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Malignant pleural effusion accounts for 22% of all pleural effusions, and affects about 300 000 patients annually (UK and USA). Approximately 50% of patients with breast cancer, 25% of those with lung cancer and >90% with pleural mesothelioma develop a symptomatic malignant pleural effusion. Thoracentesis provides effective short term symptomatic relief but most large malignant pleural effusions recur,1 and pleurodesis is then the standard treatment. A wide range of compounds have been used as pleurodesing agents, but talc is preferred by the majority of respiratory physicians worldwide.2
The Medicines and Healthcare Products Regulatory Authority (MHRA) has recently completed an urgent review of the safety of talc as a pleurodesis agent for malignant effusion, reclassifying it as a medicinal product rather than medical device.3 This review requires that from January 2008, manufacturers must submit regulatory data if they wish their talc preparation to be used for pleurodesis. This is a milestone on the path towards improved care for malignant effusion as it heralds the first time an agent for intrapleural administration will be regulated under the systems used for biologically active drugs.
Talc is a magnesium silicate hydroxide (Mg3(Si2O5)2(OH)2) and is mined, milled and sterilised prior to clinical use, although these processes still sometimes leave behind mineral or organic contaminants. The MHRA review was a response to evidence that some of the preparations produced by these processes, and considered safe for pleurodesis in the UK and USA for over 50 years, are in fact anything but. Pleurodesis preparations not sorted to remove most of the smallest talc particles (widely used in the UK and USA) are associated with clinically important hypoxaemia in humans,4 induce systemic and pulmonary inflammation after being absorbed from the pleural space5–7 and were associated with death from respiratory failure in over 2% of patients when used for pleurodesis in a large US clinical trial.8 Preparations with the smallest talc particles removed (graded talc) are associated with a reduction in this risk. In a European cohort study of 558 patients treated with graded talc, no frank episodes of acute respiratory distress syndrome occurred. Assuming that it is small talc particles which are truly causal of acute respiratory distress syndrome (and not, for example, contaminants) changing to graded talc may avert up to 250 unnecessary deaths each year—a significant improvement in care.
The lesson that intrapleural therapies can cause unexpected systemic toxicity and needs to be thoroughly assessed to ensure safety is not limited to talc. Intrapleural iodopovidone, for example, can cause visual loss9 as well as severe chest pain and hypotension.10
WHERE NOW FOR TALC?
Despite the substantial safety improvement that will follow the use of graded talc, some residual questions about safety still remain. Even in the European cohort study11—seen as the strongest evidence of graded talc safety—7/558 (∼1.5%) patients developed radiographic pulmonary infiltrate after talc administration. There was also a general increase in post-procedure oxygen requirements, which is consistent with the hypoxaemia seen in a subset of subjects after graded talc administration in human physiological studies.4 This hypoxaemia is despite the procedure being one in which substantial pleural effusions are drained, and improvement in respiratory function would be expected. These pointers hint at some residual pulmonary toxicity despite removal of most small size talc particles, and imply that vigilance for talc associated lung inflammation should be maintained in the future.
The “post-marketing” adverse event monitoring for talc will be regulated by the usual drug monitoring systems. This will encourage the highest standards of quality control as licensing will require the achievement of prespecified product standards. For talc, this seems likely to include levels of impurities and particle size. Achieving these standards will probably raise manufacturing expenditure and alter the balance of market forces, increasing the cost of “medical grade talc” in clinical use. This is the inevitable price of higher quality patient care.
WHERE TO FROM HERE?
The focus these changes will bring to pleurodesis may also spur the search for new and better pleurodesis agents. The development of pleural symphysis is a multifactorial pathway with initial inflammation and subsequent fibrosis which obliterates the pleural space. Strategies to target specific cellular mediators of the pleural inflammatory cascade are already beginning to translate into clinical trials, and efforts focusing on the development of pleural fibrosis without inflammation are ongoing.
In animal studies, intrapleural preparations of the potent profibrotic cytokine transforming growth factor β produce an effective pleurodesis.12–15 Human trials of this agent are awaited. Less selectively, several bacterial proinflammatory moieties are being explored in an attempt to therapeutically mimic the potent pleural fibrosis induced by bacterial infection. OK-43216 ,17 (derived from Streptococcus pyogenes) has been used in Asia for several decades, although experience of its use elsewhere is limited. Staphylococcus aureus superantigen,18 and motifs derived from other gram positive bacterial cell walls, have both entered early clinical trials, although definitive studies to define their efficacy and toxicity are awaited.
IS AN ENTIRELY DIFFERENT THERAPEUTIC APPROACH WARRANTED?
If an ideal pleurodesis agent that is capable of effectively controlling fluid and free from significant adverse effects does not exist, it seems reasonable to consider entirely different management strategies for malignant effusion, and to reconsider the definition of “successful” treatment. Clinical trials have tended to focus on pleural fluid recurrence or the extent of pleural symphysis as surrogate markers of success. However, breathlessness relief, and maintaining patients’ quality of life, is actually the aim of care for these patients, and this should be the clinical trial outcome of choice.
Subcutaneously tunnelled, indwelling pleural catheters are an accepted component of care for patients with symptomatic effusions who have failed pleurodesis, or where the lung is incapable of re-expansion.19 The firstline use of such a type of catheter could permit entirely outpatient care and patient controlled fluid drainage, albeit at the cost of the catheter and drainage equipment, and potential adverse events associated with the presence of the catheter. Initial early and effective fluid drainage may also reduce the likelihood of the development of multi-septated symptomatic and difficult to evacuate effusions, which can be the result of ineffective chemical pleurodesis. Spontaneous pleurodesis rates of up to 70%20 following use of these catheters have been reported in non-randomised data, and patients’ quality of life/sense of empowerment may also improve as a result of this approach.21–23 A British Lung Foundation funded clinical trial is currently addressing some of these issues and comparing the efficacy and safety of patient controlled fluid drainage by indwelling pleural catheter with standard care.
Other non-pleurodesis based options include use of a pleuroperitoneal shunt, although the need for surgical insertion and potential shunt occlusion are disadvantages to this strategy. Surgical pleurodesis (ie, parietal pleurectomy and pleural abrasion) is effective although limited to patients of exceptionally good performance status and prognosis.
Reclassification of talc for pleurodesis as a drug is a positive step. It is likely to directly improve the safety of talc pleurodesis by influencing particle size and impurity levels, and bringing it in line with all other human medicinal products. The talc debate may also spur the development of new, better pleurodesis agents, and perhaps the complete reshaping of some aspects of care for malignant pleural effusion.
Competing interests: RJOD and HED hold/have an interest in the patent rights for the use of lipoteichoic acid- t for pleurodesis, and Rocket Medical have donated indwelling catheters to a BLF funded clinical trial assessing this therapy that is led from the Oxford Pleural Unit.