Radiation therapy for preventing instrumentation track metastases in malignant pleural mesothelioma
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of radiation therapy for preventing instrumentation track metastases in malignant pleural mesothelioma.
Secondary objectives include to determine:
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the true incidence of instrumentation track metastases in contemporary MPM patient populations;
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the impact of patient characteristics (e.g. histological subtype of MPM) and intervention characteristics (e.g. maximally invasive versus minimally invasive) on the risk of developing instrumentation track metastases;
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the impact of radiation treatment on secondary patient outcomes such as quality of life, survival time, and disease‐free interval; and
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the incidence of irradiation‐induced dermatitis in MPM patients receiving prophylactic radiotherapy.
Background
Malignant pleural mesothelioma (MPM) is an often fatal neoplastic disease involving the serosal cells of the lung pleura (Robinson 2005). The risk of developing MPM is directly related to exposure to asbestos, a carcinogen once commonly found in construction materials (Hodgson 2000). The incidence of the disease has increased globally since the mid‐20th century, placing a considerable burden on public health resources (Delgermaa 2011). Many industrialised countries are predicted to reach peak MPM incidence within the next 10 years (Robinson 2012). Developing countries often do not impose asbestos restrictions and will consequently experience an increasing mesothelioma burden in the future. Considering the epidemic nature of MPM, it is imperative to establish effective clinical guidelines for the diagnosis and management of the disease through systematic evaluation of clinical trial data.
Description of the condition
The diagnosis of MPM requires histopathological specimens for confirmation. Several histological subtypes exist; the major variants include: epithelioid, sarcomatoid and mixed MPM (Husain 2012). It is not uncommon for the investigation of a suspected case of MPM to involve several invasive procedures, including thoracocentesis with cytological analysis, fine needle aspiration and direct thoracoscopic biopsy (Scherpereel 2008). A known complication of these MPM investigations is the development of instrumental track metastases (Boutin 1995). These metastatic deposits are formed by malignant mesothelioma cells which seed to the cutaneous tissues along tracts during percutaneous instrumentation. These secondary skin metastases can manifest as subcutaneous nodules (Boutin 1995). The exact mechanism by which invasive pleural procedures encourage track metastases remains unknown. It has been postulated that the key event in subcutaneous nodule pathogenesis involves interruption of the malignant cells, which typically grow in a sheet‐like pattern, with subsequent iatrogenic subcutaneous implantation of cancerous cells (Davies 2008).
These malignant deposits can cause symptoms, such as pain, which reduce the quality of life of MPM patients (O'Rourke 2007). The incidence of these symptoms is poorly documented (Davies 2008). Although symptomatic metastases may negatively impact on quality of life, they have no significant impact on median survival times (Metintas 2008).
The exact incidence of track metastases following interventions is contentious. Reported rates of malignant seeding per diagnostic procedure vary widely in the literature. Incidence rates as high as 40% of MPM patients undergoing invasive interventions have been reported (Boutin 1995). More recent studies, with data from larger patient populations, have found the rate of percutaneous seeding to be as low as 13% (Metintas 2008). Current literature suggests that different types of intervention and instrumentation may confer different levels of risk for the development of instrumentation track metastases. One study found that there is a relatively high risk (22%) of developing a subcutaneous nodule following thoracotamy (Agarwal 2006). Conversely, the incidence of metastases following less invasive procedures, such as image‐guided pleural core biopsy, has been shown to be considerably lower (4%).
Description of the intervention
The use of radiation treatment to prevent the dissemination of malignant mesothelioma cells along instrumentation tracks after disruption to the pleura is a common practice worldwide (De Ruysscher 2003: Lee 2009). Such prophylactic radiotherapy (RT) protocols are supported by evidence that administering radiation to MPM patients after invasive procedures can reduce the risk of a secondary metastasis. One randomised controlled trial (RCT) found that the risk of local dissemination can be reduced from 40% to 0% by administering RT to intervention scars (Boutin 1995). This study used only a small number of patients with MPM (n = 40) and was not blinded. Two subsequent RCTs have been conducted (Bydder 2004; O'Rourke 2007), with both of these trials concluding that the use of prophylactic RT in MPM patients did not significantly reduce the incidence of instrumentation track metastases. Despite the publication of these more recent trials, several international guidelines continue to recommend prophylactic RT for all MPM patients receiving pleural instrumentation. These include the French Speaking Society for Chest Medicine (Scherpereel 2008), the National Comprehensive Cancer Network (Ettinger 2012) and the British Thoracic Society (BTS 2007). Other international thoracic institutions, given the conflicting nature of the current literature, discourage the use of prophylactic RT following percutaneous procedures in MPM patients. These include publications from the European Society of Medical Oncology (Stahel 2009), the Cancer Care Ontario Programme (Ung 2013) and the MPM Australian guidelines (ADRI 2013).
Resolving the conflicting findings in the current literature regarding the role of prophylactic RT in MPM treatment has proved difficult. This is because methods for resolution, such as systematic meta‐analysis, are likely to meet major methodological issues, especially relating to the heterogeneity of the published trials. Substantial impediments to an effective meta‐analysis include: the low number of RCTs; the uncertainty of the true incidence of instrumentation track metastases; the uncertainty of the impact of chemotherapeutic agents on subcutaneous nodule risk; and the variation in RT techniques employed in the published trials. Despite these expected issues, a systematic meta‐analysis investigating the role of prophylactic radiation therapy in MPM found that there was insufficient evidence to support the use of RT for preventing the development of subcutaneous nodules (Ung 2006). It should be noted that all published RCTs investigating the role of prophylactic RT in MPM patients have been small, with less than 100 patients in each trial. There are currently two further trials underway, which are recruiting much larger patient populations than previous trials (Bayman 2016; Clive 2014).
Generally, RT treatment for oncological disease can cause significant local and systemic complications. However prophylactic RT, which is typically applied to the local area of instrumentation in MPM patients, appears to be generally well tolerated. Using the Radiation Therapy Oncology Group (RTOG) toxicity classification (Cox 1995), one study found that one‐third of patients experienced localised skin erythema, whilst two‐thirds of patients did not exhibit any signs of cutaneous dermatitis (Di Salvo 2008).
How the intervention might work
Mesothelioma cells have been shown to be sensitive to in vitro radiation treatments (Häkkinen 1996). The role of RT treatment in patients with malignant pleural mesothelioma is more controversial and requires further RCTs to establish its effectiveness (Chapman 2010).
The rationale underlying the use of prophylactic RT in MPM at sites of pleural interventions is that the local radiation is believed to be effective at killing sensitive, isolated mesothelioma cells before they develop a sizable tumour colony in the subcutaneous tissue (Boutin 1995).
Why it is important to do this review
This review will clarify the role of prophylactic RT for the prevention of track metastases in MPM based on published literature. There is currently conflicting evidence from randomised trials regarding the effectiveness of RT in reducing the risk of developing subcutaneous nodules after invasive interventions for MPM. This has led to inconsistencies between international guidelines regarding the clinical management of mesothelioma. By analysing relevant studies, it is the intention of the authors to resolve the existing conflicts in the literature. In the context of an increasing incidence of MPM worldwide, the findings of the review may then be used to inform clinical guidelines and ensure evidence‐based practice is implemented in the treatment of MPM.
Objectives
To assess the effects of radiation therapy for preventing instrumentation track metastases in malignant pleural mesothelioma.
Secondary objectives include to determine:
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the true incidence of instrumentation track metastases in contemporary MPM patient populations;
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the impact of patient characteristics (e.g. histological subtype of MPM) and intervention characteristics (e.g. maximally invasive versus minimally invasive) on the risk of developing instrumentation track metastases;
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the impact of radiation treatment on secondary patient outcomes such as quality of life, survival time, and disease‐free interval; and
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the incidence of irradiation‐induced dermatitis in MPM patients receiving prophylactic radiotherapy.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs). We will include full‐text studies, as well as studies published as abstract only, and unpublished studies.
Types of participants
We will include studies of adults diagnosed with malignant pleural mesothelioma (MPM) who have undergone invasive thoracic procedures.
Types of interventions
Included studies will evaluate the intervention that is prophylactic radiotherapy (RT) applied to the track site of MPM patients following invasive thoracic procedures. All trials that report employing prophylactic RT as an intervention will be included, irregardless of the radiation fraction dosing utilised.
We will compare outcomes between MPM patients who did receive prophylactic RT and those who did not receive RT.
Types of outcome measures
Primary outcomes
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Incidence of needle track or surgical site metastases
Secondary outcomes
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Time to first appearance of track metastases
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Time without pain symptoms or toxicity
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Incidence of adverse dermatological reactions to radiotherapy (based on Radiation Therapy Oncology Group (RTOG) criteria) (Cox 1995)
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Survival time
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Quality of life
Search methods for identification of studies
Electronic searches
The authors will search for eligible studies via both electronic and manual searches.
We will identify trials in electronic form using:
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the Cochrane Lung Cancer Group's Specialised Register;
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CENTRAL (Appendix 1);
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MEDLINE from 1946 to present (Appendix 2);
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Embase from 1974 to present (Appendix 3).
Where applicable, a free‐text search will also be utilised.
The search of MEDLINE will be performed using the Cochrane highly‐sensitive search strategy, sensitivity and precision‐maximizing version. The search of Embase will be performed according to the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 6.3.2.2) (Higgins 2011)
Searching other resources
The authors will also handsearch respiratory journals and oncological journals (see Appendix 4 and Appendix 5). No language, date or time‐based restrictions will be placed on the searches.
We will attempt to identify all possible eligible studies by reviewing the bibliographic references of studies selected by the first search of the review. We will identify errata or retractions from included studies published in full‐text on PubMed (www.ncbi.nlm.nih.gov/pubmed) and report the date this was performed.
We will also conduct a search of clinicaltrials.gov (clinicaltrials.gov/) and the World Health Organisation (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (apps.who.int/trialsearch/) to identify trials yet to be published.
Data collection and analysis
Selection of studies
Two authors (JE, JB) will independently screen titles and abstracts for inclusion of all the studies we identify as a result of the search and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full‐text study reports/publication and two review authors (JE, JB) will independently screen the full‐text and identify studies for inclusion, and identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third author (KF). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest of the review. We will record the selection process in sufficient detail to complete a PRISMAflow diagram and 'Characteristics of excluded studies' table.
Data extraction and management
We will use a data collection form for study characteristics and outcome data, which has been piloted on at least one study in the review. One author (JE) will extract study characteristics from included studies. We will extract the following study characteristics.
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Design and methodology: study design, randomisation, blinding, total duration of study, details of any 'run in' period, number of centres and location, study setting, withdrawals, date of study and source of funding.
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Participants: number eligible, number enrolled, number in treatment, mean age, age range, gender, severity of condition, diagnostic criteria, baseline lung function, smoking status, MPM histological subtype, inclusion criteria, and exclusion criteria.
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Interventions: intervention, comparison, concomitant medications, and excluded medications.
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Outcome: primary and secondary outcomes specified and collected, and time points reported.
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Notes: funding for trial and notable conflicts of interest for trial authors.
Two authors (JE, JB) will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by involving a third author (KF). One author (JE) will transfer data into the Cochrane Collaboration's statistical software, Review Manager 5.3 (Review Manager 2014). Data presented in the systematic review will be compared with data in study reports to ensure no errors have been made in the process of extraction. A second author (JB) will spot‐check study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies
Two authors (JE, JB) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another author (KF). We will assess the risk of bias according to the following domains:
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random sequence generation;
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allocation concealment;
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blinding of participants and personnel;
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blinding of outcome assessment;
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incomplete outcome data; and
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selective outcome reporting.
Each potential source of bias will be graded as high, low or unclear risk, and we will provide a quote from the study report together with a justification for our judgement in the 'Risk of bias' table (Higgins 2011). We will summarise the 'Risk of bias' judgements across different studies for each listed domain.
When considering treatment effects, we will take into account the risk of bias for the studies that contribute to each specific outcome.
Measures of treatment effect
We will analyse dichotomous data as risk ratios (RRs) and continuous data as mean difference (MD) or standardised mean difference (SMD). Where studies use different measurement scales, the SMD will be calculated.
We will undertake meta‐analyses only when this is likely to be meaningful, i.e. if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense.
We will narratively describe skewed data reported as medians and interquartile ranges.
Where multiple trial arms are reported in a single trial, we will include only the relevant arms. If two comparisons are combined in the same meta‐analysis, we will halve the control group to avoid double counting.
Unit of analysis issues
The unit of analysis will be the study. If cross‐over trials are identified they will be excluded from further analysis. If cluster randomised trials are identified, analysis will be at the level of the individual while allowing for the clustering in the data by using the intra‐cluster correlation co‐efficient (ICC). If this is not reported in the trial then it will be imputed from similar studies.
Dealing with missing data
We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as abstract only). Data imputation will not be utilised.
Assessment of heterogeneity
We will use the I2 statistic to measure heterogeneity among the trials in each analysis (Higgins 2011). If we identify substantial heterogeneity (I2 > 50%) we will report it and explore possible causes by prespecified subgroup analysis.
Assessment of reporting biases
We will assess selective reporting within each trial by comparing the protocol and final published study or otherwise the methods and results sections. Where reporting bias is suspected, we will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by conducting a sensitivity analysis.
We will test for publication bias using a funnel plot if there is sufficient numbers of included trials to do so. It is deemed that the inclusion of nine or fewer trials in the meta‐analysis will be insufficient for the generation of a forest plot, as it will not be possible to adequately determine chance from real asymmetry (Higgins 2011).
Data synthesis
We will use a random‐effects model to calculate the summary RRs and MDs. If meta‐analysis is not possible or appropriate, we will undertake a narrative review of the findings.
A 'Summary of findings' table will be utilised to assist in succinct identification of the key results of the review (Higgins 2011). The outcomes that will be included in this table are: incidence of needle track or surgical site metastases; time to first appearance of track metastases; and time without pain symptoms or toxicity. We will attempt to demonstrate the illustrative risk of these outcomes and define the absolute and relative magnitude of effect. An indication of the grade of evidence will also be offered, if appropriate, according to the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 12.2.1) (Higgins 2011) .
Subgroup analysis and investigation of heterogeneity
We plan to carry out the following subgroup analysis of the primary outcome:
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MPM patients undergoing thoracotomy‐type interventions versus MPM patients undergoing minimally invasive interventions;
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MPM patients receiving chemotherapy treatment (or other anti‐cancer treatment) versus MPM patients who receive only palliative management;
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patients with a histological diagnosis of epithelioid MPM versus patients with sarcomatoid MPM versus patients with mixed MPM; and
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patients receiving single dose radiotherapy versus patients receiving multiple‐dose radiotherapy.
Sensitivity analysis
We plan to carry out the following sensitivity analyses.
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Variation in inclusion criteria: removing studies deemed to vary greatly in inclusion criteria from the rest.
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Risk of bias: removing studies at high risk of bias for one or more domains.
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Analysis by treatment received versus intention‐to‐treat: including data of non‐compliant patients and comparing analysis results to the treatment received method.
