid induced protoporphyrin IX--a pilot study.

The first study of photodynamic therapy in the human gastrointestinal tract using 5 aminolaevulinic acid (ALA) induced protoporphyrin IX as the photosensitising agent is described. Eighteen patients with colorectal, duodenal, and oesophageal tumours were studied. After 30-60 mg/kg of ALA given orally, biopsy specimens of tumour and adjacent normal mucosa were taken 1-72 hours later. These specimens were examined by quantitative fluorescence microscopy for assessment of sensitisation with protoporphyrin IX. Ten patients were given a second dose of ALA a few weeks later and their tumours were treated with red laser light (628 nm). With 30 mg/kg ALA, the highest fluorescence values were detected in the duodenum and oesophagus, and the lowest in the large bowel. Doubling the ALA dose in patients with colorectal tumours gave protoporphyrin IX fluorescence intensities similar to those in patients with upper gastrointestinal lesions and improved the tumour:normal mucosa protoporphyrin IX sensitisation ratio. The treated patients showed superficial mucosal necrosis in the areas exposed to laser light. Six patients had transient rises in serum aspartate aminotransferases, two mild skin photosensitivity reactions, and five mild nausea and vomiting. In conclusion, photodynamic therapy with systemically administered ALA may be a promising technique for the treatment of small tumours and areas of dysplasia such as in Barretts oesophagus.

Photodynamic therapy for cancer of the pancreas.

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.

Photodynamic Therapy for Prostate Cancer Recurrence After Radiotherapy: A Phase I Study

PURPOSE Photodynamic therapy, using a photosensitizing drug activated by red light, can destroy localized areas of cancer with safe healing and without the cumulative toxicity associated with ionizing radiation. We used photodynamic therapy in a phase I-II study to treat patients with locally recurrent prostate cancer after radiotherapy. MATERIALS AND METHODS Patients with an increasing prostate specific antigen (PSA) and biopsy proven local recurrence after radiotherapy were offered photodynamic therapy. Three days after intravenous administration of the photosensitizer meso-tetrahydroxyphenyl chlorin, light was applied using optical fibers inserted percutaneously through perineal needles positioned in the prostate with imaging guidance. Patients were followed with PSA measurements, prostate biopsies, computerized tomography or magnetic resonance imaging and questionnaires on urinary and sexual function. RESULTS Photodynamic therapy was given to 14 men using high light doses in 13. Treatment was well tolerated. PSA decreased in 9 patients (to undetectable levels in 2) and 5 had no viable tumor on posttreatment biopsies. After photodynamic therapy, contrast enhanced computerized tomography or magnetic resonance imaging showed necrosis involving up to 91% of the prostate cross section. In 4 men stress incontinence developed (troublesome in 2 and mild in 2) which is slowly improving. Sexual potency was impaired in 4 of the 7 men able to have intercourse before photodynamic therapy, which did not improve. There were no rectal complications directly related to photodynamic therapy, but in 1 patient a urethrorectal fistula developed following an ill-advised rectal biopsy 1 month after therapy. CONCLUSIONS Photodynamic therapy is a new option that could be suitable for organ confined prostate cancer recurrence after radiotherapy. With more precise light dosimetry, it may be possible to destroy essentially all glandular tissue within the prostate with few complications. These results suggest that photodynamic therapy merits further investigation.

Photodynamic therapy using 5-aminolevulinic acid for premalignant and malignant lesions of the oral cavity.

Premalignant changes in the mouth, which are often widespread, are frequently excised or vaporized, whereas cancers are treated by excision or radiotherapy, both of which have cumulative morbidity. Photodynamic therapy (PDT) is another option that produces local tissue necrosis with light after prior administration of a photosensitizing agent. This heals with remarkably little scarring and no cumulative toxicity. This article describes the use of PDT with the photosensitizing agent 5‐aminolevulinic acid (ALA) for premalignant and malignant lesions of the mouth.

Interstitial photodynamic therapy as salvage treatment for recurrent head and neck cancer.

Interstitial photodynamic therapy (IPDT) is a technique for applying photodynamic therapy (PDT) to internal tumours using light delivered via fibres inserted percutaneously. This phase I–II study assessed the safety and efficacy of IPDT for patients with persistent or recurrent head and neck cancer unsuitable for further treatment with surgery, radiotherapy or chemotherapy, recruited for ‘last hope’ salvage treatment. Patients were sensitised with 0.15 mg kg−1 mTHPC (meso-tetrahydroxyphenyl chlorin) 4 days prior to light delivery from fibres inserted directly into the target tumour (20 J per site at 652 nm) under image guidance. In all, 45 patients were treated. Nine achieved a complete response. Five are alive and free of disease 10–60 months later. Symptomatic relief (mainly for bleeding, pain or tumour debulking) was achieved in a further 24. The median survival (Kaplan–Meier) was 16 months for the 33 responders, but only 2 months for the 12 nonresponders. The only serious complication was a carotid blow out 2 weeks after PDT. No loss of function was detected in nerves encased by treated tumours. Interstitial photodynamic therapy provides worthwhile palliation with few complications and occasional long-term survivors for otherwise untreatable advanced head and neck cancers. It is a treatment option worth adding to those available to integrated head and neck oncology teams.

Endogenous porphyrin distribution induced by 5-aminolaevulinic acid in the tissue layers of the gastrointestinal tract

The accumulation of endogenous porphyrins in rats following systemic administration of 5-aminolaevulinic acid (ALA) has been examined to assess the photosensitization characteristics of this technique for photodynamic therapy (PDT) and chemical extraction assays with fluorescence and absorbance detection of the porphyrin content have been carried out. We compared the results obtained using quantitative microfluorimetry on normal gastric and colonic tissues in rats at 0.5, 1, 2, 4 and 6 h and chemically induced duodenal tumours 2 and 4.5 h after intravenous administration of ALA at a dose of 200 mg kg-1. With chemical extraction followed by high performance liquid chromatography analysis, protoporphyrin IX (PpIX) was found to be the predominant porphyrin present, reaching peak levels of several microgrammes per gramme at 2-4 h in each type of tissue; a small amount of coproporphyrin was detected at 0.5 and 2 h in normal gastric mucosa and duodenal tumour respectively. Both the extraction assay and quantitative microfluorimetry showed that the porphyrin fluorescence builds up rapidly in the mucosal layers of the colon and stomach, reaching a maximum at 2 h, whereas lower fluorescence levels were found with a slower rate of accumulation in the corresponding muscularis layers. A significant PpIX content was found in the duodenal tumour, with a maximum of 7.1 micrograms g-1 4.5 h after ALA administration. We conclude that systemic administration of ALA can induce effective tissue sensitization with protoporphyrin IX and appears to be a promising technique for PDT.

Spectroscopic sensing of cancer and cancer therapy - Current status of translational research

Various types of optical spectroscopy have been investigated as methods to effect a noninvasive, real-time in-situ assessment of tissue pathology. All of these methods have one basic principle in common: the optical spectrum of a tissue contains information about the biochemical composition and/or the structure of the tissue, and that information conveys diagnostic information. The biochemical information can be obtained by measuring absorption, fluorescence, or Raman scattering signals. Structural and morphological information may be obtained by techniques that assess the elastic-scattering properties of tissue. These basic approaches are useful for the detection of cancer as well as for other diagnostic applications such as hemoglobin saturation, intra-luminal detection of atherosclerosis, and simply the identification of different tissue types during procedures. Optical spectroscopic measurements can also be employed in the management of disease treatment. The site-specific pharmacokinetics of chemotherapy and photodynamic therapy agents can be used to customize dosage to the patient, and diagnostic spectroscopy can be used to monitor response to treatment. In recent years clinical studies have provided indications of potential efficacy, and some of these modalities are now entering a translational research stage, with an eye to approval and commercialization. A benefit of these methods is their inherent low cost and ease of implementation, generally mediated with small portable instruments, not requiring any specialized facilities, and eventually not requiring expert interpretation. This paper reviews briefly the most common methods of diagnostic optical spectroscopy, and reviews in greater depth recent clinical translational research invoking scattering spectroscopy as the enabling technology, which has been the experience of the authors.

Local treatment of colorectal liver metastases: A comparison of Interstitial Laser Photocoagulation (ILP) and Percutaneous Alcohol Injection (PAI)

The purpose of this study was to evaluate the relative merits of two physical methods of locally destroying colorectal liver metastases-interstitial laser photocoagulation (ILP) which causes thermal necrosis, and percutaneous alcohol injection (PAI) which causes cellular dehydration and coagulative necrosis. Seventy-six liver metastases in 22 patients were treated by ILP or PAI. Both techniques were performed using local anaesthesia and intravenous sedation/analgesia. Ultrasound was used to localize the tumours and guide the needles percutaneously. ILP: Up to eight 19 G needles were inserted into the tumour, and down each needle was passed a thin optical fibre; the tumour was heated using low power laser light (2 W) for 500 s from a Nd:YAG or diode laser. PAI: 0.5-1 ml of sterile 95% absolute alcohol was injected into multiple sites of the tumour using a single 19-22 G needle. Dynamic CT scan was used to evaluate the extent of treatment-induced necrosis. Ultrasound showed echogenic changes around the needles/fibre-tips during ILP and PAI; this gave a reasonable guide to the extent of thermal damage for smaller tumours during ILP, but not during PAI. ILP: 54 tumours were treated (median size 2.7 cm). Laser-induced necrosis was clearly seen 24 h after treatment as a well-defined area of non-enhancement on the dynamic CT scan; greater than 50% necrosis of tumour volume was achieved in 87% of tumours (complete necrosis was found in 52% of tumours). PAI: 22 tumours were treated (median size 1.5 cm). Dynamic CT showed patchy areas of non-enhancement in five tumours, decreased density in seven tumours, and no change in 10 tumours; complete tumour necrosis was never achieved. There were no major complications after ILP or PAI, but pain during treatment was more common and more severe with PAI. ILP is a simple, safe and effective treatment for colorectal liver metastases; PAI is relatively ineffective for these tumours (although it has been shown to be much more effective for small hepatocellular carcinomas).

Elastic scattering spectroscopy accurately detects high grade dysplasia and cancer in Barrett's oesophagus

Background and aims: Endoscopic surveillance of Barrett’s oesophagus currently relies on multiple random biopsies. This approach is time consuming, has a poor diagnostic yield, and significant interobserver variability. Elastic scattering spectroscopy is a real time in vivo optical technique which detects changes in the physical properties of cells. The aim of this study was to assess the potential for elastic scattering to detect high grade dysplasia or cancer within Barrett’s oesophagus. Methods: Elastic scattering spectroscopy measurements collected in vivo were matched with histological specimens taken from identical sites within Barrett’s oesophagus. All biopsies were reviewed by three gastrointestinal pathologists and defined as either “low risk” (non-dysplastic or low grade dysplasia) or “high risk” (high grade dysplasia or cancer). Two different statistical approaches (leave one out and block validation) were used to validate the model. Results: A total of 181 matched biopsy sites from 81 patients, where histopathological consensus was reached, were analysed. There was good pathologist agreement in differentiating high grade dysplasia and cancer from other pathology (kappa = 0.72). Elastic scattering spectroscopy detected high risk sites with 92% sensitivity and 60% specificity and differentiated high risk sites from inflammation with a sensitivity and specificity of 79%. If used to target biopsies during endoscopy, the number of low risk biopsies taken would decrease by 60% with minimal loss of accuracy. A negative spectroscopy result would exclude high grade dysplasia or cancer with an accuracy of >99.5%. Conclusions: These preliminary results show that elastic scattering spectroscopy has the potential to target conventional biopsies in Barrett’s surveillance saving significant endoscopist and pathologist time with consequent financial savings. This technique now requires validation in prospective studies.

Photodynamic therapy using mTHPC for malignant disease in the oral cavity

Photodynamic therapy (PDT) produces local tumor necrosis, on activation of a previously administered sensitizer with non‐thermal light of an appropriate wavelength. It is attractive for treating tumors of the mouth as tissue healing is particularly good. We describe the use of the photosensitizing agent meta tetrahydroxyphenyl chlorin (mTHPC, Foscan®) for PDT of oral cancer, including patients with field cancerization. Nineteen patients with histologically confirmed oral cancer (8 with field change disease) and one with severe dysplasia, were sensitised with mTHPC intravenously. Activation was carried out 72–96 hr later with laser light at 652 nm using a range of light doses. The results were assessed clinically and histologically. Multiple biopsies were taken during the ulcerative stages to look at the effects of PDT and after healing to assess the overall treatment result. All single lesions up to stage T3 cleared after one PDT treatment (total of 6 patients). Three out of 6 T4 tumours were also cleared. Lesions in patients with field change disease did less well, only 9 of 14 T1 and T2s clearing, including 4 that required extra treatments with a higher light dose. Most healed very well, but tongue tethering was seen in 1 patient and another had necrosis in normal areas due to light scattering within the mouth. PDT using mTHPC is a promising new treatment for patients with oral cancer. Int. J. Cancer 73:25–32, 1997.