Malignant Pleural Mesothelioma: Management and Role of Radiation Therapy

Malignant pleural mesothelioma is a neoplasm derived from the mesothelial surfaces of the pleura. There are tree different mesothelioma types: Epithelioid Mesothelioma; Sarcomatoid; Biphasic /Mixed Mesothelioma. Patients with mesothelioma have a poor prognosis with a median survival ranging from 6 to 18 months depending on the stage of the disease at the time of diagnosis. Standard Management: For patients with clinical stage I-III and Epithelial or Mixed histology who are considered medically fit, surgery is recommended with extrapleural pnemonectomy (EPP) or pleurectomy/decortication (P/D). Adjuvant radiation therapy is recommended for patients with good performance status: the goal of adjuvant radiotherapy is to improve local control and it is an effective palliative treatment for relief of chest pain associated with mesothelioma. Chemotherapy alone is recommended for those who are not operable, those with clinical stage IV MPM or those with sarcomatoid histology. Radiotherapy: The target volumes delineation, defined by the radiation oncologist, is crucial because of large and irregularly shaped area at risk, high dose required for local control, the promixity of many structures as ipsilateral kidney, heart, spinal cord, esophagus, controlateral lung and the ipsilateral lung itself in inoperable cases. Actually sophisticated RT techniques such as IMRT, IGRT, and especially helical-slit IMRT (HT) might become appropriate alternatives for either definitive or palliative treatment for suitable patients based on compatible pulmonary toxicity criteria. The actual MPM guidelines suggest that the dose of radiation should be based on the purpose of the treatment. So the dose of radiation for adjuvant therapy should be 50-54 Gy with negative margins and 54-60 Gy with microscopic-macroscopic positive margins, in 1.8-2.0 Gy/day. For prophylactic radiation to surgical sites, a total dose of 21 Gy (3 x 7 Gy) is recommended.


Introduction
Malignant pleural mesothelioma (MPM) is a neoplasm derived from the mesothelial surfaces of the pleura. It typically spreads and invades locally but distant metastases to the controlateral lung, peritoneum, bone or liver can occur [1]. In 1960, the association between MPM and asbestos was first recognized and current patterns reflect a 20-40 years latency in disease development [2]. There are tree different MPM types: Epithelioid Mesothelioma, the most common type responsible for 50 to 70 percent of cases; Sarcomatoid that more often appears in other internal organs than the lungs; Biphasic / Mixed Mesothelioma that contains both the sarcomatoid and epithelioid mesothelioma cancer cells. Patients with MPM have a poor prognosis with a median survival ranging from 6 to 18 months depending on the stage of the disease at the time of diagnosis.

Pathogenesis
Mesothelioma is an insidious disease with long latency after asbestos exposure. New cases are continually diagnosed, although levels are declining with recognition of the asbestos risk and efforts to remove asbestos from the workplace. Researchers have examined the association between asbestos and respiratory ailments for decades. The majority of asbestos fibers are either amphibole (sharp, rod-like) or serpentine. The serpentine fibers make up 90% of the type seen in the US and are considered less carcinogenic than the amphibole type. These fibers are typically found in brake linings, ship building, cement, and ceiling and pool tiles. The Occupational Safety and Health Administration (OSHA) set acceptable levels of exposure at 0.2 fibers/ mL 3 for fibers 5 microns or greater and up to 5 fibers/mL 3 for smaller fibers. Inhaled asbestos fibers are trapped in the lower third of the lung, where they initiate an inflammatory response. The fibers are phagocytosed into mesothelial cells and initiate an oncogenic cascade of events that includes activation of c-Myc and c-Jun oncogenes, binding with epidermal growth factor receptors (EGFRs), and promotion of antiapoptotic genes such as Bcl-xl [3].

Clinical Presentation
Signs and symptoms associated with mesothelioma are relatively nonspecific and can be seen with almost any intrathoracic disease process, benign or malignant. Most patients have a cough, usually nonproductive. Dyspnea is also common. Chest wall pain may be a relatively unique symptom, usually described as a focal ache. Pleural effusions are common and are right sided 60% of the time. Five percent may present with bilateral effusions. Pleural plaques are common, and 1 out of 5 patients develop bibasilar fibrosis, characteristic of chronic asbestosis. Computed tomography (CT) may show pleuralbased nodularity. Magnetic resonance imaging can define invasion of the diaphragm or mediastinal structures, important in preoperative assessment. Positron emission tomography (PET) is useful because mesothelioma has hypermetabolic characteristics and PET can be used not only for staging but for posttreatment follow-up as well. Several paraneoplastic syndromes have been described with mesothelioma. These include hypercalcemia, hypoglycemia, autoimmune hemolytic anemia, hypercoagulable states, and disseminated intravascular coagulation. These syndromes are nonspecific and can be seen with a number of malignancies [4].

Diagnosis
Diagnosis of mesothelioma can be difficult. The disease is relatively uncommon and the amount of tissue obtained is often minimal and may not be adequate to perform the necessary battery of tests that can distinguish mesothelioma from other pleural-based malignancies. Histologic variability may make diagnosis challenging. The most common histologic type is epithelioid and is associated with the best prognosis. Sarcomatoid variants with characteristic spindle morphology are associated with a worse prognosis. Often, mixed epithelioid and sarcomatoid histologies can be seen. Tissue obtained by cytologic analysis of pleural fluid or blind pleural biopsy is limited and under classifies the correct histology up to 25% of the time. If pleural fluid is obtained, large volume collections should be performed and a cytospin analysis conducted to increase diagnostic accuracy. Thoracoscopic biopsies with direct visualization of pleural nodules provide the best yield. Immunohistochemical staining is important to distinguish mesothelioma from adenocarcinomas of lung origin or metastatic from other sites [5]. Calretinin is commonly positive in mesothelioma, with a reported sensitivity of 95% and specificity of 87%. Thrombomodulin has the best specificity at 92% but is less sensitive at 68%. Other useful antibodies directed against mesothelial-associated antigens include mesothelin, cytokeratin 5, Wilms' tumor-1 gene product, and HBME-1 and the nonmesothelial antigens Lewis-Y blood group (antibody BG8), MOC-31, BerEp4, CD15, and the carcinoembryonic antigen family [6].
Accurate diagnosis of mesothelioma depends on adequate tissue. Traditional diagnostic procedures have included pleural fluid cytology obtained through thoracentesis, needle biopsy of pleural tissue under CT guidance, video-assisted thoracoscopy surgery with direct visualization and biopsy of pleural nodules, and open thoracotomy. Pleural fluid is usually bloody and exudative with elevated protein, lactase dehydrogenase, and cell counts, but this finding is nonspecific and the sensitivity of pleural fluid cytology is low. Video-assisted thoracoscopy has a diagnostic accuracy of 98% in experienced hands and allows for the possibility of simultaneous pleurodesis [7,8].

Staging
Several staging systems for mesothelioma have been used over the years, almost exclusively dealing with primary pleural mesothelioma. Peritoneal mesothelioma does not have its own staging system [9]. Staging is done using the International Mesothelioma Interest Group (IMIG) INM staging system which was approved by the American Joint Committee on Cancer (AJCC) ( Table 1).

Standard Management
Once a diagnosis of pleural mesothelioma is confirmed, a thorough staging work-up should be undertaken to determine if a patient is amenable to surgical resection [4][5][6][7][8][9][10][11]. Pretreatment evaluation for patients with MPM diagnosis includes chest and abdominal CT with contrast 2) FDG-positron emission tomography (PET-CT). If possible, PET-CT scans should be obtained before pleurodesis, because talc causes pleural inflammation, which can affect the FDG-avidity. [12,13]. The work-up includes not only imaging and surgical staging as mentioned above, but a complete assessment of comorbidities, cardiac status, and pulmonary function testing. For patients with clinical stage I-III and Epithelial or Mixed histology who are considered medically fit, surgery is recommended with extrapleural pnemonectomy (EPP) or pleurectomy/decortication (P/D). Extrapleural pneumonectomy (EPP) was historically considered a potentially radical surgery. It involves the en bloc resection of lung, pleura, pericardium and diaphragm [14]. This aggressive operation is fraught with significant morbidity and many patients are not candidates due to poor cardioplomonary reserve or extent of disease [15,16]. Pleurectomy/Decortication (P/D) involves resection of the parietal and visceral pleurae, pericardium and diaphragm (if needed) leaving the lung intact and, historically, was reserved for patients who were unable to undergo EPP [17,18]. The perioperative outcome of EPP has improved significantly in recent years because of better surgical techniques and perioperative care [19,20]. (However, the long-term survival is still unsatisfactory due to high incidence of recurrence. Distant recurrence remained a problem in up to 55% of patients so it prompted the inclusion of chemotherapy into the multimodality approach [19]. Local recurrence after EPP, occurs in up to 80% of patients [15,19,. Recent evidence suggests that radiation therapy to the chest cavity after EPP, decreases this risk.
Adjuvant radiation therapy is recommended for patients with good performance status: the goal of adjuvant radiotherapy is to improve local control and it is an effective palliative treatment for relief of chest pain associated with mesothelioma. When there is no resection of disease delivery of high dose RT to the entire hemothorax in the setting of an intact lung has not been shown to be associated with significant survival benefit and the toxicity is significant. Chemotherapy alone is recommended for those who are not operable, those with clinical stage IV MPM or those with sarcomatoid histology.

Surgical Therapy of MPM
The role of surgery in the management of mesothelioma has been largely confined, for many years, to obtain tissue samples for pathological diagnosis or to achieve symptom's control by pleurodesis; nevertheless, in the last decades the increased incidence of the disease, together with first reports of long-term survivors has resulted in a more aggressive surgical approach (Figures 1 and 2).
Three surgical operations are currently available for the treatment of mesothelioma: extrapleural pneumonectomy, better known as pleuropneumonectomy (EPP), pleurectomy-decortication, and palliative pleurectomy.
Extrapleural pneumonectomy is the only one radical surgical option for the treatment of mesothelioma. It provides the best cytoreduction and allows postoperative higher radiation doses to be delivered to the ipsilateral hemithorax, after the lung has been removed; it is also the only feasible procedure when a thick tumor rind obliterates the pleural space.
Careful selection and preoperative assessment are mandatory in candidates for extrapleural pneumonectomy.
All patients need histological proven diagnosis of stage I to III pleural mesothelioma (T1/T3 disease, without cardiac involvement, N0/N2 disease and M0).
Cardio-pulmonary assessment is mandatory in all patients candidate to extrapleural pneumonectomy; to be eligible for EPP patients need a Karnofsky performance status higher than 70, normal liver and kidney function tests.
VATS indications are staging, diagnosis and palliative treatment of malignant pleural mesothelioma. Thoracoscopic exploration allows examination of parietal, visceral, diaphragmatic and mediastinal pleura; it also allows inspection of pericardium and yields high quality bioptic samples.
Talc poudrage results in a highly effective control of pleural T1 T1a Tumor limited to the ipsilateral parietal pleura, including mediastinal and diaphragramatic pleura No involvement of the visceral pleura T1b Tumor involving the ipsilateral parietal pleura, including mediastinal and diaphragramatic pleura Scattered foci of tumor also involve in the visceral pleura T2 Tumor involving each of the ipsilateral pleura surfaces (parietal, mediastinal and diaphragramatic and visceral pleura) with at least one of the following features: 9 Involvement of diaphragmatic muscle 9 Confluent visceral pleural tumor (including the fissures) or extensions of tumor from visceral pleura into the underlying pulmonary parenchyma T3 Describes locally advanced but potentially resectable tumor Tumor involving all of the ipsilateral pleura surfaces (parietal, mediastinal and diaphragramatic and visceral pleura) with at least one of the following features: 9 Involvement of the endotharacic facia 9 Extension into the mediastinal fat 9 Solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall 9 Nontransmural involvement of the pericardium T4 Describes locally advanced technically unresectable tumor Tumor involving all of the ipsilateral pleura surfaces (parietal, mediastinal and diaphragramatic and visceral pleura) with at least one of the following features: 9 Diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction 9 Diffuse transdiaphragramatic extension of tumor to the peritoneum 9 Direct extension of tumor to the contralateral pleura 9 Direct extension of tumor to one or more mediastinal organs 9 Direct extension of tumor into the spine 9 Tumor extending through to the internal surface of pericardium, with or without a pericardial effusion; or tumor involving the myocardium N-lymph nodes Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes    effusion and provides excellent palliation for patients whose general medical condition prevents a more aggressive treatment. Nevertheless thoracoscopy and talc pleurodesis facilitates subsequent extrapleural dissection and prevent intraoperative spillage of malignant cells during extrapleural pneumonectomy; it should be performed 30 to 40 days before EPP.
Mortality rate of extrapleural pneumonectomy is comparable, at present, to a standard pneumonectomy, ranging about 3.8%; accurate patient selection, advances in preoperative and intraoperative management and postoperative care are very important to achieve such low mortality.
Palliative pleurectomy is based on the partial or total resection of the parietal pleura, to control pleural effusion by creating a durable pleruodesis; pleurectomy-decortication (P/D) is instead an attempt to remove all grossly evident pleural disease, without removing the underlying lung. If the tumor has not spread to the underlying lung, P/D is performed to remove the entire tumor; P/D is associated with few complications, low mortality rates and has the best results in early stage patients. Blood loss and air leaks are the most common complications.
Decortication is performed to remove any tumor on the visceral lining; the technical goal of this procedure is the macroscopic oncological radicality and the good re-expansion of the lung.

Radiation Therapy
The role of radiotherapy in MPM is defined by symptomatic relief and palliation, prevention of neoplastic cell seeding and adjuvant therapy following surgery for early stage disease [24]. The effect of radiation monotherapy on prolonging survival is minimal so the multimodality approach has a strong locoregional treatment rationale. The target volumes delineation, defined by the radiation oncologist, is crucial because of large and irregularly shaped area at risk, high dose required for local control, the promixity of many structures as ipsilateral kidney, heart, spinal cord, esophagus, controlateral lung and the ipsilateral lung itself in inoperable cases.
The first question is on surgery's technique before RT: pleurectomy/ decortication (P/D) or extrapleural pneumonectomy (EPP)? Yan et al. reported an observational study on a cohort of 70 patients with MPM to evaluate perioperative and long term outcomes associated with EPP. Of these 70 patients, 63 (90%) had a complete cytoreduction and the remaining 7 (10%) had residual macroscopic disease. Postoperatively, 28 patients received adjuvant ipsilateral radiotherapy and 16 patients received pemetrexed combined with cisplatin or carboplatin. Eleven patients received more than 1 adjuvant therapy and 4 received neoadjuvant chemotherapy. The follow-up was complete. The median survival was 20 months (range 0-104 months) with 1-2-3-4 and 5 years survivals of 62%, 41%, 30% and 15 % respectively. Twentysix patients (37%) remained alive at the last follow-up. The present study demonstrayed a perioperative mortality of 5.7% and an overall morbidity of 37% supporting the use of EPP in carefully selected patients with MPM [25]. Adjuvant radiotherapy seems improve locoregional control of MPM. Rusch et al. performed a phase II trial of surgical resection and adjuvant high-dose henithoracic radiation for MPM. From 1995 to 1998, 88 patients were entered into the study. The operations performed included 62 EPP and 5 P/D; procedures for exploration only were performed in 21 patients. Seven patients died postoperatively. Adjuvant radiation was administered to 57 patients with a median dose of 54 Gy (range 20-64 Gy). In general radiation was well tolerated with most toxicities being of grades 1 and 2. Grade toxicities included fatigue, esophagitis, nausea and vomiting. The most serious grade 4 toxicity was an esophagopleural fistula which developed several months after the completion of radiation and required surgical intervention. Survival was estimated for the patients who underwent EPP. The median survival was 17 months and the overall survival at 3 years was 27% with a longer median survival for stage I and II tumors [23]. In another study 35 patients were treated with EPP followed by hemithoracic radiation therapy using combined photon and electron technique (median dose 54 Gy: range 45-54 Gy and 180 cGy/die). The radiation therapy target volume was the entire hemithorax, including the pleural folds and the thoracotomy and chest tube incision sites. The most common toxicities were RTOG grades 1 and 2 nausea and vomiting as well as lung, esophageal and skin toxicities resulting in a feasible and well tolerated treatment regimen with adequate dose distributions [22]. However, radiotherapy for patients with MPM and an attempt to treat the entire involved pleural surface at a potentially curative dose (60 Gy), is limited because of the large target volume, the high risk of radiation pneumonitis and the radiosenitivity of heart, mediastinum, liver and spinal cord. In this setting, more sophisticated RT techniques such as IMRT, IGRT, and especially helical-slit IMRT (HT) might become appropriate alternatives for either definitive or palliative treatment for suitable patients based on compatible pulmonary toxicity criteria. A report of 2003 studied 28 patients with MPM who underwent EPP surgery with no evidence of extrathoracic disease and were treated with postoperative radiotherapy using IMRT. They were irradiated between 2000 and 2002. Treatment was delivered once daily in five fractions/week using 6 MV photons. CTV doses were 45-50 Gy to hemithorax with boost taken to 60 Gy. The commonest side effects were nausea, anorexia, and vomiting occurring in 89% of patients and fatigue occurring in 80% of patients. Dysphagia caused by radiation esophagitis was mild or absent. At a median follow-up of 9 months (range 5-27 months) the overall survival at 1 and 2 years was 65% and 49% respectively. The disease specific survival at 1 and 2 years was 88% and 58% respectively with in-field local control of 100%. IMRT is praticable with minimal target motion; IMRT plans can irradiate the hemithorax without spreading the dose to the remaining lung [22]. This Radiothearpy technique has allowed for an increase in dose to the pleural cavity and a reduction in radiation doses to organs at risk. Kristensen et al. reports and analyses the incidence of fatal pulmonary toxicity in patients treated at Rigs hospital, Copenhagen. Twentysix patients were treated with induction chemotherapy followed by extrapleural pneumonectomy and IMRT between April 2003 and April 2006. The entire preoperative pleural surface area was treated to 50 Gy and areas with residual disease or close surgical margins were treated to 60 Gy in 30 fractions. The main toxicities were nausea, vomiting, esophagitis, dyspnea, and thrombocytopenia. Four patients (15%) experienced grade 5 lung toxicity, i.e. pneumonitis 19-40 days after the completion of radiotherapy. Patients with pneumonitis had a significantly larger lung volume fraction receiving 10 Gy or more (V10) (median: 60.3%, range 56.4-3.2%) compared to patients without pneumonitis (median: 52.6%, range: 25.6-80.3%) (p=0.02). Mean lung dose (MLD) was also significantly higher in patients who developed pneumonitis (median 13.9 Gy, range: 13.6-14.2 Gy) than in patients who did not (median=12.4 Gy, range: 8.4-15.4 Gy) (p=0.04) [26]. Helical tomotherapy is a promising method, and achieves a better dose conformity. Sterzing et al. in 2008 evaluated the potential of Helical Tomotherapy in the adjuvant radiotherapy of MPM comparing target homogeneity, conformity and normal tissue dose with step-and-shoot IMRT. Ten patients with MPM were treated in our department with 54 Gy to the hemithorax delivered by step-and-shoot IMRT. A planning comparison was performed by creating radiation plans for helical tomotherapy. Both modalities achieved excellent dose distributions while sparing organs at risk. Target coverage and homogeneity could be increased significantly with helical tomotherapy compared with step-and-shoot IMRT so could be an excellent option for adjuvant intensity-modulated radiotherapy of MPM [27].
The actual MPM guidelines suggest that the dose of radiation should be based on the purpose of the treatment. So the dose of radiation for adjuvant therapy should be 50-54 Gy with negative margins and 54-60 Gy with microscopic-macroscopic positive margins, in 1.8-2.0 Gy/ day. For prophylactic radiation to surgical sites, a total dose of 21 Gy (3x 7 Gy) is recommended. Computed Tomography (CT) is used in RT planning: each patient is simulated and treated in supine position with both arms raised above their heads positioning. The Clinical Tumor Volume (CTV) should encompass the entire pleural surface (for partial resection cases) or the entire hemithorax, surgical clips and any potential sites with residual disease. The Planning Target Volume (PTV) should consider the target motion and daily set-up errors. IMRT is a promising treatment technique that allows a more conformal highdose RT improving coverage to the hemithorax. Especially IMRT with Helical tomoterapy technique achieves a better dose conformity [28][29][30][31][32][33][34][35].

Radiation Technique after Radical Pleurectomy/ Decortication: Volumes, Prescription and Delivery
The clinical target volume (CTV) should encompass the entire pleural surface, from the lung apex down to the insertion of the diaphragm -often in the vicinity of the L2 vertebral body -including ipsilateral mediastinal lymph nodes in case of pathological N1-2 disease. Extensive elective nodal irradiation is not recommended. Thoracotomy scars should also be included in the CTV. Medially, the CTV includes the ipsilateral pericardium. Any potential sites of residual disease (positive margins, or areas of PET FDG uptake at postoperative restaging) should receive a radiation boost. IGRT should be used to minimize target motion and daily set-up errors. If it is indeed the case, an isotropic expansion of 5 mm around the CTV can be considered for planning target volume (PTV). Organs at risk should include the ipsilateral and con tralateral lung, heart, esophagus, liver, kidneys, gastrointestinal tract, and spinal cord [36][37][38][39][40][41].
Dose prescription to the median dose point of the entire PTV is 50 Gy delivered in 25 fractions (2 Gy/fraction), and a simultaneous boost to any fluorodeoxyglucose-avid areas or regions of particular concern for residual disease up to 60 Gy (2.4 Gy/fraction) [42].
Dose computation and treatment delivery are performed on the Tomo-Therapy HiArt II system (TomoTherapy Inc., Madison, WI). Image Guided Radiotherapy (IGRT) is performed by means of a Megavolt Computed Tomography (MVCT) before each daily session and positioning done using the integrated registration with the planning CT to account for set-up uncertainties [43][44][45][46][47][48].
The use of radiation therapy as adjuvant treatment is practicable.
Intensity-Modulated Radiotherapy (IMRT) especially using helical tomotherapy allows the safe delivery of high dose of radiation. It can provide a highly conformal dose to irregularly shaped target and a steep dose gradient near the critical structures. Surgery and radiotherapy could be the future for MPM treatment [49][50][51][52][53][54][55][56].