Photodynamic therapy for the treatment of advanced gastrointestinal tumours

In the study, 120 patients with advanced gastrointestinal tumours were treated by PDT; 5 mg/kg of HpD was intravenously given 48–72 h prior to PDT. The light source was an argon dye laser with an output beam of 630 nm. The irradiation time varied from 15–25 min with a power of 100–350 mW cm^–2. The entire tumour was irradiated with a light dose of 100–250 J cm^–2. Of the 120 patients, 20 had cancer of esophagus, 72 had cancer of the gastric cardia, 18 had cancer of the stomach and 10 had cancer of the rectum. Eighty-eight patients (73.3%) had a response to PDT. Twelve patients with CR were followed up for one to five years, two patients died during the two years after PDT.     

Fluorescence detection and photodynamic treatment of photosensitized tumours in special consideration of urology

Most methods of modern laser tumour therapy are physically based on the conversion of light to heat. Recently tumours have also been treated using ionizing processes for tissue ablation. Photodynamic laser therapy (PDT), however, involves light-induced non-thermal biochemical processes and the use of a photosensitizer.Several drugs are known to be stored selectively in tumours after systemic application. This transient marking can be used for diagnostic and therapeutic procedures. The marker most commonly used is dihaematoporphyrin ether/ester (DHE) intravenously injected at doses of 0.2–3.0 mg/kg bodyweight for diagnosis and therapy, respectively. The corresponding clearance intervals after injection of DHE range from 3–48 h to 25–75 h.Detection of photosensitized tumours might offer great advantages. The highly sensitive two-wavelength laser excitation method with computerized fluorescence imaging recently has been transferred to the hospital for clinical tests.Photoinduced production of singlet oxygen is claimed to be the initial process which leads to later tumour destruction and therapy. PDT has been applied to 20 patients suffering from superficial tumours (TIS GII–III) recurred after application of other treatments. The results after PDT were evaluated by three-monthly check-ups (endoscopy, cytology, bladder mapping, renal ultrasonography) as well as by computed tomography (CT) examination at 8–13 month intervals. In six patients treated by PDT no tumour recurrence has been found over the whole observation period of up to 5 years. Four patients have remained free of tumour (12 and 14 months) after repeated transurethral resection (TUR) and Nd-YAG laser therapy following PDT. Due to an initial application of insufficient irradiation four patients required a second PDT. In one patient a circumscribed dysplasia appeared at the left ostium 26 months following PDT and was treated successfully by means of thermal Nd-YAG laser irradiation following TUR. In six patients slight mucosal atypia persisted for a period of at least 2.5 years. One cystectomy had to be performed because of bladder shrinkage. The dissected bladder, however, was free of tumour.These preliminary results suggest that PDT is justified in patients who are in a worst-case situation with cystectomy recommended in case of recurrent superficial TIS bladder carcinoma and indicate the future potential of photodynamic therapy of tumours.Homogeneous irradiation of the area to be treated and a reliable light dosimetry are prerequisites for an effective tumour therapy. Standard instruments for a routine application do not exist, but are under development.     

Interstitial photodynamic therapy in the Dunning R3327-AT6 prostatic carcinoma

Interstitial photodynamic therapy (PDT) could be an alternative radical treatment for prostate cancer. The ability to predict the depth of necrosis is necessary for light treatment planning using multiple optical fibres. The extent of PDT necrosis was studied in subcutaneously implanted R3327-AT6 Dunning prostate tumours which had similar optical characteristics to human prostate. Tumour-bearing subjects were given 20 mg kg^–1 Haematoporphyrin esters (HPE) and irradiated 24 h later with 630 nm laser light. Five subjects per group were treated with increasing light doses (50–450 J cm^–1) delivered interstitially via a single 2 cm long cylindrical diffuser. After 450 J cm^–1 of irradiation, 4.3±0.8 cm³ [standard error of the mean (s.e.m.)] of tumour tissue was necrosed to a depth of 10.5±0.8 mm around the diffuser. There was an approximately linear correlation between the volume of PDT necrosis around the fibre and prescribed light dose. The mean threshold light dose for PDT effect was 18±2 J cm^–2. In this tumour with a mean photosensitizer concentration of 16±1.5g g^–1, low light doses produced tumour necrosis. PDT using multiple diffusers could destroy a relatively large tumour volume and the diffusion theory model reliably predicted the depth of necrosis.     

Catheter associated problems of multi-fibre systems in clinical excimer laser angioplasty

We report our experience in 60 patients using a recently designed 4 French ring catheter system for coronary and a 7 French ring catheter for peripheral percutaneous excimer laser angioplasty. The advantages in comparison to bare fibres comprise an improved flexibility and a central channel for insertion of guide wires to minimize the risk of mechanical vessel wall perforation. The peripheral laser catheter initially transmitted overall energies of 20 mJ pulse^–1 (51 mJ pulse^–1 mm^–2), the coronary device 4.5–5 mJ pulse^–1 (32 mJ pulse^–1 mm^–2). A 50% or more decrease of energy transmission was found in 43% of coronary catheters due to a number of blinded fibres with other fibres remaining intact. This was either due to a retrograde expansion of shock waves generated by the excimer pulse at a calcified lesion, or the result of a deleterious back-reflection of the laser light by contrast media. However, using both laser catheters ablation of plaque in vivo proved to be possible. Small mechanical defects of the catheter tips in 27% did not result in patient related complications. Our initial experience favours further improvement of ring catheters for percutaneous excimer laser angioplasty.     

Development of an alternative light source to lasers for photodynamic therapy: 2. Comparative in vivo tumour response characteristics

The performance of a low cost, table-top/portable light source was tested against an argon ion pumped dye laser for in vivo photodynamic therapy (PDT). The prototype delivers up to 1 W via a 4 mm flexible lightguide within a 30 nm bandwidth centred at any wavelength from 300 nm to 1200 nm at fluence rates of up to 8 W cm^–2. An in situ bioassay using regrowth delay of tumour T50/80 was used to quantify the relative efficacy of the prototype with a laser. The tumours were sensitized with haematoporphyrin derivative (HpD) and externally irradiated. There was no significant difference in the response of the tumour to treatment between the two light sources (p = 0.69). Mean growth delays ranged from 2 days (light dose 10 J cm^–2) to 20 days (light dose 100 J cm^–2). The estimate for the difference in means (laser minus prototype growth delay) was only 0.66 days and was not statistically significant. This in vivo study demonstrates that the prototype is equivalent to a laser in PDT effect. The device has low capital/running cost, is simple to use and is one of the most powerful, spectrally efficient non-laser PDT sources available.     

Light and drug distribution with topically administered photosensitizers

Photodynamic therapy (PDT) based on topical application of photosensitizers is currently in clinical use for the treatment of basal cell carcinoma of the skin, and it has been evaluated in animal models for photo-ablation of the endometrium. This paper presents a dosimetry model which indicates that a limiting factor in treating thick tumours will be the transport of the drug into the tumour rather than depletion of the optical distribution. The model predicts that an optical irradiation of 100 mW cm^–2 at 635 nm for 20 min, ie well below the threshold for hyperthermic reaction, will give an adequate light dose to a depth of 3 mm. The time required for photosensitizers to diffuse to this depth is in the range of 3–15 h, dependent on the diffusion properties of the tissue.     

Laser-induced shock wave lithotripsy

Summary With a high intensity Q-switched Nd-YAG laser shock waves can be generated in a liquid close to the calculus. Up to 80 mJ single pulse energy with 8 nsec pulse duration can be transmitted through flexible quartz fibers. Energy conversion and enhancement can be accomplished at the fiber tip with optical focussing of the light at the quartz tip, with irrigation solutions and with high pulse energies. Iron-III-dextran solutions (1 mg Fe³⁺/1) and magnesium chloride (50 mmol/l) increased the pressure in the laser induced breakdown up to ten times (8,000–10,000 bar). Smaller stone particles and higher efficacy in stone fragmentation could be achieved.     

Photodynamic therapy of tumours and other diseases using porphyrins

Photodynamic therapy (PDT) with porphyrins and red light (620–630 nm) is finding increasing clinical application for both the eradication of relatively small tumours and the palliation of inoperable or obstructive tumours. PDT also shows some promise for the sterilization of the tumour bed after surgical removal of neoplastic masses. Several porphyrins have been found to be accumulated and retained by tumour tissues; however, a chemically prepared derivative of haematoporphyrin, termed HpD, and a purified form of HpD, termed DHE (dihaematoporphyrin ether or ester), are most frequently used in clinical practice owing to their optimal tumour-localizing properties and low systemic toxicity in the dark. The efficiency of HpD/DHE photoactivation by red light is very low, since their extinction coefficient at wavelengths above 600 nm is below 10³ m ⁻¹ cm⁻¹. Therefore, a large number of investigations are being performed in order to improve the efficacy of PDT. One approach involves the use of porphyrin analogs (e.g., chlorins, phthalocyanines) which retain a high affinity for tumours and possess intense absorption bands in the red spectral region. Moreover, the selectivity of tumour targeting can be enhanced by transport of the photosensitizing drug with some types of lipoproteins or monoclonal antibodies. These developments are of interest also in view of the proposed extension of PDT to the treatment of other diseases, including viral and microbial infections, atheroma and psoriasis.     

The photodynamic effect of a pulsed dye laser on human bladder carcinoma cells in vitro

Summary The photodynamic effect of a pulsed flashlamp pumped dye laser on cultured human bladder carcinoma cells was studied. MGH-U1 cells were incubated for 1 h in dihaematoporphyrin ether (DHE) and then exposed to green laser light (504 nm, 20 Hz) for varying laser power densities (50–100 mW/cm² and exposure times (2–15 s), representing incident pulse energy fluences of 2.5–5 mJ/cm² and energy densities of 0.1–1.5 J/cm². The cell survival was measured by clonogenic assay and controls exposed to either laser light alone or DHE in the dark showed no cytotoxicity. Sensitised cells were killed by energy densities of less than 1 J/cm² (LD₉₀=0.54 J/cm²). This demonstrates the probable effectiveness of a pulsed dye laser for photodynamic therapy provided that pulse fluence are below the saturation threshold of the photosensitiser (10 mJ/cm²).     

Photodynamic therapy to the oral cavity,tongue and larynx: a canine normal tissue tolerance study

Photodynamic therapy (PDT) has the potential to treat early carcinomas of the oral cavity and larynx while preserving normal tissue. However, normal tissues retain the photosensitizing agents and may be activated by high light fluence and dose rates resulting in normal tissue necrosis. The effects of varying dose rates of light delivery on various tissues in the upper aerodigestive tract have not been evaluated to date and are necessary to determine a therapeutic light dose range that will result in selective tumour necrosis. Thirty adult mongrel dogs received intravenous Photofrin, 2 mg kg^–1, 48 h prior to PDT treatment. Photodynamic therapy was administered to the tongue, buccal mucosa and larynx with a microlens fibre and implantable cylindrical diffuser at various dose rates from 20 to 125 J cm^–2 at 150 mW cm^–2. At the same dose rate of light delivery, the tongue was the most sensitive organ, followed by the buccal mucosa, and last by the larynx. The differential tissue effect of identical dose rates of therapy must be taken into account when administering PDT so that selective tumour necrosis with normal tissue preservation may be achieved. This study indicates the need to perform evaluations of the effect of PDT on other tissue types in an animal model with each new photosensitizer prior to administering PDT to those areas in humans.     

Damage to Tumour and Brain by Interstitial Photodynamic Therapy in the 9L Rat Tumour Model Comparing Intravenous and Intratumoral Administration of the Photosensitiser

Summary In the 9L rat brain tumour model the damage to tumour and normal brain by photodynamic therapy after intratumoural photosensitizer administration (intratumoural PDT) was studied. Twenty four rats received an intratumoural injection of 4 or 40 mm³ haematoporphyring deriative (HpD, 5 mg ml^–1), followed by interstitial irradiation with 20 Joule (J) (630 nm) 5 h later. For comparison, seven rats were treated with 20 Joule 24 h after an intravenous injection of 10 mg kg^–1 HpD (intravenous PDT). With the chosen PDT parameters there was no important difference between the damaged areas produced by intratumoural PDT or intravenous PDT. No selective tumour kill was observed. Even though normal brain tissue was heavily damaged, vital tumour parts were still present. Intravenous PDT caused extensive diffuse damage to small blood vessels in tumour and surrounding normal brain. Intratumoural PDT was characterised by an infiltration of polymorphonuclear cells into damaged tissue, dilatation of larger blood vessels and gross haemorrhage. These results suggest an immediate vascular shutdown in the intravenous approach, while in the intratumoural approach the vasculature remained patent initially. Because of the severe side effects observed, the use of HpD seems not advisable for intratumoural PDT of brain tumours.     

Sensitivity of individual tumours to photodynamic therapy

Subcapsular tumour heterotransplantation in mice kidney can be used not only for testing the sensitivity of individual tumour cells to cytostatics and ionizing radiation but also to photodynamic therapy (PDT). PDT was used to treat three experimental tumour models and four human mammary gland carcinomas which were transplanted subcapsularly in mouse kidney; the treatment consisted of irradiation with 2×120J/cm² at the 48th and 72nd hours after the administration of Photofrin II. On the 5th day after the last treatment (day 8 after the transplantation) a different inhibition of tumour growth was observed. The antitumour activity of the PDT was most strongly expressed in the four mammary gland tumours. The poorest effect was observed in the pigmented melanoma in hamsters. A correlation between tumour differentiation and the antitumour effect of PDT was established. Individual human tumours with the same localization show different degrees of sensitivity to PDT.     

Photochemotherapy of experimental colonic tumours with intra-tumorally applied methylene blue

Introduction: Phototoxicity of intra-tumoral injected methylene blue (MB⁺) was studied in 48 experimental colonic tumours in comparison with photosan-3, Zn-phthalocyanine and tetrasulphanated ClAl-phthalocyanine. Methods: In mice, xenotransplanted subcutaneous tumours about 1 cm in diameter were treated photodynamically twice, with different sensitisers. The irradiation was performed at the sensitiser-specific wavelength, and a densitiy of 100 mW/cm² and a dose of 100 J/cm². Results: Light alone without sensitiser did not induce any effect in mice tumours. Surprisingly, Al-phthalocyanine could only be used for intratumoral injections because of toxic effects after intravenous applications in nude mice. Using MB⁺ (1%), 75% of the tumours were destroyed by a single photodynamic treatment (PDT). In addition, toxicity of MB⁺ was most intense when compared with Zn-phthalocyanine and photosan-3. However, after the second PDT, there was no statistically significant difference among these sensitisers. Dark toxicity of MB⁺ (1%) could be well demonstrated by sufficient sensitiser incorporation without irradiation, which led to a stationary tumour volume up to 3 weeks after injection. Conclusion: Intra-tumoral MB⁺ PDT is a potential treatment for inducing necrosis in vivo. With regard to tumour tissue, the selectivity of MB⁺ is high and depends on a precise local injection of the dye. Received: 25 May 1998     

Photodynamic therapy of C3H tumours in mice: Effect of drug/light dose fractionation and misonidazole

C3H mammary carcinomas transplanted to the feet of mice were treated with haematoporphyrin derivative (HPD) or Photofrin II(PII) and laser light at 630 nm. While fluence rates lower than 100 mW cm⁻² gave minimal hyperthermic effects, a slight but significant growth delay was observed in unsensitized tumours exposed to a fluence rate of 150 mW cm⁻² which induced tumour temperatures in the range 40–50°C. Different modes of fractionation of the light fluence and of the HPD dose were tested but were found to give poorer rather than better results than the application of a single light exposure 24 h after intraperitoneal injection of HPD. Different PII doses were applied together with different light fluences, keeping the product of the drug dose and light fluence constant. In the dose range 6.25–50 mg/kg body weight the resulting effect on tumours was constant, allowing for a slight effect of hyperthermia at the highest light fluences, and possibly a photodegradation of PII. Misonidazole given before photodynamic treatment (PDT) slightly reduced the effect of PDT on the tumour growth. When given after PDT, however, misonidazole improved the therapeutic results significantly.     

Histological determinants of the vascular surface in prostatic carcinoma

This study was performed to analyse the correlation between vascular surface (VS), tumour grade and stage and relative proportion of tumour cells within the tumour stroma. Specimens of 41 prostatic carcinoma were immunostained using Factor VIII-related antigen. The VS was assessed by means of stereology. In tumour-free prostatic tissue the VS was 6.7 ± 0.4 mm^–1. In pT2 tumours this value was significantly increased to about 12 mm^–1. With rising pT stage the VS significantly decreased to values of 4 in pT4 tumours. In G1 tumours the VS was 14.6 mm^–1 and significantly decreased with decreasing grade of differentiation. No significant difference was obtained between pN0 and pN + cases. A close positive correlation (r = 0.59,P < 0.001) existed between the VS and the relative proportion of tumour cells within the tumour, whereas a strong negative correlation was found between the VS and the relative amount of tumour stroma (r = 0.81,P < 0.001). The VS mainly depends on tumour differentiation and pT stage, i.e. the tumour size and the relative proportion of stroma and tumour cells within the tumour. These results are consistent with those obtained in experimental tumours. Assessment of the VS is therefore of interest in studies of tumour biology; it is of no use in predicting lymph node metastasis.     

Endoscopic photodynamic therapy in lung cancer

The main purpose of cancer therapy is to treat malignant tissue with the least damage to normal surrounding structures. Photodynamic therapy (PDT) seems to be able to fulfil this simple but fundamental premise.The mechanism of action of the photosensitizer—light system can be summarized in two main points. Chiefly, it seems to be a photodynamic process, with energy transfer from the light to the photosensitizer and from it to the oxygen molecules. Oxygen is excited and becomes singlet oxygen, which is extremely reactive and very noxious for tissues in which it develops. Secondly, a thermal mechanism related to light absorption and consequent temperature rise also seems to be involved in malignant necrosis by PDT.Thirteen males were submitted to endoscopic PDT. A total of 15 treatments were given: 2 patients were submitted to 2 sessions of PDT. Forty-eight hours after HPD administration (72 h in a few cases), the lesions were exposed to a 630 nm light from an argon-dye laser system.The total estimated energy dose delivered to the tumour surface was 90–150 J/cm² in 11 cases. All cases treated responded well and total disappearance was obtained. Median follow-up was 9.5 months (1–20 months) and the estimated energy delivered from 90–600 J/cm². No major complications were reported.     

Tetra(m-hydroxyphenyl)chlorin clinical photodynamic therapy of early bronchial and oesophageal cancers

There have been few studies to date of clinical photodynamic therapy (PDT) with tetra(m-hydroxyphenyl)chlorin (mTHPC). This paper describes the results of the authors' experience with this second-generation photosensitizer, used in the treatment of 40 early cancers of the oesophagus and the bronchi. Surface illumination of the tumour was performed, in most cases, 4 days after intravenous injection of 0.15 mg kg^–1 of mTHPC, using 652 nm or 514 nm continuous wave laser light. Endoscopic follow-up with biopsies and brushings was possible for 35 tumours: 27 (77%) showed no recurrence after disease-free follow-ups that ranged from 3 to 38 months. Major complications, all of which were after red light illumination, included one bronchial stenosis, one oesophagotracheal fistula and two probable occult perforations of the oesophagus. Photodynamic therapy with green light renders such perforations of the oesophageal wall essentially impossible at the applied conditions, and appears not to reduce the efficacy of the treatment. Skin photosensitization, which was never observed later than the first week after injection, occurred in 12 patients. Hence, PDT with mTHPC is a safe and effective treatment for early carcinomas of the oesophagus and the tracheobronchial tree.     

Human tissue levels and plasma pharmacokinetics of temoporfin (Foscan®, mTHPC)

A Phase I photodynamic therapy (PDT) clinical trial was carried out with Temoporfin (Foscan^®, mTHPC) at the Departments of Otolaryngology at Orebro Medical Center (OMC) and Long Island Jewish Medical Center (LIJMC). A range of drug doses, consisting of 0.3, 0.15, 0.075 and 0.0375 mg kg^–1, were utilized. Light treatment was performed on the sixth day after injection of the photosensitizer mTHPC. Photodynamic therapy was done on prostate cancer (six cases), bronchial cancer (one case), nasopharyngeal cancer (three cases), laryngeal cancer (eight cases), mesothelioma (one case), laryngeal papilloma (five cases) and basal cell nevus syndrome (one case). A number of patients were treated more than once. Plasma was collected and analysed at 1, 24, 48, 72, 96, 120 and 144 h and at 2 weeks post-injection, to follow the loading and clearance rate of the photosensitizer. Normal and malignant tissues were collected immediately prior to PDT, chemically extracted, and analysed for drug content spectrofluorometrically. Plasma drug levels were proportional to the dose. The half-life of the drug was 45.4 h across the entire dose range. The ratio of the drug in the tumour compared to normal adjacent mucosa was in the range of 2–3. There were no significant adverse effects. These data establish the basis for full clinical trials.     

Preparation of dental hard tissue with picosecond laser pulses

The aim of this study was to investigate the suitability of picosecond lasers for hard-tissue preparation. Using scanning electron microscopy (SEM) and histological studies, the quality of ablation was examined. There was no thermal or mechanical damage observed. The ablation rates of enamel, dentine and carious enamel and the temperature rise during tissue removal were measured. Using a fast silicon photodiode, the lifetime of the plasma was determined to be 11±3 ns (Nd-YLF, 1.25 mJ pulse^–1, pulse duration 30 ps). In order to achieve a better understanding of the ablation process, plasma parameters such as electron density [(5±3)×10¹⁷ cm^–3] and excitation temperature (4500±2000 g, Nd-YLF, 0.3 mJ pulse^–1) were obtained from emission spectra. By examining the line width of singly ionized calcium lines, a difference was found in the ablation of healthy or artificially demineralized enamel, thus allowing the selective removal of caries.     

Evaluation of the Third Generation Photosensitiser SC102 in Two Animal Models

. SC102, a poly(ethylene glycol) (PEG-2000) derivative of the second generation photosensitiser temoporfin (Foscan), was evaluated for photodynamic activity utilising two standard animal models: the rabbit, inoculated with the cottontail rabbit papilloma virus (CRPV) and the healthy canine larynx. Optimal drug dose and drug–light interval (DLI) were determined in a series of pharmacokinetic experiments using SC102 administered intravenously at doses of 3 and 30 mg/kg in our standard CRPV rabbit model. Plasma pharmacokinetics in the rabbit showed an elimination half-life of 121±20 h. Peak tumour concentration occurred at 144 h for the 3 mg/kg group and at 240 h for the 30 mg/kg group. The disposition ratio of SC102 between tumour to healthy tissue, at peak tumour levels, was approximately 4 to 1 for both dose levels. Skin tolerance to increasing 652 nm wavelength fluences was excellent. Even in those rabbits given a 30 mg/kg SC102 dose, no significant damage to the skin was observed, even when a fluence of 160 J/cm² was applied at the optimal drug–light interval of 10 days. Tumour efficacy of SC102 PDT was evaluated in rabbits previously inoculated with CRPV. One time photoactivation of a single 30 mg/kg dose of SC102 at a DLI of 10 days using a fluence of 100 J/cm² achieved a complete tumour clearance rate of 35%. Two-time photoactivation on days 6 and 10 after single administration of the same dose in a separate group of rabbits, using a fluence of 75 J/cm² on both occasions, yielded an improved cure rate of 58%. Evaluation of normal tissue tolerance to SC102 PDT was also investigated in the healthy dog larynx model 10 days after an intravenous dose of 30 mg/kg SC102. A fluence of 200 J was determined to be the maximum tolerated dose at which time there was a 4:1 ratio of SC102 between laryngeal mucosa and muscle. The photophysical and pharmacokinetic profiles of SC102 show significant differences from those of Foscan from which it is derived. In these preliminary in vivo experiments we have demonstrated the outstanding tolerance of normal tissues to SC102 PDT using high fluences. We have also shown tumour efficacy with light doses readily achievable in the clinical setting. Disposition of SC102 in the skin is low and photosensitivity risk may disappear within the drug–light interval. Based on these conclusions we believe SC102 PDT may have potential utility as an adjunct to surgical resection of tumours necessitating wide field exposure of normal tissue to activating light. Paper received 15 January 1999; accepted after revision 6 October 1999.