SMALL CELL LUNG CANCER SCLC

SMALL CELL LUNG CANCER (SCLC) 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 • 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 1. American Cancer Society (http://www.cancer.org/docroot/pro/content/pro_1_1_Cancer_Statistics _2004_presentation.asp) 2. Bray F, et al. Eur J Cancer. 2002;38:99-166. 3. Boyle P, Ferlay J. Ann Oncol. 2005;16:481-488. 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. Estimated Cancer Death Rates in the United States 2004 Men 290,890 Women 272,810 Lung and bronchus Prostate Colon and rectum 32% 10% 10% 25% Lung and bronchus 15% Breast 10% Colon and rectum Pancreas Leukemia Non-Hodgkin’s lymphoma 5% 4% 4% 6% Ovary 6% Pancreas 4% Leukemia Jemal et al. CA Cancer J Clin. 2004;54:8. LUNG CANCER Histological Types  Non-small cell lung cancer (85%) Adenocarcinoma Squamous cell carcinoma Large cell carcinoma  Small cell lung cancer (15%) 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 SCLC • • • • Epidemiology Diagnosis and Staging Biology Treatment Epidemiology of SCLC • SEER database 1978-1998 • Decrease SCLC – 1986 17.4% – 1998 13.8% NSCLC: United States Incidence Over 3 Decades 70 Incidence rate* 60 50 40 30 20 10 0 1975 1980 1985 1990 1995 2000 Year of diagnosis  The incidence of NSCLC increased by over 26% between 1974 and 1998  The incidence of SCLC decreased approximately 9% between 1998 and 2001 *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. SCLC biopsy specimen Neural enzymes, peptides and transmitters may be stored in the dense core neurosecretory granules associated with SCLC. 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_20001,00.asp. Accessed October 26, 2004. Ginsberg et al. Non–small cell lung cancer. In: Cancer: Principles & Practice of Oncology. 2001:925. Lung Cancer: Evaluation and Diagnosis Suspected lung cancer Peripheral tumor Options - Percutaneous fine needle aspiration - Bronchoscopy - Video-assisted thoracoscopy - Thoracotomy Initial evaluation: Chest x-ray CT scan PET scan* Central tumor 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. Lung cancer: chest X-ray Lung cancer: chest CT-scan Lung cancer: bronchoscopy 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) SCLC metastasis. •Liver (27%) •Bone (41%) •Adrenals (31%) •Brain (14%) •Lymph nodes, mediastinal (80%) SCLC carcinogenesis. •Initiated by tobacco smoke carcinogens. •Is SCLC derived from neuroendocrine Kulchitsky cells or stem cells? SCLC cell lines. Bone marrow aspirates were obtained from patients and mononuclear cells collected. Lymph node aspirates and other solid tumors were mechanically dissociated and cell suspensions obtained by mincing and passing through 60 gauge steel mesh. The cells were cultured in a serum free medium containing selenium, IGF-I and transferrin. SCLC cells grew as suspension cultures. SCLC cell lines. •Over a 20 year period, NCI established 113 SCLC and 110 NSCLC continuous human cell lines. A subset of SCLC is variant SCLC, which has low levels of DDC, BB and NSE. Phelps et al., J. Cell Bioc. Supp. 24:32(1996). SCLC molecular abnormalities. •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 Chromosome losses in SCLC include: 3p loss is an early event and 5q, 13q and 17p loss occurs later. SCLC molecular abnormalities. •P53 inactivation (90%) •Rb inactivation (90%) but not p16. •FHIT inactivation (75%) •BCL2 expression (85%) 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  Stage I : resection followed by adjuvant chemotherapy; 5y 35-45% II-III : chemoradiation, PCI in CR; 5y 20-25% – Extensive disease:  Chemotherapy : response 50-70%, 5y <5% Prognostic factors for survival 19 mo 10 mo 7 mo 2 mo Staging of small cell lung cancer Limited disease (within a tolerable radiation field) Extensive disease (distant metastases) 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. survival of SCLC marginally improvement of survival in 2 decades Median survival SEER database Limited Disease (Janne et al. Extensive Disease (Chute et al. J Clin Oncol 1999) Median survivals in SCLC • Very-limited disease • Limited disease • Extensive disease ~5 years 18-24 months 10 months • SCLC without treatment < 3 months Combination chemotherapy. Active combinations include: cyclophosphamide, doxorubicin, VP16(CDE), C, doxorubicin, vincristine (CAV), E, cisplatin (EP), VP-16, ifosfamide, P (VIP), and I, carboplatin, VP-16 (ICE). Approach to very-limited disease Surgery followed by chemotherapy 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 About half of patients with verylimited disease may be cured with combined-modality approach that includes surgical resection and adjuvant chemotherapy 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 -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 Approach to limited disease Limited Disease - SCLC • treatment has a small but definitively curative intent ( 5y survival: 10 – 25 % ) • combination chemotherapy is the backbone of treatment • thoracic radiotherapy significantly improves long term survival • early thoracic radiotherapy gives better results than late radiotherapy 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 ) A meta-analysis of thoracic RT in LD-SCLC 12 phase III studies Pignon et al NEJM 1992 SCLC - Meta-analysis of PCI From 7 randomised trials of PCI vs no-PCI Patients Chemo- & RT schemes Overall survival benefit 3 year survival Incidence of brain metas 987 (140 patients had ED-SCLC) various +5% (95% CI: 1 -10%) 20 vs 15% 33 vs 59% Auperin et al. NEJM 1999 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) Early vs Late Radiotherapy for LD SCLC. Meta analysis 2 year survival 3 year survival Fried et al. J. Clin. Oncol. 22,4837,2004 SCLC LD Standard of treatment Cisplatin 80 mg/m2 d1 Etoposide 120 mg/m2 d1-3 Q3wk x 4 Thoracic Radiotherapy 45 Gy 1.5 Gy/fraction bid 3 wk Turrisi et al. NEJM 1999 Approach to SCLC ED Standard of treatment for SCLC ED • Cisplatin or Carboplatin plus Etoposide – Median survival approx. 11 months – 5 year survival approx 0% • Improvement sought by – – – – Alternating chemotherapy Maintenance chemotherapy Novel agents (taxanes, topo 1 inhibitors) Biologicals Irinotecan Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive stage small cell lung cancer • irinotecan 60 mg/m2 d 1,8,15; cisplatin 60 mg/m2 d 1 q 4 weeks • etoposide 100 mg/m2 d 1,2,3; cisplatin 80 mg/m2 d 1 q 3 weeks • 154 patients (planned 230) • median survival IP 12.8 months; EP 9.4 months • at 2 years 19.5% versus 5.2% alive Noda K et al. New Engl J Med 2002 cisplatin/irinotecan versus cisplatin/etoposide in SCLC ED Japanese experience Noda et al. NEJM 2002 LBA 7004 Randomized phase III study comparing Irinotecan/Cisplatin (IP) with Etoposide/Cisplatin (EP) in patients with previously untreated, ED SCLC R a n d o m i z e Cisplatin 30 mg/m2 d 1, 8 Irinotecan 65 Q 21 Cisplatin 60 mg/m2 d 1 etoposide 120 mg/m2 d 1-3 N = 110 mg/m2 d 1, 8 N = 221 Q 21 Hanna et al. Proc. ASCO 2005, #1094 IP vs EP in SCLC ED – US experience abstract 7003 Phase III study of oral Topotecan/Cisplatin versus Etoposide/Cisplatin (EP) as firstline therapy in patients with ED SCLC Cisplatin 60 mg/m2 d 5 Topotecan 1.7 Q 21 Cisplatin 80 mg/m2 d 1 etoposide 100 mg/m2 d 1-3 N = 395 r a n d o m i z e mg/m2/d d 1-5 N = 389 Q 21 Eckardt JR et al. J Clin Oncol 2005; 23: 621s Eckardt JR et al. J Clin Oncol 2005; 23: 621s A Randomized Phase III Trial of Irinotecan plus Carboplatin versus Etoposide plus Carboplatin in Patients With Extensive Disease Small Cell Lung Cancer – IRIS Study A Hermes, B Bergman, R Bremnes, L Ek, S Fluge, C Sederholm, S Sundstrøm, L Thaning, J Vilsvik, U Aasebø and S Sörenson for the Norwegian Lung Cancer Group (NLCG) and the Swedish Lung Cancer Study Group (SLCSG) ASCO 2007 Study Design carboplatin (Chatelut AUC4) and irinotecan (175 mg/m²) iv day 1 q21 (IC, n=105) ED SCLC Stratification: •PS 0-1,2, 3-4 •age 18-70 or >70 •institution carboplatin (Chatelut AUC4) and etoposide (120 mg/m²) orally d 1-5 q21 (EC, n=104) Results IC Median survival (months) Complete response (number of patients) 1-year survival 8.5 18 34% EC 7.1 7 24% p=0.02, log rank test p=0.02 ASCO 2007, Chicago, IL Overall Survival 1 IC ,8 EC HR 1.41 (95% CI 1.06;1.87) Cum. Survival ,6 ,4 ,2 0 0 12 Time, months 24 36 ASCO 2007, Chicago, IL Maintenance therapy unsuccesfull • Chemotherapy • Biologicals: – Interferons – Marimastat – Vaccination – ZD6474 (VEGFR and EGFR inhibitor) Rationale of the study (ctd) BEC 2 is an anti-idiotypic antibody that mimics GD3, a ganglioside which is expressed on the cell membrane of most SCLC BEC 2/BCG vaccination has been shown to be safe and stimulates anti-GD3 response in patients An impressive long-term survival was observed in a small pilot study Disease–free progression in 15 patients vaccinated n=7 n=15 n=8 Grant et al., Clin Cancer Res 5, 1319, 1999 08971-08971b Design LD responding to 4-6 cycles of chemotherapy and chest radiotherapy R A N D O M I Z E Observation arm: BSC Vaccination arm: 5 vaccinations of BEC 2+BCG Stratification: Performance status (Karnofsky) 6070% vs > 80%, CR vs. PR, Institution Giaccone G et al. JCO 2005 Silva: Overall survival All randomized patients (n=515) 100 90 80 Overall Logrank test: p=0.343 70 60 50 40 30 20 10 0 0 O 180 190 N 258 257 7 14 21 28 35 42 49 56 63 70 (months) Number of patients at risk : 196 148 93 191 129 86 55 56 33 29 19 18 8 6 4 4 1 0 Treatment Observation Vaccination Silva: Progression Free Survival All randomized patients (N=515) 100 90 80 Overall Logrank test: p=0.267 70 60 50 40 30 20 10 0 0 O 196 205 N 258 257 7 14 21 28 35 42 49 56 63 70 (months) Number of patients at risk : 120 82 54 110 77 59 39 35 28 20 17 14 8 6 4 4 1 0 Treatment Observation Vaccination Humoral analysis of vaccinated patients (N=257) Positive: 71 Negative: 142 Missing: 44 100 Overal survival By Humoral response Overall Logrank test: p=0.111 90 80 70 60 50 40 30 20 10 0 0 O 111 49 N 142 71 7 14 21 28 35 42 49 56 63 (months) Number of patients at risk : 106 69 45 60 42 27 27 19 14 9 8 5 1 3 0 2 Humoral response No Yes Second line therapies • response to first-line therapy > 60% • > 95 % relapse after first-line treatment • second-line treatment often considered as indicated as part of palliation Oral Topotecan vs BSC in relapsed SCLC Stratify Relapsed Gender SCLC PS 0/1 vs 2 N = 141 TTP (<60 vs >60 d) Liver mets R A N D O M I Z E Oral Topotecan 2.3 mg/m2/day 1-5 q 3wk BSC Primary end point: survival Secondary: QoL, ORR, 6 mo survival Oral Topotecan vs BSC in relapsed SCLC Topotecan (n=71) 26 49% BSC (n=70) 14 26% HR (95%CI) P-value 0.64 P = 0.0104 MS (weeks) 6 mo survival Phase III study comparing topotecan vs. CAV as second line therapy in patients with sensitive relapse small cell lung cancer SCLC •Measurable disease •LD or ED •Response to FLT •Off therapy >60 days R A N D O M I Z E Topotecan 1.5 mg/m2 daily x 5 q 3 wks Cyclophosphamide 1000 mg/m2 Doxorubicin 45 mg/m2 Vincristine 2 mg Second line chemotherapy for SCLC. Symptom improvement Symptom Dyspnea Cough Chest pain Hemoptysis Anorexia Insomnia Hoarseness Fatigue Daily activity Topotecan (%) 27.9 24.6 25.0 26.7 32.1 33.3 32.5 2.9 26.9 CAV (%) 6.6 14.8 17.1 33.3 15.8 18.9 13.2 9.2 11.1 0.043 0.032 0.023 0.042 P value 0.002 Second line chemotherapy for SCLC: reinduction chemotherapy. Time after first line No patients Response rate (%) Response duration (mo) Author > 4.5 < 4.5 19 18 79 44 7 4 Postmus PE 1987 > 4.5 < 4.5 8 4 50 50 6 Giaccone G 1987 > 4.5 < 4.5 5 9 80 11 3 Vincent M 1988 Sensitive RR 61% Refractory RR 35% Second line chemotherapy for SCLC: influence of interval and response to first-line treatment response response 1st-line Y N period since last chemotherapy > 2.6 mo. < 2.6 mo. 10/24 0/7 9/17 2/16 RR (%) 42 0 53 12 0.016 p 0.044 Giaccone et al. J.Clin. Oncol. 6;1264,1988 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 Background: Brain metastases (BM) in SCLC • High incidence: 18% at diagnosis; 80% at 2 years • Major impact on physical and psychological functioning • Poor response to systemic therapy and brain radiotherapy • Prophylactic cranial irradiation (PCI) improves survival in patients in complete remission (Auperin et al., 1999) Does PCI have a role in patients with ED-SCLC after chemotherapy? Study Design PCI Chemotherapy (4-6 cycles) No response Any response Random 20-30 Gy in 5-12 fractions < 5 weeks 4-6 weeks No PCI Stratification: Performance score and Institute Endpoints 89% of patients were followed until progression or death Median follow-up Symptomatic brain metastases PCI (N=143) Control (N=143) N (%) N (%) 170 days 24 (16.8) 156 days 59 (41.3) Extracranial disease progression Mortality: Deaths - SCLC - Other - Unknown 122 (85.3) 109 (76.2) 98 (68.5) 10 ( 7.0) 1 ( 0.7) 133 (93.0) 125 (87.4) 115 (80.4) 8 ( 5.6) 2 ( 1.4) Type of first event PCI (N=143) N (%) Control (N=143) N (%) No event Symptomatic brain metastases - followed by extracranial progression Extracranial disease progression - followed by brain metastases Death due to other causes 14 13 (9.8) (9.1) 13 6 (4.2) 48 50 (35.0) 109 (76.2) 11 7 (4.9) 85 (59.4) 9 2 (1.4) Symptomatic brain metastases 100 90 80 70 60 50 40 30 20 10 0 0 4 8 12 16 20 24 28 32 36 1 year: 14.6% vs. 40.4% HR: 0.27 (0.16-0.44) p<0.001 Control PCI (months) Extracranial progression 100 90 80 70 60 50 40 30 20 10 0 0 4 8 12 16 20 24 28 32 36 (months) Control PCI P=0.2699 Failure-free survival 100 90 80 70 60 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 6 months: 23.4% vs. 15.5% PCI HR: 0.76 (0.59-0.96) p=0.02 Control (months) Overall survival 100 90 80 70 60 50 40 30 20 10 0 0 4 8 12 16 20 24 28 32 36 1 year: 27.1% vs. 13.3% HR: 0.68 (0.52-0.88) p=0.003 Control PCI (months) Summary • PCI significantly reduces the risk of symptomatic brain metastases (p<0.001; HR = 0.27; 14.6 vs. 40.4% at 1 yr) • No difference for the time to extra-cranial progression • 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) • PCI is well tolerated and does not adversely influence QoL/global health status Treatment of SCLC : state of the art • Limided Disease     Concomitant early radiotherapy for limited disease SCLC Cisplatin-etoposide best tested PCI for complete responders Surgery rarely used • Extensive Disease  Platinum-based chemotherapy  Second-line therapy with topotecan  PCI for responders