Malignant pleural mesothelioma and its management

Key points•The number of deaths from malignant mesothelioma is increasing and will peak at 2500 per year by 2015.•Malignant pleural mesothelioma is strongly linked to previous asbestos exposure.•The median survival is 8–14 months from the onset of symptoms, and radical surgery may extend survival by up to 10 months.•Radical pleurectomy and decortication can alleviate symptoms of chest pain and dyspnoea.•Radical pleurectomy and decortication causes major blood loss. •The number of deaths from malignant mesothelioma is increasing and will peak at 2500 per year by 2015.•Malignant pleural mesothelioma is strongly linked to previous asbestos exposure.•The median survival is 8–14 months from the onset of symptoms, and radical surgery may extend survival by up to 10 months.•Radical pleurectomy and decortication can alleviate symptoms of chest pain and dyspnoea.•Radical pleurectomy and decortication causes major blood loss. Malignant mesothelioma is a tumour of the mesothelial cells which occurs in the pleura in up to 90% of all cases, but can also occur in the peritoneum, pericardium, and testes. The term ‘mesothelioma’ is usually accepted as being synonymous with malignant mesothelioma. However, benign hyperplasia of mesothelial cells can also occur. This article describes the presentation and current treatment options for malignant pleural mesothelioma, focusing on the available surgical options, with particular emphasis on the perioperative management of radical pleurectomy and decortication. Recording of malignant mesothelioma cases began in 1968, and its incidence has been increasing; currently standing at 4.1 per 100 000.1Data collaborated by Cancer Research UK from: Office for National Statistics, ISD Scotland, Welsh Cancer Intelligence and Surveillance Unit, and Northern Ireland Cancer Registry.http://www.cancerresearchuk.org/cancer-info/cancerstats/types/Mesothelioma/Google Scholar It is five times more likely to occur in men than women, which is attributed to its link with asbestos exposure and the male dominance in occupations where this occurs. Mesothelioma currently accounts for almost 1% of all deaths of men aged 75–79 yr, and the latest UK figures show that the overall number of mesothelioma deaths per year has increased from 153 in 1968 to 2347 in 2010.1Data collaborated by Cancer Research UK from: Office for National Statistics, ISD Scotland, Welsh Cancer Intelligence and Surveillance Unit, and Northern Ireland Cancer Registry.http://www.cancerresearchuk.org/cancer-info/cancerstats/types/Mesothelioma/Google Scholar The annual number of deaths is due to peak at almost 2500 by the year 2015, following which it should decrease rapidly. Deaths resulting from malignant mesothelioma must be reported to the Coroner in order to accurately record cases, and a Coroner's post-mortem is nearly always required. The 5 yr survival rate for patients with malignant mesothelioma is 8%, with a median survival time of 8–14 months from the onset of symptoms.2British Thoracic Society Standards of Care Committee BTS statement on malignant mesothelioma in the UK.Thorax. 2007; 62: ii1-i19Crossref PubMed Scopus (177) Google Scholar Most cases of malignant mesothelioma are caused by asbestos fibres, with ∼85% of cases directly related to occupational asbestos exposure.3Yates DH Corrin B Stidolph PN Browne K Malignant mesothelioma in south east England: clinicopathological experience of 272 cases [correction appears in Thorax 1997; 52: 1018].Thorax. 1997; 52: 507-512Crossref PubMed Scopus (190) Google Scholar4Goldberg M Imbernon E Rolland P et al.The French National Mesothelioma Surveillance Program.Occup Environ Med. 2006; 63: 390-395Crossref PubMed Scopus (162) Google Scholar Asbestos, meaning indestructible in ancient Greek, is a naturally occurring mineral that was previously mined extensively throughout the world for its insulating properties. High-risk occupations include shipbuilders, construction workers, railway engineers, plumbers, boiler makers, electricians, joiners, and those involved with asbestos product manufacture and construction. Malignant mesothelioma may also occur due to ‘para-occupational’ exposures such as in those who laundered clothes contaminated with asbestos. There is considerable variation in the latency period between exposure to asbestos and death from mesothelioma, with a British study reporting a mean (sd) latency of 40 (12) yr.3Yates DH Corrin B Stidolph PN Browne K Malignant mesothelioma in south east England: clinicopathological experience of 272 cases [correction appears in Thorax 1997; 52: 1018].Thorax. 1997; 52: 507-512Crossref PubMed Scopus (190) Google Scholar Cases developing within 15 yr of exposure are rare. The blue coloured crocidolite is the most lethal form of asbestos. However, chrysotile, the white asbestos, is the most extensively used and therefore attributed to the most health problems. Exposure to other substances can also induce mesothelioma, with evidence suggesting the Turkish rock erionite as one such cause.5McDonald JC McDonald AD Mesothelioma: is there a background?.in: Bignon J Jaurand M-C The Mesothelial Cell and Mesothelioma. Marcel Dekker, New York1994Google Scholar Additionally, there is a rate of spontaneous mesothelioma of one per million per year in the UK, that is, cases that would have occurred without the mass industrial use of asbestos. Mesothelioma is not associated with cigarette smoke, intra-pleural talc, or with exposure to other building materials including fibreglass. When reviewing these patients during preoperative assessment, it is important for the anaesthetist to be aware that in the UK, financial compensation is available for those who have asbestos-induced mesothelioma, and without a diagnosis, this may not be awarded. Patients may present for a diagnostic, palliative, or radical procedure. A thorough preoperative assessment should occur as for any patient undergoing major surgery; with investigations as recommended by the National Institute of Healthcare and Clinical Excellence (NICE). Information from the multidisciplinary meeting should be available which will include a detailed occupational history, contrast-enhanced CT scanning, and pathological confirmation of malignant mesothelioma. The proposed management strategy should be based upon patient preference, current performance status, subtype of mesothelioma, and the available evidence base which is outlined in this article. If surgery is being considered, a risk model such as Thoracoscore may have been used by the surgeon to predict the risk of death, but it is not validated for this group of patients. Malignant mesothelioma typically presents with chest pain, progressive shortness of breath, and other constitutional symptoms such as a dry cough, fatigue, weight loss, night sweats, and fever. The chest pain is often difficult to control, may be described as pleuritic, dull, or diffuse, and may have neuropathic components due to involvement of intercostal or brachial plexus nerves. Dyspnoea in early stages of the disease may be caused by a pleural effusion, which is found in 90% of patients at initial presentation.6Ismail-Khan R Robinson LA Williams CC et al.Malignant pleural mesothelioma: a comprehensive review.Cancer Control. 2006; 13: 255-263Crossref PubMed Scopus (158) Google Scholar Dyspnoea occurring later may be due to the restrictive effects of pleural thickening on lung expansion. Occasionally, patients may be asymptomatic and present after finding an abnormality such as a visible mass on a chest radiograph. This is especially true if accompanied by other evidence of asbestos exposure such as pleural plaques. Death usually occurs due to inadequate local control, although metastasis to the brain, bone, and liver can occur. There is often direct involvement of mediastinal structures, but symptoms such as superior vena cava obstruction and hoarseness are rarely encountered. Disease progression with mesothelioma is not uniform; some patients will have stable respiratory function for long enough to consider radical surgery, whereas others can display rapid deterioration, resulting in worsening lung function tests and performance status, and should only be considered for palliative procedures. When reviewing the patient's medications, the anaesthetist should be familiar with the effects of possible previous chemo-radiotherapy. Myelosuppression, cachexia, and opportunistic infections may be present. Cardiotoxicity from chemotherapeutic agents may manifest as ST alterations, premature ventricular complexes, tachycardia, and low-voltage complexes on the electrocardiogram. Pulmonary fibrosis and infiltrates, which may be caused by cisplatin, may further impact on the respiratory function of the patient. It should be borne in mind that these side-effects may impair recovery after the operation. Hemi-thoracic radiation with a lung in situ is not normally performed due to the large tumour area and the incidence of toxicity to the lung and adjacent organs.2British Thoracic Society Standards of Care Committee BTS statement on malignant mesothelioma in the UK.Thorax. 2007; 62: ii1-i19Crossref PubMed Scopus (177) Google Scholar Palliative radiotherapy can provide pain relief in ∼50% of patients, and prophylactic radiotherapy may reduce seeding of tumour cells in the chest wall after invasive procedures, but without prognostic benefit. It is not clear whether chemotherapy drugs offer any benefit in pleural mesothelioma. An American trial randomized 448 patients to either pemetrexed and cisplatin or cisplatin alone. The pemetrexed and cisplatin group demonstrated an increase in the median survival of almost 3 months compared with cisplatin alone.7Vogelzang NJ Rusthoven JJ Symanowski J et al.Phase III study of pemetrexed in combination with cisplatin vs cisplatin alone in patients with malignant pleural mesothelioma.J Clin Oncol. 2003; 21: 2636-2644Crossref PubMed Scopus (2495) Google Scholar However, a randomized multicentre study of 409 patients showed no survival or quality-of-life benefit from the addition of chemotherapy to best supportive care.8Muers MF Stephens RJ Fisher P et al.Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial.Lancet. 2008; 371: 1685-1694Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar Radiological features of malignant mesothelioma include a pleural effusion and pleural thickening which may involve the mediastinal pleura (Fig. 1). Pleural plaques are seen in about 20% of malignant mesothelioma cases. Lung function testing should also be performed as the forced vital capacity may be significantly reduced by a large pleural effusion, which may need to be drained before surgery. Pathological confirmation of mesothelioma should have been sought before the preoperative assessment. As routine cytology of pleural fluid has a low sensitivity for mesothelioma, histological analysis is preferred. In the UK, the majority of patients have diagnosis confirmed with biopsies from medical thoracoscopy, which is carried out by respiratory physicians. Medical thoracoscopy involves the insertion of a rigid thoracoscope into the chest using local anaesthetic, with or without conscious sedation. In cases where medical thoracoscopy has not been able to gain a diagnostic sample, surgical thoracoscopy may be needed. Pleural mesothelioma tumours are typically one of three main subtypes: epithelioid (50–70%), sarcomatoid (5–20%), or biphasic (20–25%). Epithelioid tumours have the best prognosis (up to 16 months median survival), and the minority of patients who survive more than 3 yr virtually always have this subtype.2British Thoracic Society Standards of Care Committee BTS statement on malignant mesothelioma in the UK.Thorax. 2007; 62: ii1-i19Crossref PubMed Scopus (177) Google Scholar Sarcomatoid tumours have the poorest prognosis (5 months median survival). The staging of malignant pleural mesothelioma is based on the TNM (tumour size/location, node involvement, metastases) system. Stage I disease (T1N0M0) describes the primary tumour which is limited to the ipsilateral parietal pleura or focal visceral pleura. Stage II (T2N0M0) involves the diaphragm, confluent visceral pleura, or lung. Stage III is any T3 tumour, or any nodal involvement. Stage IV is any T4 tumour, any N3 involvement, or any metastases. Radical surgery should be considered for patients with a WHO performance status of 0 or 1 (Table 1), and histology showing an epithelioid tumour. It should not be considered in stage IV disease.Table 1World Health Organization performance status (published by Oken and colleagues9Oken MM Creech RH Tormey DC et al.Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am J Clin Oncol. 1982; 5: 649-655Crossref PubMed Scopus (8220) Google Scholar in 1982)ScoreDescription0Asymptomatic (fully active, able to carry on all pre-disease activities without restriction)1Symptomatic but completely ambulatory (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. For example, light housework, office work)2Symptomatic, <50% in bed during the day (ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours)3Symptomatic, >50% in bed, but not bedbound (capable of only limited self-care, confined to bed or chair 50% or more of waking hours)4Bedbound (completely disabled. Cannot carry on any self-care. Totally confined to bed or chair)5Death Open table in a new tab Surgery can be categorized as diagnostic, palliative, or with curative intent (Fig. 2). Radical surgery for mesothelioma includes both radical pleurectomy and decortication and extra-pleural pneumonectomy (EPP). There has been great debate over the past few years as to which surgical technique should be preferred, but EPP has largely fallen out of favour and is no longer carried out in the UK, as described later. Although radical surgery is in theory ‘potentially curative’, microscopic clearance for malignant mesothelioma cannot be achieved. Therefore, it should be emphasized to patients that radical surgery is therefore aimed at alleviating symptoms and slowing progression of mesothelioma by obtaining macroscopic clearance. Surgical thoracoscopy is carried out under general anaesthesia to allow more extensive tissue sampling, and can be combined with pleurodesis if needed. It may also be carried out as a ‘check’ procedure before embarking on more extensive surgery. The mesothelioma and video-assisted thoracoscopic surgery (MesoVATS) trial is an ongoing prospective randomized controlled trial of video-assisted thoracoscopic (VATS) pleurectomy compared with talc pleurodesis for patients with proven or suspected malignant pleural mesothelioma. It is aiming to determine whether VATS pleurectomy or talc pleurodesis is more effective at reducing accumulation of pleural effusions. Almost 200 patients have been recruited and findings are expected to be published within the next year. Non-radical tumour decortication can be performed with an aim of improving lung expansion, and debulking tumour. Decortication refers to the removal of the visceral pleura, whereas pleurectomy commonly refers to the removal of parietal pleura. When referring to mesothelioma surgery, the terms are often used interchangeably as the two pleural layers are adherent. Simple decortication may be performed for those who are deemed unfit for more radical surgery due to a rapid decline in physiological status, but who may benefit from symptom alleviation—typically this procedure would be performed by VATS. This surgery can improve symptom control,10Balduyck B Trousse D Nakas A Martin-Ucar AE Edwards J Waller DA Therapeutic surgery for non-epithelioid malignant pleural mesothelioma: is it really worthwhile?.Ann Thorac Surg. 2010; 89: 907-911Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar but survival outcomes have not been shown to be as good as with radical surgery.11Nakas A Trousse DS Martin-Ucar AE Waller DA Open lung-sparing surgery for malignant pleural mesothelioma: the benefits of a radical approach within multimodality therapy.Eur J Cardiothorac Surg. 2008; 34: 886-891Crossref PubMed Scopus (48) Google Scholar The British Thoracic Society2British Thoracic Society Standards of Care Committee BTS statement on malignant mesothelioma in the UK.Thorax. 2007; 62: ii1-i19Crossref PubMed Scopus (177) Google Scholar suggests that radical treatment should only be considered for patients with epithelioid tumours, as these patients have the longest median survival. The surgical aim is to preserve the lung, while achieving complete macroscopic clearance of the tumour, with removal of the entire parietal and visceral pleura with involved pericardium and hemi-diaphragm in most instances. The pericardium and hemi-diaphragm are reconstructed using prosthetic patches when required.11Nakas A Trousse DS Martin-Ucar AE Waller DA Open lung-sparing surgery for malignant pleural mesothelioma: the benefits of a radical approach within multimodality therapy.Eur J Cardiothorac Surg. 2008; 34: 886-891Crossref PubMed Scopus (48) Google Scholar Fibrin-based surgical sealants are routinely used to help reduce air leakage and bleeding from the lung surface. Patients require large-bore i.v. access (ideally 2), invasive arterial monitoring, central venous access, a urinary catheter, temperature monitoring, and warming devices. Central venous access should be placed on the same side as surgery, thus avoiding the risk of intra-thoracic complications on the non-operative side. Analgesia for thoracotomy pain is an important consideration due to its impact on postoperative respiratory function and complications. A thoracic epidural offers a good standard of analgesia, but should be placed before surgical incision. Extensive blood loss may compromise coagulation and therefore post-procedure neuraxial block is a relative contraindication. Paravertebral blocks and catheters are of no use in these cases as the paravertebral space is bounded antero-laterally by parietal pleura, and this is removed during surgery. A double-lumen tube should be used to enable one-lung ventilation and to allow suctioning of secretions of the collapsed lung before re-expansion. A single-lumen tube with a bronchial blocker would be problematic as partial lung inflation is at times required on the operative side to facilitate surgical resection, and secretion clearance is often less effective. As with all one-lung ventilation for thoracic surgery, ventilation strategies should be optimized to protect the non-operative lung. Care should be taken on positioning the patient in the lateral decubitus position. Pressure areas should be padded, and the patient should not be lying on monitoring wires or the urinary catheter. Additionally, the patient's face and eyes should be protected from any pressure from ventilator tubing or the double-lumen tube clamp. The use of desflurane and remifentanil can facilitate a quick emergence at the end of the procedure, as immediately post-procedure, the reduction in lung function will reduce clearance of inhaled anaesthetic. Paracetamol and antiemetics should be given intraoperatively. The use of non-steroidal anti-inflammatory drugs should be carefully considered as platelet dysfunction may exacerbate blood loss, and the increased risk of renal injury and modulation of the inflammatory response may adversely affect outcomes. Similarly, dexamethasone may be avoided as an antiemetic, as there is a risk of dampening the required inflammatory response if pleurodesis is performed. During surgery, the presence of an oesophageal bougie helps identification and preservation of the oesophagus. The bougie is then replaced by a nasogastric tube to prevent gastric distension after surgery which may compromise the diaphragmatic repair. As blood loss is significant intraoperatively, strategies to minimize this should be used. This may include the use of tranexamic acid. Ideally, preoperative anaemia should be treated before surgery, but the timing of surgery may not allow this. In our centre, the mean blood loss for radical pleurectomy and decortication is 3.5 litres (range 1.5–6.5), so an aggressive fluid replacement strategy is used from the outset of surgery, contradictory to the approach for other types of thoracic surgery. Cross-match packed red cells should be available for a radical pleurectomy and decortication, taking into account the patient's preoperative haemoglobin concentration. Additional blood products may also be required and should be guided by intraoperative results. The use of thromboelastometry for bedside coagulation testing may be useful if available. The use of cell salvage is a relative contraindication in malignancy, and as mesothelioma often seeds in chest drain and pleural biopsy sites, its risks are likely to outweigh its benefits. Before resuming two-lung ventilation, the bronchus of the non-dependent lung should be suctioned to remove blood and secretions. Patients should be extubated once spontaneous ventilation is satisfactory. A postoperative chest radiograph should be performed in the recovery area to exclude any intra-thoracic complications, and to check the positions of the central venous line, nasogastric tube, and chest drains. The chest drains should be placed on suction to facilitate lung expansion, and remain on suction until any air leak has resolved. Clinical and radiological monitoring for postoperative complications is required, meaning patients should be nursed in an appropriate high dependency area. Specific care should focus on oxygen therapy, analgesia, early ambulation with chest physiotherapy, and fluid balance (with correction of haemoglobin concentration as appropriate). Multimodal analgesia can be achieved via a thoracic epidural infusion, such as 0.125% levobupivacaine plus fentanyl, and regular paracetamol. Problematic shoulder tip pain, which is not uncommon, may improve with i.v. tramadol. A proportion of patients may require a vasopressor infusion after operation to maintain an adequate mean arterial pressure. Therefore, the postoperative destination should be able to manage this. Postoperative ventilation is rarely required and, if needed, is likely to indicate a complication of surgery. These may occur in ∼30% of patients, and are summarized in Table 2, with radiological examples shown in Figure 3.Table 2Potential complications of radical pleurectomy and decorticationHaemorrhage from the raw lung surface, major intra-thoracic vessels, or chest wallAir leak due to parenchymal disruption (∼10% of cases)—this may cause a pneumothorax and progress to a persistent non-healing air leakFailure of the collapsed lung to fully re-expand (residual space)Perioperative cardiac arrhythmias (∼20% of cases)Pleural effusion/haemothorax/empyemaThoracic duct injury—more common with right-sided surgeryRecurrent laryngeal nerve injury—more common with left-sided surgeryOesophageal injuryProsthetic patch dehiscence Open table in a new tab There are no randomized controlled trials comparing survival rates with or without this procedure, but retrospective studies show a median survival of 14.5 months with radical pleurectomy and decortication, compared with 4.5 months with best supportive care.11Nakas A Trousse DS Martin-Ucar AE Waller DA Open lung-sparing surgery for malignant pleural mesothelioma: the benefits of a radical approach within multimodality therapy.Eur J Cardiothorac Surg. 2008; 34: 886-891Crossref PubMed Scopus (48) Google Scholar, 12Zahid I Sharif S Routledge T Scarci M Is pleurectomy and decortication superior to palliative care in the treatment of malignant pleural mesothelioma?.Interact Cardiovasc Thorac Surg. 2011; 12: 812-817Crossref PubMed Scopus (22) Google Scholar, 13Shahin Y Wellham J Jappie R Pointon K Majewski A Black E How successful is lung-preserving radical surgery in the mesothelioma and radical surgery-trial environment? A case-controlled analysis.Eur J Cardiothorac Surg. 2011; 39: 360-363Crossref PubMed Scopus (9) Google Scholar Furthermore, radical pleurectomy and decortication has been shown to improve symptoms and overall quality of life.14Mollberg NM Vigneswaran Y Kindler HL et al.Quality of life after radical pleurectomy decortication for malignant pleural mesothelioma.Ann Thorac Surg. 2012; 94: 1086-1092Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar The next part of the Mesothelioma and Radical Surgery trial (MARS 2) has now received funding, and will randomize patients to either radical pleurectomy and decortication or no surgery. Until then, this procedure should be considered as the optimal maximal debulking procedure as it carries less mortality than EPP, with data suggesting preservation of quality of life, lung volumes, and respiratory reserve.14Mollberg NM Vigneswaran Y Kindler HL et al.Quality of life after radical pleurectomy decortication for malignant pleural mesothelioma.Ann Thorac Surg. 2012; 94: 1086-1092Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar EPP is no longer carried out in the UK as it has been shown to cause harm. A description of the surgery is included for completeness. It involves a pneumonectomy plus removal of all macroscopic disease, including the parietal pleura. The lung and involved pericardium and hemi-diaphragm are resected en bloc and the pericardium and hemi-diaphragm are subsequently reconstructed with prosthetic patches. After the publication of the Mesothelioma and Radical Surgery (MARS) trial, this procedure has decreased in popularity worldwide. The MARS trial was a multicentre randomized controlled trial of 50 patients to either EPP or no EPP.15Treasure T Lang-Lazdunski L Waller D et al.Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study.Lancet Oncol. 2011; 12: 763-772Abstract Full Text Full Text PDF PubMed Scopus (527) Google Scholar It assessed the benefit of performing EPP in patients who had received chemotherapy, and subsequently received radiotherapy. It found that EPP within this ‘tri-modal therapy’ offered no benefit and reduced the median survival time by 5 months. EPP also increased the number of ‘serious adverse events’ which included re-operation, and the cardiac and respiratory complications similar to those seen in radical decortication and pleurectomy (Table 2). Quality-of-life analysis also suggests that EPP impacted negatively on quality of life.15Treasure T Lang-Lazdunski L Waller D et al.Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study.Lancet Oncol. 2011; 12: 763-772Abstract Full Text Full Text PDF PubMed Scopus (527) Google Scholar However, retrospective data from the International Association for the Study of Lung Cancer16Rusch VW Giroux D Kennedy C et al.Initial analysis of the international association for the study of lung cancer mesothelioma database.J Thorac Oncol. 2012; 7: 1631-1639Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar suggest a possible benefit of EPP for patients with stage I disease, but the study has been heavily criticized. It states a median survival of 40 months for 75 patients who underwent EPP, in comparison with a median survival of 23 months for 57 patients who underwent radical pleurectomy and decortication. The data did not show any survival benefit for later stages of disease. Overall, this patient group presents significant challenges to the anaesthetist due to physiological and physical impairment, and significant cardiovascular and haematological changes perioperatively. With careful management, radical surgery can be performed to allow symptom alleviation.