Mesothelioma Malignant Pleural Mesothelioma

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Mesothelioma Malignant Pleural Mesothelioma Powered By Docstoc
					         Mesothelioma

     William G. Richards, PhD
  Brigham and Women’s Hospital




      Malignant Pleural
       Mesothelioma

• 2,000 - 3,000 cases per year (USA)
• Increasing incidence
• Asbestos (50-80%, decreasing)
  – 30 - 40 year latency
• Simian Virus 40 (SV 40)




                                       1
                 Presentation
•   Median age 60, M:F = 4-5:1
•   Dyspnea / Pleural effusion ( 80% )
•   Cough ( 60% )
•   Chest Pain ( 40-60% )
•   Bilateral Disease ( 5% )
•   Diagnosis often difficult
    – differential versus lung adenocarcinoma




              Clinical Course
• Local progression
    – lung, chest wall, mediastinum, diaphragm
• Distant metastases rare
• Rapidly fatal
    – median survival 7 months with palliation
    – 12 months with best chemotherapy




                                                 2
          Histologic subtypes
• Epithelial (50%)
• Sarcomatoid (15%)
• Mixed (35%)

• Sarcomatoid / mixed have poor prognosis




                   Staging
• Butchart (1976, EPP)
  – surgical extent of disease
• Brigham (Trimodality, 1993, revised 1999)
  – surgical margins, pN2 status
• UICC, IMIG 1994
  – pathologic TNM
• CALGB, EORTC (non-surgical, 1998)
  – histology, PS, chest pain, WBC, platelets




                                                3
                       Therapy
•   Chemotherapy
•   Radiation therapy
•   Surgery
•   Combined approaches
•   Targeted Strategies




                  Chemotherapy
• CALGB trials (Vogelzang, Kindler)
    – 8435, 8638, 8833, 8933, 9031, 9131, 9234
         • N = 347; response rates 7-26%; MST 3.9-9.8 mo.
    –   9530 gemcitabine - no CR, PR MST 4.7 mo.
    –   9631 high-dose doxorubicin - no responses
    –   9733 Irinotecan - no CR, PR MST 9.3 months
    –   39807 Capecitabine - 1 PR 4.9 mo. med. surv.
    –   30101 Gefitinib 1 CR, 1 PR 6.8 mo. med. surv.




                                                            4
                         Cisplatin

• Single agent
    – 13-14% response rate
• Cisplatin in combinations
    – 13-48% response rate
• Gemcitabine / cisplatin
    – phase II 47.6% RR, 10 mo MST
• Pemetrexed / cisplatin
    – phase III 12 mo MST vs 9 mo cisplatin alone




Phase III Pemetrexed + cisplatin versus cisplatin


                      Pemetrexed +       Cisplatin    P value
                      Cisplatin

# of patients         226                222

Response rate         41.3%              16.7%         <0.0001

Time to               5.7 months         3.9 months       0.001
progression
Survival              12.1 months        9.3 months        0.02

           Vogelzang, J Clin Oncol 21:2636-44, 2003




                                                                  5
              Radiation Therapy
• Need > 40 Gy even for palliation
• Dose limiting toxicity -
  – Lung 20 Gy
  – spinal chord, heart, esophagus 45 Gy
• Biopsy site to prevent seeding
  – Boutin Chest 108:754-8, 1995

• High dose – Memorial
  – Rusch J Thorac Cardiovsc Surg 122: 788-95, 2001




                          Surgery
• Thoracoscopy / sclerosis
  – palliation of effusion, 80-90% effective
• Pleurectomy / decortication
  – low morbidity, mortality (1-5%)
  – complete resection uncommon
• Extrapleural pneumonectomy
  – higher morbidity (25%) and mortality (4-15%)
  – more complete tumor cytoreduction
  – empty thorax permits high-dose radiotherapy




                                                      6
7
8
    Extrapleural Pneumonectomy
Complications after 328 consecutive cases
  • 30-Day Mortality 11 patients (3.4%)
  • Major or minor morbidity 198 (60%)
  • Management issues:
     – atrial fibrillation 145 (44%)
     – vocal chord paralysis 22 (6.7%)
        • early ambulation, aspiration precautions
     – Deep vein thrombosis 21 (6.4%)
        • perioperative diagnosis and management
     – Technical (patch dehiscence, hemorrhage) 20 (6.1%)
        • immediate re-operation
     – Infection (empyema, broncho-pleural fistula)
        • thoracoscopic or open drainage
        Sugarbaker, J Thorac Cardiovasc Surg 128:138-46, 2004




                                                                9
             Multimodality Therapy
   • Trimodality therapy
       – EPP, chemotherapy and radiation
       – “sandwich” adjuvant protocol:


                         Taxol               XRT           Taxol
 Extrapleural          Carboplatin        30 + 55 Gy     Carboplatin
Pneumonectomy                              Weekly
                         2 cycles           Taxol          2 cycles




                Trimodality Therapy
   •   183 Patients enrolled 1980 - 1997
   •   140 males and 43 females
   •   Mean age 57 yrs. ( range 31- 76 )
   •   Asbestos exposure - n = 132 (72%)
   •   Symptoms      - dyspnea     73%
                           - chest pain        56%
                           - cough             36%

   Sugarbaker J Thorac Cardiovasc Surg 117:54-63, 1999




                                                                       10
                                    Perioperative Results
                       • 30-day Mortality- 7 patients (3.8%)
                                 - pulmonary embolus                             3
                                 - myocardial infarction                         2
                                 - aspiration / sepsis / ARDS                    1
                                 - cardiac herniation                            1
                       • Morbidity
                                 - Major                                         24.5%
                                 - Atrial Fibrillation                           37%
                       • Median LOS 9 days (range 5 to 101)
                       Sugarbaker J Thorac Cardiovasc Surg 117:54-63, 1999




                                 Extrapleural Nodal Status
                        1

                        .8                                     Extrapleural Nodes Negative (N = 136)
Proportion Surviving




                        .6                                     Extrapleural Nodes Positive (N = 40)

                        .4
                                                                                       p = .004
                        .2

                        0

                             0         20         40         60          80          100

                                                     Months
                                     Sugarbaker J Thorac Cardiovasc Surg 117:54-63, 1999




                                                                                                       11
                                               Resection Margins
                                      1

                                      .8                                     Negative Resection Margins (N = 66)
           Proportion Surviving




                                      .6                                     Positive Resection Margins (N=110)

                                      .4
                                                                                                          p < .02
                                      .2

                                      0

                                           0        20         40         60          80          100

                                                                    Months
                                               Sugarbaker J Thorac Cardiovasc Surg 117:54-63, 1999




                                      *Revised Brigham Staging System
                                  1
                                                                                    Stage I (n = 52, MST 25 mo)
                           .8                                                       Stage II (n = 84, MST 20 mo)
Proportion Surviving




                                                                                    Stage III (n = 40, MST 16 mo)
                           .6


                           .
                           4
                           .2                                                                         p = .0011


                                  0

                                       0       12        24      36            48          60          72
                                                              Months                *Sugarbaker et al, JCO 1993
                                               Sugarbaker J Thorac Cardiovasc Surg 117:54-63, 1999




                                                                                                                    12
      Patterns of Failure After
       Trimodality Therapy

• The most common sites of failure were:
  – the ipsilateral hemithorax (35%)
  – abdomen (26%)
• Isolated distant failure were uncommon
• Future strategies should investigate methods of
  enhancing local control
                        Baldini Ann Thorac Surg 63:334-8, 1997




      Potential Sources of Local
             Recurrence
 • Free intrathoracic tumor cells shed from the
   pleural surface prior to surgery

 • Disseminated tumor cells during surgical
   manipulation, spillage

 • Residual tumor at resection margins




                                                                 13
    Multimodality Tx Current goals

• Improve local recurrence rate
    – High-dose adjuvant radiation therapy
    – Intensity modulated radiotherapy (IMRT)
    – Intracavitary chemotherapy
• Improve resectability rate
    – neoadjuvant chemotherapy




              High-dose XRT
•   Memorial Sloan Kettering CC
•   88 patients (66 EPP)
•   median 54 Gy
•   8% mortality
•   stage I, II 33.8 mo MST
•   stage III, IV 10 mo MST
•   Excellent local control
•   Relapse primarily distant
             Rusch J Thorac Cardiovsc Surg 122: 788-95, 2001




                                                               14
                               IMRT
•   MD Anderson CC
•   28 Patients
•   EPP (surgical clips to delineate CTV)
•   45-50 Gy with 60 Gy boost areas
•   Respiratory motion minimal
•   100% local control at 9 months median f/u
       Ahamad Int J Radiat Oncol Biol Phys 52:1381-8, 2002




     Intracavitary Chemotherapy
                      Malignant Pleural Mesothelioma

        Extrapleural Pneumonectomy or Pleurectomy / Decortication
      Intrathoracic/Intraperitoneal Hyperthermic Cisplatin (42 C x 1hr)
                  with IV Sodium Thiosulfate or Amifostine

                     Recommended Adjuvant Tx:
             Concurrent Cisplatin/Gemcitabine and Radiation
                          (6-8 weeks postop)

                               Surveillance
                             (every 3 months)




                                                                          15
    Lilly Sponsored phase II Trial
•   Multi-institutional participation
•   Neoadjuvant pemetrexed + cisplatin
•   Extrapleural pneumonectomy
•   High-dose hemithoracic radiation 54 GY
•   Primary endpoint - pathologic CR rate
•   Secondary endpoints - survival, clinical
    response, toxicity, pattern of relapse,
    parmacogenomic markers




                                               16
                     Future Directions
   • CALGB Trimodality concept
   • Targeted Therapy
        – gene discovery
        – small molecule inhibitors vs cytotoxics
        – preselect the right patients likely to respond to
          particular treatment strategies




                     CALGB Concept
     A phase II trial of EPP followed by radiation
          therapy and chemotherapy in MPM
               PI: Raphael Bueno, MD

                          Pemetrexed 500 mg/m2
                           +Cisplatin 75 mg/m2
      EPP                                                        IMRT
                            w/ Folic acid, B12
                            q 21d x 3 Cycles

• Trimodality therapy with state of the art chemotherapy, radiation therapy
• Specimen Collection through CALGB Lung Cancer Tissue Bank (140202)
• Comprehensive cutting edge correlative science




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