ESO-ESMO EASTERN EUROPE AND

BALKAN REGION MASTERCLASS IN

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MEDICAL ONCOLOGY
30.June-5.July 2017

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Belgrade, Serbia

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Malignant Pleural Mesothelioma

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Dragana Jovanovic
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University Hospital of Pulmonology CCS

Belgrade, Serbia
 Malignant pleural mesothelioma (MPM)

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Highly aggressive tumor - arises from mesothelial cells

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that line the serosal cavities.

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MPM occurs in patients age 60 years and older, typically

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presenting decades after an exposure to asbestos with

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gradually worsening, nonspecific pulmonary symptoms.
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Asbestos exposure the main factor involved in
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pathogenesis: MPM may occur up to 3040 yrs after
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asbestos exposure
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Difficult to treat because most patients have advanced

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disease at presentation
 Clinical presentation

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Typically presents with gradual onset symptoms, shortness
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of breath, chest pain, cough and weight loss

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Common physical findings due to a pleural effusion, which

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is almost always present.

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Most frequently clinical manifestations of MPM as

recurrent pleural effusion and/or pleural thickening
 Diagnostic work-up

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Imaging methods

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Chest X ray

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Chest CT scan (the thorax and upper abdomen)

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(occasionally Gadolinium-MR necessary, PET under debate)

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Thoracentesis with examination of the pleural effusion
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Biopsy and hystopathological confirmation + IHH
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(a) Thoracoscopy (as a pleuroscopy or as VATS) or

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(b) Ultrasound-guided true-cut biopsy

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Circulating tumour markers?

 Diagnostic imaging

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Chest radiographs a unilateral pleural

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thickening, with or without fluid, often calcified

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plaques.

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Eibel et al. Curr Opin Oncol 2003; 15: 131138.

Wang et al. Radiographics 2004; 24: 105119
 Chest CT scan

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Chest CT scan - diffuse or nodular

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pleural thickening suggestive of

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the disease.
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 Diagnosis of Mesothelioma

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The accurate diagnosis of MP Mesothelioma is

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made on hystopathological examination.

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Difficulties:

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-MPM is a very heterogeneous tumor with the ability to
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mimic almost any other form of malignant tumour
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-The pleura is a common site for metastatic disease and

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reactive changes that may be confused with MPM

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- Other uncommon benign or malignant pleural tumours

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 Samples for Diagnosis

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Pleural effusions - high risk of diagnostic error

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Small (closed) pleural biopsies

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NOT RECOMMENDED

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Image-guided (US) needle core biopsies

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Larger open or VATS surgical biopsy samples or
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debulking specimens
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Surgical resection rarely performed.

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Autopsy in some cases

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Aerts et al. Diagn Cytopathol 2006;34:523-7, Husain et al. Arch Pathol Lab Med 2009;133:1317-31, ESMO GL 2015, NCCN GL 2016.
 Diagnosis of Mesothelioma

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The tumor sample should be in sufficient quantity to

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allow immunohystochemical characterization

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Diagnosis in the context of appropriate clinical,

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radiological and/or surgical findings

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The differential diagnosis on pleural biopsy between
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MPM and pleural benign or malignant disease
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/metastasis of adenocarcinoma/ difficult in some cases,

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even with the use of IHC

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Scherpereel A. Respir Med 2007; 101: 12651276.

5 Scherpereel A. Rev Mal Respir 2006; 23: 11S511S6. Scherpereel A et al. Eur
Respir J 2010;35:479-95.
MPM NCCN v2016, ESMO GL 2015
 Diagnosis of Mesothelioma

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Fine needle biopsies - low sensitivity (~30%)

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Surgical-type samples preferred for diagnosis

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Diagnosis in >90% of cases
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Complete visual examination of

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the pleura, multiple, deep and

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large biopsies.
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Maskell et al. Lancet 2003; Metintas et al. Chest 2010; van Zandwijk et al. J Thorac Dis 2013 , Scherpereel Eur Respir J 2010; Medford
et al. Lung Cancer 2009; Zahid et al. Interact Cardiovasc Thorac Surg 2011;Greillier et al. Cancer 2007;ESMO GL 2015, NCCN GL 2016.
 Macroscopic aspect of mesothelioma

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May vary during its natural

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history

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As MPM progress, their gross

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appearance becomes more

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suggestive of MPM.

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intrapleural loculations

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Microscopic characteristics
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A varied and deceptive appearance

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in a high percentage of cases

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Travis et al, eds. WHO Classification 2015

WHO Classification of Tumors of the Pleura 2015

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 Immunohistochemical examination

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Diagnosis of MPM should always be based on biopsy

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complementary immunohystochemical examination

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At least two mesothelial markers and at least two

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(adeno) carcinoma markers should be used

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International Mesothelioma Interest Group (IMIG)

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Calretinin

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WT-1
D2-40
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CK 5/6
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Sarcomatoid MPM often does not express usual

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mesothelial markers
Immunohistochemistry of Epitheloid MM

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Lung Adc
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 Natural course

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Death is usually due to progressive dyspnea

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&

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respiratory insuffiency with

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extensive weight loss & muscle wasting
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&
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Acute abdomen or
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cardiac tamponade/constriction
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 Prognostic factors

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Stage and histology are the strongest prognostic

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factors, with sarcomatoid and biphasic histologic

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subtypes having worse outcomes compared with

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epithelioid mesothelioma.

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The pure epithelioid variant is associated with the best
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prognosis especially if the disease can be completely
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resected.
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Other poor prognostic features include poor

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performance status, age >75 years, elevated lactate

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dehydrogenase (LDH), and hematologic abnormalities

Prognostic Factors in EORTC studies

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Prognostic Factors in CALGB studies

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Pleural mesothelioma survival based upon histology

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N2 disease or mixed histology at surgery

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Nonepitheloid subtype - poorer prognosis

Rush et al JTO 2012
 Angiogenesis features strongly MPM

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VEGF and PDGF Poor Prognosis VEGF OS

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VEGFR-3 Overexpressed in MPM cells (L) and Lymphatics (R)

Strizzi et al., J Pathol. 193:468-475, 2001

Robinson and Lake, N Engl J Med 353:1591-1603, 2005 Masood et al., Int. J Cancer 104:603-610, 2003
Filho et al., Diagn. Cytopathol. 35:786-791, 2007
 Treatment options

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Multimodality therapy for patients with stages I-III

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MPM who are medically operable.

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Chemotherapy alone for not operable patients,

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those with clinical stage IV, or those with

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sarcomatoid histology.
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Medically inoperable - observation for progression
or chemotherapy
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Radiotherapy for palliation, preventive, and as a

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part of multimodality treatment

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van Zandwijk et al. J Thorac Dis 2013, ESMO GL 2015, MPM NCCN v2016
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 Surgery fo MPM

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Pleurectomy/decortication with mediastinal LN

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sampling complete removal of the pleura and

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all gross tumor

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Extrapleural pneumonectomy (EPP) with en bloc

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resection of pleura, lung, pericardium and
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diaphragm and systematic nodal dissection -
radical surgery.
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Part of multimodality treatment approach.

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Sugarbaker et al. J Thorac Cardiovasc Surg 2004; 128: 138146.

Rusch et al. J Thorac Cardiovasc Surg 2001; 122: 788795.
Weder et al. Ann Oncol 2007; 18: 11961202.
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Rush et al JTO 2012
Correlation of clinical and pathological staging in MM

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In a database study

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including 1056 cases,

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clinical staging was

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80% of clinical stage I
patients and 70% of
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stage II patients being

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upstaged following
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surgery.
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Rush et al JTO 2012

 Front-line Chemotherapy for Mesothelioma

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Improves survival of patients with unresectable MPM

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Combination doublet chemotherapy of cisplatin with pemetrexed
standard of care

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Carboplatin is an acceptable alternative to cisplatin (elderly)

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van Meerbeeck et al. J Clin Oncol 2005; Santoro et al. J Thorac Oncol 2008; Ceresoli et al. Br J Cancer 2008;
Efficacy of Cisplatin + Pemetrexed vs Cisplatin (ITT)

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Cisplatin 75 mg/m2 +/-

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Pemetrexed 500mg/m2

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Total number of cases= 456

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Number for final analysis = 448

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Event Cisplatin + Cisplatin HR P Value

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Response rate, % 41.3 16.7 < .001
Median TTP, mos 5.7 3.9 0.68 < .001
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Median OS, mos 12.1 9.3 0.77 .028

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Global QoL score 45 38 .012

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Improved symptom
51 44 .009
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distress
Vogelzang NJ, et al. J Clin Oncol. 2003;21:2636-2644.
Gralla RJ, et al. ASCO 2003. Abstract 2496.
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Slide 1

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Presented By Gerard Zalcman at 2015 ASCO Annual Meeting

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445 patients

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Positive for both PFS (primary endpoint) & OS

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OS was significantly longer 188 mos vs 161 mos HR 077; p=00167,

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at the cost of expected manageable toxic effects, therefore it should

be considered as a suitable treatment for MPM
Zalcman et al, Lancet 2016
 Chemotherapy of MPM

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Front-line Chemotherapy should be stopped in case of

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progressive disease, grade 34 toxicities or cumulative

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toxic doses or following up to six cycles in patients who

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respond or who are stable.

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Pretreatment After 4 cycles Cis/Pem

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Currently no second-line standard of care

Other acceptable 1st line ChemoTh options

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Pemetrexed and Carboplatin

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Gemcitabine and Cisplatin

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Pemetrexed

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Vinorelbine

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2nd line chemotherapy options

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Pemetrexed (if not given as 1st line)
Vinorelbine
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NCCN based on subgroup analyses from several 1st -line
Gemcitabine studies, retrospective analysis, and small phase II trials
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Maintenance therapy
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Strategy with pemetrexed after six cycles of standard

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chemotherapy in MPM
Ongoing studies with new drugs
MPM NCCN v2016
 Malignant Pleural Mesothelioma: 2017

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Majority of patients present with advanced disease and

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are not candidates for surgery

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Only FDA approved regimen is pemetrexed plus cisplatin

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(median OS 12.1 months)
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No drug approved for mesothelioma since 2004
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Several ongoing studies using different immune based

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therapies to treat mesothelioma

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 Immunotherapy for Malignant

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Pleural Mesothelioma

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Mesothelin targeted therapies

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Immune checkpoint inhibition
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Anti-CTLA4 antibodies: Tremelimumab, Ipilumab
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Anti-PDL1 antibodies: Avelumab, Durvalumab

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Anti-PD-1 antibodies: Pembrolizumab, Nivolumab

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 Selected studies of immune checkpoint

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inhibition in mesothelioma

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Single agent pembrolizumab (U Chicago Phase II Study)

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Single agent nivolumab (NivoMes Study)

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Tremelimumab and Durvalumab (NIBIT-MESO-1 Study)

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Phase II Durvalumab plus chemotherapy study (DREAM Study)
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Phase III Ipilumab plus nivolumab vs. chemotherapy as first

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line treatment for pleural mesothelioma (CHECKMATE 743)

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 KEYNOTE-028

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Pembrolizumab in KEYNOTE-028 safe and tolerable.

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PD-L1 expression in MPM is associated/correlated with disease

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extent at diagnosis and sarcomatoid subtypes and poor prognosis.

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Mesothelin Immunotherapy for Mesothelioma: 1996-2016

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 Mesothelin Immunotherapy for

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malignant pleural mesothelioma

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Two anti-mesothelin agents are currently in registration

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clinical trials for pleural mesothelioma:

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Amatuximab (first line setting)
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Anetumab ravtansine (second-line setting)
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 Radiotherapy in mesothelioma

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Palliation

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Preventive treatment

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Part of a multimodality treatment

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Palliative RT effective in temporarily relieving chest pain,
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bronchial or esophageal obstruction, or other symptomatic
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sites - no clinical evidence for RT treating pain

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Recommended for infiltration of the chest wall or

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permeation nodules by MPM usually short courses:

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10 grays (Gy) in a single fraction or 8 Gy in three fractions

Price. Oncologist 2011, Macleod et al. Lung Cancer 2014, ESMO GL MPM 2015
 Radiotherapy

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Debate whether a scar after thoracoscopy and/ or

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drainage procedures should be irradiated prophylactically

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in order to reduce the likelihood of seeding metastases.

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In general not recommended that RT is administered pre-

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or postoperatively with large fields (hemi-thoracic RT)

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outside the setting of a clinical trial.
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Advanced RT techniques recommended to optimize local
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control and avoid excessive toxicity - therefore RT to be

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delivered in specialized centers

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Improved 3D planning and intensity-modulated RT (IMRT)

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van Zandwijk et al. J Thorac Dis 2013, MPM NCCN v2016

 Radiotherapy in MPM

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RT (timing and dosing) after surgery and/or with

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ChemoTh should be discussed in a multidisciplinary

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team MDT and performed in specialized centres.

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RT can be given in an adjuvant setting after surgery

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or chemo-surgery to reduce the local failure rate, but

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no evidence for its use as a standard treatment.
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When limited or no resection - RT for an intact lung
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or after P/D, high-dose RT to the entire hemithorax

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with an intact lung - no significant survival benefit, the

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toxicity is significant. But, may be considered with

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caution.
Gupta et al 2005, Baldini et al 1997, Rusch et al 2001, MPM NCCN v2016, ESMO GL 2015
 Radiotherapy following surgery in MPM

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Post-op RT after EPP can be recommended for patients

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with good PS to improve local control, only in specialized

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centres TD 5060 Gy in 1.82.0 Gy

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IMRT in the adjuvant setting after EPP promising.

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Postoperative RT - to avoid toxicity to neighbouring
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organs, and special, tissue sparing, techniques be used
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Pattern of failure after trimodality treatment with 3D
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conformal RT (3DCRT) and highly conformal RT (HCRT) in

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39 patients: in-field recurrences only in those treated with

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3DCRT -16%. HCRT superior to 3DCRT

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van Zandwijk et al. J Thorac Dis 2013, Gomez et al, J Thorac Oncol 2013, MPM NCCN v2016
 Pleurodesis

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Active control of pleural effusion is the mainstay of

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treatment in most patients with MPM.

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Early and successful pleurodesis - symptom control

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and a trapped lung less likely to occur

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(before effusions have become loculated and/or the

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lung has become fixed and unable to expand fully).
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Pleurodesis should be performed at first relapse of
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effusion.
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Symptom control (pain, dyspnea)

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Every patient should receive at least BSC

 Response evaluation and follow-up

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The efficacy of a treatment can be assessed on:

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(a) clinical criteria - symptoms control and QoL,

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(b) imaging criteria (CT scan or PET), and
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(c) survival criteria (TTP and OS).
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Pleurodesis status should be known when

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interpreting results of CT or FDG-PET imaging

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 Conclusion

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Malignant pleural mesothelioma (MPM) is a

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highly aggressive tumor, almost always a fatal

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disease.

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Early diagnosis of crucial importance

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The accurate diagnosis of MPM is made based
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on histological and immunohystochemical
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examination.
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Active control of pleural effusion is the

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mainstay of treatment in most patients.

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