Ahmed Farouk Abd El-Hafez, MD

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1 Presented By Ahmed Farouk Abd El-Hafez, MD Lecturer of Cardiothoracic Surgery Assiut University

2 Asbestos exposure : amphibole fibers especially crocidolite asbestos Nonasbestos Causes : Silicate fibers : erionite Radiation Liquid paraffin Chronic inflammation Nonspecific industrial exposure Hereditary predisposition

3 In contrast to lung cancer, for which asbestos and smoking act as synergistic carcinogens, smoking is not a risk factor for MPM The peak age for the development of MPM is the sixth decade of life (long latency period ) Increased incidence in men

4 Arise from multipotential mesothelial or subserosal cells Exhibit a wide array of histologic patterns : Epithelial Sarcomatoid Mixed epithelial-sarcomatoid (biphasic) Transitional Desmoplastic Localized fibrous mesothelioma

5 Histochemical stains : Mucicarmine (-ve) Alcian blue or colloidal iron stain Immunohistochemistry : Calretinin Cytokeratins Vimentin Carcinoembryonic antigen (-ve) Electron microscopy

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7 Asbestos DNA damage: free radicals Nitric oxide Directly Multiple cytogenetic abnormalities Multiple clonal alterations Frequent mutations in of genes mediating apoptosis and tumor suppressor gene Over expression of the platelet-derived growth factors which regulate angiogenesis

8 Early stages of dyspnea As the tumor grows chest discomfort Localy advanced severe chest pain Final stages dyspnea and chest pain Pericardial effusion, ascites, extrathoracic metastases. Weight loss, and other uncommon symptoms

9 Early stages pleural effusion Late stages tumor encases the hemithorax Palpable soft tissue mass Palpable supraclavicular or axillary nodes Ascites Paraneoplastic syndromes : Autoimmune hemolytic anemia Hypercalcemia Hypoglycemia Syndrome of inappropriate secretion of antidiuretic hormone Hypercoagulability

10 Have abnormal electrocardiographic (ECG) and echocardiographic findings. No tumor markers are routinely used for MPM. Serum hyaluronan may be elevated

11 PA chest X-ray demonstrating the four classic findings of a patient with the clinical diagnosis of pleural mesothelioma: pleural thickening, pleural effusion, decreased thoracic volume, and no shift of the mediastinum to the affected side.

12 In early-stage large pleural effusion, Subtle pleural thickening or small, discrete, pleuralbased masses Subsequently, larger pleura-based masses become evident and are often intermixed with multiloculated effusions.

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15 Eventually, a thick confluent pleural peel develops, with encasement of the lung and obliteration of the pleural space. This can be associated with mediastinal adenopathy, direct extension of the tumor into the mediastinum, involvement of the pericardium with pericardial effusion, and extension into the chest wall or through the diaphragm

16 Preoperative tumor volume assessed by volumetric CT tumor measurement is representative of tumor stage status in MPM and can predict survival. Positron emission tomographic (PET) scanning mediastinal lymph node metastases (N2 disease), patients having distant disease (with stage IV disease), have prognostic significance

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20 No clinical findings are pathognomonic of MPM. Thoracentesis Percutaneous pleural biopsy Thoracoscopy Open pleural biopsy Immunohistochemical or electron microscopic studies for a definitive diagnosis CT scan of the chest and abdomen PET scan and MRI Bronchoscopy Laparoscopy

21 Preoperative staging evaluation includes: 1) Review pathology (including immunohistochemistry ± electron microscopy) 2) CT scan of chest and upper abdomen 3) Whole-body fluorodeoxyglucose PET scan 4) Pulmonary function tests 5) Quantitative ventilation/perfusion lung scanning 6) Radionuclide stress test

22 The natural history and prognostic factors in MPM is still limited Until recently, there was not even an accurate, universally accepted staging system TNM-based staging system developed by the International Mesothelioma Interest Group (IMIG) was accepted in 2002: Primary tumor (T): TX Primary tumor cannot be assessed T0 No evidence of primary tumor

23 T1 Tumor involves ipsilateral parietal pleura, with or without focal involvement of visceral pleura T1a Tumor involves ipsilateral parietal (mediastinal, diaphragmatic) pleura; no involvement of the visceral pleura T1b Tumor involves ipsilateral parietal (mediastinal, diaphragmatic) pleura, with focal involvement of the visceral pleura T2 Tumor involves any of the ipsilateral pleural surfaces with at least one of the following: confluent visceral pleural tumor (including fissure) invasion of diaphragmatic muscle invasion of lung parenchyma

24 T3 Describes locally advanced but potentially resectable tumor. Tumor involves any of the ipsilateral pleural surfaces with at least one of the following: invasion of the endothoracic fascia invasion into mediastinal fat solitary focus of tumor invading the soft tissues of the chest wall nontransmural involvement of the pericardium

25 T4 Describes locally advanced technically unresectable tumor Tumor involves any of the ipsilateral pleural surfaces with at least one of the following: diffuse or multifocal invasion of soft tissues of the chest wall any involvement of rib invasion through the diaphragm to the peritoneum direct extension of any mediastinal organs direct extension to the contralateral pleura invasion into the spine extension to the internal surface of the pericardium pericardial effusion with positive cytology invasion of the myocardium invasion of the brachial plexus

26 Regional lymph nodes (N) NX Regional LN cannot be assessed N0 No regional LN metastases N1 Metastases in the ipsilateral bronchopulmonary and/or hilar LN N2 Metastases in the ipsilateral mediastinal LN and/or the ipsilateral internal mammary LN N3 Metastases in the contralateral mediastinal, contralateral internal mammary, or hilar LN and/or the ipsilateral or contralateral supraclavicular or scalene LN Distant metastasis(m) MX Distant metastases cannot be assessed M0 No distant metastasis M1 Distant metastasis present

27 Stage I T1 N0 M0 Stage IA T1a N0 M0 Stage IB T1b N0 M0 Stage II T2 N0 M0 Stage III T1, T2 N1 M0 T1, T2 N2 M0 T3 N0, N1, N2 M0 Stage IV T4 Any N M0 Any T N3 M0 Any T Any N M1

28 The prognostic scoring systems of the Cancer and Leukemia Group B (CALGB) (Herndon et al, 1998): a) Performance status b) Age c) Histologic subtype d) Weight loss e) Hematologic parameters 49% had distant metastases at autopsy (Nauta et al, 1982), mainly to the liver and contralateral lung

29 Treatment options for MPM include: surgery, radiation therapy, chemotherapy, immunotherapy, supportive care, or some combination of these modalities. The choice of treatment is influenced by: the location and extent of the tumor, and the general medical condition The problem we face is due to : lack of large prospective clinical trials, Most patients have been treated in a highly individualized manner, and reported series are often small and retrospective

30 As a primary treatment considered not feasible as the doses of effective radiation therapy are not tolerated by the underlying lung or surrounding mediastinal structures. As the sole palliative treatment is generally used to palliate an area of symptomatic tumor in the chest wall or mediastinum. As an adjuvant therapy particularly after extrapleural pneumonectomy, as it is possible to deliver higher-dose irradiation to the hemithorax. Adjuvant short-course radiation therapy to the chest wall after thoracoscopy prevents the development of chest wall tumor implants after thoracoscopy.

31 Numerous phase II studies of chemotherapeutic agents pooled data showed response rates in the 20% range. Agents include doxorubicin, detorubicin, ifosfamide, cisplatin, carboplatin, mitomycin, methotrexate, edatrexate, 5-azacytidine, and 5-fluorouracil. Byrne and colleagues (1999) conducted a phase II study of combined cisplatin and gemcitabine There was a 47.6% response rate the best response rate to date Phase III international trial that compared cisplatin to cisplatin and pemetrexed response rate was 41% versus 17% for the cisplatin-only (Vogelzang et al, 2003)

32 Interferons are known to have a direct antiproliferative effect on MPM Although experimental data on mice showed promising results, clinical trials using interferon, either alone or in combination with chemotherapy have not demonstrated response rates superior to cisplatin alone. The use of interferon as an intrapleural treatment in patients with early-stage disease (free pleural space) showed a 56% overall response rate (Boutin et al, 1991)

33 Because of the limitations of radiation therapy and chemotherapy, surgical resection is still a mainstay of treatment for MPM Three cytoreductive operations have been performed: extrapleural pneumonectomy, pleurectomy-decortication, and a palliative limited pleurectomy Extrapleural pneumonectomy is an en bloc resection of the pleura, lung, ipsilateral hemidiaphragm, and pericardium

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55 Selection Criteria 1. Normal performance status 2. Predicted postoperative FEV1 > 1.0 L 3. Room air PaO2 > 65 mmhg 4. Room air PaCO2 < 45 mmhg 5. Ejection fraction > 40% 6. Mean pulmonary artery pressure < 30 mmhg 7. Epithelial histology 8. No N2 or extrapleural lymph node involvement 9. No distant or contralateral disease 10. Ability to complete a trimodality treatment program

56 Post-EPP Morbidity Atrial fibrillation Myocardial infarction Constrictive physiology Reoperation for constrictive physiology Tamponade Cardiac arrest Prolonged intubation Aspiration ARDS Tracheostomy Vocal cord paralysis Renal failure Deep vein thrombosis Pulmonary embolus Empyema Bronchopleural fistula Technical complications (Patch failure and bleeding)

57 Pleurectomy decortication is an attempt to remove all gross pleural disease without removing the underlying lung. The hemidiaphragm and pericardium are also removed and reconstructed if necessary A palliative pleurectomy involves limited resection of the parietal pleura to control a pleural effusion by creating a durable pleurodesis Another operation performed for strictly palliative purposes is thoracoscopy and talc poudrage

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64 Postoperative conplications: Postoperative bleeding: Immediate postoperative bleeding Delayed postoperative bleeding Prolonged air leak Other complications as in EPP.

65 Operative mortality of extrapleural pneumonectomy dropped from 30% to 4% (Sugarbaker et al,1999), that of pleurectomydecortication is 1.8% (McCormack et al, 1982) Resection of the tumor with wide, microscopically negative margins not feasible in MPM The goal of surgery in the multimodality treatment approach is to achieve a macroscopic complete resection, with adjuvant therapies directed at residual microscopic disease.

66 The value of extrapleural pneumonectomy (EPP) relative to pleurectomy-decortication remains controversial: EPP allows removal of the tumor en bloc, while both may allow the removal of all gross tumor. EPP cannot be performed in some patients because they have underlying cardiopulmonary disease. Pneumonectomy facilitates some forms of adjuvant treatment, especially postoperative irradiation, which can be administered to a much higher total dose

67 The long-term outcome of such a patient may be determined not by the operation but by the type and effectiveness of the adjuvant treatment Confluent sheet of tumor encasing the lung with obliteration of the pleural space is resectable only by EPP Overall survivals supports the use of P/D for early stage MPM provided that a complete resection is feasible; otherwise EPP will confer a survival advantage.

68 For stage II disease, however, EPP demonstrates a possible advantage. The focus in stage III disease should remain on the ability to achieve macroscopic complete resection, rather than N2 disease. Patients with stage IV cancers have better survival if the lung is left in place.

69 Surgical resection alone permit only the removal of gross tumor without wide surgical margins patients treated with surgical resection alone relapse rapidly. Sugarbaker and colleagues (1999) performed an EPP, followed by CAP chemotherapy or carboplatin and Taxol and subsequent hemithoracic irradiation. The overall survival rates were 38% at 2 years, but demonstrated a 35% local recurrence rate Rusch and associates (2001) performed a phase II trial of high-dose hemithoracic radiation after complete resection dramatic reduction in local recurrence rate to approximately 10%.Howver, the major area of failure was distant.

70 Therefore, they are currently conducting a phase II trial of neoadjuvant gemcitabine and cisplatin followed by EPP and adjuvant high-dose radiotherapy for patients who have bulky stage II or stage III disease at diagnosis. Photodynamic therapy (PDT) seeks to improve local control by eliminating microscopic residual disease immediately after surgical resection. Pass and associates (1997) conducted a phase III trial comparing maximum debulking surgery and postoperative cisplatin, interferon, and tamoxifen (CIT) immunochemotherapy with and without intraoperative PDT results demonstrate that PDT does not prolong survival or increase local control for MPM

71 Rusch and colleagues (1994) tested another approach in a phase II trial using a single dose of intrapleural cisplatin and mitomycin after pleurectomydecortication., follwed by adjuvent chemotherapy using also cisplatin and mitomycin The overall survival was favorable but it was associated with a high risk for local recurrence More recently, Sterman and colleagues (1998) explored the feasibility of treating early-stage MPM with intrapleural gene therapy. The herpes simplex virus thymidine kinase (HSVtk) gene could be successfully transferred to tumor via an adenovirus. Administration of the antiviral drug ganciclovir then led to selective tumor cell death Good preliminary results but more studies need to be conducted.

72 Malignant pleural mesothelioma is an uncommon and generally fatal malignancy During the past decade, pathologic diagnosis of MPM has become easier, staging methods have improved, and treatment options have increased. As a result, some patients experience longer survival. Continuing investigation into the biology and treatment of MPM is vital to improving the prognosis of this difficult neoplasm

73 Thank you

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