Extrapleural Pneumonectomy - Exposure to Asbestos
Photodynamic therapy of malignant mesothelioma of pleura
2. MATERIAL AND METHODS
Patients with biopsy-proven malignant mesothelioma as confirmed by immunohistochemistry and/or electron microscopy and tumour mass confined to one hemithorax were evaluated for surgical intervention combined with intraoperative PDT. Patients were examined by CT-scan to exclude contralateral or extrathoracic manifestations.
Consent for this experimental therapeutic modality was obtained from all patients after appropriate information. Photofrin, (Lederle, American Cyanamid, NY, USA) was dissolved in sterile 5% dextrosis and intravenously administrated at a dose of 2 mg/kg bodyweight 48 hours prior to surgery. Surgical intervention by thoracotomy and a tumour-debulking procedure of gross tumour to less than 5 mm thickness was initially performed. The thoracic cavity and eventual remaining lung surfaces were intra-operatively exposed to 630 nm light pulsed at 10 kHz from a copper vapour pumped dye laser (Cu15A and DL30, Oxford Lasers, Oxford, UK).
Light was transmitted through a single quarts fiber, either flat-cut or equipped with a sphere at the distal end (PDT systems, Santa Barbara, CA, USA). A combined cooling/ light dispersing unit containing either glycerol or dispersing medium was used to prevent destruction of the fiber tip and thus to take advantage of the full output power from the laserl5. With this system an approximately spherical light distribution was obtained.
Total power out from the light delivery system was measured by an intergrating sphere power meter (Model 2015, PDT Systems, Santa Barbara, CA, USA). Light dose (fluence) delivered to the tissue surface was estimated by calculation of the primary irradiance. The intended light fluence was 15-30 Joules/cm2. Tumour biopsies were removed prior to and after light irradiation for studies by means of fluorescence microscopy.
By this technique, the localization pattern of porphyrin fluorescence in the tissue sections could be directly observed, giving a measure of biodistribution and tissue concentration of the photosensitising drug. After surgical removal, samples were immediately immersed in liquid nitrogen and the tissue sections were cut to a thickness of 8 mm using a cryostat microtome.
The same frozen sections were subsequently stained by routine H&E staining for histological identification. Fluorescence microscopy was carried out with an Axioplan microscope (Zeiss, Elena, Germany). The filter combination used for the detection of the porphyrin fluorescence consisted of an 390-440 nm excitation filter, a 460 nm beam splitter and a > 600 nm emission filter. The fluorescence images were performed by a CCD camera (Astromed CCD 3200, Cambridge, UK).
Nine patients (2 females and 7 males aged from 41 to 70 years) were included in this study. Five patients had a history of exposure to asbestos (no. 3-7), the other 4 had no known exposure to asbestos. In 4 patients (no. 2-5) the disease had been diagnosed 6-12 months prior to the start of this study. These patients had earlier received chemotherapy and presented signs of progressive disease at the time of surgery. For the other patients the inclusion were done at time of diagnosis. Specimens to establish histological verification were generally obtained by needle-biopsies.
In 2 patients an operative procedure was neccessary to obtain representative tumour material. Patient no. 3 had a known implantation metastasis in the scar tissue after former diagnostic thoracotomi. Diagnosis based upon needle-biopsies often predicted a histopathological type of the lesions which differed from the final ones established postoperatively. There were epitheloid type lesion in 6 patients and mixed type in 3 patients. The degree of differentiation varied from I-III. Fluorescence data were established postoperatively (Table 1).
The surgical procedure was done by thoracotomy, right-sided in 6 patients and left-sided in 3. The surgical aim was to obtainl radical excision of tumour. Extrapleural pneumonectomy (EPP) was performed in 5 patients. Pleurectomy, lobectomy and partial decortication of remaining lung tissue were done in 3 patients.
Pleural resection and decortication were performed in one patient. In 7 patients the diaphragm was resected and in 3 of these, due to large tumour masses in the costophrenic sulcus, a complete ipsilateral removal of the diaphragm was performed. In 6 patients pericardial resection was done. (Table 2).
Intra-operative PDT was then performed, shielding the heart and eventually the liver/spleen from light exposure with a sheet of aluminium within sponges. The light intensity varied considerably over the treated surface because of the geometry of the thoracic cavity. The light fluence was gradually increased from 15 to 30 Joules/cm2 throughout the series, the determined fluence was considered to be a minimum dose in all areas exposed. (Patient no. 4 received 15 J/cm2, no. 2, 5 and 8 were given 20 J/cm2 and the rest 30 J/cm2).
A computerized light dosage calculation program correlated to pre-operative CT measurements was established, but due to changes of intrathoracic geometry during operation, recalculations demonstrated deviations between the intended and the given light fluence. Limited areas received less light than given above. Since only one laser and a single light delivery system were available, the light diffuser was moved into a maximum of 20 different positions to cover the entire resectional area. The time of light exposure varied from 2,5 and 9.5 hours, average 6,3 hours, and the duration of operation therefore were of unusual lenght (range: 10-20 hours, mean 17 hours).
Extemal ionizing radiation of the chest wall including all scars after thoracotomy and accessory entrances was performed postoperatively in order to prevent occurrence of metastasis (10-15 MW, 10-20 fractions, 30-40 Gy). All patients were followedup postoperatively by serial computerized tomography scans every 3 months.
New Chemotherapy Drugs
There are a number of new chemotherapy drugs garnering a great deal of attention. Alimta, Veglin and Onconase were developed for the treatment of malignant mesothelioma and other types of cancer such as lymphoma and renal cell carcinoma.