Daniel R. Doiron

Light Dosimetry in Tissue: Application to Photoradiation Therapy

Dosimetry in photoradiation therapy (PRT) is an area in need of research and development. If PRT is to be optimized and perfected for routine clinical use, methodology and techniques for predicting and monitoring the therapeutic reaction, e.g., dose, need to be developed.

Fluorescence bronchoscopy for localization of carcinoma in situ.

A fluorescence bronchoscope system has been developed for imaging lung tumors by fluorescence of a previously injected, tumor-specific agent hematoporphyrin derivative. Carcinoma in situ has been localized, but there are too many false positives and negatives. A new system has been implemented which allows rapid switching between viewing of fluorescence, and viewing of the same area under white light illumination as in conventional bronchoscopy. The excitation source is a violet krypton ion laser coupled to a fused quartz fiber light conductor, with a diverging microlens to spread the light uniformly. A third-generation, microchannel plate image intensifier amplifies the weak fluorescence for viewing and video display, recording, and analysis. A movable mirror and periscope bypasses the intensifier for normal color viewing and video display and recording, with the laser shutter closed and the white light shutter open. This facilitates accurate localization, comparison of the color and fluorescence images, and precise sampling during biopsy. The improved system should reduce the false positive rate due to biopsy sampling error, and together with the video analyzer should reduce indeterminate results.

Laser fluorescence bronchoscope for localization of occult lung tumors

A system for imaging occult bronchogenic carcinoma by the fluorescence of previously-injected, tumor-specific compound hematoporphyrin-derivative has been assembled and successfully used to locate a tumor 1 mm thick. The violet excitation source is a krypton ion laser coupled to fused quartz fiber light conductor. An electrostatic image intensifier attached to a standard flexible fiberoptic bronchoscope provides a bright image even at relatively low irradiance. A red secondary filter rejects most reflected background and autofluorescence. Sensitivity and contrast capability of the system should permit detection of a tumor less than 0.1 mm thick.

Temperature rise during photoradiation therapy of malignant tumors

This report discusses the optical and thermal distribution during photoradiation therapy of malignant tumors. Emphasis is put on the therapeutic procedure with the light dose delivered through an inserted optical fiber. Theoretical predictions and experimental results indicate that the temperature rise during the procedure may give rise to hyperthermal cell kill. The report discusses the extent of the regions with hyperthermal bioeffects in terms of tissue parameters as optical absorption and scattering, thermal conductivity, specific heat, blood flow, and optical dose parameters as optical power and exposure time.

ACTION SPECTRUM (620–640 nm) FOR HEMATOPORPHYRIN DERIVATIVE INDUCED CELL KILLING

Abstract— Monochromatic red light generated by a tunable dye laser is currently being utilized for the treatment of solid tumors with hematoporphyrin derivative (HpD) photoradiation therapy (PRT). Experiments were performed using mammalian cells to determine the most efficient wavelength of red light (620 to 640 nm range) for HpD induced cellular photoinactivation. Decrease in the clonogenic potential of Chinese hamster ovary (CHO) cells was examined following both short (I h) and extended (12 h) HpD incubation times. Maximal photosensitization was observed with wavelengths ranging from 630 to 632.5 nm and the action spectra for cell killing matched the absorption spectra for HpD bound to cells. Similar observations were obtained following both short and extended HpD‐cell incubation times. The potential relevance of these results as they relate to clinical HpD PRT are discussed.

Fluorescence Bronchoscopy for Localizing Early Bronchial Cancer and Carcinoma in Situ

The detection, diagnosis, and aggressive treatment of lung cancer in its intrabronchial or preinvasive phase has been shown to result in 5-year survival rates of over 70%–80% [16, 19, 29]. In the case of carcinoma in situ, resection may result in prolonged survival and possibly cure [4]. In contrast, stage I lung cancer is of the invasive type and includes lesions that have already extended to the ipsilateral hilar lymph nodes; the 5-year survival at this stage is at best about 40%–50%. In small peripheral lung cancers (less than 3.0 cm in diameter), visible on chest X-ray but without hilar lymph node involvement, 5-year survival can be up to 60% [18]. The goal of physicians, therefore, must be the diagnosis of preinvasive lung cancer in patients at high risk. High risk patients include heavy cigarette smokers who have smoked one package per day or more for 20 years or longer, particularly those over age 45 years. Patients at particularly high risk are heavy smokers who also have symptoms or signs related to lung cancer and especially include smokers who have also been occupationally exposed to asbestos, uranium mining, coke oven emissions, nickel, and chromates, which are known industrial carcinogens.

SnET2: clinical update

Tin Ethyl Etiopurpurin, SnET2, is a synthetic chlorin analog presently in Phase-II/III clinical trials for the treatment of cutaneous cancers. Trials to date include the treatment of basal cell carcinomas, squamous cell carcinomas, breast adenocarcinomas metastatic to the chest wall and cutaneous Kaposis sarcomas in AIDS patients. Results to date have shown significant clinical responses for drug doses between 1.0 mg/kg and 1.6 mg/kg, with the threshold for Kaposis sarcoma being slightly higher than in other indications. Light doses from 100 J/cm2 to 300 J/cm2 were delivered from 24 to 72 hours post SnET2 infusion. Induced transient skin photosensitivity at the lower therapeutic doses has been mild, lasting approximately a week. Results of the Phase I and II trials are presented.

Ineffective photodynamic therapy (PDT) in a poorly vascularized xenograft model

Haematoporphyrin derivative (HPD) photodynamic therapy (PDT) may have clinical application in the management of patients with retinoblastoma. Heterotransplantation of retinoblastoma cells into the anterior chamber of the nude mouse eye and the subsequent growth of small tumour masses has provided a model for evaluation of various therapeutic modalities. Ninety-four evaluable xenograft tumours in 54 nude mice were randomized to receive one of the following treatments: cyclophosphamide (CPM) alone, HPD-PDT alone, CPM followed by HPD-PDT, HPD-PDT followed by CPM, or saline control. Responses were demonstrated after CPM treatment in all three relevant groups. However, HPD-PDT was found to be ineffective either alone or as a contributor in the double modality treatment groups. The small tumour masses treated can be demonstrated histologically to be avascular. It is proposed that although the same retinoblastoma cells in different circumstances are responsive to HPD-PDT, no clinical response is demonstrable utilizing this model, due to the absence of tumor vascularity.

Hematoporphyrin derivative photoradiation induced damage to normal and tumor tissue of the pigmented rabbit eye

Cytotoxicity induced by hematoporphyrin derivative (HpD) photoradiation in both normal and experimental tumor tissue of pigmented rabbit eyes has been examined. In addition, documentation of HpD induced fluorescence in ocular structures has also been obtained. Acute normal ocular tissue toxicity studies demonstrated that HpD (1-10 mg HpD/kg) followed 48 hours later by a transpupil irradiation of red light (635 nm, 36-90 J/cm2) resulted in demarcated areas of retinal damage. Long term (chronic) toxicity studies have shown that the initial damage to the retina was permanent but that no damage to the cornea, lens or vitreous could be observed during a 16 month follow-up. Visual and histological documentation have been obtained, following HpD photoradiation therapy (PRT), in rabbit eyes having heterotransplanted single nodule amelanotic melanomas. A toxic effect characterized by tumor blanching, edema and hemorrhage was observed within 24 hours of treatment. Histological examination obtained 24 hours following HpD PRT illustrated massive tumor tissue necrosis and vascular disruption. HpD PRT at clinically relevant doses was also shown to be effective in selectively curing the highly malignant amelanotic iris melanoma. It is concluded that HpD PRT may prove to be an effective modality for treating certain ocular tumors.

THERMAL DISTRIBUTION DURING PHOTORADIATION THERAPY

The optical power which is delivered into the tissue during photoradiation therapy will be absorbed and converted into heat. The resulting temperature rise may result in hyperthermal contributions to the cell kill or there may be synergistic effects between hyperthermal therapy and photo-radiation therapy.