Nine patients with malignant pleural mesothelioma underwent extensive mesothelioma surgery followed by intra-operative photodynamic therapy. 2 mg/kg Photofrin was given 48 hours prior to surgery. The thoracic cavity and eventual remaining lung were exposed to 15-30 Joules/cm2 of 630 nm laser light. Tumor tissue was analysed by microscopic photometrical techniques. Five patients with mixed or epitheloid tumors with fluorescence intensity >100 grey level/pixel seemed to benefit from the given therapy.
One patient was free of disease 18 months after treatment. Two patients were treated for metastasis after 12 months with no sign of intrathoracic recurrency. Both are still alive, one without further sign of disease 32 months after initial treatment. Two patients presented generalized disease after 9 and 13 months and intrathoracic recurrency several months later. Two patients with poorly differentiated tumours and 2 patients with moderate to highly differentiated tumours, but with fluorescence intensity <100 grey level/pixel, presented recurrencies after 4 months. PDT-efficiency seems to be predicted by the intensity and distribution of drug-induced fluorescence in tumour tissue. PDT may enhance the possibility to achieve complete local tumour control after excision. Multimodal therapeutic approach of local and systemic disease seems mandatory to further improve survival.
Malignant mesothelioma is an almost invariably fatal cancer disease that occurs on serosal surfaces of the body. Induction of malignant pleural mesothelioma is most commonly caused by exposure to asbestos fibers, followed by a latency period of 20-40 years before appearance of symptoms. There is no standard therapy for such disease. Radiotherapy and chemotherapy have little effect in the treatment of malignant pleural mesothelioma and in some European countries surgery is considered to be even less effective.
Photodynamic therapy (PDT) is an investigative cancer treatment modality5-7 that has been under development during the last decades. The basis of this therapy involves the in situ activation of a photosensitizer accumulated in tumour and normal tissue by visible light, causing cell death. The specificity of the PDT-effect correlates with the biodistribulion of the photosensitizing substance. Porfimer sodium, Photofrin, is the most widely used photosensitizer in current clinical trials. PDT is mainly a local treatment and has the potential, as an adjuvant therapy, to enlarge the surgical margins and may thereby transform an incomplete surgical resection due to anatomic or structural limitations, to a complete local tumour eradication. PDT using Photofrin has been shown to be effective in human mesothelium grown as xenografts in rodents11,12 and in a few humans cases using Photophrin13 or a chlorin photosensitizer.
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 laser. 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 photosensitizing 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 outine H and 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 thoracotomy. 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 obtain1 radical excision of tumor. 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 length (range: 10-20 hours, mean 17 hours).
Exteral 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 followed up postoperatively by serial computerized tomography scans every 3 months.
There was no perioperative mortality. One patient presented a surgical complication by persisting leakage from ductus thoracicus, the patient therefore was reoperated after 21 days without further complications. One incidence of skin photosensitivity was observed, this consisted of localized skin necrosis and was treated by split-skin grafting. The event occurred in an area close to the thoracotomy and was caused by the light from lamps in the surgical theatre. One patient developed an acute respiratory distress syndrome due to Pseudomona aeroginousa infection. Short transient periods of cardiac arythmia related to statural changes were seen during the first 2 weeks in patients who had undergone complete aphragmatic (and pericardial) resection. This was surprisingly well tolerated by the patients. Hyperthermia and chest pain was observed during the first weeks. The patients did not develop neither neural and vascular alterations nor bronchial suture insufficiency. Patients were discharged from the hospital from 10 to 90 days postoperatively, the average hospitalization period was 25 days.
The patients were controlled by CT-scans every 3 months. In one patient (no. 1) no sign of recurrency has been found 18 months after treatment. One patient (no. 2) presented after 12 months an implantation metastasis in the thoracic wall. The tumour was located far from the incision, in an area of multiple punctures for evacuation of pleural effusion prior to operation. The metastasis was resected by thoracotomy and there was no sign of intrathoracic tumour. Additional radiotherapy towards the affected area was given post-operatively. The patient has since been free of disease for 32 months after the initial treatment. These two long term disease-free patients had initially presented highly differentiated tumours with homogeneous distribution of high intensity of the fluorescent photosensitizer.
Patient no. 6, presented after 12 months, a retroperitoneal metastasis located around the aorta, vena cava inferior and portal vein. The tumour was resected and PDT again performed with light fluence of 50 Joules/cm2. The fluorescence intensity of the initial pleural tumour and the metastasis was 104 and 43 grey level per pixel, respectively. At control 3 months later multiple metastases were detected within the abdomen and mediastinum, as well as in other areas distant from treated tumour sites.
Two patients (no. 4 and 5) presented multiple metastases 9 and 13 months after treatment. These metastases were initially located within the abdomen and controlateral hemithorax and were 3 months later found within the treated hemithorax. Both patients had a long history of known mesothelioma and large tumour masses at time of actual treatment. Tumours were highly differentiated and showed fluorescence intensities ranging from 176 to 248 grey level per pixel. Patient no. 3 developed recurrency after 3 months and distant metastases 5 months after treatment. The history of disease, size of tumour and its level of fluorescence intensity were identical as for the above mentioned patients, only the differentiation grade was lower.
Three patients (no. 7, 8 and 9) presented generalized disease 4-5 months after treatment, showing manifestations within the treated hemithorax as well as contralateral and intraabdominal metastases. In two of those patients the tumour had low fluorescence intensity and in the third patient, who had a tumour of mixed type with differentiation grade I, the fluorescence was of high intensity but unevenly distributed within the tumour tissue.
Prior to treatment all patients complained of chest pain. Most patients had pleural effusion that was frequently drained. During the first week after treatment patients had a severe chest pain, this was reduced during the following months and the surviving persons do not complain of any particular chest pain. No pleural drainage was to be performed in a late postoperative period for any patient.
Single modality therapeutic management has yielded few long-term survivors in malignant pleural mesothelioma. The role of surgery is generally considered to be limited. Pleurectomy/decortication is an incomplete tumour-debulking procedure and therefore ineffective as a single treatment with curative aim. Extensive surgery by EPP has been advocated as a theoretically more attractive operation because it may allow a radical excision, but only a minority of patients with mesothelioma qualify for this operation and it carries a higher risk.
Studies have shown that patients undergoing EPP have a greater tendency towards development of distant disease. The therapeutic challenge is two-fold, effective treatment regimens for malignant mesothelioma must address the problem of systemic disease as well in order to obtain local and systemic control of the malignancy. Combined treatment modality appears to offer some promise in this otherwise rapidly fatal disease.
The impact of the presented method in a small and heterogeneous patient group is difficult to evaluate. However, patients no. 2 and 6 reoperated a year after initial treatment were completely free from tumor within the thoracic cavity. During the follow-up, in 3 patients distant metastases were seen prior to recurrency within the treated hemithorax. Such results of relatively long-lasting local control were obtained in patients undergoing various surgical procedures with low mortality/morbidity.
The tumours of these patients presented photosensitizer fluorescence of even distribution and of high intensity. Patients with tumours of inhomogeneous (related to the differentiation grade) and low fluorescence intensities showed rapid recurrency and metastases. Patient no. 6, presenting a relatively high fluorescence intensity of the initial tumour and a significantly lower intensity in the metastatic tumor, showed generalized malignancy only 3 months after retreatment.
An approach by thoracoscopic PDT13 was considered not useful in these patients all of whom presented tumor masses of large size located in the costophrenic sulcus. CT scans did not offer sufficient accuracy to evaluate tumour thickness, especially in the costophrenic sulcus. We experienced improved surgical radicality As a conclusion we present the hypothesis that associated PDT-treatment has a clinical effect and that predictability of PDT-efficiency seem to be related to the distribution and intensity of the fluorescence induced by the photosensitizer in tumour. The PDT-effect may enhance the potential to complete local tumour eradication even in the case of less aggressive surgical debulking procedure. However, as clearly visualized in this study a multimodal therapeutic approach addressing to the systemic disease seems necessary to further improve mesothelioma life expectancy as well as improved access for light exposure in this area by doing complete diaphragmatic resection.
This study was financially supported by The Norwegian Cancer Society. Photosensitizer and some of the technical equipment was a gift from Lederle, American Cyanamid.
- J.C. Wagner, E.A. Sleggs and P. Marchand, "Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province," Br. J. Int. Med., 17, pp. 260-271, 1960.
- K.H. Antman, P.F. Li, R. Osteen et al., "Mesothelioma," Cancer Updates, 3, pp. 1-16, 1989.
- A.S. Alberts, G. Falkson, L. Goedhals, D.A. Vorobiof and C.A. Van Der Merwe, "Malignant pleural mesothelioma: a disease unaffected by current therapeutic maneuvers," J. Clin. Oncol., 6, pp. 527-534, 1988.
- L.W. Brady, "Mesothelioma - the role for radiation therapy," Semin. Oncol., 8, pp. 329-334, 1981.
- S.L. Marcus, "Clinical photodynamic therapy: The continuing evolution," Photodynamic therapy; basic principles and clinical apSicatimnS, B.W. Henderson and TJ. Dougherty (eds.), pp. 219-2684 Marcel Dekker, Inc., New York, 1992.
- TJ. Dougherty and S.L. Marcus, "Photodynamic therapy," Eur. J. Cancer, 28A, pp. 1734-1742, 1992.
- TJ. Dougherty, "Photodynamic therapy," Photochem. Photobiol., 58, pp. 895-900, 1993.
- J. Moan and K. Berg, "Photochemotherapy of cancer: Experimental research," Photochem. Photobiol., 5S, pp. 931-948, 1992.
- B.W. Henderson and T.J. Dougherty, "How does photodynamic therapy work?" Photochem. Photobiol., 55, pp. 145-157, 1992.
- K.R. Weishaupt, C.J. Gomer and T.J. Dougherty, "Identification of singlet oxygen as the cytotoxic agent in the photoactivation of a murine tumour," Cancer res., 36, pp. 2326-2329, 1976.
- S.L. Gibson, T.H. Foster, R.H. Feins, R.F. Raubertas, M.A. Fallon and R. Hill, "Effects of Photodynamic therapy on xenografts of human mesothelioma and rat mammary carcinoma," Br. J. Cancer, 69, pp. 473-481, 1994.
- R.H. Feins, R. Hilf, H. Ross and S.L. Gibson, "Photodynamic therapy for human malignant mesothelioma in the nude mouse," J. Surg. Res., 49, pp. 311-314, 1990.
- L. Lofgren, M. Larsson, L. Thaning and S. Hallgren, "Transthoracic endoscopic photodynamic treatment of malignant mesothelioma," (letter), The Lancet, 337, p. 359, 1991.
- H.-B. Riis, HJ. Altermatt, R. Inderbitzi, R. Hess, B. Nachbur, J.C.M. Stewart, Q. Wang, K.C. Lim, R. Bonnett, M.C. Berenbaum and U. Althaus, "Photodynamic therapy with chlorins for diffuse malignant mesothelioma: initial clinical results," Br. J. Cancer, 64, pp. 1116-1120, 1991.
- H. Heyerdahl, T. Warloe, Q. Peng, K. Svanberg, J. Moan, H.B. Steen, L.O. Svaasand and K.-E. Ciercksky, tDosimetry and light distribution systems for photodynamic therapy at the Norwegian Radium Hospital," Photodynamic Therapy of Cancer. G. Jori, J. Moan and W. Star (eds.), pp.27-36, SPIE Vol. 2078, 1993.
- V.W. Rush, S. Piantadosi and E.C. Holmes, "The role of extrapleural pneumonectomy in malignant pleural mesothelioma," J. Thorac. Cardiovasc. Surg., 102, pp. 1-9, 1991.
- L.B. Weissmann and K.H. Antman, "Incidence, presentation and promising new treatments for malignant mesothelioma." Oncology Williston Park, 3, pp. 67-72, 1989.
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