Aggressive versus symptom-guided drainage of malignant pleural effusion via indwelling pleural catheters (AMPLE-2): an open-label randomised trial

Summary

Background

Indwelling pleural catheters are an established management option for malignant pleural effusion and have advantages over talc slurry pleurodesis. The optimal regimen of drainage after indwelling pleural catheter insertion is debated and ranges from aggressive (daily) drainage to drainage only when symptomatic.

Methods

AMPLE-2 was an open-label randomised trial involving 11 centres in Australia, New Zealand, Hong Kong, and Malaysia. Patients with symptomatic malignant pleural effusions were randomly assigned (1:1) to the aggressive (daily) or symptom-guided drainage groups for 60 days and minimised by cancer type (mesothelioma vs others), performance status (Eastern Cooperative Oncology Group [ECOG] score 0–1 vs ≥2), presence of trapped lung, and prior pleurodesis. Patients were followed up for 6 months. The primary outcome was mean daily breathlessness score, measured by use of a 100 mm visual analogue scale during the first 60 days. Secondary outcomes included rates of spontaneous pleurodesis and self-reported quality-of-life measures. Results were analysed by an intention-to-treat approach. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12615000963527.

Findings

Between July 20, 2015, and Jan 26, 2017, 87 patients were recruited and randomly assigned to the aggressive (n=43) or symptom-guided (n=44) drainage groups. The mean daily breathlessness scores did not differ significantly between the aggressive and symptom-guided drainage groups (geometric means 13·1 mm [95% CI 9·8–17·4] vs 17·3 mm [13·0–22·0]; ratio of geometric means 1·32 [95% CI 0·88–1·97]; p=0·18). More patients in the aggressive group developed spontaneous pleurodesis than in the symptom-guided group in the first 60 days (16 [37·2%] of 43 vs five [11·4%] of 44, p=0·0049) and at 6 months (19 [44·2%] vs seven [15·9%], p=0·004; hazard ratio 3·287 [95% CI 1·396–7·740]; p=0·0065). Patient-reported quality-of-life measures, assessed with EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L), were better in the aggressive group than in the symptom-guided group (estimated means 0·713 [95% CI 0·647–0·779] vs 0·601 [0·536–0·667]). The estimated difference in means was 0·112 (95% CI 0·0198–0·204; p=0·0174). Pain scores, total days spent in hospital, and mortality did not differ significantly between groups. Serious adverse events occurred in 11 (25·6%) of 43 patients in the aggressive drainage group and in 12 (27·3%) of 44 patients in the symptom-guided drainage group, including 11 episodes of pleural infection in nine patients (five in the aggressive group and six in the symptom-guided drainage group).

Interpretation

We found no differences between the aggressive (daily) and the symptom-guided drainage regimens for indwelling pleural catheters in providing breathlessness control. These data indicate that daily indwelling pleural catheter drainage is more effective in promoting spontaneous pleurodesis and might improve quality of life.

Funding

Cancer Council of Western Australia and the Sir Charles Gairdner Research Advisory Group.

Introduction

Malignant pleural effusion can complicate most cancers.¹ The associated breathlessness is often distressing, debilitating, and significantly impairs quality of life.² Malignant pleural effusion accounts for more than 125 000 hospital admissions per year in the USA alone.³

Indwelling pleural catheter drainage is a new therapeutic approach for management of malignant pleural effusion, and its advantages have been confirmed in randomised trials.4, 5 Treatment with an indwelling pleural catheter significantly reduces days spent in hospital and the need for further invasive pleural procedures in patients' remaining life,⁴ compared with conventional talc slurry pleurodesis, while offering the same level of improvement in symptoms and quality of life.4, 5 Indwelling pleural catheters are increasingly being adopted worldwide as the first-line management option for malignant pleural effusion.

Research in context

Evidence before the study

Malignant pleural effusions often require pleural intervention for symptom control. Results of two multicentre trials have confirmed that an indwelling pleural catheter provides similar benefits to conventional talc slurry pleurodesis with regard to symptom control and quality of life. The AMPLE-1 randomised trial found that an indwelling pleural catheter provided added advantages over talc pleurodesis in reducing days spent in hospital, in patients' remaining lifespan, and in minimising the need for repeat invasive pleural drainage procedures. Having established the advantages and safety of indwelling pleural catheter insertion for management of malignant pleural effusions, the next step was to optimise its effectiveness by identifying its best drainage regimen. We searched PubMed for articles published before March 1, 2018, using the terms “malignant pleural effusion” AND “indwelling pleural catheter OR IPC” AND “drainage frequency” AND “breathlessness OR dyspnoea”. The only randomised controlled trial in the 11 articles found compared rates of spontaneous pleurodesis between daily drainage versus alternate-day drainage in 149 patients with malignant pleural effusions. However, many clinicians preferred drainage only when patients developed symptomatic breathlessness, as malignant pleural effusion management is mainly palliative. Aggressive (daily) versus infrequent symptom-guided drainage regimens have not been compared but have substantial implications for clinical care.

Added value of this study

The AMPLE-2 study addresses this equipoise by randomly assigning 87 patients with malignant pleural effusion to aggressive or symptom-guided drainage regimens via an indwelling pleural catheter. Both approaches provided similar breathlessness control over 60 days after randomisation. Pain scores, days spent in hospital, serious adverse events, and mortality did not differ significantly between the two groups. Aggressive drainage was associated with higher rates of pleurodesis than symptom-guided drainage and better index values on EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) quality-of-life assessment.

Implications of all the available evidence

For patients with malignant pleural effusion treated with an indwelling pleural catheter in whom early catheter removal is an important goal, daily drainage should be carried out for at least 60 days. For patients whose primary care aim is palliation, our data suggest that symptom-guided drainage offers an effective means of breathlessness control without the burden and costs of daily drainages. A recent randomised study found that talc pleurodesis can be administered via indwelling pleural catheter and enhance pleurodesis and catheter removal rate. Combining this approach with aggressive daily drainage after talc instillation to enhance the rate of successful pleurodesis should be assessed.

The logical next step is to optimise the use of this approach and hence its benefits. Few data exist to guide drainage approaches for patients with an indwelling pleural catheter. Practices vary worldwide, ranging from aggressive (daily or alternate-day) drainage, often used in centres in the USA,⁶ to drainage only when symptoms develop, which is common in the rest of the world. These differences in practice could potentially influence outcomes and complication rates.

Aggressive daily drainage arguably keeps the pleural space dry and provides best symptom control every day, whereas health-care practitioners who advocate symptom-guided drainage contend that the goal of malignant pleural effusion care is palliation and that drainage of indwelling pleural catheter is only indicated when symptoms arise. The symptom-guided approach might reduce a substantial amount of burden and consumable costs compared with daily drainage, and might reduce the risk of iatrogenic introduction of pleural infection.

Conversely, frequent indwelling pleural catheter drainage might facilitate approximation of the visceral and parietal pleura and facilitate their symphysis (so-called spontaneous pleurodesis), and allow removal of the catheter. Daily drainage has been shown to promote pleurodesis more effectively than alternate-day drainage.⁶ Whether a symptom-guided approach affects the rate of pleurodesis is unknown.

The Australasian Malignant PLeural Effusion-2 (AMPLE-2) study was designed to address the equipoise between aggressive (daily) versus symptom-guided approaches to indwelling pleural catheter drainage in patients with a malignant pleural effusion—specifically, their efficacy in breathlessness control, induction of pleurodesis, improvement of quality of life, reduction of days spent in hospital, and complication rates.⁷