MESOTHELIOMAs Dr Dharma Ram pooniaRGCI RC 18.06.16

• Rare • Pleura MC site • Peritoneum, Pericardium, Tunica Vaginalis • 72 year • most advance stage • Median OS 1 year, Cure Rare.

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ETIOLOGY • 1. Asbestos exposure.

• 20 -40 yr of exposure latency.• it also cause benign pleural disease.• Reduced use of Asbestos in USA, incidence on plateau• incidence on Rise, Russia, china, india• Smoking Increase risk of malig in Asbestos exposed one.

• In animal studies Dose Response relation is exist, but in Human studies, no clear dose-response curve to asbestos, • <5% of asbestos miners exposed to high levels of

asbestos develop mesothelioma. • Threshold level below which mesotheliomas do not

develop has not been determined. 3

MECHANISM OF ASBESTOS CARCINOGENESIS. • Asbestos Exposure • Human mesothelial cell death

HMGB1 released in EC space. • 1. Activation of Nalp3

inflammasome and interleukin (IL)-1β secretion

• 2.Macrophage accumulation Inflammatory response and tumor necrosis factor–α secretion

• These effects increase damaged cell survival.

• At same time asbestos induced genetic changes accumulated in these cells.(INK4a/ARF gene)

• Which coz mesothelioma. 4

OTHER ETIOLOGICAL FACTORS.

• Radiation exposure In childhood• Erlonite (industrial Mineral fiber)• Carbon and nickel Nanoparticles• Simian Virus 40• Gentic factors • A TSG, BAP1, mutated in higher frequency in

turkey population and implicated as causative factor. • 60-70% mesothelioma has mutated BAP1

gene. 5

PATHOLOGY • Epitheloid 60%• Tubular structures and malignant mesothelioma cells showing a

hobnail morphology with bland nuclei and abundant cytoplasm. • Sarcomatoid 10%• Mixed(Biphasic) rest.• Diagnosis is usually straight forward. • IHC may be used to r/o mimics (mets and sarcomas). • IHC —> • +ve Calretinin, WT1, D2-40, CK5/6 (pankeratin) • -ve —> epithelial markers (CEA, CD15, Ber-EP4, Moc 31), TTF1, &

B72.3 • Practically Ck+, Calretinin+, and Epithelial –ve, makes Dx. 6

CLINICAL PRESENTATION

• often high symptom burden. • Right > left 60;40% (right more volume).

• 60% nonpleuritic chest pain that classically is located posterolaterally.• Dyspnea 50-60%.• 5% and 25% of metastatic at presentation. • A chest wall mass occurs in up to 25% of

patients, often at the site(s) of prior thoracoentesis, thoracotomy site

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NATURAL HISTORY OF DISEASE • Majority of untreated patients died due to local disease

complications.• Bulk of disease compressing and cause respiratory & cardiac

dysfunctions.• Pain narcotics use cachexia• Dysphagia Cachexia.

• Extrathoracic metastases occur late in the course of disease and are not usually the direct cause of the patient’s death.

• liver, adrenal gland, kidney, and contralateral lung.

• 3% brain mets, (sarcomatoid type) 8

INITIAL EVALUATION • CXR • Pleural effusion, diffuse pleural thickening, and nodularity • Large opacity with Mediastinal shift. (50%)

• Presumed mesothelioma means —> • Large recurrent unexplained pleural effusion • pleural thickeing • specially in asbestos exposed/ family H, needs initial evaluation for Dx.

• Thoracocentasis• CECT chest• Extent, Stage n Resectability• Recently CT Volumetric assessment —> Prognostic marker. 9

• MRI • Better detect diaphragmatic and endothoracic fascia.

• PET CT• Indicated before Sx, to see N stage and Distant mets. • High FP, so prove Positive finding before decision making.

• CT abdomen, if PET CT not done, to rule out peritoneal disease.

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TISSUE DIAGNOSIS • Thoracocentasis • Cytology and cell block & IHC 84% sensitivity.

• CT guided bx• VATS Bx• If above method failed.• Under vision, adequate tissue can be taken.

• Open Biopsy • Rarely needed these days.

• For subtype classification (needs good amount of tissue.)• Open Bx 83% accuracy• Thoracoscopy 74%• Image Guided Bx 44% 11

TUMOR MARKER • Serum mesothelioma related protein (SMRP)• Sn 83%, Sp 95%.• Correlate with disease burden.• Not useful for early disease. • Optional.

• Osteopontin (OPN)• Correlate with asbestos exposure, but not correlated with

Mesothelioma. • Megakaryocyte potentiating factor• Pleural effusion fibulin 3

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STAGING 7TH EDITION AJCC • IMIG (international mesothelioma interest group)

proposed TNM and this is being accepted by AJCC.

• Survival Stage 1 through 4 • 51m, 26m, 15m and 8m.

• Staging is surgical, so without Sx, it may be inaccurate.

• PET is part of staging. 13

T1 —> tumor limited to Ipsilateral parietal pleura with or without involvment of Mediastinal pleura and Diaphragmatic pleura.

a —> Visceral pleura not involved. b. Visceral pleura involved.

T2 —> when each surface of ipsilateral PP involved with atleast one of the following invasion

* Diaghragmatic muscle * Lung parenchyma

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• T3 —> locally advanced, potentially resectable, tumor involving ipsilateral Pleura with atleast one• 1. Involvement of the endothoracic fascia

2. Extension into the mediastinal fat3. Solitary, completely resectable focus extending into the soft tissues of the chest wall4. Non transmural involvement of the pericardium.

• T4 locally advanced, technically unresectable,1. multifocal/diffuse chest wall with rib distruction 2. transdiaphragmatic Peritoneal involvment.3. contralateral pleura4. mediastinal organ5. internal surface of pericardium or myocardium 6. spine.

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• N1 " ipsilateral bronchopulmonary or hilar lymph nodes • N2 " subcarinal or the ipsilateral mediastinal lymph nodes, • including the ipsilateral internal mammary nodes • N3 " contralateral mediastinal, contralateral internal

mammary, ipsilateral, or contralateral supraclavicular lymph nodes

• Stage I"T1, no LN or mets. 52m

• StageII"T2 26m

• Stage III"T3 or N1 or N2 16m

• StageIV"T4orN3orM1 8m

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ROLE OF SURGERY

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1. DIAGNOSTICTo identify subtype

2. PALLIATIVE3. MCR – MACROSCOPIC COMPLETE RESECTION

• R0/1

• Cardiopulmonary evaluation and performance status to be considered before surgery as pt may req pneumonectomy

Mesothelioma domain of IASLC

• P/D Parietal and visceral pleurectomy to remove all gross tumor without diaphragm or pericardial resection.

• EPP ” en bloc resection of the parietal and visceral pleura with the ipsilateral lung, pericardium, and diaphragm.

• In cases where the pericardium and/or diaphragm are not involved by tumor, these structures may be left intact

• Extended P/D (resection of the diaphragm and pericardium in addition to total pleurectomy.

MCR " macroscopic complete resection/ R0 or R1 is Goal. 20

• EPP : initial Sx defined for Mesothelioma5-11.8% mortality22-82% morbidityMedian OS 9.4 to 27m

• AF, MI, Epicarditis, Respiratory failure, Thrombosis, Empyema, herniation of heart, RLN injury, BPF.

• Owing to high sx mortality, EPP alone was not shown to prolong OS,

• Phase 2 studies in 2004 to 2010, used trimodality. • Induction chemotherapy EPP Hemithorax RT.

• 3.1% mortality• 60% completed Rx• 27.7 month overall survival

• They also advised patient selection, which do better with TMT.• ! younger < 65 with good PS,

! has pure epitheloid histology,! an absence of lymph node involvement, and is! physiologically able to tolerate pneumonectomy.

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MARS * 2011 criticisms of the study includes (6 flaws)

• 1.18% operative mortality• 2. Lack of power of the

study.• 3. The crossover of

individuals from one arm to the other in six instances• 4. Only one-third of the

individuals received the full TMT.• 5. Preoperative

chemotherapy was not standardized.

Conclusions • Median survival of 14.4

months versus 19.5 months, respectively

• So Sx, not adding they said.

• First RCT to evaluate EPP as a part of multimodality therapy

• 50 patients randomised • Induction chemo - EPP -

RT

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P/D & Ext P/DLUNG PRESERVING APPROACH

• Recent 4 publications in 2012. • P/D seems to have less mortality, less morbidity, and a

comparable overall survival to EPP, so A Phase 3 RCTs started.

• MARS-2 trial Survival and/or QoL benefits.• 2x pem+Cis if stable or no progression, Either

• Ext P/D 4 chemo• or 4 more cycle of CT.

• Primary outcome OS@ 5 years. May 2017, expected.

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BETWEEN ...., EPP OR P/D ?• Flores and colleagues , 2007,MSKCC experience

• 945 patients with mesothelioma, over 20 years• 22% underwent EPP and • 19% underwent P/D• Rest no surgery.

• MCR, surgical experience, addition of pem+ cis based CT, Stage of disease, histology and symptom burden affected survival.

• Survival without Sx was inferior than with Sx. • Type of surgery, not affected Survival. • EPP a/w better local control with cost of increase morbidity.

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• a significantly higher proportion of short-term deaths in the EPP group versus the P/D group (percent mortality meta estimate; 4.5% vs 1.7%; p < 0.05).

• There was no statistically significant difference in 2-year mortality between the 2 groups

• P/D should be preferred when technically possible.

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NCCN EPP and P/D both are reasonable optionP/D is safer than EPP, but Oncological superiority not known.

FEW MORE SURGICAL ISSUES. • Do MLND in all patients.

• If MCR not feasible, surgery should be differed.

• Recent studies, if even if R2 resection can be done

without adding surgical morbidity, one should proceed

with Sx, as it is best palliation of symptom control and ?

Survival advantage.

• Partial pleurectomy is palliative procedure for Intractable

pl effusion. 26

• NCCN stage 1-3, chemotherapy should be part of MMRx.• Stage 4 & medically unresectable CT only is an option. • Pem 500mg/m2 + Cisplatin 75mg/m2, 3 weekly regimen.• Vogelzang et al landmark study: pem became Rx part. • An EORTC trial investigate the timing of the chemotherapy in

combination with extended P/D. • MAPS trial adding Avastin in unresectable good PS patients, 2.7

m OS benefit, but role in surgical patients ?• Pem + carbo• Gem + Cis• Gem + Vinorelbine• Intra operative, Hyper thermic intrapleural CT are investigational

CHEMOTHERAPY

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RADIATION • Definitive RT need of Large dose and vital organs• Definitive CTRT • Few retrospective series 88% RR, 12% durable CR . Chen et al• So may an option for nonsurgical candidates, but robust data

lacking. investigational • Adjuvant RT, post EPP• MSKCC, Rusch et al, survival benefit shown. • IMRT and RT planning with PET CT scan, reduce toxicity and

improve tolerance.• 50-60Gy/1.8-2#• Hemithorax RT entire hemithorax, incisions and drain sites.

• NCCN Post EPP, RT should be given if one can tolerate. 28

• Adjuvant RT post P/D• Its highly toxic and not found to improve Survival, hence not

indicated. MSKCC series. • Still some centers use it, NCCN says No.• Brachytherpay or intraop RT too are not indicated.

• Palliation • Pain 30-40Gy with each # > than 4 gy, excellent pain control.• Bronchial and esophageal obstruction.• Brain mets , Painful bone mets.

• Prevention of scar recurrence • 20-50% chance• Data conflicting• 21Gy/ 3Gy x 7

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SUPPORTIVE CARE• To control pleural effusion• Repeated thoracentesis• Talc pleurodesis• Pleur X catheter• Pleurectomy - better survival, Qol

• Pain – • narcotics,• epidural, • local Rt

NOVEL TREATMENTAPPROACHES

• Angiogenesis Inhibition – Bevacizumab,

thalidomide, sunitinib and sorafenib .• Ribonuclease Inhibitors – Ranpirnase• Histone Deacetylase Inhibitors - vorinostat• Mesothelin directed therapy - amatuximab

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SURGICAL STEPS

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SUMMARY

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• Highly aggressive disease - 51 months ,26 months , 15 months

and 8 months

• Trimodality therapy – 60 % have 30 month of median survival

• Surgery - EPP vs P/D

• Prevention is the key to success in fighting against mesothelioma

• Thanking you..

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