Update on Small Cell Lung Cancer
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1 Welcome to Master Class for Oncologists Session 4: 10:00 AM - 10:45 AM San Francisco, CA October 23, 2009 Speaker: Bruce E. Johnson, MD Professor of Medicine, Dana-Farber Cancer Institute and Harvard Medical School Presenter Disclosure Information The following relationships exist related to this presentation: Bruce E. Johnson has received consulting fees from Genzyme. Bruce E. Johnson receives patent royalties for a patent on epidermal growth factor receptor testing. 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. 3 4 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% 5 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;
2 Pathology and Molecular Pathogenesis Pathology and Molecular Pathogenesis: Smoking Markers of Neuroendocrine Differentiation Chromogranin A Synaptophysin CD56 or Neural Cell Adhesion Molecule (NCAM) Small cell lung is the most closely linked with cigarette smoking. > 97% of patients have a history of cigarette smoking. Squamous cell carcinoma and large cell carcinoma have an intermediate association with smoking. Approximately 80% of patients have a history of cigarette smoking. Adenocarcinoma is the least closely linked to cigarette smoking. Approximately 70% of patients have a history of cigarette smoking. 7 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; Pathology and Molecular Pathogenesis: Bcl-2 and Hedgehog Signaling Bcl-2 is overexpressed in most small cell lung cancers. Oral Bcl-2 inhibitor, ABT-263 1, gossypol, and obatoclax (GX15-070) are in directed phase I and II trials for patients with SCLC. Hedgehog signaling presents in most small cell lung cancers. 3 Systemic hedgehog signaling antagonists (GDC-0449 and IPI-926) are being studied in small cell lung cancer in phase I trials as well Tse C, et al. Cancer Res. 2008;68(9): Rudin CM, et al. J Clin Oncol. 2008;26(6): Watkins DN, et al. Nature. 2003;422(6929): Presentation Presentation Lung cancer typically presents in patients after the age of 50 and the percentage of women with SCLC has risen from 28% in the 1970s to 50% in Symptom or Sign Local Percentage Symptom or Sign Systemic Percentage The symptoms and signs of lung cancer are not specific and are commonly found in heavy cigarette smokers. Cough Dyspnea 50% 40% Weight Loss Weakness 50% 40% Chest Pain 35% Anorexia 30% Hemoptysis Hoarseness 20% 10% Paraneoplastic Syndrome Fever 15% 10% 11 Govindan R, et al. J Clin Oncol. 2006;24(28):
3 Presentation: Paraneoplastic Syndromes Presentation: Paraneoplastic Syndromes Syndrome Protein %Pts with SCLC Sodium Serum Hyponatremia of Malignancy Hypercalcemia of Malignancy Ectopic ACTH Syndrome Acromegaly Arginine Vasopressin and Atrial Natriuretic Peptide Parathyroid Hormone Related Peptide Adrenocorticotrophic Hormone Growth Hormone Releasing Hormone 15 <1% 3% <1% SERUM LEVELS Feb-99 Mar-99 Apr-99 May-99 Jun-99 Jul-99 DATE Staging Initial Evaluation: History, Physical examination, Complete blood counts, Chemistries including liver function tests and creatinine Imaging: Chest radiograph, Chest CT scan with liver and adrenals, Head MRI, Bone or PET scan Diagnosis: Needle aspiration of chest mass, Fiberoptic bronchoscopy, or Mediastinoscopy Pathological review by experienced pulmonary pathologist Staging Metastatic Sites The staging classification for these patients is a simple two-stage Veterans Administration Lung Study Group System, updated in 1989 by the International Association for the Study of Lung Cancer. Limited Stage: Disease confined to one hemithorax with regional lymph nodes including either ipsilateral or bilateral hilar, mediastinal, and supraclavicular lymph node metastases and without ipsilateral pleural effusion that fit within a tolerable chest radiation field Extensive Stage: Disease beyond these boundaries Bone-35% Liver-25% Bone marrow-20% Brain-20% Extrathoracic lymph nodes-5% Subcutaneous masses-5%
4 Prognostic Factors Factors Consistently Reported Good Performance Status Limited Stage Disease Female Gender Caucasian Factors Inconsistently Reported Normal Serum Sodium Younger Age Absence of Liver or Brain Mets Normal Liver Function Tests Audience Response Question? 1. A patient presents with small cell lung cancer confined to the right upper lobe and mediastinum with adequate pulmonary reserve. Systemic combination chemotherapy with etoposide and cisplatin is recommended. The recommendations for chest radiotherapy are: No chest radiotherapy is needed. 2. Chest radiotherapy should start with the first or second cycle of chemotherapy. 3. Chest radiotherapy should start with the third or fourth cycle of chemotherapy. 4. Chest radiotherapy should be given after the chemotherapy finishes. 22 Pretreatment 2 Years after Treatment Limited Stage Small Cell Lung Cancer BID PE PE PE PE randomize PE PE PE PE BID PCI Cisplatin - 80; Etoposide 100/Q 21 days in sequential, Q28 days in concurrent. PCI: 24 Gy 1.5 Gy BID to 45 Gy 23 Takada M, et al. J Clin Oncol. 2002;20(14): Takada M, et al. J Clin Oncol. 2002;20(14):
5 Limited Stage Small Cell Lung Cancer randomize BID PE PE PE PE QD PE PE PE PE PCI Platinum - 60; Etoposide 120/Cycle Q21 days. PCI: 25 Gy 25 Turrisi AT 3rd, et al. N Engl J Med. 1999;340(4): Turrisi AT 3rd, et al. N Engl J Med. 1999;340(4): randomize CEV CEV CEV CEV PE PE PE PE QD CEV PE PCI CEV = Cyclo- 1000; Epi 50; VCR 2.0/Cycle Q21 days. PCI: 30 Gy PE = Cisplatin - 75; Etoposide - 100/Cycle Q21 days PCI: 30 Gy 27 Sundstrom S, et al. J Clin Oncol. 2002;20(24): Sundstrom S, et al. J Clin Oncol. 2002;20(24): 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. Patients with a solitary pulmonary nodule and a diagnosis of small cell lung cancer should undergo evaluation for resection (2-3%). Patients should have mediastinoscopy because 20% will have positive lymph nodes. Patients should be treated with adjuvant chemotherapy following resection Strand TE, et al. Thorax. 2006;61(8):
6 Surgery for Small Cell Lung Cancer Audience Response Question? IASLC proposed TNM stage A patient presents with small cell lung cancer confined to the right upper lobe and mediastinum with adequate pulmonary reserve. Systemic combination chemotherapy with etoposide and cisplatin is recommended. The recommendations for chest radiotherapy are: 1. No chest radiotherapy is needed. 2. Chest radiotherapy should start with the first or second cycle of chemotherapy. 3. Chest radiotherapy should start with the third or fourth cycle of chemotherapy. 4. Chest radiotherapy should be given after the chemotherapy finishes. Shepherd FA, et al. J Thoracic Oncol. 2007;2:1067 2: Audience Response Question? 2. A patient presents with small cell lung cancer with involvement of the left upper lobe, mediastinum, and thoracic spine. Chemotherapy is recommended 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 tested thus far. 3. Giving high doses of chemotherapy with autologous bone marrow transplantation will prolong their. 4. Adding the antiangiogenic agent, thalidomide, to combination chemotherapy prolongs Noda K, et al. N Engl J Med. 2002;346(2): Humblet Y, et al. J Clin Oncol. 1987;5(12): Irinotecan for Irinotecan for 154 patients with extensive stage small cell lung cancer Randomized to 4 cycles of irinotecan 60 mg/m 2 IV on days 1, 8, and 15 plus cisplatin 60 mg/m 2 on day 1 on 28 day cycle vs etoposide 100 mg/m 2 on days 1, 2, and 3 plus cisplatin 80 mg/m 2 on day 1 every 3 weeks Followed for response rate, time to progression, and Noda K, et al. N Engl J Med. 2002;346: Noda K, et al. N Engl J Med. 2002;346:
7 Irinotecan for Irinotecan for 651 patients with extensive stage small cell lung cancer Randomized to 4 cycles of irinotecan 60 mg/m 2 IV on days 1, 8, and 15 plus cisplatin 60 mg/m 2 on day 1 on 28 day cycle vs etoposide 100 mg/m 2 on days 1, 2, and 3 plus cisplatin 80 mg/m 2 on day 1 every 3 weeks Followed for response rate, time to progression, and 37 Lara PN, et al. J Clin Oncol. 2009;27: Lara PN, et al. J Clin Oncol. 2009;27: Strategies for 784 patients given oral topotecan plus cisplatin vs etoposide plus cisplatin patients with limited and extensive stage SCLC treated with transplant doses of ifosfamide, carboplatin, and etoposide (Tx) vs standard doses of the same drugs patients with limited and extensive stage SCLC treated with etoposide and cisplatin +/- thalidomide 3 Patients with extensive stage small cell lung cancer should be treated with 2 drugs which produce moderate myelosuppression. Etoposide and cisplatin remains the standard treatment. Patients with small cell lung cancer treated with intensive chemotherapy (adding paclitaxel or autologous transplant doses) do not live longer than patients treated with standard doses Eckardt JR, et al. J Clin Oncol. 2006;24(13): Leyvraz S, et al. J Natl Cancer Inst. 2008;100(8): Lee SM, et al. J Natl Cancer Inst. 2009;101: Audience Response Question? A patient presents with small cell lung cancer with involvement of the left upper lobe, mediastinum, and thoracic spine. Chemotherapy is recommended. 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 tested thus far. 3. Giving high doses of chemotherapy with autologous bone marrow transplantation will prolong their. 4. Adding the antiangiogenic agent, Thalidomide to combination chemotherapy prolongs. 41 Lara, et al. J Clin Oncol. 2009;27: ; Leyvraz S, et al. J Natl Cancer Inst. 2008;100(8): ; Lee SM, et al. J Natl Cancer Inst. 2009;101:
8 Audience Response Question? Prophylactic Cranial Irradiation for Limited Stage 3. 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 only patients with limited stage small cell lung cancer with a response to treatment 2. Prophylactic cranial irradiation is recommended for patients with both limited and extensive stage small cell lung cancer after completion of their treatment 3. Prophylactic cranial irradiation has no impact on but reduces the chance of getting brain metastases 4. Prophylactic cranial irradiation can reduce the risk of brain metastases and prolong Auperin, et al. N Engl J Med. 1999;341: Prophylactic Cranial Irradiation for Extensive Stage Prophylactic Cranial Irradiation Patients with SCLC have a 60-80% actuarial risk of developing brain metastases within 2 years after the start of treatment. PCI has been shown to prolong for patients with both limited and extensive SCLC who have a response to chemotherapy. PCI ( cgy) administered at the time of complete remission can reduce the chance of developing the brain metastases by 50-67%. 45 Slotman B, et al. N Engl J Med. 2007;357(7): Audience Response Question? 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 only patients with limited stage small cell lung cancer with a response to treatment 2. Prophylactic cranial irradiation is recommended for patients with both limited and extensive stage small cell lung cancer after completion of their treatment 3. Prophylactic cranial irradiation has no impact on but reduces the chance of getting brain metastases 4. Prophylactic cranial irradiation can reduce the risk of brain metastases and prolong
9 Relapsed Disease Relapsed Disease 211 patients with sensitive relapsed SCLC (complete or partial response and off chemotherapy for > 60 days) Randomized to either topotecan 1.5 mg/m 2 /day IV on days 1-5 or standard doses of cyclophosphamide, doxorubicin, and vincristine (CAV) Followed for response rate, time to progression, and 49 von Pawel J, et al. J Clin Oncol. 1999;17: von Pawel J, et al. J Clin Oncol. 1999;17: Relapsed Disease Relapsed Disease 141 patients with relapsed SCLC not deemed to be candidates for further intravenous chemotherapy Randomized to either topotecan 2.3 mg/m 2 /day PO on days 1-5 or best supportive care Followed for response rate, time to progression, and 51 O Brien ME, et al. J Clin Oncol. 2006;24(34): O Brien ME, et al. J Clin Oncol. 2006;24(34): Topotecan Versus Amrubicin for Relapsed SCLC Topotecan Versus Amrubicin for 59 Pts with Relapsed SCLC 59 patients with relapsed SCLC with sensitive (36) or refractory (23) relapsed disease were randomized in Japan Randomized to either topotecan 1.0 mg/m 2 /day IV on days 1-5 or amrubicin 40 mg/m 2 on days 1 to 3 every three weeks Followed for response rate, time to progression, and 53 Inoue A, et al. J Clin Oncol. 2008;26: Inoue A, et al. J Clin Oncol. 2008;26:
10 Thank you for attending Master Class for Oncologists 55 Questions & Answers? 57 10
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