Asbestos Lung Cancer - Asbestos Lawyer
Gene Therapy
Experimental studies in rodents have demonstrated that it is possible to transfer the herpes simplex thymidine kinase (HSVtk) gene to mesothelioma cells using an adenovirus vector, and subsequently treat with the antiviral drug ganciclovir to kill the mesothelioma cells, thereby eliminating tumor nodules [64]. This form of treatment is effective experimentally even when only a small percentage of mesothelioma cells is transduced, suggesting that there is an important "bystander effect" also [64, 65].
However, currently available viral vectors are less efficient at delivering genes to tumor cells interspersed in a dense, fibrous stroma, as in mesenchymal (sarcomatous) or mixed histology mesotheliomas [66]. Because of this problem and poor penetration of bulky tumor, it is likely that this type of gene therapy will need to be combined with either debulking or radical surgery.
Following the experimental work in animals, trials have begun to evaluate gene therapy clinically [66]. A phase I clinical trial of recombinant adenovirus containing HSVtk gene injected intrapleurally followed by systemic treatment with ganciclovir for 14 days has revealed good tolerance of therapy but some side effects. These included fever, anemia, transient liver enzyme elevations and bullous skin eruptions in some patients. Gene transfer was documented in 11 out of 20 patients [67]. Since this initial report, a new adenoviral vector has been developed which appears to be as effective with less toxicity [68]. Phase II trials have yet to be reported. Studies of gene transfer in malignant pleural effusions have revealed that chondroitin sulphates markedly inhibit gene transfer by interacting with the vector in solution. The authors suggest that drainage of the pleural effusion prior to treatment should allow more efficient gene transfer [69].
Another approach in gene therapy involves restoration of a gene product usually absent in mesothelioma cells. The gene product p16IKN4a can be re-expressed in mesothelioma cells following transfer with an adenovirus.
Experimentally this has been shown to inhibit tumor formation, arrest tumor growth and diminish tumor size and spread [70]. Several other chromosomal losses have been identified in mesothelioma, suggesting that some may contain putative tumor suppressor genes [71-73]. The therapeutic possibilities of gene restoration therapy clearly need to be explored also.
Photodynamic Therapy
Photodynamic therapy involves administration of a tumor-localizing photosensitizing agent followed by activation of the agent by light of a wavelength specific to its absorption spectrum. The most commonly used photosensitizers are porphyrin-related compounds which bind to various cytoplasmic membranes within the cell. Light activation in the presence of molecular oxygen causes oxidative damage at the subcellular level, leading to cell death [74]. Cytotoxicity also occurs as the result of vascular damage, impaired blood supply and local hypoxia [75]. It is thought that a heightened immune response to the tumor may also be induced [76]. Experimental work with nude mice bearing human mesothelioma tumors has shown that mesothelioma is locally sensitive to photodynamic therapy. Various photosensitizing agents and light dosing regimes have been investigated [77-80], together with studies to define the optimum time interval between sensitizer administration and light activation [81]. Currently available technology limits effective light treatment penetration to about 1 cm [82], which means that intrapleural photodynamic therapy must be combined with debulking or radical surgery in most cases.
The literature contains several anecdotal reports of small numbers of mesothelioma patients treated with photodynamic therapy in combination with various types of debulking surgery, and there are two reports from one center of a phase II study which yielded results inferior to other published surgical series in the literature [83, 84]. Only one phase III study has been reported [85]. This also showed no benefit for photodynamic therapy in terms of survival or local disease control in patients also treated with a combination of debulking surgery, cisplatin, IFN- and tamoxifen [85].
Not only has photodynamic therapy proved to be ineffective clinically in trials reported to date, but there is also concern about its damaging effect on normal and healing tissues. Concern has been raised particularly about the risk of bronchopleural [84, 86] and esophagopleural [86-88] fistula, and in one series the combination of pleuropneumonectomy and intracavitary photodynamic therapy was associated with a mortality of 28.6% [84].
A small number of enthusiastic scientists and physicians continue to investigate photodynamic therapy in mesothelioma using newer technology and different photosensitizing agents in combination with various additional treatment modalities. Further trials are awaited with interest. However, on currently available evidence, it seems unlikely that this type of therapy will become part of the standard treatment for mesothelioma in the near future.
Palliative Therapy
In patients whose performance status is poor or whose tumor has reached an advanced stage (III or IV), palliative therapy may have a role in helping to relieve the pain of chest wall involvement or the dyspnea due to recurrent pleural effusion. Radiotherapy has already been mentioned as a means of controlling chest wall pain. Strong opiates will almost certainly be required also, and in patients with intolerable pain, cordotomy may need to be considered. In patients with recurrent pleural effusion, thoracoscopy and instillation of talc can be useful to induce pleural adhesion [89], but only if the underlying lung is not so restricted by tumor on its surface that it will not expand sufficiently to reach the chest wall. If the lung has little or no tumor on its surface, outpatient management may be possible, using a small-bore catheter and a drainage bag in conjunction with sclerotherapy [90]. Pleuroperitoneal shunts are inadvisable as they risk seeding tumor into the peritoneal cavity. If the lung is restricted by tumor and recurrent effusions are troublesome, local treatment with chemotherapy, radiotherapy or immunotherapy may be worthwhile as a means of shrinking tumor on the lung surface sufficiently to allow re-expansion. However the natural history of advanced disease is that eventually the lung becomes fixed in a position midway between full expansion and complete collapse by contiguous tumor and progressive fluid formation ceases.
It has been suggested on theoretical grounds that cytokine inhibitors may have a role in palliative therapy by helping to control pain and cytokine-mediated paraneoplastic effects such as cachexia, fever and the thrombophilia associated with thrombocytosis [52]. No clinical studies have been reported.
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