Incidence of Pleural and Peritoneal Mesothelioma
The initial discovery of mesothelioma can be traced back to 1767 when Dr. Joseph Lieutaud, an anatomy pathologist in France, first identified a tumour in the chest wall of a young boy . Mesothelioma is a rare, aggressive form of cancer that develops from transformed cells originating in the mesothelium, which is the protective lining covering many of the body's internal organs. Mesothelioma arises in the pleura but also occurs in the peritoneum, the tunica vaginalis, and the pericardium . Mesothelioma tends to have a local progression. While disseminated disease has sometimes been reported in a very late stage of the disease [3– 7], patients usually die from local progression.
In Canada, there are 459 new reported cases of mesothelioma per year , compared to 3,000 in the United States of America. According to Connelly RR et al, the incidence of mesothelioma in the United States is 10 cases per million people per year . Men are more commonly affected than women, with a male predominance of 90%. While there is a correlation between increasing age and reported cases, there is no peak and the mean age at diagnosis is 60 years.
The number of cases recorded in the Quebec Tumour Database from 1982 to 2002 (for the province of Quebec, Canada; see table 1) reveals that the incidence of pleural and peritoneal mesothelioma was higher for men than women. The overall annual rate of increase from 1982 to 2002 in Quebec was estimated to be 3.6%, which was lower than that measured from 1982 to 1996. In comparison to the international level, only Australia and Scotland showed significant increases in mesothelioma among women .
|Rate per 100,000 people per year:||1.98||0.41||0.15||0.09|
The primary risk factor for mesothelioma is asbestos exposure. Asbestos is a generic terms for a group of six naturally occurring silicate minerals classified as either serpentine or amphibole. The amphibole (rod-like) group contains five types: amosite, crocidolite, anthophyllite, tremolite, and actinolite. Serpentine (chrysotile) asbestos has a sheet or layered structure and differs from the amphibole varieties both structurally and chemically. Chrysotile, the only asbestos mineral in the serpentine group, is the main form of asbestos still mined. It is generally accepted that chrysotile asbestos is less dangerous and does less damage to the lungs than the amphiboles. Although 70% to 80% of pleural mesothelioma cases are associated with asbestos exposure, the lifetime risk of developing pleural mesothelioma among asbestos workers is thought to be 10% . Furthermore, despite the lack of evidence between the relationship of asbestos exposure and peritoneal mesothelioma, one study indicates that this correlation is less significant than that between asbestos exposure and pleural mesothelioma .
Asbestos is still used industrially for its fire-resistance and sound-absorption properties. The association between asbestos and mesothelioma was first documented in South African miners . Moreover, the Occupational Safety and Health Administration (OSHA) established that 0.2 fibres per cubic millilitre of air is the standard acceptable exposure rate for fibres longer than 5 μm .
Construction, boiler, and shipyard workers are at increased risk. Other sources of exposure may include a spouse or close relatives of asbestos workers. Patients from certain regions of the world (i.e. Greece, Central Turkey, California, and Bulgaria) also have endogenous environmental asbestos exposure as their soil contains high level of tremolite asbestos fibres [15–19]. Furthermore, greater environmental exposure increases incidence of mesothelioma and is also proportionate to the latency period [20–21].
In the majority of patients, the disease develops after a latency period of up to 40 years after initial exposure . Fortunately, today's strict industry standards have significantly reduced asbestos exposure by 100 to 1,000 times compared to the past . For example, Great Britain recorded fewer annual deaths related to mesothelioma in 1968  than in 2001 [1,84,8], largely due to the latency period. The peak in mesothelioma deaths is expected to occur in 2015 (2,450 deaths) . Nevertheless, the rate of deaths in Great Britain associated with mesothelioma is expected to drop significantly after 2015, most likely because of reduced asbestos exposure and stricter industry standards.
Although it was once thought that smoking could lead to mesothelioma, we now know that is not the case. It does, however, increase the risk associated with asbestos exposure .
3.2. Carbon nanotubes
Carbon nanotubes are stronger than steel yet lighter than aluminum. As a result, they can be found in a wide range of items such as high-performance bicycle frames, textiles (i.e. waterproofing fabrics), body armour, and concrete. Nevertheless, animal studies have demonstrated that carbon nanotubes can produce mesothelioma-like changes and may therefore cause mesothelioma [26,27]. Furthermore, it has been suggested that the mechanism involved may be either attributed to "changes in gene expression, epigenetic changes, and receptor-mediated or other intracellular signalling cascades" .
3.3. Radiation therapy
Ionizing radiation to supradiaphragmatic fields appears to be a risk factor for developing mesothelioma. Data from patients treated with radiation therapy for Hodgkin's lymphoma , non-Hodgkin's lymphoma , and testicular cancer  revealed an excess rate of mesothelioma. Although the reported number of mesotheliomas was small, the risks were statistically significant. This might be the result of broader radiation therapy for Hodgkin's and non-Hodgkin's lymphoma, since mantle-field radiation had once been the standard method of treatment. Afterwards, extended-field radiation therapy became the standard of care. Since today’s preferred method of radiation therapy for lymphomas is involved-field radiation, the incidence of mesotheliomas in patients with Hodgkin's or non-Hodgkin's lymphomas should drop because the smaller radiation-therapy fields should result in fewer secondary neoplasms. Moreover, since mediastinal radiation therapy is no longer given for testicular seminomatous germ-cell tumours, such patients should evidence a decrease in radiation-induced mesothelioma.
3.4. Genetic factors
Another cause for mesothelioma may be the nuclear deubiquitinase enzyme BAP1, which plays an important role in transcriptional deregulation in the pathogenesis of mesothelioma. BAP1 deubiquitinase is known to target histones (proteins that package DNA in the cell nucleus) and HCF1 (a transcriptional co-factor involved in the cell cycle), which also affects the E2F and Polycomb (a group of genes that codifies a family of transcription factors) target genes. Inactivating mutations of BAP1 were found in about one quarter of mesothelioma tumour tissues tested [32, 33]. Common genetic changes, involving the loss of the tumour suppressor genes p14, p16 , NF-2 , and P53, have been associated with mesothelioma .
3.5. Viral oncogenes
Simian virus 40 (SV4 0) continues to raise controversy, as it has been suggested that SV40 may have been a contaminant in the poliomyelitis vaccine in the 1950s and 1960s. A review of mesothelioma case studies have revealed an important presence of SV40 nucleic acid in affected patients. SV40 is a DNA polyomavirus, which is thought to suppress tumour genes of the retinoblastoma family by a peptide known as SV40 large T antigen [36–40].
The histopathologic subtypes of mesothelioma are epithelioid (40%), mixed or biphasic (35%), and sarcomatous or mesenchymal (25%). Needle biopsy mesothelioma can often be mistaken for adenocarcinoma. Mesothelioma under electron microscopy reveals cells with long microvilli with a needle-like shape and form. Mesothelioma is positive for calretinin, vimentin, WT1, and cytokeratin, but negative for periodic acid-shift stain, mucicarmine stain, carcinoembryonic antigen, and Leu-M1. Adenocarcinoma under electron microscopy reveals short microvilli .
Inhaled asbestos fibres create lung irritation that may lead to scarring, fibrosis, and plaques. On a cellular level, injuries caused by asbestos fibres can be followed by cell repair. Repeated cell injuries, however, may lead to DNA-strand impairment and transform into malignancy . It has also been suggested that long, thin asbestos fibres are generally more carcinogenic than shorter, thicker ones and interfere more with mitosis, causing chromosome abnormalities leading to cell transformation and neoplastic progression . Mesothelial cells may have increased interleukin-6 secretion, which would result in increased production of vascular endothelial growth factor (VEGF), a signal protein produced by tumour cells that stimulates angiogenesis .
6. Clinical presentation
Dyspnea and non-pleuritic chest pain are the most common presenting symptoms of mesothelioma. X-rays often reveal recurrent pleural effusion or pleural thickening, which should prompt the clinician to suspect mesothelioma .
Early malignant pleural mesothelioma presents as small pleural nodules. As the tumour progresses, the nodules increase in number and coalesce to form a thickened tumour. As the tumour replaces the pleural fluid that lies between the two pleura, the parietal and visceral pleura fuse. This results in dyspnea and hypoxemia, which are often refractory to supplemental oxygen when deoxygenated blood is shunted through the encased lung.
Mesothelioma spreads by direct extension  and seeding throughout the pleural space, including fissures, diaphragmatic, and pericardial surfaces; through the chest wall; and into the mediastinum and lymph nodes. The malignancy may also extend into the abdominal cavity. Metastasis, although uncommon, may occur in the opposite lung, brain, and other extrathoracic sites.
7. Physical exam
The performance status should be evaluated. Visual inspection may reveal thorax nodules or ulcers and scoliosis may be observed towards the side of the malignancy . The clinician should look at all sites of previous instrumentation for evidence of tumour seeding. Unilateral dullness to percussion at the lung base may be observed. Decreased air entry on the involved side may also be perceived.
8. Lab work
Tests should include a CBC, electrolytes, creatinine, and a complete metabolic panel. Serum soluble mesothelin-related peptide and osteopontin levels could be performed, although most Canadian centres do not currently do so.
Mesothelin is a glycoprotein usually expressed on normal mesothelial cells but is overexpressed in epithelioid and mixed mesotheliomas [48, 49]. A meta-analysis showed that sensitivity ranged from 19% to 68%, depending on the criteria chosen to establish positivity . The glycoprotein osteopontin is also overexpressed in mesothelioma, but a study pointed to lower diagnostic accuracy than mesothelin in patients with suspected malignant mesothelioma .
9.1. CT scan
Thoracic, abdominal, and pelvic CT scans with contrast are useful in staging the disease. Pleural thickening is the most common finding on CT scans (92% of mesothelioma patients). Pleural thickening is defined as either extension of more than 8 cm in the craniocaudal direction or more than 5 cm of the chest wall when visualized in cross section, or when the pleural thickness exceeds 3 mm [52–54].
The second most common finding is involvement of the fissure (about 85% of cases), followed by pleural effusion (75% of patients). Other findings include contraction of a hemithorax, contralateral shift of the mediastinum, chest-wall involvement, and rib destruction [55–58]. As the disease progresses, irregular pleura-based masses are common and the interlobular fissures are often involved. CT scanning may underestimate the extent of disease.
Although CT scanning is used for tumour detection, its accuracy for detecting intrathoracic lymph-node involvement is limited [59, 60]. Mesothelioma spreads into paraesophageal nodes, pulmonary-ligament nodes, and diaphragmatic nodes more commonly than other lung cancers.
Combining magnetic resonance imaging (MRI) with CT scanning may improve evaluation of the local extent of disease. MRI helps to determine chest-wall, diaphragmatic, or apical invasion as well as transdiaphragmatic tumour growth .
10. Surgical staging
Although radiographic staging evaluation is warranted, accurate staging is only possible at the time of surgery in a substantial number of patients. Pulmonary-function tests are often performed prior to surgery. For surgical staging, mediastinoscopy or endobronchial ultrasound is used in the case of suspicious nodes. An open biopsy or CT-guided core biopsy is acceptable, but thoracenthesis or video-assisted thorascopic surgery (VATS) is preferred. If necessary, based on the CT scan, laparoscopy can be used to rule out transdiaphragmatic extension, and VATS to rule out contralateral disease.
11. TNM staging of mesothelioma
The TNM (Tumour, Node, Metastasis) Classification is used by both the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC). The 2010 version is the most recent.
|Tx:||Primary tumour cannot be assessed|
|T0:||No evidence of primary tumour|
|T1:||Tumour limited to the ipsilateral parietal pleura, with or without mediastinal pleura and with or without diaphragmatic pleural involvement|
|T1a:||No involvement of the visceral pleura|
|T1b:||Tumour also involving the visceral pleura|
|T2:||Tumour involves each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following:|
|(1) Involvement of diaphragmatic muscle|
|(2) Extension of tumour from visceral pleura into underlying pulmonary parenchyma|
|T3:||Locally advanced but potentially resectable tumour. Tumour involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following:|
|(1) Involvement of the endothoracic fascia|
|(2) Extension into the mediastinal fat|
|(3) Solitary completely resectable focus of tumour extending into the soft tissue of the chest wall|
|4) Nontransmural involvement of the pericardium|
|T4:||Locally advanced, technically unresectable tumour. Tumour involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following:|
|(1) Diffuse extension or multifocal masses of tumour in the chest wall, with or without associated rib destruction|
|(2)Direct diaphragmatic extension of the tumour to the peritoneum|
|(3)Direct extension of the tumour to a mediastinal organ|
|(4)Direct extension of the tumour to the contralateral pleura|
|(5)Direct extension of the tumour into the spine|
|(6)Tumour extending through to the internal surface of the pericardium with or without a pericardial effusion or tumour involving the myocardium|
|Nx:||Regional lymph nodes cannot be assessed|
|N0:||No regional lymph-node metastases|
|N1:||Metastases in the ipsilateral bronchopulmonary and/or hilar lymph nodes|
|N2:||Metastases in the subcarinal or ipsilateral mediastinal lymph node (including ipsilateral internal mammary and peridiaphragmatic nodes)|
|N3:||Metastases in the contralateral mediastinal, internal, mammary, or hilar nodes and/or the ipsilateral or contralateral supraclavicular or scalene lymph nodes|
|Mx:||Distant metastasis cannot be assessed|
|M0:||No distant metastasis|
|IV||T4 and any NMO|
|Any T and N3M0|
|Any T and any N and M1|
12. Differential diagnosis
Even though most pleural tumours are malignant, the differential diagnosis also includes benign tumours and inflammatory reactions.
Primary tumours, such as fibrosarcoma and malignant fibrous histiocytoma, can present in a similar fashion and infiltrate like sarcomatous mesotheliomas. Metastatic diseases that can involve the pleura and mimic epithelioid mesothelioma include breast, lung, lymphoma, thymoma, stomach, kidney, ovarian, and prostate cancer. Finally, benign chronic organized empyema can also mimic pleural thickening.
The median survival of patients with mesothelioma is poor, ranging from 7 to 17 months . The overall survival (OS) rate at 5 years is 9%. Even with new therapy interventions, the overall patient survival rate has not been significantly improved. In some specific cases, in which patients were specifically chosen due to their localized disease, treatment with aggressive multimodality therapy improved their survival rates.
The first thing to consider when treating mesothelioma is whether the tumour is resectable or not. Since the tumour spreads by direct extension, only 5% of mesotheliomas are resectable at diagnosis. Usually T1 to T3 and N0-1 tumours are considered resectable. T4 and N2-3 tumours are considered unresectable. Mediastinoscopy has to be performed to rule out N2-N3 lymph nodes. In addition, patients with sarcomatoid histology have a poorer prognosis and should not be considered for extrapleural pneumonectomy . Patients must be able to tolerate trimodal therapy, since it is important to ensure that they do not have postoperative morbidities without deriving the full benefits of surgery.
The treatment paradigms for resectable mesothelioma are:
If the tumour is unresectable:
A combination of chemotherapy is the standard treatment. Prophylactic drain-site irradiation should be considered.
Talc pleurodesis with a pleural catheter or pleurectomy may also be considered to palliate symptoms of pleural effusion.
Prior to surgery, it is important to have proper patient selection. Patients must have:
Performance status of 0–1
PaO2 of more than 65 mm Hg
PaCO2 of less than 45 mm Hg
A predicted post op FEV1 of more than 1 L
An ejection fraction of more than 40%
A mean pulmonary arterial pressure of less than 30 mm Hg
An epithelioid histology
14.1. Extrapleural Pneumonectomy (EPP)
EPP involves the removal of parietal pleura, lung, pericardium, and ipsilateral diaphragm. Mediastinal node dissection is usually performed. Finally, a graft is inserted to prevent herniation of abdominal contents through the diaphragmatic defect. Although no survival benefit was observed from randomized trials, observational studies indicated that EPP is the only intervention that has been demonstrated to result in long-term, disease-free survival in highly selected patients with favourable prognostic indication . In a review of 83 patients who underwent EPP, the observed 5-year survival rate was 15% .
The benefits of EPP is that it allows complete resection or at least a cytoreduction, permitting higher radiation doses to be delivered safely to the ipsilateral hemithorax. This procedure has the disadvantage of being technically complex and associated with significant perioperative morbidity and mortality. Complications include atrial fibrillation (44.2%), prolonged intubation (7.9%), vocal-cord paralysis (6.7%), deep-vein thrombosis (6.4%), technical complications (patch dehiscence, haemorrhage, or both; 6.1%), tamponade (3.6%), acute respiratory-distress syndrome (3.6%), cardiac arrest (3%), constrictive physiology (2.7%), aspiration (2.7%), renal failure (2.7%), empyema (2.4%), tracheostomy 1.8%, myocardial infarction (1.5%), pulmonary embolus (1.5%), and bronchopleural fistula (0.6%) . In extensive experience, the early postoperative mortality rate approaches 7%  but can be as high as 30%. The mean survival (MS) rate after surgery is 4 to 20 months.
14.2. Pleurectomy/Decortication (P/D)
In case of more advanced disease, mixed histology, and medically high-risk operable patients, pleurectomy/decortication is preferred over EPP. Pleurectomy/decortication is performed in two phases. Phase 1 is pleurectomy and involves removing the pleural lining. Phase 2 is decortication, which is the removal of any tumour growing inside the lining. The procedure's perioperative mortality is 4% .
Retrospective studies have indicated that parietal pleurectomy and decortication may be as efficient as extrapleural pneumonectomy . When comparing EPP to PD, it was observed that PD patients had a greater local recurrence of disease, while EPP patients experienced higher mortality and surgical morbidity.
15. Radiotherapy (RT)
15.1. Adjuvant radiation therapy after EPP
Radiation therapy is a local treatment that uses ionizing radiation to destroy tumour cells. As mentioned above, aggressive surgery alone does not improve survival. Observational data do not provide evidence that adjuvant RT following pleurectomy offers a survival benefit . That notwithstanding, the MSKCC phase-II trial with hemithorax radiotherapy to 54 Gy following EPP showed improved mean survival rates at 34 months for stage I-II disease and at 10 months with later-stage disease compared to historical controls . In addition to a small survival benefit demonstrated in the MSKCC study, the rationale for using radiation therapy is local control. The disease is of a diffuse nature and manipulating the exposed tumour during EPP puts the entire ipsilateral chest wall, diaphragm insertion, pericardium, mediastinum, and bronchial stump at a very high risk of local recurrence, as high as 80% of patients, as reported in . The evaluation of high-dose radiation therapy showed that the use of adjuvant radiation decreased the risk of local recurrence to 13% .
Mesothelioma is considered a tumour sensitive to external-beam radiation therapy. The recommended postoperative doses are 50 Gy for negative surgical margins, 54 to 60 Gy for close or positive margins, and 60 Gy for gross tumours [79–83]. The radiation dose has to be limited, however, due to the treatment required to the entire hemithorax and the sensitivity of critical organs such as the heart, lungs, oesophagus, liver, kidneys, and spinal cord to radiation .
Treatment volumes include ipsilateral mediastinum even for node-negative tumours. The superior border should include the thoracic inlet. The medial border should include the trachea, subcarinal lymph nodes, and the vertebral body. The inferior border is the insertion of the diaphragm, ranging from L1 to L4. Radiation oncologists should be careful to include the anteromedial pleural reflection of the sternopericardial recess, the medial and inferior extent of the crus of the diaphragm, and the inferior insertion of the diaphragm in the treatment volume. Nowadays, radiation therapy is delivered using three-dimensional conformal radiation therapy (3DCRT) or intensity-modulated radiation therapy (IMRT) [70, 71, 84, 85]. IMRT can be delivered according to the method published by the MDACC experiment using 13 to 27 fields with 8 to 11 gantry angles with 100 segments/fields. The target volume was the entire hemithorax, all surgical clips, all sites of instrumentation, and the ipsilateral mediastinum with an initial dose to 45-50 Gy, with a boost to 60 Gy for a close/positive margin. The two-year survival rate was 62% and the three-year disease-free survival (DFS) rate was 45% for negative lymph nodes and epithelioid histology. Five patients with stage-I disease had a three-year DFS of 100%. IMRT has the potential to decrease pulmonary toxicity if correct treatment algorithms are applied.
In order to decrease the side effects of radiation therapy, several dose-volume restrictions are applied. The V20 (the volume receiving 20 Gy or more) of the lung must not exceed 7%, since Rice DC et al.  showed a relative risk of 42% for fatal pneumonitis. The oesophagus V55 should be less than 30%; the liver V30 should be less than 30%. The kidneys V15 should be less than 20%; the heart V40 less than 50%; the spinal cord V45 less than 10%; no volume should be more than 50 Gy.
15.2. Radiation therapy to the biopsy site
A debate in radiation oncology for mesothelioma remains whether to offer radiation therapy to inoperable patients following an invasive procedure or following a biopsy in order to avoid needle-tract seeding from the tumour. The incidence of tumour seeding along the biopsy tract may range from 0% to 43% and may lead to the formation of painful subcutaneous lesions . Three randomized trials [88–90] evaluated RT following thoracoscopy or thoracotomy to prevent tumour seeding. The radiation-therapy regimen was generally 3 fractions of 7 Gy (total of 21 Gy). O’Rouke et al. showed, in their randomized trial with 61 patients, that prophylactic radiation therapy to drain sites did not statistically reduce the rate of seeding. Boutin’s study (40 patients) revealed a clear benefit of radiation at the biopsy site with reduction of biopsy-tract metastasis from 40% to 0% (p < 0.00 1). At the Hôtel-Dieu de Québec Hospital, however, Marie-Anne Froment et al.  reported a benefit of radiation therapy to avoid needle-tract seeding from the tumour. At 6 months, local progression-free survival for the intervention sites was 91% with prophylactic radiation therapy and 74% without irradiation (p = 0.00 2). During follow-up, 6 patients (13%) in the treated group had tumour invasion of the subcutaneous tissue compared to 40 patients (33%) in the group without radiation (p = 0.00 8). Because recurrence is morbid and this treatment is easily feasible, Hôtel-Dieu de Québec Hospital generally offers radiation therapy to such patients.
15.3. Side effects of radiation therapy after EPP
The side effects of radiation therapy can be classified according to time of occurrence: acute, intermediate, or late. Acute effects, if they appear, are expected to start during treatment and be resolved within 3 months following treatment. Potential acute side effects are fatigue, skin reactions, nausea, vomiting, dysphagia, odynophagia, and cough. Potential intermediate side effects include pneumonitis and Hermitte’s syndrome. If intermediate side effects occur, they usually do so 3 months after treatment and resolve within 6 months. Finally, potential late effects would occur 6 months following treatment and could include pulmonary fibrosis, pericarditis, restrictive cardiomyopathy, myocardial infarction, congestive heart failure, and radiation myelopathy.
Anthracyclines have historically been the most commonly used pharmacologic agents, with reported response rates of 19% . Recent trials using platinum in combination with folate analogues have improved cytotoxic activity against mesothelioma. The preferred treatment during these recent trials was a combination of chemotherapy incorporated with a trimodal regimen, as adjuvant or neoadjuvant chemotherapy options are either pemetrexed/cisplatin or gemcitabine/cisplatin.
16.1. Adjuvant chemotherapy
Patients treated with EPP, followed by radiation therapy and adjuvant chemotherapy, had a median survival rates of 36 % and 14% at two to five years, respectively. Historically, the chemotherapy used was doxorubicin, cyclophosphamide, and cisplatin for four to six cycles . A Harvard retrospective  review of 183 patients treated with a trimodality approach using adjuvant chemotherapy of Cytoxan/Adriamycin/cisplatin (CAP) or carboplatin/Taxol with concurrent radiation therapy followed by adjuvant chemotherapy had an overall mean survival rate of 19 months and a 5-year overall survival (OS) rate of 15%.
16.2. Neoadjuvant chemotherapy
The rationale for using neoadjuvant chemotherapy prior to surgery is that it may increase tolerance and improve response to surgery. A multicenter phase-II trial  evaluated the role of neoadjuvant chemotherapy prior to EPP and RT. The chemotherapy consisted of four cycles of pemetrexed plus cisplatin. The median survival rate of the patients who completed the therapy was 29 months; the two-year survival rate was 61%. De Perrot et al.  reported a median survival rate of 59 months in a subgroup of patients who had completed trimodal therapy with neoadjuvant chemotherapy, EPP, and then RT. The median survival rate was less than 14 months for the patients who did not complete the treatment regimen.
16.3. Combination chemotherapy
Combination-chemotherapy regimens using pemetrexed and platinum-based agents have yielded superior outcomes than single agents. Volgezang NJ et al.  showed that, for unresectable tumours, cisplatin/pemetrexed improved the response rate of 17% vs. 40% and the MS rate from 9 to 12 months compared to cisplatin alone. In 2004, pemetrexed became the first agent to receive Food and Drug Administration (FDA) approval for use in combination with cisplatin. The combination of pemetrexed and carboplatin were studied in two phase-II studies, the response rates and mean survival rates were 18.6% and 12.7 months in the Ceresoli study  and 25% and 14 months in the Castagneto study .
Several trials [97, 98] have evaluated the addition of gemcitabine, a cytidine analogue. Only 38% of patients received the four cycles as prescribed and the response rate was 26% among those who completed the treatment . It should be noted that the study only included early-stage mesothelioma. Vinca alkaloid-containing regimen was compared to MVP (mitomycin, vinblastine, and cisplatin) in terms of symptom control. The median survival benefit was an additional 2 months .
16.4. Single-agent chemotherapy
Pemetrexed as a single agent has been studied. In one phase-II trial , the study design was revised to incorporate folic acid and cynocobalamin in addition to dexamethasone. The median progression-free survival was 16.3 months in the pemetrexed/vitamin-supplemented group versus 9.5 months for the pemetrexed group. Other single agents such as gemcitabine, anthracyclines, and taxanes have been tested but resulted in low response rates, such as 10%
16.5. Chemotherapy side effects
Cisplatin and carboplatin are platinum analogues. The potential side effects of platinum agents include dose-limiting myelosuppression, nausea, vomiting, renal impairment, hearing impairment, and peripheral neuropathy. Pemetrexed is an antifolate compound. Potential side effects include myelosuppression, nausea, skin rash, alopecia, diarrhoea, and fatigue.
17. Molecular target therapy
Recent anticancer agents focus on molecular targets such as surface receptors and cell-signalling proteins. Although it has been shown that mesothelial cells express the vascular endothelial growth factor (VEGF) receptor, a recent study  failed to demonstrate survival improvement with bevacizumab. Erlotinib, a tyrosine-kinase inhibitor of the epidermal growth-factor receptor (EGFR), was tested in a phase-II trial. EGFR is expressed primarily in the epithelial subtype of mesothelioma. Of the 63 patients who were enrolled, only 29 were assessed for outcomes; no objective responses were reported .
18. Prognosis and overall survival
The European Organisation for Research and Treatment of Cancer (EORTC) reviewed data for 204 adults who were enrolled in five consecutive phase-II trials over nine years. The EORTC poor prognostic factors  for mesothelioma are:
White-blood-cell count greater than 8.3 X 109/ dL
Performance status (PS) 1-2
For low risk: 1-year OS rate is 40%; 2-year OS rate is 14%. For high risk: 1-year OS rate is 12% and 2-years OS rate is 0%. The MS rates are 4 and 12 months, respectively.
19. Palliative treatment
Surgical procedures, radiation therapy, and chemotherapy can be used to palliate symptoms.
Large pleural effusions can cause persistent dyspnea and pain. Complete drainage of the pleural effusion by tube thoracostomy or video thoracoscopy followed by the introduction of an irritative agent to obliterate the pleural space can provide palliation. There is an ongoing randomized trial in the United Kingdom comparing the palliative benefits of VATS pleurectomy to talc pleurodesis.
19.2. Radiation therapy
In the case of palliative treatments, radiation therapy can be used for pain relief. Either 30 Gy in 10 fractions or 20 Gy in 5 fractions can be delivered. Furthermore, palliative radiation therapy with daily dose of 4 Gy appears to be more effective than fractionations of less than 4 Gy for a total dose of 20 to 40 Gy to relieve pain associated with skin nodules in the CW. Radiation therapy can alleviate symptoms in 50% of patients .
For unresectable tumours, palliative chemotherapy with cisplatin/pemetrexed or cisplatin/gemcitabine can be used. There are no standard second line of chemotherapy. Therefore, a combination or single agent such as gemcitabine, vinorelbine, paclitaxel, or docetaxel may be considered.
The highest risk factor for mesothelioma is exposure to asbestos. Treatment for mesothelioma involves a trimodal approach for early-stage disease, which includes surgery, radiation, and systemic chemotherapy. In the case of locally advanced disease, nonsurgical candidates, or metastatic disease, surgery, chemotherapy, or radiation therapy can be used. Mesothelioma has a poor prognosis, but recent studies of pemetrexed and platinum-analogue combination therapies have demonstrated improved response rates over other treatments. Although conducting research on mesothelioma is extremely difficult, since it is an uncommon disease, further study is required to improve patient outcomes.
AP Anterior-posterior field
BAP1 A gene that encodes a nuclear localizing protein with a ubiquitin carboxy-terminal hydrolase domain that gives BAP1 its deubiquitinase activity.
CBC Complete blood count
CW Chest wall
DFS Disease-free survival
E2F Group of genes that codifies a family of transcription factors
EGFR Epidermal growth-factor receptor
EORTC European Organisation for Research and Treatment of Cancer
EPP Extrapleural pneumonectomy
FDA Food and Drug Administration
HCF1 A transcriptional cofactor involved in the cell cycle
MS Mean survival
MVP Mitomycin, vinblastine, and cisplatin
NF-2 Neurofibromatosis type-2 gene
OS Overall survival
P14 Tumour suppressor gene
P16 Tumour suppressor gene
P53 Tumour suppressor gene
PA Posterior-anterior field
PS Performance status
RT Radiation therapy
VATS Video-assisted thoracoscopic surgery
VEGF Vascular endothelial growth factor
WT1 Wilm’s tumour gene
Pass HI, Carbone M. Malignant mesothelioma: Advances in pathogenesis, diagnosis, and translational therapies. Springer Verlag; 2005a.
Robinson BW, Lake RA. Advances in malignant mesothelioma. N Engl J Med 2005, Oct 13;353(15):1591-603.
Gordon W, Antman KH, Greenberger JS, Weichselbaum RR, Chaffey JT. Radiation therapy in the management of patients with mesothelioma. Int J Radiat Oncol Biol Phys 1982, Jan;8(1):19-25.
Rusch VW. Pleurectomy/decortication and adjuvant therapy for malignant mesothelioma. Chest 1993, Apr;103(4 Suppl):382S-4S.
Butchart EG, Ashcroft T, Barnsley WC, Holden MP. Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experience with 29 patients. Thorax 1976, Feb;31(1):15-24.
Jaklitsch MT, Grondin SC, Sugarbaker DJ. Treatment of malignant mesothelioma. World J Surg 2001, Feb;25(2):210-7.
Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A lung cancer study group trial. J Thorac Cardiovasc Surg 1991, Jul;102(1):1-9.
Lung Tumour Group. B.C. Cancer agency; Available from: http://www.bccancer.bc.ca/PPI/TypesofCancer/Mesothelioma/default.htm. Accessed 5 May 2012.
Connelly RR, Spirtas R, Myers MH, et al:Demographic patterns for mesothelioma in the United States. J Natl Cancer Inst 1987; 78:1053-1060.
Institut national de santé publique Québec. Dossier amiante; Available from: http://www.inspq.qc.ca/dossiers/amiante/infos.asp?e=cp. Accessed 28 July 2012.
Selikoff IJ, Hammond EC, Seidman H. Latency of asbestos disease among insulation workers in the United States and Canada. Cancer 1980, Dec 15;46(12):2736-40.
Boffetta P, Epidemiology of peritoneal mesothelioma: a review. Ann Oncol. 2007;18(6):985.
Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothelioma and asbestos exposure in the north western cape province. Br J Ind Med 1960, Oct; 17: 260-71.
Occupational Safety & Heath Administration. Occupational Exposure to Asbestos; Available from http://www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=FEDERAL_REGISTER&p_id=12429 . Accessed November 27 2012.
Metintas M, Ozdemir N, Hillerdal G, Uçgun I, Metintas S, Baykul C, et al. Environmental asbestos exposure and malignant pleural mesothelioma. Respir Med 1999, May;93(5):349-55.
Senyiğit A, Babayiğit C, Gökirmak M, Topçu F, Asan E, Coşkunsel M, et al. Incidence of malignant pleural mesothelioma due to environmental asbestos fiber exposure in the southeast of turkey. Respiration 2000;67(6):610-4.
Senyiğit A, Bayram H, Babayiğit C, Topçu F, Nazaroğlu H, Bilici A, Leblebici IH. Malignant pleural mesothelioma caused by environmental exposure to asbestos in the southeast of Turkey: CT findings in 117 patients. Respiration 2000;67(6):615-22.
Metintas S, Metintas M, Ucgun I, Oner U. Malignant mesothelioma due to environmental exposure to asbestos: Follow-up of a turkish cohort living in a rural area. Chest 2002, Dec;122(6):2224-9
Pan XL, Dan Hw, Wang W et al. Residential proximity to naturally occuring asbestos and mesothelioma risk in California. Am J Respir Crit Care Med 2005; 172: 1019.
Hansen J, de Klerk NH, Musk AW, Hobbs MS. Environmental exposure to crocidolite and mesothelioma: exposure-response relationships. AM J Respi Crit care MEd 1998; 157:69.
Pira E, Pelucchi C, Buffoni L et al. Cancer mortality in a cohort of asbestos textile workers. Br J Cancer 2005; 92:580.
Carbone M, Kratzke RA, Testa JR. The pathogenesis of mesothelioma. Semin Oncol 2002, Feb;29(1):2-17.
Health Canada. Health risks of asbestos; Available from: http://www.hc-sc.gc.ca/hl-vs/alt_formats/pacrb-dgapcr/pdf/iyh-vsv/environ/asbestos-amiante-eng.pdf. Accessed 27 July 2012.
Hodgson JT, Mc Elvenny DM, Darnton AJ, et al. The expected burden of mesothelioma mortality in Great Britain from 2002 to 2050. Br J Cancer 2005; 92:587.
Muscat JE, Wynder EL. Cigarette smoking, asbestos exposure, and malignant mesothelioma. Cancer Res 1991, May 1;51(9):2263-7.
Takagi A, Hirose A, Nishimura T, Fukumori N, Ogata A, Ohashi N, et al. Induction of mesothelioma in p53+/- mouse by intraperitoneal application of multi-wall carbon nanotube. J Toxicol Sci 2008, Feb;33(1):105-16.
Poland CA, Duffin R, Kinloch I, Maynard A, Wallace WA, Seaton A, et al. Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat Nanotechnol 2008, Jul;3(7):423-8.
Mossman BT, Lippmann M, Hesterberg TW, Kelsey KT, Barchowsky A, Bonner JC. Pulmonary endpoints (lung carcinomas and asbestosis) following inhalation exposure to asbestos. J Toxicol Environ Health B Crit Rev 2011;14(1-4):76-121.
Teta MJ, Lau E, Sceurman BK, Wagner ME. Therapeutic radiation for lymphoma: Risk of malignant mesothelioma. Cancer 2007, Apr 1;109(7):1432-8.
Tward JD, Wendland MM, Shrieve DC, Szabo A, Gaffney DK. The risk of secondary malignancies over 30 years after the treatment of non-hodgkin lymphoma. Cancer 2006, Jul 1;107(1):108-15.
Travis LB, Fosså SD, Schonfeld SJ, McMaster ML, Lynch CF, Storm H, et al. Second cancers among 40,576 testicular cancer patients: Focus on long-term survivors. J Natl Cancer Inst 2005, Sep 21;97(18):1354-65.
Bott M, Brevet M, Taylor BS, Shimizu S, Ito T, Wang L, et al. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat Genet 2011, Jul;43(7):668-72.
Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet 2011, Oct;43(10):1022-5.
Altomare DA, Menges CW, Xu J, Pei J, Zhang L, Tadevosyan A, et al. Losses of both products of the cdkn2a/arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis. PLoS One 2011;6(4):e18828.
Thurneysen C, Opitz I, Kurtz S, Weder W, Stahel RA, Felley-Bosco E. Functional inactivation of NF2/merlin in human mesothelioma. Lung Cancer 2009, May;64(2):140-7.
De Luca A, Baldi A, Esposito V, Howard CM, Bagella L, Rizzo P, et al. The retinoblastoma gene family prb/p105, p107, prb2/p130 and simian virus-40 large t-antigen in human mesotheliomas. Nat Med 1997, Aug;3(8):913-6.
Pass HI, Donington JS, Wu P, Rizzo P, Nishimura M, Kennedy R, Carbone M. Human mesotheliomas contain the simian virus-40 regulatory region and large tumor antigen DNA sequences. J Thorac Cardiovasc Surg 1998, Nov;116(5):854-9.
Ramael M, Nagels J, Heylen H, De Schepper S, Paulussen J, De Maeyer M, Van Haesendonck C. Detection of SV40 like viral DNA and viral antigens in malignant pleural mesothelioma. Eur Respir J 1999, Dec;14(6):1381-6.
McLaren BR, Haenel T, Stevenson S, Mukherjee S, Robinson BW, Lake RA. Simian virus (SV) 40 like sequences in cell lines and tumour biopsies from australian malignant mesotheliomas. Aust N Z J Med 2000, Aug;30(4):450-6.
Gazdar AF, Carbone M. Molecular pathogenesis of malignant mesothelioma and its relationship to simian virus 40. Clin Lung Cancer 2003, Nov;5(3):177-81.
Kushitani K, Takeshima Y, Amatya VJ, Furonaka O, Sakatani A, Inai K. Immunohistochemical marker panels for distinguishing between epithelioid mesothelioma and lung adenocarcinoma. Pathol Int 2007, Apr;57(4):190-9.
Kamp DW, Israbian VA, Preusen SE, Zhang CX, Weitzman SA. Asbestos causes DNA strand breaks in cultured pulmonary epithelial cells: Role of iron-catalyzed free radicals. Am J Physiol 1995, Mar;268(3 Pt 1):L471-80.
Ault JG, Cole RW, Jensen CG, Jensen LC, Bachert LA, Rieder CL. Behavior of crocidolite asbestos during mitosis in living vertebrate lung epithelial cells. Cancer Res 1995, Feb 15;55(4):792-8.
Adachi Y, Aoki C, Yoshio-Hoshino N, Takayama K, Curiel DT, Nishimoto N. Interleukin-6 induces both cell growth and VEGF production in malignant mesotheliomas. Int J Cancer 2006, Sep 15;119(6):1303-11.
Pisani RJ, Colby TV, Williams DE. Malignant mesothelioma of the pleura. Mayo Clin Proc 1988, Dec;63(12):1234-44.
Hillerdal G. Malignant mesothelioma 1982: Review of 4710 published cases. Br J Dis Chest 1983, Oct;77(4):321-43.
Antman KH. Natural history and epidemiology of malignant mesothelioma. Chest 1993, Apr;103(4 Suppl):373S-6S.
Chang K, Pai LH, Pass H, Pogrebniak HW, Tsao MS, Pastan I, Willingham MC. Monoclonal antibody K1 reacts with epithelial mesothelioma but not with lung adenocarcinoma. Am J Surg Pathol 1992, Mar;16(3):259-68.
Ordóñez NG. Value of mesothelin immunostaining in the diagnosis of mesothelioma. Mod Pathol 2003, Mar;16(3):192-7.
Hollevoet K, Reitsma JB, Creaney J, Grigoriu BD, Robinson BW, Scherpereel A, et al. Serum mesothelin for diagnosing malignant pleural mesothelioma: An individual patient data meta-analysis. J Clin Oncol 2012, May 1;30(13):1541-9.
Grigoriu BD, Scherpereel A, Devos P, Chahine B, Letourneux M, Lebailly P, et al. Utility of osteopontin and serum mesothelin in malignant pleural mesothelioma diagnosis and prognosis assessment. Clin Cancer Res 2007, May 15;13(10):2928-35.
McLoud TC. CT and MR in pleural disease. Clin Chest Med 1998, Jun;19(2):261-76.
Leung AN, Müller NL, Miller RR. CT in differential diagnosis of diffuse pleural disease. AJR Am J Roentgenol 1990, Mar;154(3):487-92.
Aberle DR, Gamsu G, Ray CS. High-resolution CT of benign asbestos-related diseases: Clinical and radiographic correlation. AJR Am J Roentgenol 1988, Nov;151(5):883-91.
Alexander E, Clark RA, Colley DP, Mitchell SE. CT of malignant pleural mesothelioma. AJR Am J Roentgenol 1981, Aug;137(2):287-91.
Grant DC, Seltzer SE, Antman KH, Finberg HJ, Koster K. Computed tomography of malignant pleural mesothelioma. J Comput Assist Tomogr 1983, Aug;7(4):626-32.
Miller WT, Gefter WB, Miller WT. Asbestos-related chest diseases: Plain radiographic findings. Semin Roentgenol 1992, Apr;27(2):102-20.
Wang ZJ, Reddy GP, Gotway MB, Higgins CB, Jablons DM, Ramaswamy M, et al. Malignant pleural mesothelioma: Evaluation with CT, MR imaging, and PET. Radiographics 2004;24(1):105-19.
Heelan RT, Rusch VW, Begg CB, Panicek DM, Caravelli JF, Eisen C. Staging of malignant pleural mesothelioma: Comparison of CT and MR imaging. AJR Am J Roentgenol 1999, Apr;172(4):1039-47.
Marom EM, Erasmus JJ, Pass HI, Patz EF. The role of imaging in malignant pleural mesothelioma. Semin Oncol 2002, Feb;29(1):26-35.
Sørensen JB, Ravn J, Loft A, Brenøe J, Berthelsen AK, Nordic Mesothelioma Group. Preoperative staging of mesothelioma by 18f-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography fused imaging and mediastinoscopy compared to pathological findings after extrapleural pneumonectomy. Eur J Cardiothorac Surg 2008, Nov;34(5):1090-6.
Plathow C, Staab A, Schmaehl A, Aschoff P, Zuna I, Pfannenberg C, et al. Computed tomography, positron emission tomography, positron emission tomography/computed tomography, and magnetic resonance imaging for staging of limited pleural mesothelioma: Initial results. Invest Radiol 2008, Oct;43(10):737-44.
Wilcox BE, Subramaniam RM, Peller PJ, Aughenbaugh GL, Nichols Iii FC, Aubry MC, Jett JR. Utility of integrated computed tomography-positron emission tomography for selection of operable malignant pleural mesothelioma. Clin Lung Cancer 2009, Jul;10(4):244-8.
Bénard F, Sterman D, Smith RJ, Kaiser LR, Albelda SM, Alavi A. Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography. Chest 1998, Sep;114(3):713-22.
Yildirim H, Metintas M, Entok E, Ak G, Ak I, Dundar E, Erginel S. Clinical value of fluorodeoxyglucose-positron emission tomography/computed tomography in differentiation of malignant mesothelioma from asbestos-related benign pleural disease: An observational pilot study. J Thorac Oncol 2009, Dec;4(12):1480-4.
Curran D, Sahmoud T, Therasse P, van Meerbeeck J, Postmus PE, Giaccone G. Prognostic factors in patients with pleural mesothelioma: The european organization for research and treatment of cancer experience. J Clin Oncol 1998, Jan;16(1):145-52.
Balduyck B, Trousse D, Nakas A, Martin-Ucar AE, Edwards J, Waller DA. Therapeutic surgery for nonepithelioid malignant pleural mesothelioma: Is it really worthwhile? Ann Thorac Surg 2010, Mar;89(3):907-11.
Baldini EH, Recht A, Strauss GM, DeCamp MM, Swanson SJ, Liptay MJ, et al. Patterns of failure after trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg 1997, Feb;63(2):334-8.
Kutcher GJ, Kestler C, Greenblatt D, Brenner H, Hilaris BS, Nori D. Technique for external beam treatment for mesothelioma. Int J Radiat Oncol Biol Phys 1987, Nov;13(11):1747-52.
Ahamad A, Stevens CW, Smythe WR, Liao Z, Vaporciyan AA, Rice D, et al. Promising early local control of malignant pleural mesothelioma following postoperative intensity modulated radiotherapy (IMRT) to the chest. Cancer J 2003;9(6):476-84.
Forster KM, Smythe WR, Starkschall G, Liao Z, Takanaka T, Kelly JF, et al. Intensity-modulated radiotherapy following extrapleural pneumonectomy for the treatment of malignant mesothelioma: Clinical implementation. Int J Radiat Oncol Biol Phys 2003, Mar 1;55(3):606-16.
Krug LM, Pass HI, Rusch VW, Kindler HL, Sugarbaker DJ, Rosenzweig KE, et al. Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 2009, Jun 20;27(18):3007-13.
De Perrot M, Feld R, Cho BC, Bezjak A, Anraku M, Burkes R, et al. Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol 2009, Mar 20;27(9):1413-8.
Trousse DS, Avaro JP, D'Journo XB, Doddoli C, Astoul P, Giudicelli R, et al. Is malignant pleural mesothelioma a surgical disease? A review of 83 consecutive extra-pleural pneumonectomies. Eur J Cardiothorac Surg 2009, Oct;36(4):759-63.
Sugarbaker DJ, Jaklitsch MT, Bueno R, Richards W, Lukanich J, Mentzer SJ, et al. Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies. J Thorac Cardiovasc Surg 2004, Jul;128(1):138-46.
Flores RM, Pass HI, Seshan VE, Dycoco J, Zakowski M, Carbone M, et al. Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: Results in 663 patients. J Thorac Cardiovasc Surg 2008, Mar;135(3):620-6, 626.e1-3.
Aisner J. Current approach to malignant mesothelioma of the pleura. Chest 1995, Jun;107(6 Suppl):332S-44S.
Rusch VW, Rosenzweig K, Venkatraman E, Leon L, Raben A, Harrison L, et al. A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2001, Oct;122(4):788-95.
Maasilta P. Deterioration in lung function following hemithorax irradiation for pleural mesothelioma. Int J Radiat Oncol Biol Phys 1991, Mar;20(3):433-8.
Hilaris BS, Nori D, Kwong E, Kutcher GJ, Martini N. Pleurectomy and intraoperative brachytherapy and postoperative radiation in the treatment of malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 1984, Mar;10(3):325-31.
Lee TT, Everett DL, Shu HK, Jahan TM, Roach M, Speight JL, et al. Radical pleurectomy/decortication and intraoperative radiotherapy followed by conformal radiation with or without chemotherapy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2002, Dec;124(6):1183-9.
Yajnik S, Rosenzweig KE, Mychalczak B, Krug L, Flores R, Hong L, Rusch VW. Hemithoracic radiation after extrapleural pneumonectomy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2003, Aug 1;56(5):1319-26.
Weder W, Kestenholz P, Taverna C, Bodis S, Lardinois D, Jerman M, Stahel RA. Neoadjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. J Clin Oncol 2004, Sep 1;22(17):3451-7.
Rice DC, Stevens CW, Correa AM, Vaporciyan AA, Tsao A, Forster KM, et al. Outcomes after extrapleural pneumonectomy and intensity-modulated radiation therapy for malignant pleural mesothelioma. Ann Thorac Surg 2007, Nov;84(5):1685-92; discussion 1692-3.
Miles EF, Larrier NA, Kelsey CR, Hubbs JL, Ma J, Yoo S, Marks LB. Intensity-modulated radiotherapy for resected mesothelioma: The duke experience. Int J Radiat Oncol Biol Phys 2008, Jul 15;71(4):1143-50.
Rice DC, Smythe WR, Liao Z, Guerrero T, Chang JY, McAleer MF, et al. Dose-dependent pulmonary toxicity after postoperative intensity-modulated radiotherapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2007, Oct 1;69(2):350-7.
Lee C, Bayman N, Swindell R, Faivre-Finn C. Prophylactic radiotherapy to intervention sites in mesothelioma: A systematic review and survey of UK practice. Lung Cancer 2009, Nov;66(2):150-6.
McAleer MF, Tsao AS, Liao Z. Radiotherapy in malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2009, Oct 1;75(2):326-37.
Boutin C, Rey F, Viallat JR. Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy. Chest 1995, Sep;108(3):754-8.
O'Rourke N, Garcia JC, Paul J, Lawless C, McMenemin R, Hill J. A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma. Radiother Oncol 2007, Jul;84(1):18-22.
Froment MA, Fréchette E, Dagnault A. Prophylactic irradiation of intervention sites in malignant pleural mesothelioma. Radiother Oncol 2011, Nov;101(2):307-10.
Berghmans T, Paesmans M, Lalami Y, Louviaux I, Luce S, Mascaux C, et al. Activity of chemotherapy and immunotherapy on malignant mesothelioma: A systematic review of the literature with meta-analysis. Lung Cancer 2002, Nov;38(2):111-21.
Sugarbaker DJ, Flores RM, Jaklitsch MT, Richards WG, Strauss GM, Corson JM, et al. Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: Results in 183 patients. J Thorac Cardiovasc Surg 1999, Jan;117(1):54-63; discussion 63-5.
Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003, Jul 15;21(14):2636-44.
Ceresoli GL, Zucali PA, Favaretto AG, Grossi F, Bidoli P, Del Conte G, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol 2006, Mar 20;24(9):1443-8.
Castagneto B, Botta M, Aitini E, Spigno F, Degiovanni D, Alabiso O, et al. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM). Ann Oncol 2008, Feb;19(2):370-3.
Byrne MJ, Davidson JA, Musk AW, Dewar J, van Hazel G, Buck M, et al. Cisplatin and gemcitabine treatment for malignant mesothelioma: A phase II study. J Clin Oncol 1999, Jan;17(1):25-30.
Favaretto AG, Aversa SM, Paccagnella A, Manzini Vde P, Palmisano V, Oniga F, et al. Gemcitabine combined with carboplatin in patients with malignant pleural mesothelioma: A multicentric phase II study. Cancer 2003, Jun 1;97(11):2791-7.
Muers MF, Stephens RJ, Fisher P, Darlison L, Higgs CM, Lowry E, 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, May 17;371(9625):1685-94.
Scagliotti GV, Shin DM, Kindler HL, Vasconcelles MJ, Keppler U, Manegold C, et al. Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol 2003, Apr 15;21(8):1556-61.
Dowell JE, Dunphy FR, Taub RN, Gerber DE, Ngov L, Yan J, et al. A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma. Lung Cancer 2012, Jul 4.
Garland LL, Rankin C, Gandara DR, Rivkin SE, Scott KM, Nagle RB, et al. Phase II study of erlotinib in patients with malignant pleural mesothelioma: A southwest oncology group study. J Clin Oncol 2007, Jun 10;25(17):2406-13.
Bottomley A, Coens C, Efficace F, Gaafar R, Manegold C, Burgers S, et al. Symptoms and patient-reported well-being: Do they predict survival in malignant pleural mesothelioma? A prognostic factor analysis of EORTC-NCIC 08983: Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma. J Clin Oncol 2007, Dec 20;25(36):5770-6.
De Graaf-Strukowska L, van der Zee J, van Putten W, Senan S. Factors influencing the outcome of radiotherapy in malignant mesothelioma of the pleura--a single-institution experience with 189 patients. Int J Radiat Oncol Biol Phys 1999, Feb 1;43(3):511-6.