Asian Cardiovasc Thorac Ann 2006;14:206-209
© 2006 Asia Publishing EXchange Ltd
Management of Malignant Mesothelioma by Decortication and Adjunct Phototherapy
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{at}bigpond.com.au, Level 5, 55 Victoria Parade, Fitzroy, Victoria 3065, Australia.
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ABSTRACT
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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.
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INTRODUCTION
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Malignant mesothelioma is one of the few malignancies that originates in the pleural space. It usually follows previous asbestos exposure and there is often a long lag period of 30 to 40 years from the time of exposure to development of malignancy.1 The mean survival from the time of diagnosis is 9 months, and treatment has had little impact on overall survival.2–6 Some survival benefit was reported in patients having multimodality treatment, but a reliable cure remains elusive.2 In 1989, we started a program of full decortication with adjunct phototherapy after administration of hematoporphyrin derivative (Hpd), along with targeted radiotherapy. The results of the first 100 patients treated have been analyzed.
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PATIENTS AND METHODS
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Patients were selected for radical treatment if they had proven mesothelioma limited to one hemithorax and no discernible involvement of the mediastinum. All patients were in American Society of Anesthesiologists risk grade 0–1, with no significant comorbidity. They ranged in age from 23 to 76 years, with a mean age of 63 years and 5 months. There were 87 males and 13 females. Staging was in accordance with the International Mesothelioma Interest Group, and all patients selected were in stage I.7 The main modality used for staging was high-resolution computed tomography (HRCT) but patients treated later in the series also had positron emission tomography (PET) when it became available. The results of PET scanning in diagnosis and follow-up have been somewhat variable and a formal evaluation of its usefulness is being undertaken.
The majority of patients presented with dyspnea and effusion and only a few presented with constant chest pain as the main symptom. One patient with known asbestos-related changes had undergone a biopsy for pleural thickening that had become more prominent, but he was essentially asymptomatic. Although patients presenting with an effusion usually had malignant cells on cytology and a presumptive diagnosis of malignant mesothelioma had often been made, a firm diagnosis on cytology alone was not accepted because of the ease of confusion with adenocarcinoma, so they all had a video-assisted thoracoscopic biopsy or an open biopsy. The majority of tumors (52%) were classified as being mixed type (Table 1
). Hematoporphyrin derivative was given intravenously at a dose of 5 mg·kg–1 24 hours preoperatively. The Hpd was made by our pharmacy and is relatively cheap. The more refined commercial products were not used on the grounds of cost and availability. Although this drug has excellent activity, the skin is sensitized to sunlight for up to 2 months, whereas the time of skin sensitization is shorter with the more refined commercial products. Assays of Hpd in tissue were carried out by Dr. J Hill at the Royal Melbourne Hospital and showed that the malignant mesothelioma in 20 patients studied had taken up approximately 3.5 times as much Hpd as control muscle biopsies. Postmortem studies are not available.
At operation, a full posterolateral thoracotomy was performed. Decortication of the tumor was carried out as completely as possible, removing the parietal pleura and any tumor on the surface of the lung, and taking care to open all the fissures. Mediastinal lymph nodes were sampled to check the staging but no adjustments were necessary. The pleural space was given 2 hours of treatment with a red laser providing monochromatic light at 630 nm, attempting to give 100 joules·cm–2 to all areas. Initially, a gold vapor laser was used but this proved cumbersome and unreliable so we switched to an Nd:YAG laser (Laserscope, San Jose, CA, USA) passed through a Laserscope dye box to give a pure red light. The light penetrates up to 6 mm (Refs 8,9) and any areas of doubtful clearance were marked out with metal clips for later strip radiotherapy. The wound edges were carefully protected with adherent drapes, but most patients had some degree of skin burning adjacent to the incision, from stray laser light.
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RESULTS
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There were 2 deaths in these 100 patients. One patient died intraoperatively after the aorta was damaged while removing a tumor adhering to it, and one died postoperatively from respiratory failure secondary to pneumonia. The mean postoperative hospital stay was 9 days (range, 4–61 days). Cutaneous burns were frequent but generally not severe. There were 44 other complications in 38 patients (Table 2). The Kaplan-Meier survival curve is shown in Figure 1 and compared to that of 17 matched patients treated prior to this series by decortication alone before phototherapy was introduced (13 males and 4 females, with a mean age of 67 years).
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Figure 1. Kaplan-Meier survival curves of 17 patients who had decortication alone (pre-PDT) and 100 patients who had phototherapy and decortication therapy (PDT).
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Median survival increased from 250 to 440 days, with a few long-term survivors. The mean survival of a series of patients treated by radiotherapy after surgery at the local Peter MacCallum Cancer Institute was similarly 9 months. (Ref 3) There seemed to be no difference in outcome between patients who presented primarily with pain and those with an effusion, nor was the duration of symptoms prior to treatment a significant factor in the outcome. Patients with epithelioid tumors appeared to do marginally better than those with mixed and sarcomatous tumors, however the difference was not significant.
Seven patients obtained good local control but developed distal metastases later and were offered cisplatin-based cytotoxic chemotherapy, but this had no lasting benefit. Radiotherapy was preferred for a local recurrence. In 6 patients, a late recurrence was suspected because of increasing pain, but it was successfully palliated in all cases; 3 became long-term survivors. As chest radiographs after surgery are often difficult to interpret because of postoperative changes, a baseline HRCT scan was routinely performed, and subsequent surveillance involved plain chest radiographs with a further HRCT scan if any suspicious areas were noted. PET scans demonstrated local recurrence in several cases but also gave negative results in biopsy-proven recurrence in others, and its place in routine follow-up is not yet clear.
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DISCUSSION
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The association between asbestos products and malignant mesothelioma was first reported in 1960.10 There are several types of asbestos, but the worst health hazard is crocidolite which is found in the Orange Reef of South Africa and Wittenoom Gorge in West Australia. The development of malignant mesothelioma in Australia is expected to continue to rise until 2020, despite recognition of the dangers of asbestos and control of its use.11 Many patients show signs of asbestosis before developing malignant mesothelioma: calcified pleural plaques, particularly over the diaphragm, and interstitial fibrosis of the lungs. The number of patients with asbestosis who go on to develop malignant mesothelioma is unclear.4 Once asbestos fibers have been inhaled, they are trapped in the periphery of the lung, which produces a tissue reaction to isolate them. They cannot be removed but as there is an increased incidence of lung cancer in patients who both smoke and have been exposed to asbestos, the importance of stopping smoking must be stressed to patients with asbestosis.12
Malignant mesothelioma is easily confused with adenocarcinoma and an adequate biopsy is essential for diagnosis. Treatment by a single modality has generally proven ineffective.2,5 Butchart and colleagues13 first proposed pleuropneumonectomy with excision of the diaphragm and pericardium if necessary; however, this has significant mortality and is only suitable for a minority of cases. Surgery alone does not improve survival, but surgery combined with radiotherapy and chemotherapy has been beneficial.2,14 Ball and Cruickshank3 showed that patients who had pleurodesis and radiotherapy did not survive longer but had an extended symptom-free period postoperatively. HRCT is the most useful modality for staging, but magnetic resonance imaging and PET have also been used.15 Aggressive treatment is really only suitable for stage I tumors. Mediastinal involvement is a contraindication to aggressive treatment and mediastinoscopy has been advocated in all patients being considered for surgery.16
The results of this study are encouraging, but a better comparison would have been achieved by a randomized study; however, the emotional and litigious aspects of this disease made this impossible to perform. Phototherapy as an adjunct treatment in the management of cancer has been studied for many years.8,9,17 A sensitizer is given, which is preferentially taken up by malignant cells, and activated by light of a suitable wavelength. Red light of 630 nm activates Hpd which interacts with molecular oxygen to give singlet oxygen that acts directly on the tumor as a toxin and also damages its blood supply.8,9 Due to the irregular shape of the pleural space, measuring the total light delivered to a particular area is difficult, and the amount of light required to adequately activate the photosensitizer is unknown.8,9,17 The only treatment regimes that have prolonged survival to date have been multimodality approaches, and these are only suitable for patients with early stage disease.2,4,14 Further improvement in treatment will depend on better methods of early detection and new approaches such as immunotherapy or targeted cytotoxic chemotherapy. If phototherapy is to progress beyond an experimental approach, a stronger photosensitizer is needed, which is cleared from the body more quickly and can be activated by targeted chemicals.
In view of this early experience, we advocate that stage I patients under 72 years of age who are in good physical condition should be offered cisplatin-based induction cytotoxic chemotherapy followed by full surgical decortication and adjunct phototherapy, giving a local cytotoxic boost, and then conformal radiotherapy to any areas of doubtful clearance.18 The patient should be closely followed up and further chemoradiotherapy given if recurrence of the tumor is detected. The recent availability of a tumor marker, mesothelin, may help in the early detection of recurrence, which can be difficult following surgery and radiotherapy.19 Hopefully this disease will eventually disappear as the use of asbestos is controlled, but as this is unlikely to occur for many years, we still need to pursue new treatments.
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ABSTRACT
INTRODUCTION
