© 2008 American Thoracic Society doi: 10.1164/rccm.200804-616ED
Malignant Pleural EffusionsFixing the Leaky Faucet
Oxford Center for Respiratory Medicine
Centre for Respiratory Research Malignant pleural effusion affects over 150,000 patients each year in the United States, often depriving patients with cancer of their quality of life, and is associated with significant health care costs (1). Metastatic adenocarcinomas, especially from primary lung and breast cancers, are the commonest causes. Pulmonologists, in an international survey of 859 participants (2), were generally dissatisfied with available treatments, including pleurodesis, for malignant pleural effusions. For decades, research efforts have focused on developing more potent pleurodesing agents and on drainage techniques but have yet to produce significant breakthroughs. Talc pleurodesis, first introduced in 1930s, remains the mainstay of treatment.
The study by Stathopoulos and colleagues (3), in this issue of the Journal (pp. 50–59), is both topical and exciting. In a murine model of malignant pleural effusions, administration of zoledronic acid significantly reduced pleural effusion and tumor load, and prolonged survival. This study is timely because the principle and safety of pleurodesis have increasingly been questioned. The Medicines and Healthcare Products Regulatory Agency in the United Kingdom has recently sought to reexamine the safety and licensure of talc preparations (4). Talc pleurodesis has a suboptimal success rate ( Stathopoulos and coworkers examined an appealing management approach through targeting the formation of malignant effusions. This has been a challenging task, hampered by a lack of suitable preclinical models. Animals with intact immunity can usually eliminate injected human cancer cells. Prior studies of malignant effusions had to use mice rendered immunodeficient, which prohibited the study of host defense interactions or evaluation of therapeutic compounds. The authors have recently overcome this hurdle by developing a model of malignant pleural effusions in immunocompetent mice using murine (Lewis) lung adenocarcinoma cells (9). This model represents a giant step forward for translational research in pleural malignancies. Malignant pleural diseases involve a complex interplay among metastatic cancer cells, resident mesothelial cells, and inflammatory cells (10). An array of mediators produced by these cells, and those derived from systemic circulation, induce vascular permeability, plasma extravasation, and resultant fluid accumulation. Antiangiogenic compounds that can reduce tumor neovascularization and vascular hyperpermeability are therefore attractive therapeutic candidates for pleural malignancies (11). This study is the first to examine the effect of bisphosphonates in pleural diseases. Recent literature suggests that nitrogen-containing bisphosphonates, among which zoledronic acid is the most potent, have strong antiangiogenic and anticancer activities (12). Patients with cancer who were given zoledronic acid had reduced circulating levels of vascular endothelial growth factor (VEGF), a key mediator of pleural vascular hyperpermeability (12). Although bioavailability of zoledronic acid in the pleura is unknown, bisphosphonates are structurally similar to technetium Tc 99m hydroxymethylene diphosphonate, a bone scintigraphic tracer known to diffuse readily into malignant pleural effusions (13). Zoledronic acid inhibits the mevalonate pathway and prenylation of small G-proteins in cancer cells and impairs their survival, migration, invasion, and angiogenesis (12, 14). Additional immunomodulatory actions against cancer have also been reported (14). Zoledronic acid is active against many cancer cell types in vitro and in vivo (13, 14). In the model of pleural adenocarcinoma used by Stathopoulos and colleagues, treated mice had an approximately 50% reduction of pleural effusion volume, resulting from reduced tumor deposits, inhibition of neovascularization, and decreased vascular permeability. Treatment with zoledronic acid reduced tumor load—from enhanced apoptosis and alteration of proinflammatory and angiogenic mediators—and prolonged survival. Successful application of antiangiogenics to stop effusion formation in pleural malignancy can potentially revolutionize clinical care and negate the need for interventional procedures, such as pleurodesis. This approach may benefit patients with trapped lung (malignant encasement prohibiting full lung expansion), in whom pleurodesis is contraindicated (1). It could potentially provide dramatic symptom control for dyspnea, and improve quality of life. Zoledronic acid is clinically available, affordable, and well tolerated (11). The results from Stathopoulos and colleagues lay the foundation for clinical assessment of zoledronic acid in malignant effusions. In particular, whether the therapeutic effects of zoledronic acid against murine Lewis carcinomas apply to human cancers will require evaluation by clinical trials. This report is a proof-of-principle study in which malignant effusion was examined in a compartmentalized fashion because adenocarcinoma cells were introduced intrapleurally. In humans, metastatic malignancies are not confined to the pleura; mortality is dictated strongly by tumor spread outside the pleural cavity. It is questionable whether the survival benefits suggested by this study would hold true if the tumor is present systemically. On the other hand, mesothelioma is a universally fatal cancer of rising incidence and is largely confined within the pleural cavity. Zoledronic acid has shown activity in a peritoneal model of mesothelioma (15); patients with pleural mesothelioma would be an ideal population for early-phase trials. In the study by Stathopoulos and colleagues, zoledronic acid inhibited cancer cell growth independently of effects on Rho-A and angiogenic cytokines, such as VEGF. The possibility of synergism between zoledronic acid and other antiangiogenics and/or chemotherapeutic agents in pleural malignancies deserves exploration (14). It has been suggested that zoledronic acid may have a direct antinociceptive mechanism—a potential added benefit for those with chest pain from cancer infiltration of the parietal pleura. In this animal study, zoledronic acid was equally effective when administered near the time of tumor injection (preventive model) or delayed until malignant effusion developed (regression model). The concept of preventing metastatic pleural disease is intriguing. With advances of cancer genetics and epidemiology, it may be possible in the future to identify patients with cancer at high risk of developing pleural effusions, for which a preventive approach may be possible. Malignant pleural effusion is a growing problem. This report rekindles interest in tackling this important clinical issue by attacking the root of the problem—excessive fluid formation. It also provides a validated preclinical model that will help provide much needed insight into the pathophysiology of malignant pleural diseases. Antiangiogenic agents have shown early promise against benign recurrent exudative effusions (16). The benefits of ‘turning off’ pleural fluid formation may well extend beyond pleural effusions of malignant etiologies. Acknowledgments The authors received research grants from the Medical Research Council (UK) and Rosetrees Trust. FOOTNOTES Conflict of Interest Statement: Y.C.G.L. is a co-investigator of a British Lung Foundation funded randomized trial on indwelling pleural catheters; the catheters used in the trial are provided free by Rocket UK, Ltd. S.W. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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75%), even in selected patients in whom lung reexpansion is achieved (
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