Interventions for the management of malignant pleural effusions

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To ascertain the optimal management strategy for malignant pleural effusion in adults over the age of 16 based on current evidence. We will evaluate the different pleurodesis agents and methods of pleurodesis administration, along with a variety of methods that have been proposed to improve pleurodesis success rates. In addition, we will compare instillation of a sclerosant into the pleural cavity with indwelling pleural catheters as a means to obtain an effective pleurodesis. Importantly we will assess the safety of the different interventions and their adverse effect profiles and we will attempt to ascertain which treatment approach is most acceptable to patients.

Background

Malignant pleural effusion is a common clinical problem, with an estimated annual incidence of at least 150,000 in the USA alone (American Thoracic Society 2000). Fifteen percent of patients diagnosed with cancer will develop pleural effusion during the course of their disease and it often confers a poor prognosis (Rodrîguez-Panadero 1989). Breathlessness results from compression of the underlying lung and impaired diaphragmatic and chest wall movement. This dyspnoea and the need for recurrent hospital attendances and procedures has a detrimental impact on the quality of life of patients with advanced cancer. Current management strategies include fluid drainage and talc pleurodesis, which have limited success rates and often require repeated procedures. The optimal drainage and pleurodesis method and agent remains a subject of debate (Roberts 2010). A newer approach involves the insertion of an indwelling pleural catheter under local anaesthesia to allow fluid drainage to be performed in the community. The precise role for this technique is yet to be fully defined (Roberts 2010).

Description of the condition

Malignant pleural effusion is a condition whereby fluid accumulates in the pleural cavity, caused by direct pleural invasion by tumour cells resulting in increased permeability of the pleural microvessels and involvement of local lymph nodes causing reduced fluid reabsorption (Rodrîguez-Panadero 2008). The most common primary sites which metastasise to the pleura are lung cancer in men and breast cancer in women, but other sites include lymphoma, genitourinary and gastrointestinal malignancy (DiBonito 1992; Sears 1987). In addition the pleura may be the primary site of the malignancy, as is the case in mesothelioma. Survival depends on the histological type of cancer, with lung cancer having a poor prognosis and mesothelioma surviving longer (Bielsa 2008). Performance status also helps to predict prognosis (Burrows 2000), and hence the strategy used to manage the fluid may be different depending on these factors. Pleural malignancy can be diagnosed by a number of methods. The gold standard would be histocytological confirmation by either cytological analysis of pleural fluid or a pleural biopsy, which may be obtained by a variety of methods (image guided or blind pleural biopsy, thoracoscopy or surgery). Depending on the clinical situation, confirmation of malignancy elsewhere and an otherwise unexplained (usually exudative) effusion may also be attributed to malignancy.

Description of the intervention

A number of different approaches may be used to manage malignant pleural effusion and the chosen method is likely to depend on a variety of factors, including the clinical state of the patient, clinician and patient preference and the local availability of the various techniques. The current mainstay of treatment in malignant pleural effusions is removal of the pleural fluid with an intercostal chest tube followed by instillation of a sclerosant into the pleural cavity (pleurodesis) in an attempt to prevent fluid re-accumulation. The optimal strategy for pleurodesis with regards to the size of chest drain, patient positioning, use of analgesia and type of sclerosant is still the subject of debate (Roberts 2010). 

When the pleural effusion is divided into smaller discrete pockets by fibrous septations within the pleural cavity (the fluid is loculated), complete drainage of the fluid using a chest tube may not be possible. Fibrinolytics (such as streptokinase and urokinase) may be instilled via the chest tube in attempt to break up the loculations but the exact role for this technique is yet to be fully established (Davies 1999; Gilkeson 1999; Hsu 2006).

An alternative strategy for fluid drainage and pleurodesis is the use of thoracoscopy. This can either be performed under conscious sedation (local anaesthetic thoracoscopy) using either a flexible or rigid thoracoscope, or as a surgical procedure under general anaesthetic. Either way, the pleural fluid is removed and a fibreoptic camera is used to visualise the pleural cavity, loculations can be broken down and biopsies may be taken to gain a histological diagnosis. In the context of thoracoscopy, pleurodesis can either be performed at the end of the procedure, by way of talc insufflation (talc poudrage), or the following day by means of a talc slurry through the chest drain inserted after the procedure (Rahman 2010).

A newer approach in the management of malignant pleural effusion is the use of indwelling pleural catheters. These are chest tubes, which are tunnelled under the skin and allow the drain to stay in for longer periods of time. Intermittent fluid drainage can then be performed in the community and by so doing prevent recurrent hospital attendances for patients with advanced cancer. They have an established role in the management of pleural effusions in patients with 'trapped lung', but are increasingly being used for the primary management of malignant effusions as an alternative to chemical pleurodesis (Davies 2012). In many patients, after a period of time with regular drainage, the drain output reduces and spontaneous pleurodesis occurs, allowing the drain to be removed again without recurrence of the effusion (Tremblay 2006).

In certain clinical scenarios, none of the above options may be suitable and simple pleural fluid aspiration or medical management of a patient's breathlessness with alternative techniques (for example opiates) may be deemed more appropriate. This may be the case for patients in the terminal phase of their illness where invasive techniques are felt best to be avoided.

How the intervention might work

Pleurodesis aims to produce fibrosis of the pleura by chemical or mechanical (surgical) means in order to obliterate the pleural space and by so doing prevent fluid recurrence. For pleurodesis to be successful the visceral and parietal pleural surfaces must be apposed and hence if lung expansion is incomplete, pleurodesis is more likely to fail. If the effusion is loculated, the chest tube may not access all the discrete pockets of fluids. In this situation, fibrinolytic have been used to break up the loculations and allow more complete drainage and aid subsequent pleurodesis (Davies 1999;Gilkeson 1999; Hsu 2006).

In cases of 'trapped lung', where full lung expansion is not possible due to the visceral pleura being thickened with a 'peel' or endobronchial obstruction, pleural apposition will also not occur and results in pleurodesis being less effective. This can significantly limit the treatment options for these patients. The use of indwelling pleural catheters may be used in this situation. They allow intermittent drainage of the fluid and also stimulate an inflammatory reaction within the pleura, resulting in spontaneous pleurodesis in up to 50% of patients (Putnam 2000).

Why it is important to do this review

Due to the advent of newer pleural interventions, such as thoracoscopy and indwelling pleural catheters, the management options available to patients with malignant pleural effusions are enlarging. The possibilities are often costly and require invasive procedures which are unpleasant for the patient and may require a hospital admission. This review will help to delineate the specific role and technique for the more established strategy of chest drainage and pleurodesis and also identify evidence for the use of these newer management strategies. This review will include an update of a Cochrane systematic review first published in 2004 'Pleurodesis for malignant pleural effusions' (Shaw 2004), and will subsequently help to inform national guidelines in this area.

Objectives

To ascertain the optimal management strategy for malignant pleural effusion in adults over the age of 16 based on current evidence. We will evaluate the different pleurodesis agents and methods of pleurodesis administration, along with a variety of methods that have been proposed to improve pleurodesis success rates. In addition, we will compare instillation of a sclerosant into the pleural cavity with indwelling pleural catheters as a means to obtain an effective pleurodesis. Importantly we will assess the safety of the different interventions and their adverse effect profiles and we will attempt to ascertain which treatment approach is most acceptable to patients.

Methods

Criteria for considering studies for this review

Types of studies

We will only include reports of randomised controlled trials (RCTs) in this review. This will include randomised cross-over trials and cluster randomised trials. We will consider single and multi-centre studies.

Types of participants

Inclusion
  • Adults over the age of 16

  • Symptomatic pleural effusion resulting from an underlying malignant process (of any type and stage)

Exclusion
  • Studies recruiting both malignant and non-malignant participants with no clear distinction between the two groups in the results section

  • Studies evaluating the effect of a drug administered via any method other than the intra-pleural route

  • Studies including patients with effusions within a variety of body cavities (e.g. pleural, peritoneal and/or pericardial), where the effect of the treatments in the subgroup of patients with pleural effusions can not be distinguished in the results section

Types of interventions

We will identify studies by comparing the following.

  • Type of sclerosant.

  • Mode of administration of sclerosant (thoracoscopic pleurodesis and bedside pleurodesis).

  • Bedside or thoracoscopic pleurodesis and indwelling pleural catheter insertion.

  • Techniques used to optimise pleurodesis success rate, namely:

    1. chest drain size;

    2. type of analgesia given;

    3. duration of drainage after instillation of sclerosant;

    4. patient positioning after pleurodesis (for example, patient rotation);

    5. use of intrapleural fibrinolytic.

A thoracoscopic procedure entails drainage of the pleural fluid and direct visualisation of the pleural space and may be performed under general anaesthetic or sedation. Talc poudrage is the technique whereby a sclerosant is instilled into the pleural cavity during a thoracoscopy. Instillation of sclerosant at the bedside through a chest drain is known as a 'bedside pleurodesis' or 'slurry'.

Types of outcome measures

Primary outcomes
  1. Efficacy of pleurodesis

Definitions of pleurodesis success vary significantly between studies and although current practice would define this by a lack of recurrence of symptoms or need for a repeat pleural intervention to manage the effusion, in some older studies, less clinically relevant definitions may have been used (for example, reaccumulation of effusion on radiology). These studies will still be included in the review and the method used to define pleurodesis will be documented for all studies in the assessment of the risk of bias.

For the purposes of the primary outcome, the following hierarchy of preferences will be used to judge pleurodesis failure (with the highest of these reported by any particularly study to be used):

  • need for a repeat pleural procedure to manage recurrence of the effusion, or ongoing drainage of pleural fluid from an indwelling pleural catheter (if applicable);

  • evidence of significant pleural fluid reaccumulation on radiology (for example, chest x-ray or ultrasound);

  • pleurodesis failure in the opinion of the trial investigators.

Similarly, the time point used to define pleurodesis efficacy will be selected using the following hierarchy of preferences:

  • 2-4 months;

  • > 4-7 months;

  • > 7- 11 months;

  • >11-12 months;

  • < 2 months;

  • >12 months.

Patients who die before the time point at which pleurodesis efficacy is being assessed, but were deemed to have had a successful pleurodesis until their death, will be included as a pleurodesis success. Similarly, if they were deemed to have had a pleurodesis failure prior to their death (as judged by any of the above criteria) they will be classified as a pleurodesis failure. If data are not available regarding the efficacy of pleurodesis prior to their death, they will be excluded from the analysis.

Secondary outcomes
  • Adverse effects and complications due to interventions

  • Patient reported control of breathlessness, as measured by a valid and reliable scale (for example, visual analogue scale, numeric rating scale or dyspnoea/breathlessness specific multidimensional scale)*

  • The participants' quality of life and symptom control (including pain), as measured by a valid and reliable scale*

  • Relative costs of the comparative techniques as reported by the individual trials*

  • The overall mortality in the short, medium and long term

  • Median survival

  • Duration of inpatient stay in days (both total length of stay and from time of intervention until discharge)*

  • Patient acceptability of the interventions as judged by a valid scale (for example, visual analogue scale or numeric rating scale)*

* if available

Search methods for identification of studies

Electronic searches

To identify studies for inclusion in this review, search strategies were developed for the following databases:

  • the Cochrane Controlled Trials Register (CENTRAL) (The Cochrane Library);

  • MEDLINE (Ovid);

  • EMBASE(Ovid);

  • CINAHL;

  • Web of Science Science Citation Index Expanded (SCI-EXPANDED) and Social Sciences Citation Index (SSCI).

The search strategy can be viewed in Appendix 1.

Searching other resources

We will screen the reference lists from the included studies for additional publications. We will also search the reference lists from relevant chapters in key resources, such as the British Thoracic Society Pleural Disease Guidelines 2010Roberts 2010.

Data collection and analysis

Selection of studies

All titles and abstracts retrieved by the search will be screened for relevance by one author (AC). Potentially eligible studies will be identified and we will obtain the full papers. Two authors (AC and NM) will independently assess each study for inclusion to the review and any disagreement will be resolved through discussion or by a third author (NP).

Data extraction and management

Data from each included study will be extracted independently by two of the authors (AC, NM, NP, RB). Disagreements will be resolved through discussion and referral to a third author. Data collected will include the following.

  • Publication details including:

    • title, author(s), date, country and other citations details;

    • study aim and design.

    • primary and secondary outcomes;

    • number of participants randomised.

  • Participant characteristics including:

    • cancer type;

    • confounding variables.

  • Details of the interventions and comparison group including type of intervention, duration, dose, mode of administration and number of doses.

  • Primary and secondary outcome measures (as detailed above) and data on adverse events and complications.

  • Study quality, including:

    • assessment of risk of bias;

    • whether intention to treat analysis was used;

    • whether a power calculation was performed;

    • comparability of study groups at baseline.

Additional data will be requested by authors as required. Data suitable for pooling will be entered into the Cochrane Collaboration's statistical software, Review Manager 2013, by one author (AC).

Assessment of risk of bias in included studies

This section is taken from the PaPaS template for protocols. We will limit inclusion to studies that are randomised as a minimum.

Two of the review authors (AC, NP, RB, NM) will independently assess risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and adapted from those used by the Cochrane Pregnancy and Childbirth Group, with any disagreements resolved by discussion. We will assess the following for each study.

Random sequence generation (checking for possible selection bias)

We will assess the method used to generate the allocation sequence as: low risk of bias (any truly random process, e.g. random number table; computer random number generator); unclear risk of bias (method used to generate sequence not clearly stated). Studies using a non-random process (e.g. odd or even date of birth; hospital or clinic record number) will be excluded.

Allocation concealment (checking for possible selection bias)

The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We will assess the methods as: low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes); unclear risk of bias (method not clearly stated). Studies that do not conceal allocation (e.g. open list) will be excluded.

Blinding of outcome assessment (checking for possible detection bias)

We will assess the methods used to blind study participants and outcome assessors from knowledge of which intervention a participant received. We will assess the methods as: low risk of bias (study states that it was blinded and describes the method used to achieve blinding, e.g. identical tablets; matched in appearance and smell); unclear risk of bias (study states that it was blinded but does not provide an adequate description of how it was achieved); high risk of bias (study not blinded or no mention of blinding in the methodology).

Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We will assess the methods used to deal with loss to follow up for each of the given studies. Due to the challenges of inevitable missing outcome data given the predictable attrition of patients due to death in the palliative care population, we will take into account whether missing data has been justified, whether the rate is similar in the different treatment arms, whether the treatment being evaluated was felt to have an impact on the degree of missing outcome data and whether an intention to treat analysis has been attempted. We will assess the methods used to deal with incomplete data as: low risk (Rate of missing data is balanced between the treatment arms, seems reasonable and has been justified. Data has been analysed according to the patients randomised treatment allocation. A suitable imputation method may have been used to account for missing data); unclear risk of bias (insufficient information given to allocate trial to 'high' or 'low' risk group); high risk of bias (imbalanced missing outcome data between the treatment arms or missing outcome data felt to be related to the true outcome.  Reasons for loss to follow up poorly justified. No attempt at ITT analysis. Inappropriate imputation used).

Selective Outcome Reporting

We will assess the studies for selective outcome reporting using the following criteria: low risk of bias (all outcomes pre-defined and reported, for example in a published protocol, or all clinically relevant and reasonably expected outcomes were reported); uncertain risk of bias (unclear whether all pre-defined and clinically relevant outcomes were reported); high risk of bias (one or more clinically relevant and reasonably expected outcome was not reported and data on these outcomes were likely to have been recorded).

Size of study (checking for possible biases confounded by small size)

We will assess studies as being at low risk of bias (≥ 200 participants per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); high risk of bias (< 50 participants per treatment arm).

Other sources of bias

This section will be used to report other biases, which are detected but do not fit into the above categories (for example, industry bias, academic bias or other methodological flaws that may have caused bias). We will assess the methods used to deal with other sources of bias as: low risk (the trial appears to be free from other potential biases); unclear risk of bias; high risk of bias (other source of bias identified).

Measures of treatment effect

For proportions (dichotomous outcomes), such as pleurodesis efficacy and mortality, we will calculate the risk ratio (RR) with 95% confidence intervals (CIs). For continuous data (such as length of hospital stay and cost) we will estimate the mean difference (MD) with 95% CIs. We will calculate the number needed to treat (NNT) to benefit for efficacy outcomes, and the number needed to harm (NNH) for adverse events.

Ordinal outcome measures (for example, breathlessness scales and quality of life data) will be converted to continuous outcomes as long as the scale is long enough. If different scales are used by the included studies, the standardised mean difference will be used.

Unit of analysis issues

If repeated observations on the same participants have occurred during the trial (for example, pleurodesis success rate at different time points), we will analyse these separately. Only one measure per participant will be used for the primary endpoint (Primary outcomes).

For the purpose of meta-analysis, if a study has multiple doses for a certain substance, we will combine and compare all relevant experimental intervention groups with the combination of all relevant control groups.

For cross over trials, we will analyse data using paired-wise analysis taking into account the cross-over design. We will use the generic inverse variance method.

If meta-analysis is planned containing cluster randomised trials, we will use the generic inverse variance method.

Dealing with missing data

We will attempt to contact the study authors of included studies to clarify any missing data. We will impute the missing standard deviations based on the average standard deviations from the other included studies if standard deviations for mean scores have not been reported and it is not possible to obtain the information from the authors. We will only include data for those participants whose results are known if an intention to treat analysis is not reported by the study. However, we will address the potential impact of this missing data in the risk of bias table.

Assessment of heterogeneity

We will extract data from study reports regarding clinical heterogeneity such as details on intervention and control treatment, participant characteristics and the outcomes evaluated.

We expect a degree of clinical heterogeneity between the included study results because of the different methods which can be used to define pleurodesis failure and the different time points it can be assessed at. We will therefore use the random-effects model for the primary outcome measure and the fixed-effects model for sensitivity analysis.

We will quantify the heterogeneity across studies using the I2 statistic, which will be interpreted taking into account the magnitude and direction of effect as well as the confidence interval. Assessments of whether or not a meta-analysis is appropriate will be made on the basis of clinical rather than statistical heterogeneity.

Assessment of reporting biases

We will perform searches in multiple databases to ensure all potentially eligible studies are identified (Electronic searches). The review authors will be alert to duplicated publication of results when analysing the studies to ensure each participant is only included once in the analysis.

If unpublished studies are identified, efforts will be made to obtain sufficient information in order for them to be included in the analysis. The same applies for data published in abstract format.

In studies published in a language other than English, every effort will be made to obtain a translation of at least the abstract. If sufficient information is available, the study may then be included in the analysis.

Data synthesis

We will perform meta-analysis to describe the overall results if the studies are considered clinically similar enough for this to be appropriate. Since we expect some clinical heterogeneity between studies (for example due to different definitions of pleurodesis success and different time points used), we believe that the assumption of a single fixed intervention effect across included studies is unlikely to be valid. Our primary analyses will therefore employ random-effects models. Since pooled effect estimates from random-effects models give relatively more weight to smaller studies, which is often considered undesirable, we will however perform sensitivity analyses using fixed-effect meta-analysis models. Meta-analysis will be performed using the Cochrane Collaboration's statistical software, Review Manager 2013.

For continuous data we will use the MD and 95% CIs. We will use the random-effects model if meta-analysis is performed(as we are expecting clinical heterogeneity). We will perform a check to identify if the data are skewed. If this is the case, the data may be analysed on a log scale.

If cluster randomised trials are included in the analysis, we will use the generic inverse-variance method.

To provide a comprehensive assessment of the relative efficacy of the many available pleurodesis agents, we will present pair wise comparisons of the individual agents where possible. In addition, we will perform a multiple interventions meta-analysis. and compare the findings.

If studies are assessed to be unsuitable for meta-analysis, or should insufficient studies be identified for meta-analysis to be performed, we will present data by means of a narrative synthesis. Convergence between the meta-analysis results and the narrative review will be viewed as an indication of strong evidence of the effect.

The adverse effects reported in the studies will be summarised in a qualitative manner, as there is unlikely to be sufficient data to perform meta-analysis.

Subgroup analysis and investigation of heterogeneity

If sufficient data exists, we will conduct subgroup analyses comparing:

  • the method by which pleurodesis failure was defined;

  • the time point at which pleurodesis efficacy was assessed (≤ 6 months and > 6 months after the intervention);

  • different tumour types;

  • baseline performance status;

  • age of participants (young, middle aged and old);

  • the presence or absence of trapped lung.

Sensitivity analysis

We will perform sensitivity analysis according to the methodological quality and robustness of the results where available. The sensitivity analyses will be selected from important elements of the risk of bias tool where studies with high risk of bias are identified.

Acknowledgements

Cochrane Review Group funding acknowledgement: The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane PaPaS Group. Disclaimer: The views and opinions expressed in this review are those of the authors and do not necessarily reflect those of the NIHR, National Health Service (NHS) or the Department of Health.

Appendices

Appendix 1. MEDLINE search strategy (via Ovid)

1   exp Pleural Effusion/
2   (pleura* adj5 (effusion* or fluid*)).mp.
3   1 or 2
4   exp Neoplasms/
5   (cancer* or tumor* or tumour* or neoplas* or carcinom* or malignan*).mp.
6   4 or 5
7   randomized controlled trial.pt.
8   controlled clinical trial.pt.
9   randomized.ab.
10  placebo.ab.
11  clinical trials as topic.sh.
12  randomly.ab.
13  trial.ti.
14  7 or 8 or 9 or 10 or 11 or 12 or 13
15  3 and 6 and 14

key:

mp = protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier

pt = publication type

sh = subject heading

ab = abstract

ti = title

What's new

DateEventDescription
21 August 2014AmendedUpdated the authors' Declaration of Interest statements.

Contributions of authors

The protocol was written collaboratively by all authors. 

AC will conduct the title search and collect the full-text papers.

AC, NP, RB and NM will perform the data extraction.

AC will enter the data in RevMan.

HJ will provide statistical support.

AC and NM will write the final report.

AC and NM will be responsible for the update.

Declarations of interest

NM has received research funding from CareFusion. He has also received honoraria from CareFusion for medical advisory board meetings in the past, although is not actively involved in any at present. This has no direct link with the Cochrane Review.

AC has received an educational grant and support for conference travel costs from CareFusion in 2012, unrelated to this review.

HJ has received honoraria from Novartis Pharma AG for consultancy on statistical methodology.

RB has received honoraria for educational lectures from AstraZeneca and GlaxoSmithKline, and educational grants from Novartis and GlaxoSmithKline.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • None, Other.

Ancillary