Radical multimodality therapy for malignant pleural mesothelioma
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the benefits and harms of radical multimodal treatment options (including surgery ± radiotherapy ± photodynamic therapy ± systemic therapy) in people with malignant pleural mesothelioma compared to palliative treatments and of the different radical multimodality treatment combinations compared to each other.
Background
Description of the condition
Mesothelioma is a malignant tumour arising from the mesothelial cells lining the pleura (65% to 70%), peritoneum (30%), pericardium or testis (1% to 2%) (Bridda 2007). The major histological subtypes of mesothelioma include sarcomatoid, epithelioid and biphasic. Malignant pleural mesothelioma (MPM) is an aggressive and almost always fatal tumour. Peak incidence occurs in the fifth and sixth decades of life and more commonly affects men (Mott 2012). Amphibole asbestos is implicated in the carcinogenesis of MPM in many cases. Other possible aetiological factors include simian virus 40, exposure to radiation and erionite (Robinson 2012). Genetic factors may also play a role ; for instance BAP1 tumour predisposition syndrome (BAP1‐TPDS) is associated with many malignancies including malignant mesothelioma. Somatic mutations may be also linked to MPM development (Testa 2011).
The incidence of MPM varies around the world. The highest rates (up to 30 cases per million population) are in industrialised countries especially Australia, the UK and Belgium associated either with mining of the mineral or with high usage in many industries until the 1980s. The incidence of MPM is expected to rise between 2015 and 2025 (Bianchi 2007; Robinson 2012). Based on the World Health Organization (WHO) mortality data for 1994 to 2008, the crude and age‐adjusted mortality rates for all mesothelioma deaths were 6.2 and 4.9 per million population, respectively. It has also been predicted that the increasing and poorly regulated use of asbestos in low‐income countries will mean that numbers of mesothelioma‐related deaths in those countries will increase in the next decades (Algranti 2015).
The diagnosis of MPM is problematic because the disease develops at an average of 40 years after exposure to asbestos. Between 10% and 90% of people present with either dyspnoea or chest pain; other symptoms include chest discomfort, pleuritic pain, or systemic symptoms such as tiredness, fever, sweats or weight loss. Mesothelioma may also be asymptomatic (Chapman 2006).
Overall, the prognosis of people with MPM is poor with a median overall survival rate of between six and nine months; fewer than 5% survive to five years (Van Meerbeeck 2011). According to the WHO classification of pleural tumours for 2015, sarcomatoid and biphasic subtypes have poorer prognoses than the epithelioid subtype (Galateau‐Salle 2016). However, the pleomorphic epithelioid subtype has been shown to have worse outcomes than all other epithelioid subtypes and similar survival to sarcomatoid and biphasic subtypes (Brčić 2014; Kadota 2011).
Several staging systems are used for MPM (Chapman 2006). The tumour/node/metastasis (TNM) staging system proposed by the International Mesothelioma Interest Group (IMIG) was used until recently (Armato 2013) but was replaced in 2016 by a new TNM staging system (Rusch 2016).
Computerised tomography (CT) of the chest with contrast is the standard imaging method for evaluating the extent of the pleural disease; magnetic resonance imaging (MRI) is recommended only in special situations when more precise delineation of the tumour is needed (Heelan 1999). Positron emission tomography (PET) scanning may sometimes be used for localisation of tumour sites, distant metastases or early response to treatment as part of a research protocol (Baas 2015).
Description of the intervention
Number of different therapeutic strategies are used in the management of people with MPM. Treatment choice depends on patient‐ and disease‐related factors (Baas 2015). Therapies can be broadly classified into those with palliative intent and those with curative (or radical) intent.
Palliative strategies
Palliative strategies include radiotherapy, chemotherapy, pleurodesis (obliterating the potential pleural space by introducing a sclerosing substance) and pain control. Palliative strategies are more likely to be used in older, frail people with poor performance status or advanced disease that cannot be managed by other local therapies.
Palliative radiotherapy
Palliative radiotherapy is aimed at relieving pain from tumour growth (Baas 2015). However, recent studies have shown no compelling evidence supporting its routine use (Macleod 2014; MacLeod 2015).
Curative (radical) strategies
Surgical resection (either extrapleural pneumonectomy or pleurectomy/decortication) can be preceded or followed by chemotherapy, radiotherapy, or both. In this review, radical multimodality therapy will mean the use of a combination of radical surgery together with other local and/or systemic therapies with the aim of eradicating the disease. This shall include surgery ± radiotherapy ± photodynamic therapy ± systemic therapy.
Surgical resection
There are two principal surgical approaches used with curative intent: extrapleural pneumonectomy (EPP) and pleurectomy/decortication (Bertoglio 2016).
Peri‐operative radiotherapy
It has been suggested that peri‐operative radiotherapy (particularly using newer radiotherapy techniques such as intensity modulated radiation therapy) may reduce the probability of tumour recurrence after surgery and improve patient outcomes (Abdel‐Rahman 2017). Initially, a phase II trial evaluating post‐operative radiotherapy with a dose of 54 Gy to patients who underwent extrapleural pneumonectomy or pleurectomy/decortication showed a 17‐month median survival which was longer than historical cases (Rusch 2001). However, the results of a more recent Swiss randomised study do not support the routine administration of postoperative radiotherapy after extrapleural pneumonectomy (Stahel 2015). One study has shown that radiation therapy after EPP may be associated with fatal pneumonitis (Allen 2006). Pre‐operative radiotherapy followed by EPP has been evaluated in a single arm phase II trial in patients with epithelioid type but this approach will need further evaluation on a large randomised trial (De Perrot 2016).
Peri‐operative chemotherapy or immunotherapy
Pre‐ and postoperative chemotherapy or immunotherapy, or both, may reduce the risk of local and distant relapse of MPM. Pre‐operative (induction) treatment may decrease tumour volume and make radical surgical resection more possible. Some studies have evaluated the concept of trimodality therapy (induction chemotherapy followed by surgery and postoperative radiotherapy). Despite promising results from single arm phase II studies (Van Schil 2010; Weder 2012), the effectiveness of this approach has not been confirmed (Stahel 2015; Treasure 2011).
Intra‐operative photodynamic therapy
Intra‐operative photodynamic therapy has been combined with pleurectomy/decortication and chemotherapy in one retrospective study (Friedberg 2017). The same design is being evaluated in a number of prospective studies and the results are awaited.
How the intervention might work
Surgical resection
The aim of surgery for people with MPM is macroscopic resection of as much visible tumour as possible. In the past, terms such as extra pleural pleurectomy (EPP) and pleurectomy/decortication(P/D) have been used without adequate or agreed definitions. However, most international guidelines do not support the routine use of surgery for people with MPM outside clinical trial settings (Baas 2015; Scherpereel 2010). The following definitions of surgery have been proposed:
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EPP ‐ removal of the lung, a portion of the diaphragm, and the parietal and visceral pleura and pericardium;
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Extended P/D ‐ is the same procedure as EPP but the lung is left in situ;
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P/D or total pleurectomy ‐ removal of all gross tumour without resection of the diaphragm or the pericardium; and
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Partial pleurectomy ‐ removal of parietal or visceral pleura or both without removal of the gross tumour (Rusch 2016).
Potential harms arising from surgery may include: bleeding, venous thromboembolism, pulmonary complications (such as respiratory distress, pulmonary infections), cardiac complications (such as atrial fibrillation and myocardial infarction) and gastro‐intestinal complications (such as nausea, vomiting, paralytic ileus) (Sugarbaker 1999).
Radiation therapy
Radiation therapy aims to achieve maximum tumour control with minimal risk of normal tissue damage. This aim has been enhanced by the use of newer technologies such as intensity modulated radiation therapy and image‐guided radiation therapy (Runxiao 2016).
Radiation may be used as an adjuvant therapy after surgery or as part of trimodality approach including chemotherapy and surgery. But it is not yet recommended as a standard treatment (Baas 2015). The rationale for perioperative radiotherapy in MPM is to promote local control by eradicating microscopic disease at the site of surgery (Abdel‐Rahman 2017).
The possible side effects of thoracic radiotherapy for pleural mesothelioma may include pneumonitis, oesophagitis, skin reactions and acute and delayed cardiac effects (Allen 2006).
Chemotherapy
Chemotherapy is the first and second line of treatment of unresectable tumours. Following a landmark study in 2003, the combination of pemetrexed and cisplatin has been considered the standard systemic therapy for MPM (Vogelzang 2003). This combination has been used in most studies evaluating triple modality therapy with surgical resection and postoperative radiation therapy. Pemetrexed is a folate antimetabolite that interferes with nucleic acid synthesis (Manegold 2003); cisplatin works by interfering with DNA replication (Pruefer 2008). The rationale for using perioperative chemotherapy is to promote local and systemic control of the disease through eradicating disease both at the site of surgery as well as in other parts of the body. Preoperative chemotherapy may also increase the resectability of MPM (Abdel‐Rahman 2015).
Expected toxicities following cytotoxic chemotherapy include myelosuppression, asthenia, nausea and vomiting, renal and hepatic toxicities (Vogelzang 2003; Zalcman 2016).
Immunotherapy
Immune checkpoint inhibitors are considered one of the most important advances in cancer management in the past decade. They work by inhibiting immune checkpoints including cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) or programmed cell death protein‐1 (PD‐1) or its ligand (PD‐L1); thus, they would enhance the anti‐tumour activity of cytotoxic T‐ lymphocytes (Mohamed 2017; Wolchok 2013). A number of early phase clinical studies have been recently reported evaluating the use of some immune checkpoint inhibitors in the management of MPM (Calabro 2013; Calabro 2015).
Photodynamic therapy
Intra‐operative photodynamic therapy works by directly targeting residual disease in the pleural space following lung‐sparing surgical interventions (Friedberg 2012). It is a form of phototherapy that aims to cause cell death and involves the combined use of light and a chemical substance with photosensitising properties, in conjunction with molecular oxygen (Saini 2016). Together with other local and systemic therapies for MPM, it may enhance local control of the disease (Friedberg 2012).
Why it is important to do this review
The prognosis of MPM is generally poor and single modality treatment cannot cure it. However, the studies that explored the multimodality treatment protocols incorporating local therapies and systemic therapies have shown conflicting results and 'a best strategy' has not yet been agreed . Moreover, the cost of multimodality treatment is higher than for single therapies. For all these reasons, it is important to do this review to clarify the value of radical multimodality therapy for MPM.
Objectives
To assess the benefits and harms of radical multimodal treatment options (including surgery ± radiotherapy ± photodynamic therapy ± systemic therapy) in people with malignant pleural mesothelioma compared to palliative treatments and of the different radical multimodality treatment combinations compared to each other.
Methods
Criteria for considering studies for this review
Types of studies
We will include parallel group randomised controlled trials (RCTs) of multimodal therapy for people with malignant pleural mesothelioma that measured at least one of the following endpoints: overall survival, progression‐free survival, quality of life (QoL), or serious adverse events for this review. We will consider studies regardless of language or publication status.
Types of participants
Patients with histologically diagnosed non metastatic malignant pleural mesothelioma (stages I, II or III) regardless of treatments received during the study will be included.
Types of interventions
We will assess radical multimodality therapy including any combinations of surgery (including extrapleural pneumonectomy and pleurectomy/decortication), radiation therapy, photodynamic therapy or chemotherapy.
The following comparisons will be considered:
Radical multimodality treatments versus palliative treatment:
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Surgery combined with chemotherapy compared with chemotherapy alone.
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Surgery combined with radiotherapy and chemotherapy compared with chemotherapy alone.
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Surgery combined with radiotherapy, chemotherapy and photodynamic therapy compared with chemotherapy alone.
Comparison of different radical multimodality treatments:
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Surgery combined with radiotherapy and chemotherapy compared with chemotherapy combined with surgery.
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Surgery combined with radiotherapy, chemotherapy and photodynamic therapy compared with chemotherapy combined with surgery.
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Surgery combined with radiotherapy, chemotherapy and photodynamic therapy compared with chemotherapy combined with surgery and radiation therapy.
Types of outcome measures
The following outcome measures will be considered in this review.
Primary outcomes
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Overall survival to be reported either as hazard ratio and /or median overall survival (defined as the median time from randomisation to death from any cause).
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Quality of life measured using standardised and validated instruments.
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Adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 (CTCAE 2009).
Secondary outcomes
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Median progression‐free survival (defined as the time from randomisation to progression of the disease).
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Postoperative complications (including bleeding, empyema, fistula, pneumopathy, arrhythmias).
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All treatment‐related deaths (including peri‐operative deaths or deaths due to pneumonitis or organ dysfunction).
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Locoregional and distant recurrence rates at one year.
Search methods for identification of studies
Electronic searches
We will search the following databases:
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Cochrane Lung Cancer Group's Specialized Register;
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Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane, latest issue) (Appendix 1);
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MEDLINE, accessed via PubMed (1946 to present) (Appendix 2); and
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Embase (Ovid SP) (1980 to present) (Appendix 3).
We will perform the search of MEDLINE using the Cochrane highly sensitive search strategy ‐ Sensitivity maximising version (2008 revision) as described in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 6.4.11.1 and detailed in box 6.4.b) (Higgins 2011).
We will also conduct a search of ClinicalTrials.gov (www.ClinicalTrials.gov) and the World Health Organization (WHO) trials portal (http://apps.who.int/trialsearch/). We will not impose language or publication restrictions.
Searching other resources
We will handsearch reference lists of included studies, relevant chapters and review articles for trials of interest . We will search conference proceedings of relevant oncology, pulmonology and thoracic surgery meetings (2013 to present).
Data collection and analysis
We will summarise data using standard methodologies of The Cochrane Collaboration (Higgins 2011). We will perform the analyses using Review Manager 5.3 (RevMan 2014).
Selection of studies
Two review authors (HM, ME) will independently screen titles and abstracts for inclusion of all the potential studies we identify as a result of the search.
We will retrieve the full‐text study reports/publications and two review authors (HM, ME) 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 review author (OA or ZE). 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 in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram (Moher 2009), and 'Characteristics of excluded studies' table. We will not impose any language restrictions.
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 review author (HM or ME) will extract study characteristics from included studies and this will be cross‐checked by another review author (HM or ME). We will extract the following study characteristics.
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Methods: study design, total duration of study, details of any run‐in period, number of study centres and their locations, study setting, withdrawals, and date of study.
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Participants: N, mean age, age range, gender, stage , diagnostic criteria, inclusion criteria, and exclusion criteria.
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Interventions: intervention, comparison, concomitant medications, and excluded medications.
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Outcomes: primary and secondary outcomes specified and collected (see Primary outcomes; Secondary outcomes), and time points reported.
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Notes: funding for trial, and notable conflicts of interest of trial authors.
Two review authors (HM, ME) will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if outcome data are not reported in a usable way. We will resolve disagreements by consensus or by involving a third review author (OA or ZE). One review author (HM or ME) will transfer data into the Review Manager file (RevMan 2014). We will double‐check that data are entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (HM or ME) will check study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies
Two review authors (HM, ME) will independently assess the included studies for risk of bias using Cochrane's tool for assessing risk of bias in randomised controlled trials (Higgins 2011). We will assess risk of bias according to the following six domains for all included studies assigning assessments as low, unclear or high risk of bias.
1. Allocation sequence generation
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Sequence was generated using a random number table or a computer (low risk of bias);
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Sequence generation method was not specified even if the trial was stated to be randomised (unclear risk of bias);
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Sequence generation method applied a non‐random process, e.g. hospital record number, dates of birth or admission (high risk of bias).
2. Allocation concealment
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Allocation could not have been foreseen in advance of or during enrolment. Allocation was controlled by a centralised system or undertaken using consecutively numbered sealed opaque envelopes (low risk of bias);
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Method used to conceal allocation was not described even if the trial was stated to be randomised (unclear risk of bias);
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Trial was not blinded; allocation was known during the trial (high risk of bias).
3. Blinding of participants, personnel and outcome assessors
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Effective double or triple‐blind designs are sometimes not appropriate for use in anticancer therapy trials because of toxicity risks; moreover, radiotherapy cannot be blinded. We will assess risk of bias separately for personnel, participants, outcomes assessors and different outcomes, as applicable.
4. Incomplete outcome data
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Missing data were unlikely to deviate treatment effects from plausible values. Sufficient methods, such as multiple imputation, were employed to handle missing data (low risk of bias).
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Insufficient information to assess if missing data together with methods used to handle missing data were likely to induce bias on results (unclear risk of bias).
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Demonstration that: results were likely to be biased due to missing data, or reasons for missing outcome data were likely to be related to the true outcome, or imbalance in numbers or reasons for missing data among intervention groups; or for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was sufficient to induce clinically‐relevant bias in the intervention effect estimate; or for continuous outcome data, plausible effect size (difference in mean or standardised mean difference) among missing outcomes was sufficient to induce clinically‐relevant bias in observed effect size; or as‐treated analysis conducted with substantial departure from the intervention assigned at randomisation to intervention; or potentially inappropriate application of simple imputation (high risk of bias).
5. Selective outcome reporting
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If the original trial protocol is available, the outcomes should be those called for in that protocol. If no protocol is available, then outcomes listed in the methods section of an article should be those whose results are reported. (low risk of bias).
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Outcomes defined in the study protocol (or the article methods section if the protocol is not available) were not reported fully in the study report, or it was unclear if data on these outcomes were recorded (unclear risk of bias).
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High risk: one or more pre‐defined outcomes in the protocol (or the article methods section if the protocol is not available) were not reported.
6. Other sources of bias
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Trial appeared to be free of other bias domains that could put it at risk of bias (low risk of bias).
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Trial may or may not have been free of other bias domains that could put it at risk of bias (unclear risk of bias).
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There were other factors in the trial that could put it at risk of bias.
We will assess trials to be at overall low risk of bias if all domains are assessed at low risk of bias. We will assess trials to be at high risk of bias if assessed at unclear or high risk of bias in one or more domains.
We will resolve any differences in opinion by discussion. We will consult a third author (OA or ZE) to arbitrate decisions if necessary.
Assessment of bias in conducting the systematic review
We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.
Measures of treatment effect
We will enter the outcome data for each study into the data tables in Review Manager 5 to calculate the treatment effects (RevMan 2014). We will use risk ratio for dichotomous outcomes, and mean differences or standardised mean differences for continuous outcomes.
We will undertake meta‐analyses only where this is meaningful i.e. if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense.
Dealing with missing data
We will contact investigators or study sponsors to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified only as an abstract). 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.
If numerical outcome data are missing, such as standard deviations or correlation coefficients, and they cannot be obtained from the authors, we will calculate these from other available statistics such as P values according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Assessment of heterogeneity
We will use the Chi² test to assess heterogeneity. We will also use the I² statistic to quantify heterogeneity. Values greater than or equal 50% will be considered as substantial heterogeneity and will be investigated further in subgroup analyses (Higgins 2002).
Assessment of reporting biases
If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible small study and publication biases (Egger 1997; Macaskill 2001).
Data synthesis
We will pool data from studies we judge to be clinically homogeneous using Review Manager 5 software (RevMan 2014). If more than one study provides usable data in any single comparison, we will perform a meta‐analysis.
GRADE and 'Summary of findings' table
We will create a 'Summary of findings' table using the following outcomes:overall survival, progression‐free survival, quality of life, and serious adverse events. For adverse events, we will use a summary end point (total risk for all serious adverse events). We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the meta‐analyses for the prespecified outcomes. We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEpro GDT software (GRADEpro GDT 2014). We will justify all decisions to down‐ or up‐grade the quality of studies using footnotes, and we will make comments to aid the reader's understanding of the review where necessary.
Subgroup analysis and investigation of heterogeneity
Where possible, we will conduct subgroup analyses to evaluate the effect of intervention for each of the following groups:
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Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 ("fully active, able to carry on all pre‐disease performance without restriction") to 1 ("restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light house work, office work") compared to status 2 ("ambulatory and capable of all self care but unable to carry out any work activities; up and about more than 50% of waking hours") (ECOG‐ACRIN);
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Tumour stage considering the adequacy of the staging; and
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Histology (e.g. epithelioid versus sarcomatoid versus biphasic).
Sensitivity analysis
We will perform sensitivity analyses if significant heterogeneity among studies is found. We will consider the quality of the included studies when performing sensitivity analyses. We will also investigate the effects of intention‐to‐treat analysis, adequacy of allocation concealment (blinding), incomplete reporting of the review's primary outcome (HRs for death estimated from the study report or provided by the study authors). We will analyse low risk of bias compared to high risk of bias trials.
