Early Lung Cancer Detection and Treatment Program

Early Lung Cancer Detection and Treatment Program Gregory M. Loewen DO FCCP Director, Pulmonary Medicine Roswell Park Cancer Institute 3/28/2008 RPCI Lung Cancer Prevention Program 1 Thoracic Oncology Team Early Lung Cancer Detection and Treatment Program Program Overview Autofluorescence Bronchoscopy applications Bronchoscopy and early detection Therapeutics for high risk patients Overview: Early Lung Cancer Detection and Treatment Program Screening Programs Basic Science Therapeutics 3/28/2008 RPCI Lung Cancer Prevention Program 4 Early Lung Cancer Detection patient and tissue resources Bronchoscopy biopsies Blood Serum Plasma Screening Clinic patient Bronchial Epithelial cell culture Buccal cells Epidemiology questionnaire Attorney referral for asbestos evaluation Self-referral through broadcast and printed media MD referral through grand rounds and educational outreach 3/28/2008 RPCI Lung Cancer Prevention Program 5 Autofluorescence Bronchoscopy Tissue Archive Over 500 patients have undergone AF bronchoscopy at RPCI; over 200 have had more than one bronchoscopy. over 3000 biopsies Biopsies linked to Clinical/Epi database In situ Carcinoma Squamous dysplasia Squamous metaplasia Normal Epithelium, With tobacco smoke exposure 3/28/2008 RPCI Lung Cancer Prevention Program 6 Autofluorescence Bronchoscopy applications Autofluorescence Imaging Systems D-LIGHT, SAFE, and LIFE Exploit the natural “autofluorescence” of the bronchial epithelium Detect preclincal radiographically occult central lung cancers white light image fluorescent image Carcinoma in Situ Abnormal sputum cytology 423/561 smokers (30 pk/year) had sputum atypia; 4/14 cancers detected by AF bronchoscopy, and 9/14 detected by CT chest. ---McWilliams A, AJRCCM 2003 50 patients with positive cytology underwent AF and WL bronchoscopy; 28 cancers were detected with both; 39 borderline lesions were detected; 9/39 by AF alone; multicentric lesions in 21/50 patients. --Sato M, Lung Cancer 2001 Investigation of CIS 28 patients referred for evaluation of severe dysplasia, carcinoma in situ, or microinvasive squamous cell carcinoma detected by WLB. All 28 underwent AF bronchoscopy with biopsy; 2 patients proved to have metaplasia; and 6 additional lesions were detected in the remaining 26 patients, increasing detection of multicentricity by 3 fold. Pierad P Lung Cancer 2004 Post–resection Surveillance: metachronous primary lung cancer 25 patients with NED underwent post-resection AF bronchoscopy; 4 cases of intraepithelial neoplasia were detected; AF increased sensitivity by 3-fold. -Weigel TL, Ann Surg Onc 2000 73 AF bronchoscopies performed in 51 patients; median 13 months post-resection; intraepithelial neoplasia in 3/51 detected by AF, and 1 invasive carcinoma detected by WL and AF. -Weigel TL, Ann Thor Surg 2001 Post–resection Surveillance: metachronous primary lung cancer 29/46 patients with completely resected lung (18) or H&N (11) primary carcinoma underwent AF bronchoscopy q 4-6 months post operatively; 11/46 (24%) developed squamous cell carcinoma; multicentric disease was common; the number of suspicious lesions at baseline (e.g. >3) was predictive of SCC. Patients without suspicious lesions on baseline AF bronchoscopy (19) did not acquire SCC at up to 80 months of follow up. --Pasic A, Lung Cancer 2003 Secondary Chemoprevention Author Heimburger Lee Kurie Agent Folate/b12 Isotretinoin 4hp retinamide N 33 152 139 Endpoint Metaplasia Meta/Dysplasia Index Metaplasia Detection Sputum WL bronch WL bronch result negative negative negative Lam Arnold Van Poppel McLarty Lam Kohlhafl ADT Etretinate B-carotene B-carotene Retinol Inh. Retinol 112 150 150 755 81 11 Dysplasia Dysplasia Metaplasia Dysplasia Meta/Dysplasia Index Meta/Dys AF bronch Sputum Sputum Sputum AF bronch AF bronch positive negative negative negative negative positive Bronchoscopy and early detection Central Lung Cancer in perspective Squamous cell is the 2nd most common form of lung cancer in North America and Japan; most common form of lung cancer in Europe It is estimated that 173,770 new cases of lung cancer will be identified in 2004; this suggests that 43,000 cases of squamous cell lung cancer will be diagnosed. What is early Central lung cancer? T0 (or tis) = Carcinoma-in-situ Microinvasive squamous cell lung cancer is: T1 Radiographically Occult lung cancer is (usually): T1 A Tumor < 3cm, and < lobar bronchus is: T1 Of 1561 lung cancer cases seen at RPCI since 1998, 25% were squamous cell carcinoma, 0.4% were carcinoma in situ and 0.4 were microinvasive carcinoma Stage 0 Stage TNM System IA M0 T1 N0 IB M0 IIA M0 IIB M0 M0 IIIA M0 M0 IIIB M0 M0 Figure 1. Kaplan-Meier survival estimate for the whole cohort (1,296 patients) by stage of disease (1986 classification 7 ). T2 T1 T2 T3 T3 T1-3 T4 T1-4 T1-4 N0 N1 N1 N0 N1 N2 N0-2 N3 N1-3 IV M1 Buccheri Chest 2000 Detection of early lung cancer in high risk patients? “Lung cancer screening Is not recommended” ---2003 ACCP statement “In high-risk patients, physicians may decide to have these screening tests done on an individual basis” --- 2003 ACS statement For disease screening to be effective, three criteria must be met: 1. the disease must have a meaningful preclinical phase (e.g. CIS) 2. the preclinical phase must be detectable (e.g. AF bronchoscopy) 3. the preclinical disease must be treatable with effective therapy (e.g. PDT) The case for preclinical lung cancer Patients with positive sputum cytology and negative radiographs had an 85-90% 5 year survival in the NCI trials of the 70’s This finding has been replicated in subsequent trials, with overall survival rates from 55% - 85% in sputum-detected cases (Bechtel 1994, Saito 1992) The natural history of untreated squamous cell carcinoma in situ is usually progression to invasive carcinoma. (Sutedja) Two kinds of Early Detection Surveillance: Close observation of a person or group, especially one under suspicion Screening: The examination of a group of usually asymptomatic individuals to detect those with a high probability of having or developing a given disease Stedman’s Medical Dictionary 2002 Lung Cancer risk factors Active Cigarette (>20PY) Passive Cigarette (>40-80PY) Asbestos Exposure COPD (FEV1<70%) Smoking Smoking Relative Risk 10.0 1.2 Population Frequency 30% 90% 15.1 7.0 ? 3-13% Diet (Fruits and Vegetables >5 servings/day) Selenium (>0.63 µg/g) Family History (Parent/Child/Sib) 0.5 33% 0.5 20% 2.4 4-10% Primary AF bronchoscopy surveillance 241 high risk patients with occupational exposure to carcinogens including asbestos (146), prior Lung cancer (25) and prior H&N cancer (15) underwent AF bronchoscopy; 21 patients (9%) had squamous dysplasia/CIS; There was correlation with active smoking, duration of asbestos exposure, and concomitant lung cancer. --Paris C, Eur Resp J 2003 244 high risk patients: 1) symptomatic smokers (136), 2) prior Lung cancer (79) or 3) prior H&N cancer (29); 42 cases of dysplasia/cis (17%) were identified, and 39 cases of invasive carcinoma. Correlation with prior surgery for Sq. cell, and pack-year was observed. High grade lesions were most frequently found in patients with prior resected lung cancer --Morot-Sibolot D, Chest 2002 Squamous cell lung cancer and CT imaging Mayo CT trial: 1520 participants lung underwent CT screening: cancer was found in 45, squamous cell in 13 (28%), an additional two cases of cis were identified with sputum cytology. Crestanello J Cardiovasc Thorac Surg 2004 ELCAP trial: 1000 high risk individuals underwent CT screening; 34 lung cancers were identified with initial and repeat screening: 4 were squamous cell (11%). No cases of cis were identified. Henschke C Cancer 2001 Retrospectively, CT of microinvasive squamous cell carcinoma detected by bronchoscopy can distinguish between bronchial wall thickening, endobronchial nodules, and cartilage invasion, and mucosal thickening. Han NJ 2002, Saida Y 1996 Bimodality Surveillance: Rationale Early central lung cancers (squamous cell) are detected with bronchoscopy but may not be seen on spiral CT. Squamous cell lung cancer accounts for a significant fraction of lung cancer. Upper endoscopy and colonoscopy are routinely used for primary screening. Sensitivity of sputum cytology is disappointing Bimodality Lung Cancer Surveillance trial: Eligibility Cancer NED > 2 years Asbestos-related disease Smoking >20 pack years Emphysema (FEV-1 <70%) Bimodality Lung Cancer Surveillance trial : Design All patients undergo low-dose (LD) spiral CT of the chest without contrast, chest x-ray, sputum collection, and AF bronchoscopy. The endpoint of the trial is cancer detection: cases detected by AF bronchoscopy and sputum will be compared with cases detected by spiral CT and chest radiograph for concordance. Bimodality Surveillance: Recruitment strategies Asbestos attorney outreach: law firms, asbestos clinic and local unions. Physician outreach: medical grand rounds and medical society presentations, and color brochure stands for local physician offices. Direct community outreach: through support groups (e.g. New Voice club, Easy Breathers, ALCASE) and local media Bimodality Surveillance: Accrual as of June 2004 Asbestos Clinic (ELCAP) CT Screening Community MD RPCI Clinics Media Other 38 (24%) 11 (7%) 16 (10%) 45 (28%) 44 (27%) 7 (4%) Bimodality Lung Cancer Surveillance trial : Preliminary findings 161 patients have completed LD spiral CT, chest radiograph, sputum cytology, and AF bronchoscopy without complications. 9 (5.5%) lung cancers have been identified: 2 carcinoma in situ, 5 adenocarcinoma (T1), 1 small cell carcinoma, and 1 occult bronchial carcinoid. 2 patients with laryngeal carcinoma in situ were identified. Bimodality Surveillance results: Demographics 120 100 80 60 40 20 0 51 (32%) were current smokers, 95 (59%) were former smokers, Risk and 1 never smoker. The Factors n=161 median exposure density was 48 pack years. There were 118 (73%) males, and 43 (27%) females. The majority had at least one pulmonary symptom, including 94 (58%) with chronic cough, 111 (70%) with dyspnea, 7 asbestos copd cancer (4%) with trace hemoptysis, Condition Prevalence and 9 (6%) with pleuritic pain. Bimodality Surveillance : Results: Histology of AF bronchoscopy biopsies Findings Normal Inflammation Metaplasia Dysplasia, Mild to Severe Carcinoma In-Situ Carcinomas N 26 (14.4%) 16 (8.9%) 82 (45.6%) 19 (10.6%) 2 (1.1%) 3 (1.7%) Bimodality Screening: Surrogate Endpoint Comparison Meta/dysplasia or SPN > 5mm * * * Therapeutics for high risk patients Clinical Trials: Chemoprevention Selenium: phase III primary intergroup trial Gefitinib: phase III adjuvant trial (BR19) Calcitriol: secondary chemoprevention RPCI initiative ADT: secondary chemoprevention CALGB consortium HPPH (Photochlor) for PDT: properties and implications Properties Activated by higher wavelength: 665 nm Implications Improved tissue penetration, and possible improved response ? Toxicity Lack of significant skin photosensitivity Improved patient acceptance for palliative care. HPPH PDT in early central lung cancer Phase I trial for for microinvasive carcinoma ranges light doses from 75-150 J/cm, with fixed drug dose of 4 mg/kg. Pilot data: 7 LC patients treated, well-tolerated, no photosensitivity Plans for R21 application Conclusions Central squamous lung cancer has a meaningful preclinical phase. Primary AF bronchoscopy for detection of preclinical central lung cancer is feasible and safe in high risk patients. Early detection of central lung cancer provides the setting for new therapeutic interventions. Early Lung Cancer Detection and Treatment Program Prevention Mary Reid PhD Andrew Hyland PhD Raj Natarajan PhD Michael Cummings PhD Martin Mahoney MD MPH James Marshall PhD Genetics, Cell Biology Heinz Baumann PhD Photodynamic Therapy Thomas Dougherty PhD Barbara Henderson PhD Pathology DongFeng Tan MD Enriquita Nava MD Surgical Oncology Todd Demmy MD Chukmere Nwogu MD Medical Oncology Nithya Ramnath MD James Schwarz MD Donald Trump MD Pulmonary Gregory M. Loewen DO Sandy Jacob RN Radiology Donald Klippenstein MD Zachary Grossman MD Translational Research Candace Johnson PhD