In this blog for respiratory and palliative care physicians, Dr Vineeth George, Dr Radhika Banka and Professor Najib Rahman look at the latest Cochrane evidence on the optimal management strategy for patients with malignant pleural effusions.
“So doc, what would you choose?”
For those of us who deal with malignant pleural effusions (MPE) this is not an uncommon question. It’s usually heard at least once a week, often after discussion of multiple treatment options, and usually after the patient involved has been subjected to at least one diagram from those whose art skills haven’t progressed since the first grade.
Yet even for specialists in the area this is a vexed question with an elusive answer. For decades there was little in the way of choice. Patients underwent the insertion of a chest drain with subsequent admission to the ward for intrapleural instillation of a sclerosant such as talc, to promote pleurodesis, which would limit fluid recurrence and this formed the basis for most trials.
However, the last decade has seen major advances in our ability to manage MPEs and a number of high-quality studies have examined the benefits of various drainage strategies. Patients now have a myriad of management options, and modern treatment algorithms can often mean that pleural fluid control can occur outside of hospital. However, this has made decision making increasingly complex both for patients and the healthcare professionals caring for them.
A Cochrane Review from the Cochrane Pain, Palliative and Supportive Care Group, published in April 2020, aimed to identify the most effective approach to achieve pleurodesis in adults with malignant pleural effusion. It provides a synthesis of the latest research, in particular incorporating a number of recent trials which have examined drainage strategies for indwelling pleural catheters (IPC). To do this, the authors performed a network meta-analysis (NMA) to allow comparison of the multiple interventions and pleural fluid drainage strategies now available.
What does the evidence tell us?
This review identified 80 randomised controlled trials (RCTs) of pleural interventions, involving 5507 adult patients with symptomatic MPE. 55 of these studies, evaluating 21 interventions, were included in the primary NMA.
This demonstrated that compared to placebo, talc slurry is probably effective at inducing pleurodesis (moderate-certainty evidence). It also appears to have a lower rate of pleurodesis failure than bleomycin or doxycycline (low-certainty evidence).
Although a number of other agents appeared to rank high in the primary network analysis they were only evaluated by small, poor quality studies. The authors concluded that these were insufficient to provide conclusions for routine clinical practice.
The network meta-analysis also suggested that talc poudrage, where talc is directly instilled at thoracoscopy, is likely to have a comparable rate of pleurodesis failure when compared to talc slurry, and this finding was more pronounced when analysis was limited to studies with low levels of bias.
The use of an IPC with a conservative drainage regimen was also considered to be likely to be less effective at inducing pleurodesis than talc poudrage or slurry (moderate-certainty evidence). The rate of pleurodesis appears to increase if the IPC is drained daily, or if talc is administered through the catheter. However, these strategies were still ranked below talc poudrage and slurry in the NMA. Conversely, direct meta-analysis of three studies comprising of over 300 patients in total has shown that individuals with an IPC are less likely to need any further pleural intervention. IPCs were also found to be cost effective and were associated with a reduced length of stay when used in patients with limited survival.
There were insufficient data to perform NMAs on secondary outcomes such as breathlessness, quality of life or mortality. However, direct meta-analysis of two of the randomized controlled trials suggests that there is no difference in breathlessness assessed on a visual analogue scale in patients receiving IPCs compared to those receiving chest drain and pleurodesis.
Analysis of the adverse effects was limited by low certainty evidence but suggested that there was little difference between interventions in the risk of developing fever or procedure-related pain compared with talc slurry.
Limitations and areas of uncertainty
The authors note that there was a substantial risk of bias in several studies and evidence was downgraded in the primary NMA and a number of the other analyses. Rates of attrition were high throughout and the vast majority of studies were not blinded. However, this is unsurprising given the poor life expectancy associated with malignant pleural disease and the nature of the pleural interventions themselves.
Like previous reviews in the area, this review is also limited by the heterogeneity of the trials involved. Varying definitions of pleurodesis failure were used with 19 (24%) of the studies using radiological criteria alone. Furthermore, widely varying timepoints were used to assess pleurodesis effectiveness and a range of doses were used for many of the pleurodesis agents. Although these were anticipated, and their handling specified a priori they may still have impacted on the results of the NMA.
Towards patient-centred care
This review is scientifically robust and offers new insight into the management of MPEs. However, pleurodesis is only a small part of the MPE story. Perhaps the most alarming finding is how little patient-centered data we truly have.
Only 3 of the 80 trials (3.8%) reported the patient acceptability of interventions. No trial assessed quality of life as a primary outcome or reported on the continuing burden of domiciliary IPC drainage.
For many of our patients the true impact of a malignant pleural effusion and its management are not apparent until catheters are tunneled in place or talc laid down.
Many are surprised by the lengths of hospital admission, the ensuing pain or the relatively high rates of procedure failure in real world settings. Others gradually see their living rooms, which were once a personal haven filled with the odd spot of TV, their dog and a glass of wine, transformed into clinical spaces by thrice-weekly healthcare intrusion for IPC drainage.
The reality is that anticipating these responses and guiding our patients through the available options remains as hard as ever.
However, things are changing. Recent trials have demonstrated an increasing focus on patient-centred outcomes. The OPTIMUM study, which is due to report shortly, will evaluate quality of life as a primary outcome in patients who are randomized to receive talc either via a chest drain or an IPC. Web based decision-making tools will limit the number of diagrams that need to be drawn in clinics around the world.
This combination of innovative strategies and emerging data will help us to move beyond what ‘(we) would do’ and help our patients decide what they would want.
Join in the conversation on Twitter with @CochraneUK and @CochranePaPaS leave a comment on the blog. Please note, we cannot give medical advice and we will not publish comments that link to commercial sites or appear to endorse commercial products.
Dipper A, Jones HE, Bhatnagar R, Preston NJ, Maskell N, Clive AO. Interventions for the management of malignant pleural effusions: a network meta‐analysis. Cochrane Database of Systematic Reviews 2020, Issue 4. Art. No.: CD010529. DOI: 10.1002/14651858.CD010529.pub3.
Declaration of interest:
Vineeth George reports personal fees from Teva UK Ltd, outside the submitted work. Radhika Banka has nothing to disclose. Najib Rahman reports grants and personal fees from Rocket Medical UK, grants from BD USA, personal fees from Cook Medical, during the conduct of the study.