Current Management of Malignant Mesothelioma

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					Current Management of Malignant
         Mesothelioma
Pleural plaques




 • Pleural plaques




Asbestosis




                     Pleural mesothelioma
    Asbestos Exposure in MPM




• Evident in 70-80% of those affected
World production of asbestos




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

• Manufacturing of Asbestos           •   Oil refinery Workers
  products                            •   Power plants
• Shipyard workers                    •   Automobile reapir
• Navy veterans                       •   Maintenance workers
• Miners and Drillmen                 •   Steel mills
• Demolition Workers                  •   Refineries
• Railroad workers                    •   Sand or abrasive manufacturers
• Construction (insulation) workers   •   Paper Mills
• Maritime Workers                    •   Drywall Removers
            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
             MPM Incidence in NSW


• Peak number approaching 200 cases/year

• What about the Asbestos present in Society (1/3 of
  houses contaminated)
      Mesothelioma in Europe




Peak leveling off between 2010 and 2015?
     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
Asbestos consumption and
  mesothelioma deaths




                   Lin, Lancet 2007
Continued Exposure in the Third World
            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
            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
             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
           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
Early Diagnosis
                       Mesothelin

• Mesothelin is a cell surface glycoprotein, expressed
   on normal mesothelial cells and > 90% of
   mesotheliomas (binds to CA125)
• Soluble mesothelin-related proteins in serum
         Robinson, Lancet 2003   Cristaudo, Clin Cancer Res 2007




•Target for antibody therapy
                  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
Chemotherapy for Malignant
     Mesothelioma
          Chemotherapy Spectrum


• Anthracyclines (Doxorubicin)
• Taxanes (Paclitaxel)
• Vinca Alkaloids (Vinorelbine)
• Antimetabolites: Edatrexate, Gemcitabine,
  Pemetrexed & Raltitrexed
• Combinations: Cisplatin, Carboplatin
      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
Pemetrexed + Cisplatin vs Cisplatin Selected
          Grade 3/4 Toxicity (%)

                                ALIMTA +
                                Cisplatin       Cisplatin
    All Patients                (n=226)          (n=222)

  Possible Drug Related Death      4                2
  Neutropenia                     28                2
  Thrombocytopenia                 6                0
  Febrile Neutropenia              2                1
  Vomiting                        13                4
  Stomatitis                       4                0
  Diarrhea                         4                0


                                            Vogelzang , JCO 2003
                    Phase III Pemetrexed + Cisplatin vs
                             Cisplatin in MPM
              1.0
                                              Pemetrexed + Cisplatin (n=226)
              0.9                             Cisplatin (n=222)
              0.8                                                      Pem/cis     Cis
              0.7                       Median survival (mo)             12.8      9.0
Survival(%)




                                        HR                                    0.74
              0.6
                                        p-value                              0.003
              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
Pemetrexed + Cisplatin vs Cisplatin:
   Symptomatic improvement




                             Gralla, ASCO 2002
  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 Pemetrexed+Cisplatin
or Pemetrexed+Carboplatin with vitamin
supplementation.
                           P+Cis        P+Cb
                          (n=745)      (n=752)
ORR, %                      26.3         21.7
(95% Cl)                (23.2, 29.6) (18.8, 24.8)
Median TTPD, mos             7.0          6.9
                                                     Kaplan-Meier analysis of time to progressive disease
(95% CI)                  (6.7, 8.3)   (6.6, 7.7)    (months), in Chemonaive patients with MPM, who
                                                     received pemetrexed + cisplatin, or pemetrexed +
                                                     carboplatin. Please note that median survival could not
1-Year Survival Rate, %     63.1         64.0
                                                     be estimated due to high censoring rate.
(95% Cl)                (50.7, 75.5) (53.3, 74.6)


                                                    Santoro A, et al., J Thor Oncol, 2007: in press
Combined Modality Therapy
ExtraPleural Pneumonectomy (EPP) + RT

• EPP with adjuvant chemotherapy and radiotherapy:
    Brigham: 176/183 pts: MST 19 months,

     periop. mortality 3.8%, 35% local failure
     Sugarbaker 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 11%
     Rusch, JTCVS 2001
ExtraPleural Pneumonectomy (EPP) + Chemo


  •   EPP and adjuvant chemotherapy
      (n=12), MST 13 months, feasibility?
      Taverna, ESMO 2000

  •   Pilot study of neoadjuavant chemotherapy
      followed by EPP (n=19), MST 23 months,
      good feasibility
      Weder, JCO 2004

  •   SAKK multicenter phase II (n=61 pts, operated 45),
      MST 19.8 months, 23 months for operated patients
      Weder and Stahel, Ann Oncol 2007
         Multimodality therapy (cont’d)


• 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
         Randomized Phase III Second Line
    Pemetrexed + BSC vs. BSC in Previously Treated
                  Advanced MPM
                     2nd line
    N = 240          PS 0 - 2                            PFS
                                                          0.0148
                 Randomize
      Primary objective: Overall Survival


    Pemetrexed 500
                                      BSC
       + BSC

                           P+BSC              BSC
                           (n=123)          (n=120)      Survival
ORR, %                          19%            2%        p=0.7434


Median PFS, mos               3.6              1.5
(95% CI)                   (3.0, 4.4)       (1.5, 1.9)

OS, mos                       8.4               9.7
(95% Cl)                  (6.2-10.5)        (8.4-10.9)


                                                               Jassem, ESMO 2006
    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
    Immunotherapy



•   Interleukin 2
•   Interferon
•   Interferon + chemo
•   More targeted approaches ?
      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
    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
Placebo-controlled randomized phase II trial
  of gemcitabine/cisplatin ± bevacizumab

   Progression-free survival
                                   VEGF above
                                     median
             Bevacizumab
             Placebo




                                  VEGF below
                                    median




                               Kindler, WCLC 2007
                        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
                    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?

				
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