Current Management of Malignant Mesothelioma

1
Current Management of Malignant Mesothelioma

• Nico van Zandwijk
• Bernie Banton Centre
• University of Sydney
• Australia

ALF Gold Coast 20-8-2008
2
Pleural plaques

• Pleural plaques

Asbestosis
Pleural mesothelioma
3
Asbestos Exposure in MPM

• Evident in 70-80 of those affected

4
World production of asbestos
www.hiroshima-u.ac.jp/er/recources
5
Occupations and Locations with an Increased Risk
of Asbestos Exposure

• Manufacturing of Asbestos products
• Shipyard workers
• Navy veterans
• Miners and Drillmen
• Demolition Workers
• Railroad workers
• Construction (insulation) workers
• Maritime Workers

• Oil refinery Workers
• Power plants
• Automobile reapir
• Maintenance workers
• Steel mills
• Refineries
• Sand or abrasive manufacturers
• Paper Mills
• Drywall Removers

6
Epidemiology of MPM

• Peak Asbestos Consumption in Australia in 1975
  (90 in asbestos cement industry)
• First documented MPM case in Australia in 1947
• The incidence of mesothelioma is expected to
  increase and peak between 2015 and 2020
• The median latency period from first exposure to
  clinical manifestation is around 40 years
• Genetic predisposition for MPM is likely

7
MPM Incidence in NSW

• Peak number approaching 200 cases/year
• What about the Asbestos present in Society (1/3
  of houses contaminated)

8
Mesothelioma in Europe

• Peak leveling off between 2010 and 2015?

9
Latency period of Malignant Pleural Mesothelioma

• Data collected by the Italian mesothelioma
  registry in the period 1993-2000 median latency
  44.6 years

Marinaccio, EJC 2007
10
Asbestos consumption and mesothelioma deaths
Lin, Lancet 2007
11
Continued Exposure in the Third World
12
Clinical recommendations I

• Histology Gold Standard (review recommended)
  Epithelial, Sarcomatous and Mixed Types
• Staging CT recommended, MRI can be useful
• PET is promising
• TNM system
• Prognostic scores (CALGB and EORTC) also based on
  PS, histology, weight loss and white blood
  (thrombocyte) count

13
Clinical recommendations II Surgery

• Extrapleural pneumonectomy with resection of
  hemidiaphragme and pericardium en bloc has the
  potential for a radical treatment and this
  approach is generally combined with chemotherapy
  and/or adjuvant radiotherapy
• Palliative oprocedures include parietal
  pleurectomy, decortication or pleurodesis

14
Clinical recommendations III Radiotherapy

• Limited by the risk of high-dose irradiation of
  underlying lung
• Effective in palliation
• Modern techniques for high-dose RT after EPP with
  curative intent
• Profylaxis of port metastases

15
Clinical recommendations IV Chemotherpy

• Chemotherapy provides symptom relief
• cisplatin pemetrexed has become the standard of
  care as chemotherapy regimen (Vogelzang et al)
• Current studies examining neoadjuvant
  chemotherapy followed by extrapleural
  pneumonectomy include combined cisplatin and
  pemetrexed chemotherapy

16
Early Diagnosis
17
Mesothelin

• Mesothelin is a cell surface glycoprotein,
  expressed on normal mesothelial cells and gt 90
  of mesotheliomas (binds to CA125)
• Soluble mesothelin-related proteins in serum
• Target for antibody therapy

Robinson, Lancet 2003
Cristaudo, Clin Cancer Res 2007
18
Osteopontin

• Cell surface glycoprotein, binding to integrin
  and CD 44 receptors
• Elevated serum levels of Osteopontin in MPM
  compared with controls Pass et al, NEJM 2005
• Immunohistochemistry
• Osteopontin expression in other tumours

19
Chemotherapy for Malignant Mesothelioma
20
Chemotherapy Spectrum

• Anthracyclines (Doxorubicin)
• Taxanes (Paclitaxel)
• Vinca Alkaloids (Vinorelbine)
• Antimetabolites Edatrexate, Gemcitabine,
  Pemetrexed Raltitrexed
• Combinations Cisplatin, Carboplatin

21
MVP Symptom Relief in MPM

• 150 patients
• RR 15 (95 CI 9-21)
• Symptom improvement 69
• Dyspnea 50
• Cough 62
• Pain 71
• Malaise 39
• Median survival 7 months
• 1-year and 2-year survival 31 and 11

Middleton, Ann Oncol 1998 Andreopoulou, Ann
Oncol 2004
22
Pemetrexed Cisplatin vs Cisplatin Selected
Grade 3/4 Toxicity ()
ALIMTA Cisplatin Cisplatin (n226)
(n222) 4 2 28 2 6 0 2 1 13 4 4 0 4 0
Possible Drug Related Death Neutropenia Thromb
ocytopenia Febrile Neutropenia Vomiting Stomatitis
Diarrhea
All Patients
Vogelzang , JCO 2003
23
Phase III Pemetrexed Cisplatin vs Cisplatin in
MPM
1.0
Pemetrexed Cisplatin (n226)
0.9
Cisplatin (n222)



0.8
0.7
0.6
Survival()
0.5

0.4

0.3
0.2
0.1
0.0
0
5
10
15
20
25
30
Time(months)
Vogelzang et al. J Clin Oncol 2003 21
2636-2644 Vogelzang et al, WCLC 2005, updated
survival
24
Pemetrexed Cisplatin vs Cisplatin Symptomatic
improvement
Gralla, ASCO 2002
25
Pemetrexed with Cisplatin or Carboplatin Results
of Expanded Access Program
Manegold, WCLC 2007
26
Chemonaive pts with MPM Pemetrexed
International EAP
The Expanded Access Program (EAP) provided
access to therapy for European patients with
MPM. Total of 1704 chemo-naïve MPM patients
received treatment with PemetrexedCisplatin or
PemetrexedCarboplatin with vitamin
supplementation.
Kaplan-Meier analysis of time to progressive
disease (months), in Chemonaive patients with
MPM, who received pemetrexed cisplatin, or
pemetrexed carboplatin. Please note that
median survival could not be estimated due to
high censoring rate.
Santoro A, et al., J Thor Oncol, 2007 in press
27
Combined Modality Therapy
28
ExtraPleural Pneumonectomy (EPP) RT

• EPP with adjuvant chemotherapy and radiotherapy
• Brigham 176/183 pts MST 19 months, periop.
  mortality 3.8, 35 local failureSugarbaker
  JTCVS 1999 Baldini, ATS 1997
• EPP with high dose hemithoracic radiotherapy
  Increase of local tumor control, more toxicity?
• 13 local only failure vs 55 distal only
  failure, 61/88 EPP MST 17 mo, periop. mortality
  11Rusch, JTCVS 2001

29
ExtraPleural Pneumonectomy (EPP) Chemo

• EPP and adjuvant chemotherapy (n12), MST 13
  months, feasibility?Taverna, ESMO 2000
• Pilot study of neoadjuavant chemotherapy followed
  by EPP (n19), MST 23 months, good
  feasibilityWeder, JCO 2004
• SAKK multicenter phase II (n61 pts, operated
  45), MST 19.8 months, 23 months for operated
  patientsWeder and Stahel, Ann Oncol 2007

30
Multimodality therapy (contd)

• Intrapleural chemotherapy pleurectomy High
  morbidity van Ruth, Chest 2003
• Intrapleural Photodynamic therapy pleurectomy
  Significant morbidity, some long term survivors
  Pass, Ann Surg Oncol 1997, Schouwink, Ann Thor
  Surg 2003
• Induction Chemotherapy Extrapleural
  Pneumonectomy (EPP) feasible in carefully
  selected patients (PET scanning, Mediastinoscopy)
  Long term survival altered pattern of
  recurrent disease EORTC 2008

31
A Multicenter Phase II Trial of Neoadjuvant
Pemetrexed Plus Cisplatin (PC) Followed by
Extrapleural Pneumonectomy (EPP) and Hemithoracic
Radiation (RT) for Stage IIII Malignant Pleural
Mesothelioma (MPM)

• L. M. Krug, H. Pass, V. W. Rusch, H. L. Kindler,
  D. Sugarbaker, K. Rosenzweig, J. S. Friedberg,
• K. Pisters, C. K. Obasaju, N. J. Vogelzang

Krug LM, et al., J Clin Oncol, 2007 ASCO Vol 25,
No. 18S, 2007 7561
32
Pem/Cis Surgery and RT for Stage IIII MPM
Endpoint pathologic complete response rate
Krug LM, et al., J Clin Oncol, 2007 ASCO Vol 25,
No. 18S, 2007 7561
33
Pem/Cis Surgery and RT for Stage IIII MPM
Results
Krug LM, et al., J Clin Oncol, 2007 ASCO Vol 25,
No. 18S, 2007 7561
34
Pem/Cis Surgery and RT for Stage IIII MPM

• Results subgroup analysis

Krug LM, et al., J Clin Oncol, 2007 ASCO Vol 25,
No. 18S, 2007 7561
35
Pem/Cis Surgery and RT for Stage IIII MPM
Surgical results

• Among the 56 (n75 in ITT) patients considered
  for surgery
• there were 23 right EPPs, 27 left EPPs
• 6 patients explored did not have EPP
  (unresectable disease)
• EPP completion rate was 89 for patients
  considered for surgery after chemotherapy
• Overall, 67 of the patients treated on the study
  were resectable by EPP
• Following surgery, disease stage was improved
  (18), not changed (38), worsened (27), or
  unknown (18)

Krug LM, et al., J Clin Oncol, 2007 ASCO Vol 25,
No. 18S, 2007 7561
36
Pem/Cis Surgery and RT for Stage IIII MPM
Conclusions

• Largest multicenter trial testing trimodality
  therapy in MPM to date
• Chemotherapy administered without difficulty and
  with a reasonable response rate, 3 pCRs (5.3)
  were observed
• Preliminary survival is below that reported by
  other researchers for patients undergoing
  multimodality therapy but still has a high
  censorship rate at this early time point
• Preliminary subgroup analysis suggests that
  response to chemotherapy has the greatest impact
  on overall survival

Krug LM, et al., J Clin Oncol, 2007 ASCO Vol 25,
No. 18S, 2007 7561
37
Randomized Phase III Second Line Pemetrexed
BSC vs. BSC in Previously Treated Advanced MPM
PFS
0.0148
Survival
p0.7434
Jassem, ESMO 2006
38
Phase III Second-line Chemotherapy

• Doxorubicin /- Onconase
• ranpirnase, Alphacell corp
• selective degradation of t-RNA ? apoptosis
• To recruit 300 patients started 1997
• Vorinostat
• suberoylanilide hydroxamic acid, SAHA, Zolinza,
  Merck
• Binds to histone deacetylase in nucleus
• After 220 patients interim analysis now 660
  planned

www.clinicaltrials.gov
39
Immunotherapy

• Interleukin 2
• Interferon
• Interferon chemo
• More targeted approaches ?

40
Clinical trial with Anti-Mesothelin Antibodies

• SS1P (recombinant immunotoxin)
• Phase I DLTs were reversible pleuritis,but no
  pericarditis. 34 pts, including 21 with
  mesothelioma MR 4, SD 19 including 2 with
  resolution of ascites
• Phase II in combination with gemcitabine
  initiated
• MORAb-009 (humanized antibody)
• Elicits ADCC, inhibits mesothelin binding to MU16
• Phase I ongoing

Hassan, Lung Cancer 2006 Clin Cancer Res 2007
41
Other targets for MPM treatment

• Angiogenesis VEGF 4 isoforms that bind to 3
  Receptors SU 5416, bevacizumab, thalidomide,
  PTK 787
• EGFR (70 staining, PM epitheloid form)
  gefitinib and erlotinib negative Govindan, Clin
  Cancer Res 2005, ASCO 2004
• Imatinib (against c-Kit) negative Mathy, Lung
  Cancer 2005

42
Placebo-controlled randomized phase II trial of
gemcitabine/cisplatin bevacizumab
Progression-free survival
VEGF above median
Bevacizumab Placebo
VEGF below median
Kindler, WCLC 2007
43
Conclusions

• With its rising incidence Malignant Mesothelioma
  is becoming an increasing problem
• Pemetrexed a platinum is optimal first-line
  therapy for unresectable disease with improvement
  of
• survival
• Symptoms / lung function
• QOL
• No established role for targeted agents yet
• Multi-modality therapy for early disease is
  feasible, but effect on outcome is unknown

44
Future

• Importance of Primary Prevention Minimize
  Exposure/ Education to avoid atmospheric
  pollution
• Molecular Characterization of MPM
• Discovery of New Treatment Targets
• Unique cohorts of high risk individuals ?
  chemoprevention
• Early Detection What are side effects of
  screening?