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SMALL CELL LUNG CANCER (SCLC)

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SMALL CELL LUNG CANCER (SCLC)

  1. 1. SMALL CELL LUNG CANCER (SCLC) <ul><li>G. Giaccone </li></ul><ul><li>Chief Medical Oncology Branch </li></ul><ul><li>National Cancer Institute </li></ul><ul><li>Bethesda, Maryland </li></ul>
  2. 2. U.S. Cancer Mortality: Men CA Cancer J Clin 2006
  3. 3. U.S. Cancer Mortality: Women CA Cancer J Clin 2006
  4. 4. Worldwide Prevalence of Lung Cancer <ul><li>According to WHO, >1.2 million new cases of lung and bronchial cancer diagnosed each year worldwide, and approximately 1.1 million deaths annually </li></ul><ul><ul><li>Lung/bronchial cancer single largest cause of cancer deaths in US, accounting for 32% of cancer deaths in men and 25% in women in 2004 1 </li></ul></ul><ul><ul><li>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 2004 3 </li></ul></ul><ul><ul><li>American Cancer Society ( http://www.cancer.org/docroot/pro/content/pro_1_1_Cancer_ Statistics_2004_presentation.asp ) </li></ul></ul><ul><ul><li>Bray F, et al. Eur J Cancer . 2002;38:99-166. </li></ul></ul><ul><ul><li>Boyle P, Ferlay J. Ann Oncol . 2005;16:481-488. </li></ul></ul>
  5. 5. Lung Cancer Demographics <ul><li>Second most frequently diagnosed cancer in the United States </li></ul><ul><ul><li>~12% of all new diagnoses </li></ul></ul><ul><ul><li>~173,770 individual cases in 2004 </li></ul></ul><ul><ul><li>Median age at diagnosis is approximately 70 years </li></ul></ul><ul><ul><li>Over 1/3 of all diagnoses are made in patients over 75 years of age </li></ul></ul><ul><li>Leading cause of cancer deaths in the United States </li></ul><ul><ul><li>~160,440 patients will die in 2004 </li></ul></ul><ul><ul><li>32% and 25% of all cancer deaths in American men and women, respectively </li></ul></ul>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. 6. Estimated Cancer Death Rates in the United States 2004 Men 290,890 Women 272,810 25% Lung and bronchus 15% Breast 10% Colon and rectum 6% Ovary 6% Pancreas 4% Leukemia Lung and bronchus 32% Prostate 10% Colon and rectum 10% Pancreas 5% Leukemia 4% Non-Hodgkin’s 4% lymphoma Jemal et al. CA Cancer J Clin. 2004;54:8.
  7. 8. LUNG CANCER Histological Types <ul><li>Non-small cell lung cancer (85%) </li></ul><ul><ul><li>Adenocarcinoma </li></ul></ul><ul><ul><li>Squamous cell carcinoma </li></ul></ul><ul><ul><li>Large cell carcinoma </li></ul></ul><ul><li>Small cell lung cancer (15%) </li></ul>
  8. 9. SCLC <ul><li>Mostly caused by cigarette smoke </li></ul><ul><li>Kills approximately 30,000 people each year in the US </li></ul><ul><li>Is a neuroendocrine tumor </li></ul><ul><li>Highly sensitive to chemotherapy and radiotherapy, but recurrence is common </li></ul>
  9. 10. SCLC <ul><li>Epidemiology </li></ul><ul><li>Diagnosis and Staging </li></ul><ul><li>Biology </li></ul><ul><li>Treatment </li></ul>
  10. 11. Epidemiology of SCLC <ul><li>SEER database 1978-1998 </li></ul><ul><li>Decrease SCLC </li></ul><ul><ul><li>1986 17.4% </li></ul></ul><ul><ul><li>1998 13.8% </li></ul></ul>
  11. 12. NSCLC: United States Incidence Over 3 Decades <ul><li>The incidence of NSCLC increased by over 26% between 1974 and 1998 </li></ul><ul><li>The incidence of SCLC decreased approximately 9% between 1998 and 2001 </li></ul>*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. 0 10 20 30 40 50 60 70 1975 1980 1985 1990 1995 2000 Year of diagnosis Incidence rate*
  12. 15. Lung Cancer: Common Signs and Symptoms <ul><li>Symptoms related to the primary tumor </li></ul><ul><ul><li>Cough, hemoptysis, wheeze and stridor, dyspnea, and/or pneumonitis </li></ul></ul><ul><li>Symptoms related to metastases </li></ul><ul><ul><li>Bone pain, abdominal pain, headache, weakness, and/or confusion </li></ul></ul><ul><li>Generalized symptoms </li></ul><ul><ul><li>Fatigue, malaise, and/or loss of appetite </li></ul></ul>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.
  13. 16. Lung Cancer: Evaluation and Diagnosis 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. Suspected lung cancer
  14. 17. Lung cancer: chest X-ray
  15. 18. Lung cancer: chest CT-scan
  16. 19. Lung cancer: bronchoscopy
  17. 20. Staging of SCLC <ul><li>Physical examination </li></ul><ul><li>Serum chemistries and whole blood cell counts </li></ul><ul><li>CT scan of chest and upper abdomen </li></ul><ul><ul><li>US upper abdomen </li></ul></ul><ul><li>FDG PET scan </li></ul><ul><ul><li>Bone scan </li></ul></ul><ul><li>CT or MRI of the brain </li></ul><ul><li>Bone marrow biopsy (optional) </li></ul>
  18. 22. <ul><li>Initiated by tobacco smoke carcinogens. </li></ul><ul><li>Is SCLC derived from neuroendocrine Kulchitsky cells or stem cells? </li></ul>
  19. 25. <ul><li>Allelic loss (3p, 4p, 4q, 5q, 8p, 9p, 10q, 13q, 17p, 22q) </li></ul><ul><li>Microsatellite instabilities (35%) </li></ul><ul><li>MYC overexpression (30%) </li></ul><ul><li>Stem cell factor, c-kit overexpression (30%) </li></ul><ul><li>Bombesin/ Gastrin releasing peptide ( BB/GRP ), GRP receptor, IGF-I receptor </li></ul>
  20. 27. <ul><li>P53 inactivation (90%) </li></ul><ul><li>Rb inactivation (90%) but not p16. </li></ul><ul><li>FHIT inactivation (75%) </li></ul><ul><li>BCL2 expression (85%) </li></ul>
  21. 28. Small cell lung carcinoma <ul><li>Rapid growth and early metastases </li></ul><ul><li>Staged in limited vs extensive disease (based on possibility of chest radiation in one field) </li></ul><ul><ul><li>Limited disease: </li></ul></ul><ul><ul><ul><li>stage I : resection followed by adjuvant chemotherapy; 5y 35-45% </li></ul></ul></ul><ul><ul><ul><li>Stage II-III : chemoradiation, PCI in CR; 5y 20-25% </li></ul></ul></ul><ul><ul><li>Extensive disease: </li></ul></ul><ul><ul><ul><li>Chemotherapy : response 50-70%, 5y <5% </li></ul></ul></ul>
  22. 29. Prognostic factors for survival 19 mo 10 mo 7 mo 2 mo
  23. 30. Staging of small cell lung cancer Limited disease (within a tolerable radiation field) Extensive disease (distant metastases)
  24. 31. DEFINITION OF DISEASE EXTENSION <ul><li>Very-limited disease : confined to one hemithorax without mediastinal lymph node involvement . </li></ul><ul><li>Limited disease : confined to one hemithorax including the contralateral lymph nodes (all within radiation field). </li></ul><ul><li>Extensive disease : beyond these bounderies. </li></ul>
  25. 32. survival of SCLC <ul><li>marginally improvement of survival in 2 decades </li></ul>Limited Disease (Janne et al. Cancer 2002) Median survival SEER database Extensive Disease (Chute et al. J Clin Oncol 1999)
  26. 33. Median survivals in SCLC <ul><li>Very-limited disease ~5 years </li></ul><ul><li>Limited disease 1 8-24 months </li></ul><ul><li>E xtensive disease 10 months </li></ul><ul><li>SCLC without treatment < 3 months </li></ul>
  27. 35. Approach to very-limited disease Surgery followed by chemotherapy
  28. 36. Survival of patients with SCLC according to lymph node involvement pTN1M0 (n=51) pTN2M0 (n=32) Eur J Cardiothorac Surg, 5:306;1991 pTN0M0 (n=63)
  29. 37. About half of patients with very-limited disease may be cured with combined-modality approach that includes surgical resection and adjuvant chemotherapy
  30. 38. preoperative SCLC <ul><li>1 randomized study </li></ul><ul><li>328 patients (N2 excluded) </li></ul><ul><li>5 courses CAV q 3 wks + radiotherapy thorax and brain + thoracotomy </li></ul><ul><li>randomized if > PR </li></ul><ul><li>217 responders (90 CR, 127 PR) </li></ul><ul><li>146 randomized </li></ul>Lad T et al. Chest 1994; 106: 320S
  31. 39. -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
  32. 40. Approach to limited disease
  33. 41. Limited Disease - SCLC <ul><li>treatment has a small but definitively curative intent ( 5y survival: 10 – 25 % ) </li></ul><ul><li>combination chemotherapy is the backbone of treat-ment </li></ul><ul><li>thoracic radiotherapy significantly improves long term survival </li></ul><ul><li>early thoracic radiotherapy gives better results than late radiotherapy </li></ul>
  34. 42. limited disease - SCLC <ul><li>cisplatin and etoposide are most easily combined within concurrent chemoradiation protocols ( Turrisi et al ) </li></ul><ul><li>BID radiotherapy gives better local control and better long term survival than QD (5y survival %: 26% Turrisi et al, NEJM 99 ) </li></ul><ul><li>PCI significantly improves survival by 4-5 % at 5 years when given to complete responders ( Auperin et al ) </li></ul>
  35. 43. A meta-analysis of thoracic RT in LD-SCLC 12 phase III studies Pignon et al NEJM 1992
  36. 44. 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
  37. 45. <ul><li>With once-daily RT: <5% acute Grade 3-4 esophagitis </li></ul><ul><li>With concurrent chemo-RT: 25-52 % acute G3-4 esophagitis </li></ul><ul><li>Risk of acute high-grade esophagitis associated with a length of irradiated organ of >10 cm </li></ul><ul><li>Risk of late toxicity associated with >50 Gy delivered to >32% of the esophageal volume & when any portion of esophageal circumference receives >80 Gy. </li></ul><ul><li>Use of involved-fields significantly reduces the length of irradiated esophagus. </li></ul>Risk of radiation esophagitis with CT-RT (refs Choi 99; Hirota 01; Rusch 01; Senan 02; Vokes 02)
  38. 46. Early vs Late Radiotherapy for LD SCLC. Meta analysis 2 year survival 3 year survival
  39. 47. SCLC LD Standard of treatment Cisplatin 80 mg/m 2 d1 Etoposide 120 mg/m 2 d1-3 Q3wk x 4 Thoracic Radiotherapy 45 Gy 1.5 Gy/fraction bid 3 wk Turrisi et al. NEJM 1999
  40. 48. Approach to SCLC ED
  41. 49. Standard of treatment for SCLC ED <ul><li>Cisplatin or Carboplatin plus Etoposide </li></ul><ul><ul><li>Median survival approx. 11 months </li></ul></ul><ul><ul><li>5 year survival approx 0% </li></ul></ul><ul><li>Improvement sought by </li></ul><ul><ul><li>Alternating chemotherapy </li></ul></ul><ul><ul><li>Maintenance chemotherapy </li></ul></ul><ul><ul><li>Novel agents (taxanes, topo 1 inhibitors) </li></ul></ul><ul><ul><li>Biologicals </li></ul></ul>
  42. 50. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive stage small cell lung cancer <ul><li>irinotecan 60 mg/m 2 d 1,8,15; cisplatin 60 mg/m 2 d 1 q 4 weeks </li></ul><ul><li>etoposide 100 mg/ m 2 d 1,2,3; cisplatin 80 mg/ m 2 d 1 q 3 weeks </li></ul><ul><li>154 patients (planned 230) </li></ul><ul><li>median survival IP 12.8 months; EP 9.4 months </li></ul><ul><li>at 2 years 19.5% versus 5.2% alive </li></ul>Irinotecan Noda K et al. New Engl J Med 2002
  43. 51. cisplatin/irinotecan versus cisplatin/etoposide in SCLC ED Japanese experience Noda et al. NEJM 2002
  44. 52. Randomized phase III study comparing Irinotecan/Cisplatin (IP) with Etoposide/Cisplatin (EP) in patients with previously untreated, ED SCLC Randomize Cisplatin 30 mg/m 2 d 1, 8 Irinotecan 65 mg/m 2 d 1, 8 Q 21 Cisplatin 60 mg/m 2 d 1 etoposide 120 mg/m 2 d 1-3 Q 21 LBA 7004 N = 221 N = 110
  45. 53. IP vs EP in SCLC ED – US experience
  46. 54. Phase III study of oral Topotecan/Cisplatin versus Etoposide/Cisplatin (EP) as first-line therapy in patients with ED SCLC randomize Cisplatin 60 mg/m 2 d 5 Topotecan 1.7 mg/m 2 /d d 1-5 Q 21 Cisplatin 80 mg/m 2 d 1 etoposide 100 mg/m 2 d 1-3 Q 21 abstract 7003 Eckardt JR et al. J Clin Oncol 2005; 23: 621s N = 389 N = 395
  47. 55. Eckardt JR et al. J Clin Oncol 2005; 23: 621s
  48. 56. ASCO 2007
  49. 60. Maintenance therapy unsuccesfull <ul><li>Chemotherapy </li></ul><ul><li>Biologicals: </li></ul><ul><ul><li>Interferons </li></ul></ul><ul><ul><li>Marimastat </li></ul></ul><ul><ul><li>Vaccination </li></ul></ul><ul><ul><li>ZD6474 (VEGFR and EGFR inhibitor) </li></ul></ul>
  50. 61. Rationale of the study (ctd) <ul><li>BEC 2 is an anti-idiotypic antibody that mimics GD3, a ganglioside which is expressed on the cell membrane of most SCLC </li></ul><ul><li>BEC 2 /BCG vaccination has been shown to be safe and stimulates anti-GD3 response in patients </li></ul><ul><li>An impressive long-term survival was observed in a small pilot study </li></ul>
  51. 62. n=8 n=7 n=15 Disease–free progression in 15 patients vaccinated Grant et al., Clin Cancer Res 5, 1319, 1999
  52. 63. 08971-08971b Design R A N D O M I Z E Observation arm : BSC Vaccination arm : 5 vaccinations of BEC 2+BCG Stratification: Performance status (Karnofsky) 60-70% vs > 80%, CR vs. PR, Institution LD responding to 4-6 cycles of chemotherapy and chest radiotherapy Giaccone G et al. JCO 2005
  53. 66. Humoral analysis of vaccinated patients (N=257) <ul><li>Positive: 71 </li></ul><ul><li>Negative: 142 </li></ul><ul><li>Missing: 44 </li></ul>O N Number of patients at risk : Humoral response 111 142 106 69 45 27 14 8 1 0 49 71 60 42 27 19 9 5 3 2 No Yes Overal survival By Humoral response Overall Logrank test: p=0.111 (months) 0 7 14 21 28 35 42 49 56 63 0 10 20 30 40 50 60 70 80 90 100
  54. 67. Second line therapies <ul><li>response to first-line therapy > 60% </li></ul><ul><li>> 95 % relapse after first-line treatment </li></ul><ul><li>second-line treatment often considered as indicated as part of palliation </li></ul>
  55. 68. Oral Topotecan vs BSC in relapsed SCLC Relapsed SCLC N = 141 Stratify PS 0/1 vs 2 Gender TTP (<60 vs >60 d) Liver mets RANDOMIZE Oral Topotecan 2.3 mg/m 2 /day 1-5 q 3wk BSC Primary end point: survival Secondary: QoL, ORR, 6 mo survival
  56. 69. Oral Topotecan vs BSC in relapsed SCLC 26% 49% 6 mo survival 0.64 P = 0.0104 14 26 MS (weeks) HR (95%CI) P -value BSC (n=70) Topotecan (n=71)
  57. 70. Phase III study comparing topotecan vs. CAV as second line therapy in patients with sensitive relapse small cell lung cancer <ul><li>SCLC </li></ul><ul><li>Measurable disease </li></ul><ul><li>LD or ED </li></ul><ul><li>Response to FLT </li></ul><ul><li>Off therapy >60 days </li></ul>RANDOMIZE Topotecan 1.5 mg/m 2 daily x 5 q 3 wks Cyclophosphamide 1000 mg/m 2 Doxorubicin 45 mg/m 2 Vincristine 2 mg
  58. 71. Second line chemotherapy for SCLC. Symptom improvement
  59. 72. Second line chemotherapy for SCLC: reinduction chemotherapy. Sensitive RR 61% Refractory RR 35%
  60. 73. Second line chemotherapy for SCLC: influence of interval and response to first-line treatment
  61. 74. Prophylactic cranial irradiation in extensive disease small cell lung cancer (EORTC 08993-22993) Ben Slotman, Corinne Faivre-Finn, Gijs Kramer † , Elaine Rankin, Michael Snee, Matthew Hatton, Pieter Postmus, Laurence Collette, Murielle Mauer, Suresh Senan, on behalf of the EORTC Radiation Oncology and Lung Cancer Groups Slotman et al. NEJM 2007
  62. 75. Background: Brain metastases (BM) in SCLC <ul><li>High incidence: 18% at diagnosis; 80% at 2 years </li></ul><ul><li>Major impact on physical and psychological functioning </li></ul><ul><li>Poor response to systemic therapy and brain radiotherapy </li></ul><ul><li>Prophylactic cranial irradiation (PCI) improves survival in patients in complete remission (Auperin et al., 1999) </li></ul>Does PCI have a role in patients with ED-SCLC after chemotherapy?
  63. 76. Study Design PCI 20-30 Gy in 5-12 fractions No PCI Random Any response Stratification: Performance score and Institute < 5 weeks 4-6 weeks No response Chemotherapy (4-6 cycles)
  64. 77. Endpoints 156 days 170 days Median follow-up 2 ( 1.4) 1 ( 0.7) - Unknown 8 ( 5.6) 10 ( 7.0) - Other 115 (80.4) 98 (68.5) - SCLC 125 (87.4) 109 (76.2) Mortality: Deaths 133 (93.0) 122 (85.3) Extracranial disease progression 59 (41.3) 24 (16.8) Symptomatic brain metastases N (%) N (%) Control (N=143) PCI (N=143) 89% of patients were followed until progression or death
  65. 78. Endpoints 156 days 170 days Median follow-up 2 ( 1.4) 1 ( 0.7) - Unknown 8 ( 5.6) 10 ( 7.0) - Other 115 (80.4) 98 (68.5) - SCLC 125 (87.4) 109 (76.2) Mortality: Deaths 133 (93.0) 122 (85.3) Extracranial disease progression 59 (41.3) 24 (16.8) Symptomatic brain metastases N (%) N (%) Control (N=143) PCI (N=143) 89% of patients were followed until progression or death
  66. 79. Type of first event 50 (35.0) 13 (9.1) Symptomatic brain metastases 48 13 - followed by extracranial progression 85 (59.4) 109 (76.2) Extracranial disease progression 2 (1.4) 7 (4.9) Death due to other causes 9 11 - followed by brain metastases 6 (4.2) 14 (9.8) No event N (%) N (%) Control (N=143) PCI (N=143)
  67. 80. (months) 0 4 8 12 16 20 24 28 32 36 0 10 20 30 40 50 60 70 80 90 100 PCI Control 1 year: 14.6% vs. 40.4% HR: 0.27 (0.16-0.44) p<0.001 Symptomatic brain metastases
  68. 81. Extracranial progression (months) 0 4 8 12 16 20 24 28 32 36 0 10 20 30 40 50 60 70 80 90 100 P=0.2699 Control PCI
  69. 82. (months) 0 3 6 9 12 15 18 21 24 27 0 10 20 30 40 50 60 70 80 90 100 PCI Control 6 months: 23.4% vs. 15.5% HR: 0.76 (0.59-0.96) p=0.02 Failure-free survival
  70. 83. (months) 0 4 8 12 16 20 24 28 32 36 0 10 20 30 40 50 60 70 80 90 100 PCI Control 1 year: 27.1% vs. 13.3% HR: 0.68 (0.52-0.88) p=0.003 Overall survival
  71. 84. Summary <ul><li>PCI significantly reduces the risk of symptomatic brain metastases (p<0.001; HR = 0.27; 14.6 vs. 40.4% at 1 yr) </li></ul><ul><li>No difference for the time to extra-cranial progression </li></ul><ul><li>PCI significantly prolongs failure-free survival and overall survival (Overall survival: p=0.003; HR = 0.68 ; 27.1 vs. 13.3% at 1 yr) </li></ul><ul><li>PCI is well tolerated and does not adversely influence QoL/global health status </li></ul>
  72. 85. Treatment of SCLC : state of the art <ul><li>Limided Disease </li></ul><ul><ul><li>Concomitant early radiotherapy for limited disease SCLC </li></ul></ul><ul><ul><li>Cisplatin-etoposide best tested </li></ul></ul><ul><ul><li>PCI for complete responders </li></ul></ul><ul><ul><li>Surgery rarely used </li></ul></ul><ul><li>Extensive Disease </li></ul><ul><ul><li>Platinum-based chemotherapy </li></ul></ul><ul><ul><li>Second-line therapy with topotecan </li></ul></ul><ul><ul><li>PCI for responders </li></ul></ul>
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