Most commonly, PM patients present with non-specific respiratory symptoms and chest pain. These are clinically indistinguishable from complaints associated with asbestosis, other forms of pneumoconiosis and even pneumonia or congestive heart failure. This fact underlines the need for a detailed anamnesis that may reveal previous exposure to asbestos or erionite.

Most affected individuals are elder men who experience exertional dyspnea that progressively worsens until breathing difficulties are noted at rest. Lung function impairment may also be related to dry cough, wheezing and hoarseness. Some patients report hemoptysis. Pleural tumors like PM may interfere with production and clearance of pleural fluid, which results in malignant pleural effusion. Adhesions between both layers of the pleura as well as infiltration of the thoracic wall and irritation of intercostal nerves are the pathophysiological equivalents of chest pain.

PM patients rarely suffer from paraneoplastic syndrome, and despite their infiltrative growth. PM may metastasize to distant sites.

• Weight Loss

  Common peritoneal mesothelioma symptoms include bloating, abdominal pain, bowel changes, lack of appetite and unexplained weight loss. [asbestos.com]

  A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. [orpha.net]

  Chest pain and breathlessness are the most common, and usually earliest presenting, symptoms of pleural mesothelioma Weight Loss Unexplained weight loss is cited as a symptom in about a third of pleural mesothelioma cases. [mesotheliomacenter.org]

• Recurrent Pleural Effusion

  Most often, this involves draining recurrent pleural effusions and performing pleurodesis. Pain should be managed with simple analgesics such as paracetamol, with the addition of opioids, and anti-inflammatory medications for nociceptive pain. [cancerforum.org.au]

  Indwelling pleural catheters (IPC) are a definitive alternative to pleurodesis for management of recurrent pleural effusions [ 12, 13 ]. [academic.oup.com]

  For palliative treatment, thoracoscopy with pleurodesis can be used to control symptomatic pleural effusions and lessen pain. Recurrent pleural effusions can be treated by talcum pleurodesis with 93% efficacy ( 19 ). [aerzteblatt.de]

• Pleural Effusion

  Abstract We present the case of a 33-year-old male patient suffering from lymphocytic pleural effusion, as a result of pleural mesothelioma. [ncbi.nlm.nih.gov]

  The chest CT assessments during admission revealed marked pleural effusion and mediastinal lymphadenopathy. [hindawi.com]

  Diagnosis of Pleural Mesothelioma On initial examination by a doctor, 80% to 95% of patients show pleural effusion on x-ray, the rest show little or no fluid. [mesotheliomaweb.org]

• Cough

  Pleural Mesothelioma Symptoms Chest pain Coughing up blood Difficulty swallowing Dry cough Fatigue Fever Fluid in the lungs (pleural effusion) Night sweats Shortness of breath (dyspnea) Weight loss As the disease becomes more advanced, new and worsening [mesothelioma.com]

  Persistent cough Dry cough Coughing up blood Painful coughing Loss of appetite Difficulty swallowing Fatigue Respiratory complications Lumps under the skin of the chest Peritoneal Mesothelioma (Abdomen or gastrointestinal) Patients most often experience [mesotheliomahelp.org]

  The following are symptoms of pleural mesothelioma: Breathlessness (dyspnea) Chronic cough Hoarseness Coughing up blood (hemoptysis) Chest pain Unexplained weight loss Fatigue Pleural effusions Fever, chills and night sweats A person who has a history [napolilaw.com]

  Pleural Mesothelioma Symptoms Faint or harsh breathing Dry cough or wheezing Pleural effusions (fluid buildup around the lungs) Coughing up blood (hemoptysis) Body aches and fatigue Blood clotting disorders Chest pains Shortness of breath Reduced chest [asbestos.com]

  […] your chest Blood when you cough This type of cancer will be difficult to find because many of the symptoms are seen with illnesses that are more common. [mesotheliomaexplained.com]

• Dyspnea

  After a long latency period, this condition manifests with nonspecific symptoms, e.g., coughing and dyspnea, which are caused by fibrotic changes in the lungs. [amboss.com]

  […] of all purchases to WHO’s COVID-19 Solidarity Response Fund Royalty-Free Vector pleural mesothelioma, vector illustration, illustration, mesothelioma, pleural, vector, asbestos, asbestosis, cancer, cavity, cells, chemotherapy, chest, cough, disease, dyspnea [dreamstime.com]

  The most frequent clinical manifestations are chest pain, dyspnea and pleural effusion. Metastases usually locate at lymphatic nodes, contralateral lung, liver, kidneys and adrenal glands. [scielo.isciii.es]

  In this case, the patient met the typical triad of signs of heart failure (dyspnea, lower leg oedema), pericardial effusion, and pericarditis, which was only seen intraoperatively. [hindawi.com]

  Typical presenting features are chest pain and dyspnea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. [orpha.net]

• Dry Cough

  Pleural Mesothelioma Symptoms Faint or harsh breathing Dry cough or wheezing Pleural effusions (fluid buildup around the lungs) Coughing up blood (hemoptysis) Body aches and fatigue Blood clotting disorders Chest pains Shortness of breath Reduced chest [asbestos.com]

  Symptoms of the cancer commonly include shortness of breath, chest pain, dry cough and fatigue. Diagnosis typically consists of multiple tests, including scans and biopsies. [mesothelioma.com]

  More general symptoms include dry cough, fatigue, night sweats and weight loss. Diagnosis of Pleural Mesothelioma On initial examination by a doctor, 80% to 95% of patients show pleural effusion on x-ray, the rest show little or no fluid. [mesotheliomaweb.org]

  They don’t always develop right away and often mimic more common illnesses:[6] Chronic bronchitis Asthma Pneumonia Lung Cancer Symptoms of pleural mesothelioma may include:[6] Shortness of breath Difficulty swallowing A persistent dry cough Coughing up [mesothelioma.net]

• Malignant Pleural Effusion

  Use of an Implantable Pleural Catheter For “Trapped Lung” Syndrome In Patients With Malignant Pleural Effusion. Chest. 2001; 119 :1641–6. [ PubMed ] [ Google Scholar ] 12. Lee YC, Fysh ET. [ncbi.nlm.nih.gov]

  Pleural tumors like PM may interfere with production and clearance of pleural fluid, which results in malignant pleural effusion. [symptoma.com]

  Pleural mesothelioma PT 14.1 10038738 - Respiratory, thoracic and mediastinal disorders 10046099 Unspecified pleural effusion LLT 14.1 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) 10026673 Malignant pleural effusion PT [clinicaltrialsregister.eu]

  Thoracoscopic talc versus tunneled pleural catheters for palliation of malignant pleural effusions. [academic.oup.com]

  pleural effusion, pleural wall thickening, circumferential pleural thickening involving the mediastinal pleura, nodular pleural thickening (Tuberc Respir Dis (Seoul) 2013;74:74) Prognostic factors Epithelioid histology is favorable Sarcomatoid histology [pathologyoutlines.com]

• Abdominal Pain

  A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. [orpha.net]

  Minor surgical procedures such as pleurocentesis or paracentesis are often used to drain fluid buildup and alleviate symptoms like difficulty breathing and chest or abdominal pain. [mesothelioma.com]

• Chest Pain

  Typical presenting features are chest pain and dyspnea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. [orpha.net]

  The authors describe a case of deciduoid pleural mesothelioma in a 40-year-old-woman who presented with right pleuritic chest pain, with no history of asbestos exposure, treated with chemotherapy followed by surgery and who died postoperatively. [ncbi.nlm.nih.gov]

  Chest pain Chest pain is often nonspecific, and may sometimes be felt in upper abdomen, shoulder, or arm. [mesotheliomacenter.org]

  Most commonly, PM patients present with non-specific respiratory symptoms and chest pain. [symptoma.com]

• Heart Disease

  For instance, sufferers of pericardial mesothelioma (which affects the lining of the heart) often notice symptoms similar to heart disease. In the case of pleural mesothelioma, the symptoms are similar to lung cancer. [mesotheliomatreatmentcenters.org]

  Overall Health and Lifestyle Choices Having other chronic conditions, such as asbestosis, chronic bronchitis, emphysema (COPD), obesity, diabetes or heart disease, can decrease life expectancy after a mesothelioma diagnosis. [asbestos.com]

  disease, heart arrhythmia and peripheral artery disease. [en.wikipedia.org]

• Muscle Weakness

  Mesothelioma Symptoms To Watch For: Pain Over half of all pleural mesothelioma patients have muscle weakness and body aches in the lower, back or sides of the chest. [mesotheliomahelp.org]

  The most common mesothelioma symptoms include: Dry cough or wheezing Shortness of breath (dyspnea) Respiratory complications Pain in the chest or abdomen Fever or night sweats Pleural effusion (fluid around the lungs) Fatigue Muscle weakness How Do You [asbestos.com]

• Flushing

  HIPEC flushes the abdominal area with the goal of removing any infected cells that were not removed during cytoreductive surgery. [1800lawfirm.com]

• Confusion

  Additionally, its symptoms can be easily confused with common respiratory ailments such as influenza, bronchitis, or pneumonia. [mesotheliomalawyercenter.org]

  This cancer has been confused for the flu, laryngitis, pneumonia, chronic obstructive pulmonary disease, and other more common lung or respiratory conditions, and also misdiagnosed as other lung cancers, like adenocarcinoma. [thelyonfirm.com]

  Some may want to confuse mesothelioma with lung cancer, which is caused by smoking because they have similar characteristics; inhaling microscopic particles that attack the lungs develops both. [shraderlaw.com]

  Asbestosis is a type of asbestos lung disease that does originate in the lungs and is often confused with mesothelioma. Pleural Mesothelioma Cancer Pleural mesothelioma cancer represents about 75 percent of all mesothelioma cases. [allaboutmalignantmesothelioma.com]

Workup consists in diagnostic imaging, obtainment and analysis of tissue samples as well as an assessment of the patient's overall condition.

Computed tomography scans are the diagnostic approach of choice since plain radiography is not sufficiently sensitive for detection or exclusion of PM. However, plain radiographic images may reveal increased quantities of pleural fluid, and the presence of pleural effusion does not only indicate the site of lesion but also serves to evaluate the patient's condition during follow-ups.

Analyses of fine-needle aspirates may suffice to confirm a tentative diagnosis of PM in patients with an occupational history of asbestos exposure. Though, in general, a reliable diagnosis can't be made without obtaining a biopsy sample. This is usually done by means of thoracoscopy, a procedure that simultaneously allows for the drainage of excess pleural fluid, possibly pleurodesis and tumor staging [10]. In case a thoracoscopy is contraindicated, an ultrasound-guided Tru-Cut biopsy should be obtained for subsequent histopathological analysis.

Laboratory analyses of blood samples are usually conducted. Frequent findings are leukocytosis and elevated concentrations of inflammatory markers like acute-phase proteins. Patients may also present anemia and thrombocytosis, which are considered to be adverse prognostic factors [9]. Levels of serum lactate dehydrogenase are often increased. With regards to tumor markers, levels of soluble mesothelin-related protein are elevated in PM patients while concentrations of carcinoembryonic antigen aren't [11].

• Pleural Mass

  We herein report the first case of "dry" MPM successfully diagnosed via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in a 73-year-old man presenting with a pleural mass in the right costovertebral recess, adjacent to the [ncbi.nlm.nih.gov]

  CT scans are more definitive, and may show not only the effusion, but the presence of pleural masses as well as the size certain lymph nodes; MRI is more sensitive in determining chest wall invasion and spread of disease through the diaphragm; PET may [mesotheliomaweb.org]

  […] and anterior margins of the chest wall +/- mediastinal lymphadenopathy +/- pleural effusion CT CT is most commonly used for imaging assessment of mesothelioma, and sufficient for accurate staging of disease in most patients. pleural mass or nodular thickening [radiopaedia.org]

  As tumors develop on the pleural surface, they grow to form a sheath-like mass around the lung. Pleural Mesothelioma Symptoms Many don’t notice the symptoms of pleural mesothelioma right away. People brush them off, especially the elderly. [mblynchfirm.com]

• Left Pleural Effusion

  Four years after the diagnosis of lymphoma, she presented with a left pleural effusion. Large biopsies of the pleura showed a malignant mesothelioma, biphasic type, and pleural plaques. [ncbi.nlm.nih.gov]

  A chest X-ray showed left pleural effusion. A thoracoscopic pleural biopsy specimen from the left side gave a pathological diagnosis of malignant pleural mesothelioma (MPM), epithelioid type. [link.springer.com]

• Pleural Effusion on Chest X-Ray

  […] absent or reduced breath sounds on affected side Diagnosis Pleurocentesis; : bloody (exudative) pleural effusion Imaging (chest x-ray and CT) ;: Multiple nodular, pleural lesions (pleural thickening) Ipsilateral hemothorax Reduced size of ipsilateral [amboss.com]

• Pleural Effusion

  Abstract We present the case of a 33-year-old male patient suffering from lymphocytic pleural effusion, as a result of pleural mesothelioma. [ncbi.nlm.nih.gov]

  The chest CT assessments during admission revealed marked pleural effusion and mediastinal lymphadenopathy. [hindawi.com]

  Diagnosis of Pleural Mesothelioma On initial examination by a doctor, 80% to 95% of patients show pleural effusion on x-ray, the rest show little or no fluid. [mesotheliomaweb.org]

Surgical resection, (neo-)adjuvant chemo- and radiotherapy are the mainstays of PM treatment, but indications for either combination of those therapeutic approaches are still a matter of debate [12].

Although complete surgical resection is recommended, it is often not feasible due to diagnostic delays and either primary or secondary diffuse tumor growth. In this context, pleurectomy is to be performed. Extrapleural pleuropneumectomy is sometimes advised to minimize the likelihood of residual tumor cells being left behind, but this radical surgical intervention requires highly specialized surgeons, is still associated with high mortality, and does not prolong median survival times [13].

Chemotherapy is not recommended if the patient's Karnofsky score is below 60%, unless their life quality is severely restricted by aggressive and rapid tumor growth that cannot be controlled by any other means. Similarly, irradiation is usually applied as a palliative measure. Additionally, adjuvant radiotherapy may prevent local recurrence if the tumor could be resected in its entirety.

PM patients that suffer from malignant pleural effusion may benefit from pleurodesis, a procedure that may hinder the renewed accumulation of pleural fluid. In contrast, symptoms of restrictive lung disease resulting from fibrotic tissue covering the lobes of the lung may indicate decortication.

Since patients suffering from PM present with unspecific symptoms and generally don't report exposure to asbestos or similar minerals that occurred decades ago, diagnosis of PM is usually delayed by several months after the onset of symptoms. Consequently, even non-diffuse mesothelioma are often unresectable at the time of diagnosis and only palliative treatment can be provided. Thus, the patient's prognosis is often poor, with median survival times of only 4 to 12 months [7]. Male sex, old age, chest pain, loss of appetite, weight loss and impairment of lung function have been shown to be unfavorable prognostic factors [8]. Additionally, more severe alterations of blood cell counts and levels of inflammatory markers are likely associated with a poorer prognosis [9].

The single most important risk factor for PM is exposure to asbestos, and furthermore, a causative role in PM pathogenesis has been proven for erionite [2].

• Asbestos is a general term describing different types of silicate minerals that all share the common feature of a high aspect ratio, i.e., those minerals form very long but thin crystals. These asbestos fibers are fragile and may release even smaller particles, the so-called asbestos dust. The corresponding crystals measure few micrometers and are thus able to penetrate into the lower respiratory tract and possibly even into the alveolar sacs. Here, they may induce chronic inflammation, fibrosis and eventually malignant transformation.
  With regards to differences among distinct types of asbestos, amphiboles are generally considered to be more carcinogenic than serpentines. Crocidolite fibers measure less than 0.25 µm in diameter, penetrate the lung and persist for particularly long periods of time in the pleura. Thus, according to current knowledge, crocidolite is the most dangerous type of amphibole asbestos.
• Erionite is a naturally occuring, asbestos-like mineral that is currently not used for any purpose. However, miners working with other zeolites - that are utilized in distinct industrial branches - may be at risk of erionite exposure because of co-occurrence. PM related to erionite exposure has mainly been reported in Turkey.

To date, it is not known whether radiation exposure or viral infectious diseases predispose for PM. Infection with Simian virus 40 has repeatedly been related to PM pathogenesis [3]. Possibly, virus infection further increases the risk of developing pleural neoplasms after exposure to the aforedescribed minerals, rather than directly inducing malignant transformation of epithelial cells.

As has been indicated above, exposure to asbestos is the main risk factor for PM. Asbestos has been used in construction and textile industry, in paper production and ship building, among others, after being extracted in asbestos mines. Accordingly, miners, employees of the construction and processing industries and eventually those people using the respective end products are at highest risks of exposure to asbestos. Most of these people are males, and this may partially explain while four out of five PM patients are men [1].

The previously given description applies to several millions of workers worldwide. Nevertheless, PM is a rare type of neoplasm. Highest incidence rates are reported in Australia and Great Britain [3]. In both countries, the overall incidence is 29 per 1,000,000 inhabitants. During the last years, slight increases have been observed in PM incidence, but this development is mainly ascribed to improved diagnostics and more reliable identification of PM patients. In general, it is to be expected that PM incidence rates decrease in industrialized nations due to the reduction of asbestos use in these geographical regions. However, this trend will only become observable after a time lag of about 40 years, which is the mean time from asbestos exposure to diagnosis of PM. In large parts of the developing world, asbestos use continues unchanged.

It has been estimated that 43,000 people die each year from PM [4], but according to the World Health Organization, the overall mortality due to PM is more than twice as high [1].

The pleura consists of a parietal and visceral layer that line the thoracic cavity and those organs it contains, respectively. The outermost layer of the pleura is the mesothelium, a single layer of epithelial cells. Parietal and visceral mesothelium are separated by a very thin film of pleural fluid, and only few cell layers are between the visceral mesothelium and the alveolar sacs. These short distances are easily overcome by asbestos fibrils and similar carcinogenic crystals. Thus, exposure to asbestos is not only related to an increased risk of pulmonary cancer but also of PM.

Minerals that reach the pleural space are deposited on the mesothelium and constitute a persistent stimulus of macrophages, which aim at clearing those crystals. Distinct pro-inflammatory factors, e.g., interleukins and tumor necrosis factor-α (TNF-α), are released by activated macrophages and induce a chronic inflammation [2]. Moreover, mesothelial cells augment their expression of TNF-α receptors, and binding of that cytokine provokes the activation of NF-κB signaling pathways, which ultimately enhances the survival of mesothelial cells after exposure to asbestos [5]. Besides the activation of intracellular pathways and subsequent overexpression of oncogenes and proto-oncogenes, asbestos fibrils may also directly interact with nucleic acids of exposed cells [6]. Consequently, exposure to asbestos increases the risk of mesothelial cells with reduced capacities of apoptosis to accumulate chromosomal aberrations and gene defects. Monosomy of chromosome 22 as well as extensive rearrangements on chromosomes 1, 3, 6 and 9 are aberrations commonly found in PM.

Since asbestos exposure is the main risk factor for PM, any measure to reduce and replace asbestos-containing materials at people's workplaces and homes also contributes to decreasing their individual risk of this disease. To this end, modern standards have been implemented in construction and processing industries, and national laws regulate maximum times of exposure depending on the local asbestos burden. The interested reader is encouraged to consult applicable regulations with the respective authorities in their home country. Ideally, asbestos exposure is avoided completely because the one-hit theory applies to the development of PM.

To date, screening programs to detect PM in patients with a known history of asbestos exposure have not been implemented.

Mesothelium is the technical term for the single epithelial layer of serous membranes like pleura, peritoneum and pericardium. Neoplasms originating from the mesothelium are generally malignant and the vast majority of mesothelioma affect the pleura [1]. Nevertheless, pleural mesothelioma (PM) is still a rare entity. Increasing incidence rates presumably result from improved diagnostics and a heightened awareness of the disease.

PM is a form of occupational cancer, typically associated with previous exposure to asbestos fibres and dust. Since several decades may pass from exposure to this carcinogenic material until malignant transformation of mesothelial cells, it is often a major challenge to establish the link between a patient's working environment and chest pain, dyspnea and further respiratory symptoms.

According to the aforedescribed etiology of PM, it may also be considered a late sequelae of asbestosis, a form of pneumoconiosis. It is generally diagnosed in elder men; their prognosis is poor. Median survival times after diagnosis are less than a year because tumors are typically non-resectable. Patients may benefit from surgery, chemo- and radiotherapy as well as palliative treatment, though, since these measures may provide relieve from symptoms and improve life quality.

Mesothelium is the medical term for the epithelial layer of serous membranes lining the thoracic and abdominal cavity as well as the heart sac. In detail, these membranes are referred to as pleura, peritoneum and pericardium. Tumors originating from the mesothelium are called mesothelioma; and if they affect the inner lining of the thoracic wall or lungs, they are designated pleural mesothelioma (PM).

PM are rare malignant neoplasms, most commonly induced by prolonged and intense exposure to asbestos. However, inhalation of asbestos fibers and dust does not immediately provoke tumor growth, but several decades may pass until first symptoms manifest. Thus, PM are typically diagnosed in elder patients with an occupational history of asbestos exposure.

Initially, patients may merely experience breathing difficulties under exercise, but symptoms progressively worsen. Non-productive cough, bloody sputum and wheezing may be noted. Many PM patients additionally claim chest pain. Because these non-specific symptoms don't allow for a reliable diagnosis of PM, computed tomography scans and biopsies have to be carried out.

Since treatment options are very limited - often only palliative therapy can be provided - preventive measures are of utmost importance to avoid the development of PM. In this context, reduction of asbestos exposure and replacement of asbestos-containing materials is highly recommended. Ideally, asbestos fibers and dust are not inhaled at all.

1. Delgermaa V, Takahashi K, Park EK, Le GV, Hara T, Sorahan T. Global mesothelioma deaths reported to the World Health Organization between 1994 and 2008. Bull World Health Organ. 2011; 89(10):716-724, 724a-724c.
2. Yang H, Testa JR, Carbone M. Mesothelioma epidemiology, carcinogenesis, and pathogenesis. Curr Treat Options Oncol. 2008; 9(2-3):147-157.
3. Robinson BM. Malignant pleural mesothelioma: an epidemiological perspective. Ann Cardiothorac Surg. 2012; 1(4):491-496.
4. Driscoll T, Nelson DI, Steenland K, et al. The global burden of disease due to occupational carcinogens. Am J Ind Med. 2005; 48(6):419-431.
5. Yang H, Bocchetta M, Kroczynska B, et al. TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis. Proc Natl Acad Sci U S A. 2006; 103(27):10397-10402.
6. Nymark P, Lindholm PM, Korpela MV, et al. Gene expression profiles in asbestos-exposed epithelial and mesothelial lung cell lines. BMC Genomics. 2007; 8:62.
7. Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005; 366(9483):397-408.
8. van Zandwijk N, Clarke C, Henderson D, et al. Guidelines for the diagnosis and treatment of malignant pleural mesothelioma. J Thorac Dis. 2013; 5(6):E254-307.
9. Burgers JA, Damhuis RA. Prognostic factors in malignant mesothelioma. Lung Cancer. 2004; 45 Suppl 1:S49-54.
10. Greillier L, Cavailles A, Fraticelli A, et al. Accuracy of pleural biopsy using thoracoscopy for the diagnosis of histologic subtype in patients with malignant pleural mesothelioma. Cancer. 2007; 110(10):2248-2252.
11. van den Heuvel MM, Korse CM, Bonfrer JM, Baas P. Non-invasive diagnosis of pleural malignancies: the role of tumour markers. Lung Cancer. 2008; 59(3):350-354.
12. Stahel RA, Riesterer O, Xyrafas A, et al. Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. Lancet Oncol. 2015; 16(16):1651-1658.
13. Treasure 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(8):763-772.