Welcome to Master Class for Oncologists Miami, FL December 19, 2009 Session 4: 3:30 PM - 4:15 PM Small Cell Lung Cancer: Best Practices and Recent Advances 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: Dr Johnson serves as a consultant and receives patent honoraria from Genzyme. 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; 2004. 6 1
Pathology and Molecular Pathogenesis Markers of Neuroendocrine Differentiation Chromogranin A Synaptophysin Pathology and Molecular Pathogenesis: Smoking CD56 or Neural Cell Adhesion Molecule (NCAM) 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; 2004. 8 Pathology and Molecular Pathogenesis: Smoking Pathology and Molecular Pathogenesis: Bcl-2 and Hedgehog Signaling 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. 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. 9 1. Tse C, et al. Cancer Res. 2008;68(9):3421-3428. 2. Rudin CM, et al. J Clin Oncol. 2008;26(6):870-876. 10 3. Watkins DN, et al. Nature. 2003;422(6929):313-317. 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 2002. The symptoms and signs of lung cancer are not specific and are commonly found in heavy cigarette smokers. 11 12 Govindan R, et al. J Clin Oncol. 2006;24(28):4539-4544. 2
Presentation Presentation: Paraneoplastic Syndromes Symptom or Sign Local Cough Percentage 50% Symptom or Sign Systemic Weight Loss Percentage 50% Syndrome Hyponatremia of Malignancy Protein Arginine Vasopressin and Atrial Natriuretic Peptide %Pts with SCLC 15 Dyspnea Chest Pain Hemoptysis Hoarseness 40% 35% 20% 10% Weakness Anorexia Paraneoplastic Syndrome Fever 40% 30% 15% 10% Hypercalcemia of Malignancy Ectopic ACTH Syndrome Acromegaly Parathyroid Hormone Related Peptide Adrenocorticotrophic Hormone Growth Hormone Releasing Hormone <1% 3% <1% 13 14 Presentation: Paraneoplastic Syndromes Sodium Serum SERUM LEVELS 150 145 140 135 130 125 120 115 110 Feb-99 Mar-99 Apr-99 May-99 Jun-99 Jul-99 DATE 15 16 Staging 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 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 17 18 3
Metastatic Sites Prognostic Factors Bone-35% Liver-25% Bone marrow-20% Brain-20% Extrathoracic lymph nodes-5% Subcutaneous masses-5% 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 19 20 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: 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. 21 22 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 Pretreatment 2 Years after Treatment 24 Takada M, et al. J Clin Oncol. 2002;20(14):3054-3060. 4
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 Takada M, et al. J Clin Oncol. 2002;20(14):3054-3060. 26 Turrisi AT 3rd, et al. N Engl J Med. 1999;340(4):265-271. 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 Turrisi AT 3rd, et al. N Engl J Med. 1999;340(4):265-271. 28 Sundstrom S, et al. J Clin Oncol. 2002;20(24):4665-4672. 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. 29 Sundstrom S, et al. J Clin Oncol. 2002;20(24):4665-4672. 30 5
Surgery for Small Cell Lung Cancer Patients with a solitary pulmonary nodule and a diagnosis of small cell lung cancer should undergo evaluation for resection (2-3%). IASLC proposed TNM stage Patients should have mediastinoscopy because 20% will have positive lymph nodes. Patients should be treated with adjuvant chemotherapy following resection. Shepherd FA, et al. J Thoracic Oncol. 2007;2:1067 2:1067-1077. 1077. 31 Strand TE, et al. Thorax. 2006;61(8):710-715. 32 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: 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. 33 34 Irinotecan for 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 survival. 4. Adding the antiangiogenic agent, thalidomide, to combination chemotherapy prolongs survival. 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 survival 35 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. 36 Noda K, et al. N Engl J Med. 2002;346:85-91. 6
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 survival Noda K, et al. N Engl J Med. 2002;346:85-91. 38 Lara PN, et al. J Clin Oncol. 2009;27:2530-2535. Irinotecan for Strategies for 784 patients given oral topotecan plus cisplatin vs etoposide plus cisplatin 1 140 patients with limited and extensive stage SCLC treated with transplant doses of ifosfamide, carboplatin, and etoposide (Tx) vs standard doses of the same drugs 2 724 patients with limited and extensive stage SCLC treated with etoposide and cisplatin +/- thalidomide 3 39 Lara PN, et al. J Clin Oncol. 2009;27:2530-2535. 40 1. Eckardt JR, et al. J Clin Oncol. 2006;24(13):2044-2051. 2. Leyvraz S, et al. J Natl Cancer Inst. 2008;100(8):533-541. 3. Lee SM, et al. J Natl Cancer Inst. 2009;101:1049-1057. 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. 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 survival. 4. Adding the antiangiogenic agent, Thalidomide to combination chemotherapy prolongs survival. 41 42 Lara, et al. J Clin Oncol. 2009;27:2530-2535; Leyvraz S, et al. J Natl Cancer Inst. 2008;100(8):533-541; Lee SM, et al. J Natl Cancer Inst. 2009;101:1049 7
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 survival but reduces the chance of getting brain metastases 4. Prophylactic cranial irradiation can reduce the risk of brain metastases and prolong survival 43 44 Prophylactic Cranial Irradiation for Limited Stage Prophylactic Cranial Irradiation for Extensive Stage 45 Auperin, et al. N Engl J Med. 1999;341:476-484. 46 Slotman B, et al. N Engl J Med. 2007;357(7):664-672. 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 survival for patients with both limited and extensive SCLC who have a response to chemotherapy. PCI (2400-3600 cgy) administered at the time of complete remission can reduce the chance of developing the brain metastases by 50-67%. 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 h both limited and extensive stage small cell lung cancer after completion of their t 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 tastases and prolong survival 47 48 8
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 survival 49 50 von Pawel J, et al. J Clin Oncol. 1999;17:658-667. 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 survival 51 von Pawel J, et al. J Clin Oncol. 1999;17:658-667. 52 O Brien ME, et al. J Clin Oncol. 2006;24(34):5441-5447. Relapsed Disease Topotecan Versus Amrubicin for 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 survival 53 O Brien ME, et al. J Clin Oncol. 2006;24(34):5441-5447. 54 Inoue A, et al. J Clin Oncol. 2008;26:5401-5406. 9
Topotecan Versus Amrubicin for 59 Pts with Relapsed SCLC Inoue A, et al. J Clin Oncol. 2008;26:5401-5406. 55 56 Questions & Answers Thank you for attending Master Class for Oncologists 58 10