Zervos MD, Bizekis C, Pass HI.

Department of Cardiothoracic Surgery, Division of Thoracic Surgery, New York University School of Medicine, New York, USA. zervom01@med.nyu.edu

Abstract

Purpose of review: Mesothelioma is an aggressive malignancy of the pleura with poor survival. There will be approximately 3000 cases of mesothelioma in the United States annually. Multimodality treatment including neoadjuvant chemotherapy in selected individuals followed by extrapleural pneumonectomy and radiation has been studied in recent trials for its effects on disease free and overall survival This review provides a general overview of malignant mesothelioma with a summary of the most significant articles from within the past year as well as from the past.

Recent findings: Areas of recent interest include the evaluation of osteopontin and mesothelin as new tumor markers for mesothelioma. New phase III trials have been performed to evaluate the use of combined chemotherapy regimens.

Summary: Malignant mesothelioma is a very difficult malignancy to treat. Patients with the disease usually have an occupational asbestos exposure, and in some, viral exposure with SV40. There have been many historical treatments including combinations of local control with surgery and radiation as well as attempts to prevent systemic failure with chemotherapy. Novel therapies including intrapleural chemotherapy, photodynamic therapy and hyperthermic perfusion have also been used with some success. Finally there are several attempts at immunomodulating and targeted treatments, which are in phase I/II trials.

Matzi V, Maier A, Woltsche M, Smolle-Jüttner FM.

Department of Surgery, Division of Thoracic and Hyperbaric Surgery, University Medical School, Auenbruggerplatz 29, A-8036 Graz, Austria.

Abstract

The aim of this study was to evaluate the additional effect of intraoperative photodynamic therapy (PDT) under hyperbaric oxygenation (HBO) when compared with decortication alone. From 1/1993 to 8/2002, palliation with decortication was done in 25 patients suffering from advanced malignant pleural mesothelioma. Fourteen patients received additional intraoperative PDT under HBO. The surgery and PDT/HBO was done 48 h after photosensitization with a polyhematoporphyrin, 2 mg/kg/BW using a diode laser delivering red light at 630 nm through a microlens. The light dose was calculated for 300 J with a distance of 1 cm from the tumor surface. At 6-month follow up local tumor control and survival showed a significant difference in both groups. Although the study only includes a small number of patients not allowing definite conclusions, it indicates that the additional PDT/HBO represents a safe and technically feasible approach in the palliative setting of advanced malignant mesothelioma of the pleura.

Keywords: Pleural mesothelioma; Photodynamic therapy

Olivier Pittet^a, David Petermann^a, David Michod^b, Thorsten Krueger^a, Cai Cheng^a, Hans-Beat Ris^a, and Christian Widmann^b

^aDivision of Thoracic Surgery, University of Lausanne, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
^bDepartment of Physiology and Cellular Biology and Morphology, University of Lausanne, Switzerland

Received 12 January 2007; revised 27 March 2007; accepted 24 April 2007. Available online 1 May 2007.

Abstract

Background: 5,10,15,20-Tetrakis(m-hydroxyphenyl)chlorin (mTHPC)-mediated photodynamic therapy (PDT) has shown insufficient tumor selectivity for the treatment of pleural mesothelioma. Tumor selectivity of mTHPC-PDT may be enhanced in the presence of the TAT-RasGAP317–326 peptide which has the potential to specifically sensitize tumor cells to cytostatic agents.

Materials and methods: H-meso-1 and human fibroblast cell cultures, respectively, were exposed to two different mTHPC doses followed by light delivery with and without TAT-RasGAP317–326 administration. mTHPC was added to the cultures at a concentration of 0.04 μg/ml and 0.10 μg/ml, respectively, 24 h before laser light illumination at 652 nm (3 J/cm2, 40 mW/cm2). TAT-RasGAP317–326 was added to the cultures immediately after light delivery at a concentration of 20 μM. The apoptosis rate was determined by scoring the cells displaying pycnotic nuclei. Cell viability was measured by using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay.

Results: Light delivery associated with 0.04 μg/ml mTHPC resulted in a significantly higher apoptosis rate in the presence of TAT-RasGAP317–326 than without in H-meso-1 cells (p < 0.05) but not in fibroblasts. In contrast, 1.0 μg/ml mTHPC and light resulted in a significantly higher apoptosis rate in both H-meso-1 cells and fibroblasts as compared to controls (p < 0.05) but the addition of TAT-RasGAP317–326 did not lead to a further significant increase of the apoptosis rate of both H-meso-1 cells and fibroblasts as compared to mTHPC and light delivery alone.

Conclusion: TAT-RasGAP317–326 selectively enhanced the effect of mTHPC and light delivery on H-meso-1 cells but not on fibroblasts. However, this effect was mTHPC dose-dependent and occurred only at a low sensitizer dose.

Keywords: Photodynamic therapy; mTHPC; Mesothelioma; Apoptosis; H-Meso-1 cell cultures; TAT-RasGAP317–326

Yusa T.

Chiba Pleural Tumor Study Group.

Abstract

In Japan, it is predicted that mesothelioma will rapidly increase in the future. Malignant pleural mesothelioma that accounts for approximately 90% of mesothelioma as a whole has a median survival time of approximately nine months which is considered a poor prognosis. As for the treatment of this disease,extrapleural pneumonectomy or pleurectomy/decortication are available for those patients who can be surgically operated on. However, since a complete cure rate is low when only surgical treatment is performed, generally a multimodality treatment is performed wherein chemotherapy and/or radiotherapy are combined. For chemotherapy, a large-scale randomized phase III study demonstrated that a treatment using two agents: pemetrexed, which is a new multitargeted antifolate, and cisplatin is effective. Pemetrexed will be the drug of first choice for mesothelioma in the future. As other treatment methods, chemohyperthermia, treatments using various kinds of cytokines and angiogenesis inhibitors, genetic treatment and photodynamic therapy have been attempted. The current treatment results for this disease are very poor, and there has been a strong demand for establishing an effective treatment method.

Opitz I, Krueger T, Pan Y, Altermatt HJ, Wagnieres G, Ris HB.

Thoracic Surgery Service, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

Abstract

Efficacy and tumour selectivity of photodynamic therapy with two clinically approved sensitizers (mTHPC, verteporfin) were assessed for focal intracavitary photodynamic therapy (PDT) in rodents with malignant pleural mesothelioma (MPM) at recommended drug-light conditions and at escalating sensitizer dosages. MPM tumours were generated in 15 Fischer rats by subpleural mediastinal tumour cell injection followed after 5 days by intracavitary PDT with light delivery monitored by in situ dosimetry. Animals were intravenously sensitized either with mTHPC (0.1 mg/kg, n = 3; 0.2 mg/kg, n = 3) followed after 4 days by illumination with 20 J/cm(2) at 652 nm, or with verteporfin (0.6 mg/kg, n = 3; 1.2 mg/kg, n = 3) followed after 20 min by illumination with 100 J/cm(2) at 689 nm. Three untreated tumour-bearing animals served as controls. Histological evaluation of the treated tumour and of adjacent normal organs was performed 10 days after tumour implantation. The extent of PDT-induced tumour necrosis was compared to the non-necrosed area and expressed in percentage. A locally invasive growing MPM tumour (3.1 +/- 1 mm diameter) without spontaneous necrosis diameter was found in all animals. For both sensitizers, focal intracavitary PDT was well tolerated at drug-light conditions recommended for clinical applications. Mediastinal organs were spared for both sensitizers but verteporfin resulted in a higher extent of tumour necrosis (80%) than mTHPC (50%). Drug dose escalation revealed a higher extent of PDT-related tumour necrosis for both sensitizers (mTHPC 55%, verteporfin 88%), however, verteporfin-PDT was associated with a higher toxicity than mTHPC-PDT.

Charles P Clarke, MBBS, Simon R Knight, MBBS, Freddy J Daniel, MBMS, Siven Seevanayagam, MBBS

Austin Health, Heidelberg, Victoria, Australia

For reprint information contact: CP Clarke, MBBS Tel: 61 3 9419 2477 Fax: 61 3 9417 1694 Email: clarkecp@bigpond.com.au

Abstract

Malignant mesothelioma is a relatively rare tumor that originates in the pleural space and almost invariably results from exposure to asbestos. Between September 1989 and December 1999, 100 patients were managed with curative intent using a combination of full decortication, adjunct phototherapy after administration of hematoporphyrin derivative, and strip radiotherapy to any areas where adequate clearance was not obtained. The survival curve was compared to that of 17 matched patients treated by decortication alone. Median survival increased from 250 to 440 days in the combined treatment group.

Krueger T, Pan Y, Tran N, Altermatt HJ, Opitz I, Ris HB.

Thoracic Surgery Unit, University Hospital of Lausanne, CH-1011 Lausanne, Switzerland

Abstract

Background and Objective: Experimental assessment of anticancer effect, normal tissue damage, and toxicity of intrathoracic mTHPC-mediated photodynamic therapy (PDT) combined to surgery in malignant pleural mesothelioma (MPM) bearing rats.

Study Design/Materials and Methods: Six days after implantation of syngenic malignant mesothelioma cells in the left chest cavity of Fischer rats (n = 21) and 4 days after sensitization (0.1 mg/kg mTHPC), a left-sided pneumonectomy was performed, followed by intraoperative light delivery (652 nm, fluence 20 J/cm(2)), either by spherical illumination of the chest cavity (fluence rate 15 mW/cm(2)) or by focal illumination of a tumor area (fluence rate 150 mW/cm(2)). Controls comprised tumor-bearing untreated animals, tumor-bearing animals undergoing pneumonectomy, and tumor-bearing animals undergoing pneumonectomy and light delivery without sensitization or sensitization without light delivery. No thoracocentesis was performed during follow-up.

Results: An invasively growing sarcomatous type of mesothelioma was found in all animals at day 10, without tumor necrosis in control animals. PDT resulted in 0.5-1 mm deep inhomogeneous tumor necrosis after spherical, and in a 1-2 mm deep tumor necrosis after focal illumination. No injury to mediastinal organs was observed, neither after PDT with spherical nor with focal light delivery except focal interstitial lung fibrosis at the mediastinal area of the opposite lung. All animals with pneumonectomy followed by spherical PDT of the entire tumor-bearing chest cavity died within 72 hours whereas all other animals survived. All animals that died presented massive pleural effusion.

Conclusions: PDT following pneumonectomy in mesothelioma bearing rats was technically feasible and allowed to study its effect on tumor and normal tissues. PDT-related tumor necrosis was observed after spherical and focal light delivery, however, pneumonectomy followed by PDT with spherical light delivery to the tumor-bearing chest cavity resulted in fatal complications.

Ris HB.

Division of Thoracic Surgery, Centre Hospitalier Universitaire Vaudoise (CHUV), CH 1011 Lausanne, Switzerland.

Abstract

Malignant pleural mesothelioma (MPM) is increasingly observed in industrial countries. Despite concerted efforts and combined treatments including surgery, chemotherapy and irradiation patients eventually succumb from relentless local progression of the disease. Recent publications have demonstrated an improved response rate with the cytostatic agent pemetrexed which will be tested in a neoadjuvant setting followed by surgery. However, effective tumor control requires new loco-regional treatment modalities, eventually in combination with neoadjuvant chemotherapy. Intraoperative photodynamic therapy (PDT) of the chest cavity has been proposed as an attractive treatment concept for MPM since a selective treatment of the tumor bed following resection has the potential to improve local tumor control. It has been shown to afford tumor destruction in patients with mesothelioma but efficiency and selectivity is not yet sufficient for routine clinical application. Experimental work on MPM has shown that tumor selectivity of PDT depend on treatment conditions and can be improved by structural modification and improved targeting of the sensitizers. Refinements of PDT for mesothelioma will depend on a more detailed understanding of the pathways for preferential sensitizer accumulation within the tumor as well as on synergistic effects between PDT and chemotherapeutic agents.