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SMALL CELL LUNG CANCER (SCLC) and TKIs in NSCLC

SMALL CELL LUNG CANCER (SCLC) and TKIs in NSCLC. G. Giaccone Chief Medical Oncology Branch National Cancer Institute Bethesda, Maryland. U.S. Cancer Mortality: Men. CA Cancer J Clin 2006. U.S. Cancer Mortality: Women. CA Cancer J Clin 2006. Worldwide Prevalence of Lung Cancer.

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SMALL CELL LUNG CANCER (SCLC) and TKIs in NSCLC

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  1. SMALL CELL LUNG CANCER (SCLC) and TKIs in NSCLC G. Giaccone Chief Medical Oncology Branch National Cancer Institute Bethesda, Maryland

  2. U.S. Cancer Mortality: Men CA Cancer J Clin 2006

  3. U.S. Cancer Mortality: Women CA Cancer J Clin 2006

  4. Worldwide Prevalence of Lung Cancer • According to WHO, >1.2 million new cases of lung and bronchial cancer diagnosed each year worldwide, and approximately 1.1 million deaths annually • Lung/bronchial cancer single largest cause of cancer deaths in US, accounting for 32% of cancer deaths in men and 25% in women in 20041 • In Europe, about 400,000 new cases of lung and bronchial cancer diagnosed each year,2 with 341,800 deaths (about 20% for all cancers) reported in 20043 • American Cancer Society(http://www.cancer.org/docroot/pro/content/pro_1_1_Cancer_Statistics_2004_presentation.asp) • Bray F, et al. Eur J Cancer. 2002;38:99-166. • Boyle P, Ferlay J. Ann Oncol. 2005;16:481-488.

  5. Lung Cancer Demographics • Second most frequently diagnosed cancer in the United States • ~12% of all new diagnoses • ~173,770 individual cases in 2004 • Median age at diagnosis is approximately 70 years • Over 1/3 of all diagnoses are made in patients over 75 years of age • Leading cause of cancer deaths in the United States • ~160,440 patients will die in 2004 • 32% and 25% of all cancer deaths in American men and women, respectively Jemal et al. CA Cancer J Clin. 2004;54:8. SEER Cancer Statistics Review, 1975-2001. At: http://seer.cancer.gov/csr/1975_2001/. Accessed October 22, 2004.

  6. Estimated Cancer Death Rates in the United States 2004 Men 290,890 Women 272,810 Lung and bronchus 32% Prostate 10% Colon and rectum 10% Pancreas 5% Leukemia 4% Non-Hodgkin’s 4%lymphoma 25% Lung and bronchus 15% Breast 10% Colon and rectum 6% Ovary 6% Pancreas 4% Leukemia Jemal et al. CA Cancer J Clin. 2004;54:8.

  7. Activated proto-oncogenes in lung cancer

  8. Inactivated tumor suppressor genes in lung cancer

  9. Unbalanced translocation causing LOH in adenocarcinoma of the lung 7 cell lines and 3 primaries Ogiwara H et al. Oncogene 27, 4788, 2008

  10. Select gene mutations in NSCLC • P53 50-70% • Kras 20% (30% adenocarcinoma) • P16 29% (adenocarcinoma) • EGFR 10-30% (20% adenocarcinoma) • LKB1 26% (34% adenocarcinoma) • NTRK 10% pulmonary NE tumors • EML-4-ALK 6.7% • PIK3CA 1.6% • MEK1 1%

  11. TK and relative hazard to develop metastases in early NSCLC Muller-Tidow C et al. Cancer Res 65 1778, 2005

  12. LUNG CANCER Histological Types • Non-small cell lung cancer (85%) • Adenocarcinoma • Squamous cell carcinoma • Large cell carcinoma • Small cell lung cancer (15%)

  13. SCLC • Mostly caused by cigarette smoke • Kills approximately 30,000 people each year in the US • Is a neuroendocrine tumor • Highly sensitive to chemotherapy and radiotherapy, but recurrence is common

  14. SCLC • Epidemiology • Diagnosis and Staging • Biology • Treatment

  15. Epidemiology of SCLC • SEER database 1978-1998 • Decrease SCLC • 1986 17.4% • 1998 13.8%

  16. NSCLC: United States Incidence Over 3 Decades 70 • The incidence of NSCLC increased by over 26% between 1974 and 1998 • The incidence of SCLC decreased approximately 9% between 1998 and 2001 60 50 40 Incidence rate* 30 20 10 0 1975 1980 1985 1990 1995 2000 Year of diagnosis *Rates are per 100,000 and are age-adjusted to the 2000 US standard population. SEER Cancer Statistics Review, 1975-2001. At: http://seer.cancer.gov/csr/1975_2001/. Accessed October 22, 2004.

  17. Lung Cancer: Common Signs and Symptoms • Symptoms related to the primary tumor • Cough, hemoptysis, wheeze and stridor, dyspnea, and/or pneumonitis • Symptoms related to metastases • Bone pain, abdominal pain, headache, weakness, and/or confusion • Generalized symptoms • Fatigue, malaise, and/or loss of appetite American Society of Clinical Oncology. At: http://asco.org/ac/1,1003,_12-002611-00_18-0026183-00_19-00-00_20-001,00.asp. Accessed October 26, 2004. Ginsberg et al. Non–small cell lung cancer. In: Cancer: Principles & Practice of Oncology. 2001:925.

  18. Lung Cancer: Evaluation and Diagnosis Suspected lung cancer Initial evaluation: Chest x-ray CT scan PET scan* Peripheral tumor Central tumor Options - Percutaneous fine needle aspiration - Bronchoscopy - Video-assisted thoracoscopy - Thoracotomy Options - Sputum cytology - Bronchoscopy - Percutaneous fine needle aspiration - Thoracotomy *Some metastases visible by CT scan only. CT = computed tomography; PET = positron emission tomography. Ginsberg et al. Non–small cell lung cancer. In: Cancer: Principles & Practice of Oncology. 2001:925. Rivera et al. Chest. 2003;123(suppl):129S.

  19. Lung cancer: chest X-ray

  20. Lung cancer: chest CT-scan

  21. Lung cancer: bronchoscopy

  22. Staging of SCLC • Physical examination • Serum chemistries and whole blood cell counts • CT scan of chest and upper abdomen • US upper abdomen • FDG PET scan • Bone scan • CT or MRI of the brain • Bone marrow biopsy (optional)

  23. Initiated by tobacco smoke carcinogens. • Is SCLC derived from neuroendocrine Kulchitsky cells or stem cells?

  24. Allelic loss (3p, 4p, 4q, 5q, 8p, 9p, 10q, 13q, 17p, 22q) • Microsatellite instabilities (35%) • MYC overexpression (30%) • Stem cell factor, c-kit overexpression (30%) • Bombesin/ Gastrin releasing peptide (BB/GRP), GRP receptor, IGF-I receptor

  25. P53 inactivation (90%) • Rb inactivation (90%) but not p16. • FHIT inactivation (75%) • BCL2 expression (85%)

  26. Small cell lung carcinoma • Rapid growth and early metastases • Staged in limited vs extensive disease (based on possibility of chest radiation in one field) • Limited disease: • stage I : resection followed by adjuvant chemotherapy; 5y 35-45% • Stage II-III : chemoradiation, PCI in CR; 5y 20-25% • Extensive disease: • Chemotherapy : response 50-70%, 5y <5%

  27. Prognostic factors for survival 19 mo 10 mo 7 mo 2 mo

  28. Staging of small cell lung cancer Limited disease (within a tolerable radiation field) Extensive disease (distant metastases)

  29. DEFINITION OF DISEASE EXTENSION • Very-limited disease: confined to one hemithorax without mediastinal lymph node involvement. • Limited disease: confined to one hemithorax including the contralateral lymph nodes (all within radiation field). • Extensive disease: beyond these bounderies.

  30. survival of SCLC marginally improvement of survival in 2 decades Median survival SEER database Extensive Disease (Chute et al. J Clin Oncol 1999) Limited Disease (Janne et al. Cancer 2002)

  31. Median survivals in SCLC • Very-limited disease ~5 years • Limited disease 18-24 months • Extensive disease 10 months • SCLC without treatment < 3 months

  32. Approach to very-limited disease Surgery followed by chemotherapy

  33. Survival of patients with SCLC according to lymph node involvement pTN0M0 (n=63) pTN1M0 (n=51) pTN2M0 (n=32) Eur J Cardiothorac Surg, 5:306;1991

  34. About half of patients with very-limited disease may be cured with combined-modality approach that includes surgical resection and adjuvant chemotherapy

  35. preoperative SCLC • 1 randomized study • 328 patients (N2 excluded) • 5 courses CAV q 3 wks + radiotherapy thorax and brain + thoracotomy • randomized if > PR • 217 responders (90 CR, 127 PR) • 146 randomized Lad T et al. Chest 1994; 106: 320S

  36. -resection rate 83% -19% complete resection -9% only NSCLC as residual disease median survival -all 12 months; -randomized 16 months Lad T et al. Chest 1994; 106: 320S

  37. Approach to limited disease

  38. Limited Disease - SCLC • treatment has a small but definitively curative intent ( 5y survival: 10 – 25 % ) • combination chemotherapy is the backbone of treat-ment • thoracic radiotherapy significantly improves long term survival • early thoracic radiotherapy gives better results than late radiotherapy

  39. limited disease - SCLC • cisplatin and etoposide are most easily combined within concurrent chemoradiation protocols (Turrisi et al ) • BID radiotherapy gives better local control and better long term survival than QD (5y survival %: 26% Turrisi et al, NEJM 99 ) • PCI significantly improves survival by 4-5 % at 5 years when given to complete responders (Auperin et al )

  40. A meta-analysis of thoracic RT in LD-SCLC 12 phase III studies Pignon et al NEJM 1992

  41. SCLC - Meta-analysis of PCI From 7 randomised trials of PCI vs no-PCI Patients 987 (140 patients had ED-SCLC) Chemo- & RT schemes various Overall survival benefit +5% (95% CI: 1 -10%) 3 year survival 20 vs 15% Incidence of brain metas 33 vs 59% Auperin et al. NEJM 1999

  42. Risk of radiation esophagitis with CT-RT • With once-daily RT: <5% acute Grade 3-4 esophagitis • With concurrent chemo-RT: 25-52% acute G3-4 esophagitis • Risk of acute high-grade esophagitis associated with a length of irradiated organ of >10 cm • Risk of late toxicity associated with >50 Gy delivered to >32% of the esophageal volume& when any portion of esophageal circumference receives >80 Gy. • Use of involved-fields significantly reduces the length of irradiated esophagus. (refs Choi 99; Hirota 01; Rusch 01; Senan 02; Vokes 02)

  43. Early vs Late Radiotherapy for LD SCLC. Meta analysis 2 year survival 3 year survival Fried et al. J. Clin. Oncol. 22,4837,2004

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