Update on Small Cell Lung Cancer Pathology and Molecular

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					                                                                                          Welcome to                                                                                            Session 4:
                                                                   Master Class for Oncologists                                                                                           4:00 PM - 4:45 PM


                                                 Los Angeles, CA                                                                                              Update on Small Cell Lung Cancer

                                                  October 3, 2008                                                                                                               Speaker:
                                                                                                                                                                           Bruce E. Johnson, MD
                                                                                                                                                                           Professor of Medicine,
                                                                                                                                                                       Dana-Farber Cancer Institute and
                                                                                                                                                                           Harvard Medical School




                                                         Presenter Disclosure Information                                                                              Update on Small Cell Lung Cancer

                  The following relationships exist related                                                                                         •   Pathology and Molecular Pathogenesis
                  to this presentation:                                                                                                             •   Presentation
                                                                                                                                                    •   Staging
                  • Bruce E. Johnson has received consulting fees from
                    Genzyme.                                                                                                                        •   Treatment
                  • Bruce E. Johnson receives patent royalties for a patent on
                                                                                                                                                    •   Prophylactic Cranial Irradiation
                    epidermal growth factor receptor testing.
                                                                                                                                                    •   Relapsed Small Cell Lung Cancer
                  Off Label/Investigational Discussion
                  In accordance with Pri-Med Institute policy, faculty have
                  been asked to disclose discussion of unlabeled or
                  unapproved use(s) of drugs or devices during the course of
                  their presentations.




                        Pathology and Molecular Pathogenesis                                                                                                                          Small Cell Lung Cancer


   • Non-Small Cell Lung Cancer                                                                                   87%

   • Small Cell Carcinoma                                                                                         13%

           –       Small Cell Carcinoma                                                                           >90%

           –       Variant – (Combined Small Cell Carcinoma)                                                      <10%




Travis WD, et al. World Health Organisation Classification of Tumors. Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart.
4th ed. WHO: Geneva, Switzerland; 2004.




                                                                                                                                                1
                                                                                                                                                              Pathology and Molecular Pathogenesis: Bcl-2 and
                        Pathology and Molecular Pathogenesis                                                                                                                              Hedgehog Signaling


   • Markers of Neuroendocrine Differentiation                                                                                                         • Bcl-2 Overexpressed in Most Small Cell Lung Cancer

           –         Chromogrannin A                                                                                                                   • Oral Bcl-2 Inhibitor, ABT-26311, and an antisense
                                                                                                                                                         nucleotide directed against Bcl-2, Oblimersen2, are In
           –         Synaptophysin                                                                                                                       Directed Phase I and II Trials for Patients with SCLC

           –         CD56 or Neural Cell Adhesion Molecule                                                                                             • Hedgehog Signaling Present in Most Small Cell Lung
                           (NCAM)                                                                                                                        Cancer3

                                                                                                                                                       • Systemic Hedgehog Signaling Antagonists are being
                                                                                                                                                         Studied in Small Cell Lung Cancer in Phase I trials as
                                                                                                                                                         well
                                                                                                                                                    1. Tse C, et al. Cancer Res. 2008;68(9):3421-3428.
Travis WD, et al. World Health Organisation Classification of Tumors. Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart.       2. Rudin CM, et al. J Clin Oncol. 2008;26(6):870-876.
4th ed. WHO: Geneva, Switzerland; 2004.                                                                                                             3. Watkins DN, et al. Nature. 2003;422(6929):313-317.




                                      Update on Small Cell Lung Cancer                                                                                                                                                                Presentation


   • Pathology and Molecular Pathogenesis                                                                                                              • Lung Cancer Typically Presents in Patients after the Age
                                                                                                                                                         of 50 and the Percentage of Women with SCLC has
   • Presentation                                                                                                                                        risen from 28% in the 1970s to 50% in 2002

   • Staging                                                                                                                                           • The Symptoms and Signs of Lung Cancer are not
                                                                                                                                                         Specific and are Commonly Found in Heavy Cigarette
   • Treatment                                                                                                                                           Smokers

   • Prophylactic Cranial Irradiation

   • Relapsed Small Cell Lung Cancer

                                                                                                                                                    Govindan R, et al. J Clin Oncol. 2006;24(28):4539-4544.




                                                                                                           Presentation                                                Presentation; Paraneoplastic Syndromes


  Symptom or                           Percentage                        Symptom or                               Percentage                                      Syndrome                                  Protein                 %Pts
                                                                                                                                                                                                                                    with
  Sign                                                                   Sign                                                                                                                                                       SCLC
  Local                                                                  Systemic
                                                                                                                                                                  Hyponatremia of                           Arginine Vasopressin and 15
  Cough                                50%                               Weight Loss                              50%                                             Malignancy                                Atrial Natriuretic Peptide

  Dyspnea                              40%                               Weakness                                 40%                                             Hypercalcemia of                          Parathyroid Hormone     <1%
                                                                                                                                                                  Malignancy                                Related Peptide
  Chest Pain                           35%                               Anorexia                                 30%
                                                                                                                                                                  Ectopic ACTH                              Adrenocorticotrophic    3%
  Hemoptysis                           20%                               Paraneoplastic                           15%                                             Syndrome                                  Hormone
                                                                         Syndrome
                                                                                                                                                                  Acromegaly                                Growth Hormone          <1%
  Hoarseness                            10%                                Fever                                    10%                                                                                     Releasing Hormone




                                                                                                                                                2
                     Presentation; Paraneoplastic Syndromes                                    Update on Small Cell Lung Cancer


                                  Sodium Serum                                 • Pathology and Molecular Pathogenesis

                                                                               • Presentation
               150
SERUM LEVELS




               145                                                             • Staging
               140
               135
               130                                                             • Treatment
               125
               120
                                                                               • Prophylactic Cranial Irradiation
               115
               110
                     Feb-99   Mar-99   Apr-99   May-99   Jun-99   Jul-99       • Relapsed Small Cell Lung Cancer
                                         DATE




               Update on Small Cell Lung Cancer; Staging                          Update on Small Cell Lung Cancer; Staging


  • Initial Evaluation: History Physical Examination,                          • The Staging Classification for These Patients Is a Simple
    Complete blood counts, Chemistries including Liver                           Two-stage Veterans Administration Lung Study Group
    Function Tests and Creatinine                                                System, updated in 1989 by International Association for
                                                                                 the Study of Lung Cancer
  • Imaging: Chest radiograph, Chest CT scan with Liver
    and Adrenals, Head MRI, Bone or PET Scan
                                                                                  – Limited Stage: Disease Confined to One Hemithorax with
                                                                                    Regional Lymph Nodes including Either Ipsilateral or Bilateral
  • Diagnosis: Needle Aspiration of Chest Mass, Fiberoptic                          Hilar, Mediastinal, and Supraclavicular Lymph Node Metastases
    Bronchoscopy, or Mediastinoscopy                                                and Without Ipsilateral Pleural Effusion That Fit Within a
                                                                                    Tolerable Chest Radiation Field

  • Pathological Review by Experienced Pulmonary
                                                                                  – Extensive Stage: Disease Beyond these Boundaries
    Pathologist




                                                                                                     Update on Small Cell Lung Cancer;
      Update on Small Cell Lung Cancer; Metastatic Sites
                                                                                                                    Prognostic Factors

  • Bone-35%
                                                                               Factors Consistently Reported     Factors Inconsistently Reported

  • Liver-25%                                                                     Good Performance Status             Normal Serum Sodium

  • Bone Marrow-20%
                                                                                    Limited Stage Disease                  Younger Age

  • Brain-20%
                                                                                       Female Gender               Absence of Liver or Brain Mets
  • Extrathoracic Lymph Nodes-5%
                                                                                         Caucasian                  Normal Liver Function Tests
  • Subcutaneous Masses-5%




                                                                           3
                                      Update on Small Cell Lung Cancer                                                                                                     ?
   • Pathology and Molecular Pathogenesis                                               1. Update on Small Cell Lung Cancer
                                                                                                A patient presents with small cell lung cancer confined to the
   • Presentation                                                                               right upper lobe and mediastinum with adequate pulmonary
                                                                                                reserve. Systemic combination chemotherapy with etoposide
   • Staging                                                                                    and cisplatin is recommended. The recommendations for
                                                                                                chest radiotherapy are:
   • Treatment; Limited Stage and Extensive Stage
                                                                                        1.      No chest radiotherapy is needed.
   • Prophylactic Cranial Irradiation                                                   2.      Chest radiotherapy should start with the first or second cycle of
                                                                                                chemotherapy.
   • Relapsed Small Cell Lung Cancer                                                    3.      Chest radiotherapy should start with the third or fourth cycle of
                                                                                                chemotherapy.
                                                                                        4.      Chest radiotherapy should be given after the chemotherapy finishes.




                                             Update on Small Cell Lung Cancer:
                                                                                               Update on Small Cell Lung Cancer: Limited Stage
                                          Limited Stage Small Cell Lung Cancer
                                                                                                                       Small Cell Lung Cancer


                                                                                                                       BID

                                                                                                                      PE               PE          PE    PE
                                                                                                randomize




                                                                                                                                                              BID    PCI

                                                                                                                      PE               PE          PE    PE


                                                                                       Cisplatin - 80; Etoposide - 100 / Q 21 days in Sequential.
                                                                                       Q28 days in Concurrent. PCI: 24 Gy 1.5 Gy BID to 45 Gy
                        Pretreatment                         2 Years after
                                                              Treatment
                                                                                     Takada M, et al. J Clin Oncol. 2002;20(14):3054-3060.




                                             Update on Small Cell Lung Cancer:                   Update on Small Cell Lung Cancer: Limited Stage
                                          Limited Stage Small Cell Lung Cancer                                           Small Cell Lung Cancer



                                                                                                                                      BID
                                                                                                                randomize




                                                                                                                                      PE          PE    PE      PE

                                                                                                                                             QD                      PCI

                                                                                                                                      PE          PE    PE      PE


                                                                                     Platinum - 60; Etoposide - 120 / Cycle Q 21 days PCI: 25 Gy


Takada M, et al. J Clin Oncol. 2002;20(14):3054-3060.                                Turrisi AT 3rd, et al. N Engl J Med. 1999;340(4):265-271.




                                                                                 4
                                              Update on Small Cell Lung Cancer:                                                    Update on Small Cell Lung Cancer:
                                           Limited Stage Small Cell Lung Cancer                                                 Limited Stage Small Cell Lung Cancer




                                                                                          randomize
                                                                                                         CEV                CEV                  CEV   CEV   CEV

                                                                                                                                                        QD         PCI

                                                                                                           PE                 PE                 PE    PE    PE


                                                                                          CEV=Cyclo- 1000; Epi – 50; VCR 2.0 / Cycle Q 21 days PCI: 30 Gy

                                                                                               PE=Cisplatin - 75; Etoposide - 100 / Cycle Q 21 days PCI: 30 Gy


Turrisi AT 3rd, et al. N Engl J Med. 1999;340(4):265-271.                             Sundstrom S, et al. J Clin Oncol. 2002;20(24):4665-4672.




                                              Update on Small Cell Lung Cancer:                                                    Update on Small Cell Lung Cancer:
                                           Limited Stage Small Cell Lung Cancer                                                 Limited Stage Small Cell Lung Cancer


                                                                                         • Patients With Limited Stage SCLC Should Be Treated
                                                                                           With Concurrent Chest Radiotherapy with Etoposide
                                                                                           Plus Cisplatin. These Patients Lived Longer Than
                                                                                           Patients Treated With Chemotherapy Alone.

                                                                                         • The Chest Radiotherapy Should Start with Cycle 1 or 2.

                                                                                         • The Chest Radiotherapy Should be Given Twice Daily
                                                                                           over Three Weeks.




Sundstrom S, et al. J Clin Oncol. 2002;20(24):4665-4672.




                                              Update on Small Cell Lung Cancer:
                                           Limited Stage Small Cell Lung Cancer
                                                                                                                            Update on Small Cell Lung Cancer


   • Patients with a Solitary Pulmonary Nodule and a                                     •       Pathology and Molecular Pathogenesis
     Diagnosis of Small Cell Lung Cancer Should Undergo                                  •       Presentation
     Evaluation for Resection (2-3%)                                                     •       Staging
                                                                                         •       Treatment; Limited Stage and Extensive Stage
   • Patients Should have Mediastinoscopy Because 20%                                    •       Prophylactic Cranial Irradiation
     Will Have Positive Lymph Nodes
                                                                                         •       Relapsed Small Cell Lung Cancer
                                                                                         •       Second Malignancies
   • Patients Should be Treated with Adjuvant Chemotherapy
     Following Resection




Strand TE, et al. Thorax. 2006;61(8):710-715.




                                                                                  5
                                                                                                                            Update on Small Cell Lung Cancer: Irinotecan for
                                                                                                        ?                           Extensive Stage Small Cell Lung Cancer

   2. Update on Small Cell Lung Cancer                                                                          Number of                   Regimens of Etoposide Cisplatin versus                                             Median                1 Year
                                                                                                                 Patients                       Irinotecan Cisplatin Regimens                                                  Survival             Survival
           A patient presents with small cell lung cancer with
           involvement of the left upper lobe, mediastinum, and                                                  154                     Etop 100 mg X 3 and CP 80 mg q 3 wks                                                 9.4
                                                                                                                                                                                                                                                   38%
                                                                                                                Japanese                 versus Irinotecan 60 mg q wk X 3 and CP 60                                           12.8
           thoracic spine. Chemotherapy is recommended.                                                         NEJM 2002                mg q 4 wks                                                                           P=0.002
                                                                                                                                                                                                                                                   58%


   1.      Irinotecan plus cisplatin is more effective for patients with extensive stage small                  331                      Etop 120 mg X 3 and CP 60 mg q 3 wks
           cell lung cancer than etoposide plus cisplatin.                                                                                                                                                                    10.2 Mo              35%
                                                                                                                Caucasian                Irinotecan 65 mg q wk X 2 and CP 30 mg q
   2.      Etoposide cisplatin is as effective as other chemotherapy regimens that have been
                                                                                                                                                                                                                              9.3 MO               35%
                                                                                                                JCO 2006                 wk X 2 every 3 wks
           tested thus far.
   3.      Giving high doses of chemotherapy with autologous bone marrow transplantation                        645                      Etop 100 mg X 3 and CP 80 mg q 3 wks
           will prolong their survival.
                                                                                                                Caucasian                versus Irinotecan 60 mg q wk X 3 and CP 60                                           8.9 Mo               33%
                                                                                                                (SWOG)                   mg q 4 wks                                                                           9.7 Mo               39%
   4.      Adding the antiangiogenic agent, Thalidomide to combination chemotherapy
           prolongs survival.                                                                                   ASCO 2008

                                                                                                                Noda K, et al. N Engl J Med. 2002;346(2):85-91. Hanna N, et al. J Clin Oncol. 2006;24(13):2038-2043. Natale RB, et al. Presented at: American
Noda K, et al. N Engl J Med. 2002;346(2):85-91. Humblet Y, et al. J Clin Oncol. 1987;5(12):1864-1873.           Society of Clinical Oncology Annual Meeting; 2008. Abstract 7512.




           Update on Small Cell Lung Cancer: Strategies for                                                                                              Update on Small Cell Lung Cancer:
                   Extensive Stage Small Cell Lung Cancer                                                                                           Extensive Stage Small Cell Lung Cancer


   • 784 Given Oral Topotecan plus cisplatin versus                                                                • Patients With Extensive Stage Small Cell Lung Cancer
     Etoposide plus Cisplatin1                                                                                       Should Be Treated With 2 or More Drugs Which Produce
                                                                                                                     Moderate Myelosuppression. Etoposide Cisplatin
   • 140 Limited and Extensive Stage Patients treated with                                                           remains the Standard Treatment.
     Transplant Doses of Ifosfamide, Carboplatin and
     Etoposide (Tx) versus standard doses of the same                                                              • Patients with Small Cell Lung Cancer Treated with
     drugs2                                                                                                          Intensive Chemotherapy (Adding Paclitaxel or
                                                                                                                     Autologous Transplant Doses) Do Not Live Longer Than
   • 724 Patients with limited and extensive stage treated                                                           Patients Treated with Standard Doses.
     with etoposide and cisplatin +/- thalidomide3


        Eckardt JR, et al. J Clin Oncol. 2006;24(13):2044, 2006,
        Leyvraz S, et al. J Natl Cancer Inst. 2008;100(8):533-541.
        Siow-Ming L, et al. J Thorac Oncol. 2007;2(8):S306-S307.




                                                                                                                                                                  Update on Small Cell Lung Cancer:
                                       Update on Small Cell Lung Cancer                                                                                              Prophylactic Cranial Irradiation

   • Pathology and Molecular Pathogenesis                                                                          • Pts With SCLC Have a 60-80% Actuarial Risk of
                                                                                                                     Developing Brain Metastases Within 2 Years After the
   • Presentation                                                                                                    Start of Treatment

   • Staging                                                                                                       • PCI Has Been Shown to Prolong Survival for Patients
                                                                                                                     with both Limited and Extensive SCLC with a Response
   • Treatment; Limited Stage and Extensive Stage                                                                    to Chemotherapy

   • Prophylactic Cranial Irradiation                                                                              • PCI (2400-3600 cGy) Administered at the Time of
                                                                                                                     Complete Remission Can Reduce the Chance of
   • Relapsed Small Cell Lung Cancer                                                                                 Developing the Brain Metastases by 50-67%




                                                                                                            6
                                                                                                                                                         Update on Small Cell Lung Cancer:
                                                                                               ?                                                            Prophylactic Cranial Irradiation

   3. Update on Small Cell Lung Cancer
      A patient with limited stage small cell lung cancer undergoes
      chemotherapy and chest radiotherapy. The radiographic imaging
      after the completion of treatment shows a complete response. The
      considerations about using prophylactic cranial irradiation for
      patients with small cell lung cancer and a response to treatment
      include:
   1.      Prophylactic cranial irradiation is recommended for patients with limited stage
           small cell lung cancer with a response to treatment
   2.      Prophylactic cranial irradiation is recommend for patients with both limited and
           extensive stage small cell lung cancer with a response to treatment
   3.      Prophylactic cranial irradiation has no impact on survival but reduces the chance
           of getting brain metastases
   4.      Prophylactic cranial irradiation can reduce the risk of brain metastases and prolong
           survival                                                                                    Slotman B, et al. N Engl J Med. 2007;357(7):664-672.




                                                                                                                                                         Update on Small Cell Lung Cancer:
                                      Update on Small Cell Lung Cancer                                                                                                   Relapsed Disease


   •     Pathology and Molecular Pathogenesis                                                             • 141 Patients with Relapsed SCLC not Deemed to be
   •     Presentation                                                                                       Candidates for Further Intravenous Chemotherapy
   •     Staging
   •     Treatment; Limited Stage and Extensive Stage                                                     • Randomized to Either Topotecan 2.3 mg/m2/day PO on
   •     Prophylactic Cranial Irradiation                                                                   Days 1-5 or Best Supportive Care
   •     Relapsed Small Cell Lung Cancer
   •     Second Malignancies                                                                              • Followed for Response, Time to Progression and
                                                                                                            Survival




                                                                                                       O’Brien ME, et al. J Clin Oncol. 2006;24(34):5441-5447.




                                                  Update on Small Cell Lung Cancer:
                                                                  Relapsed Disease
                                                                                                                                             Update on Small Cell Lung Cancer


                                                                                                          • Pathology and Molecular Pathogenesis

                                                                                                          • Presentation

                                                                                                          • Staging

                                                                                                          • Treatment; Limited Stage and Extensive Stage

                                                                                                          • Prophylactic Cranial Irradiation

                                                                                                          • Relapsed Small Cell Lung Cancer

O’Brien ME, et al. J Clin Oncol. 2006;24(34):5441-5447.




                                                                                                   7
                                                                                         ?                                                                                                               ?
1. Update on Small Cell Lung Cancer                                                                 2. Update on Small Cell Lung Cancer
     A patient presents with small cell lung cancer confined to the                                         A patient presents with small cell lung cancer with
     right upper lobe and mediastinum with adequate pulmonary                                               involvement of the left upper lobe, mediastinum, and
     reserve. Systemic combination chemotherapy with etoposide
                                                                                                            thoracic spine. Chemotherapy is recommended.
     and cisplatin is recommended. The recommendations for
     chest radiotherapy are:                                                                        1.      Irinotecan plus cisplatin is more effective for patients with extensive stage small
                                                                                                            cell lung cancer than etoposide plus cisplatin.
                                                                                                    2.      Etoposide cisplatin is as effective as other chemotherapy regimens that have been
1.   No chest radiotherapy is needed.                                                                       tested thus far.
2.   Chest radiotherapy should start with the first or second cycle of                              3.      Giving high doses of chemotherapy with autologous bone marrow transplantation
     chemotherapy.                                                                                          will prolong their survival.
                                                                                                    4.      Adding the antiangiogenic agent, Thalidomide to combination chemotherapy
3.   Chest radiotherapy should start with the third or fourth cycle of
                                                                                                            prolongs survival.
     chemotherapy.
4.   Chest radiotherapy should be given after the chemotherapy finishes.
                                                                                                 Noda K, et al. N Engl J Med. 2002;346(2):85-91. Humblet Y, et al. J Clin Oncol. 1987;5(12):1864-1873.




                                                                                         ?
3. Update on Small Cell Lung Cancer
   A patient with limited stage small cell lung cancer undergoes
   chemotherapy and chest radiotherapy. The radiographic imaging
   after the completion of treatment shows a complete response. The
   considerations about using prophylactic cranial irradiation for
   patients with small cell lung cancer and a response to treatment
   include:                                                                                                                        Thank you for attending
1.   Prophylactic cranial irradiation is recommended for patients with limited stage                                             Master Class for Oncologists
     small cell lung cancer with a response to treatment
2.   Prophylactic cranial irradiation is recommend for patients with both limited and
     extensive stage small cell lung cancer with a response to treatment
3.   Prophylactic cranial irradiation has no impact on survival but reduces the chance
     of getting brain metastases
4.   Prophylactic cranial irradiation can reduce the risk of brain metastases and prolong
     survival




               Questions & Answers



                                      ?

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