Slide 1: Quantitative Optical Spectroscopy of the Uterine Cervix
Quantitative Optical Spectroscopy of the Uterine Cervix: A cost effective way to detect and manage cervical disease Nahida Chakhtoura, MD, Leo Twiggs, MD, Timothy DeSantis, MD Claudia Werner, MD, William Griffith III, MD, Lisa Flowers, MD Manocher Lashgari, MD, Daron Ferris, MD, Edward Wilkinson, MD
Slide 2: Clinical Rationale: Cervical Cancer Screening
Clinical Rationale Cervical Cancer Screening Current triage methods are not optimal • Misses significant disease • Delays in diagnosis • Excessive false positive rate • Result in unnecessary cost and morbidity LuViva Advanced Cervical Scan Miami UNIVERSITY OF
Slide 3: Clinical Rationale: Need for New Technology
Clinical Rationale Cervical Cancer Screening • Need for new technology • Evaluate the efficacy of quantitative optical spectroscopy • Compare the efficacy of our approach with that of the current standard of care in the US • HPV + Pap • Colposcopy + Biopsy LuViva Advanced Cervical Scan Miami UNIVERS
Slide 4: Objective
Objective Cervical Cancer Screening Precolposcopy triage techniques need high negative predictive values and specificity ØALTS Trial showed that current triage of colposcopy after referral for ASC US/HPV+ and LSIL patients would still miss between 30% to 40% of CIN3 disease ØALTS TrialOnly about
Slide 5: Multimodal Spectroscopy
Multimodal Spectroscopy Light In – Multiple wavelengths used Spectrometer to penetrate different tissue depths Results 1. Fluorescence Spectra Reveal metabolic changes associated with neoplasia 2. Reflectance Spectra – Reveal morphological changes associated with neoplasia LuViva Advanced Cervical
Slide 6: What do we measure?
What do we measure? • Biochemistry: Fluorescence 300500 nm excitation – NADH, FAD, Tryptophan – Collagen, Elastin – Porphyrin • Morphology: Reflectance 350900 nm – Increase in Nuclear/Cytoplasmic ratio – Hyperchromasia – Loss of cellular differentiation – Angiogenesis LuViva Advanced Cervical Scan
Slide 7: Precursors to Invasive Cervical Cancer
Precursors to Invasive Cervical Cancer Spectroscopy light penetrates below surface layer LuViva Advanced Cervical Scan Miami UNIVERSITY OF
Slide 8: Cervical Spectroscopy Device
Cervical Spectroscopy Device Cervical Neoplasia Detection System (CNDS) • Measures fluorescence and reflectance spectra at multiple points on the cervix • Low cost device and single patient use disposable • Built in video colposcope – permits see and treat in the same visit and reimbursable in US us
Slide 9: Benefits of Cervical Spectroscopy
Benefits of Cervical Spectroscopy • Immediate results • Objective, more accurate test • Less discomfort • Saves Time – Exam time: 12 minute test – vs. 1520 minute colposcopy – Less time chasing patients for return visits • Reduced cost to patient and healthcare system • Underserved populations LuV
Slide 10: Multimodal Spectroscopy: Cervical Maps of Patient with Dysplasia
Multimodal Spectroscopy Cervical Maps of Patient with Dysplasia HOLD CONTACT TUBE AGAINST Biopsy sites marked with X’s CERVIX Results LuViva Advanced Cervical Scan Miami UNIVERSITY OF
Slide 11: Spectral Output of Cervical Tissue
Spectral Output of Cervical Tissue Squamous Normal = Blue Transition Zone = Green High Grade Dysplasia = Red LuViva Advanced Cervical Scan Miami UNIVERSITY OF
Slide 12: Cervical Maps of Patient with Metaplasia
Cervical Maps of Patient with Metaplasia Metaplasia Biopsy sites marked with X’s LuViva Advanced Cervical Scan Miami UNIVERSITY OF
Slide 13: Cervical Maps of Patient with Normal Cervix
Cervical Maps of Patient with Normal Cervix LuViva Advanced Cervical Scan Miami UNIVERSITY OF
Slide 14: Cervical Maps of Patient with CIN 2+
Cervical Maps of Patient with CIN 2+ CIN 1 CIN 2+ Biopsy sites marked with X’s LuViva Advanced Cervical Scan Miami UNIVERSITY OF
Slide 15: Cervical Maps of Patient with CIN
Cervical Maps of Patient with CIN 2 LuViva Advanced Cervical Scan Miami UNIVERSITY OF
Slide 16: Cervical Maps of Patient with CIN
Cervical Maps of Patient with CIN 3 LuViva Advanced Cervical Scan Miami UNIVERSITY OF
Slide 17: Cervical Maps of Patient with CIN
Cervical Maps of Patient with CIN 3 LuViva Advanced Cervical Scan Miami UNIVERSITY OF
Slide 18: Methodology: Study Design
Methodology Study Design 1 • Prospective doubleblinded pivotal trial – Clinicians blinded to spectral output – Technical team blinded to clinical results (history, colposcopy, cytology, histology, HPV test) • IRB approval at – University of Texas Southwestern Medical Center, Dallas – University of
Slide 19: LuViva Advanced Cervical Scan
LuViva Advanced Cervical Scan
Slide 20: Methodology: Study Design
Methodology Study Design 2 • All colposcopies performed by one of 2 experienced colposcopists • Pathology QA: agreement by 2 of 3 pathologists (1 site / 2 outside pathologists) LuViva Advanced Cervical Scan Miami UNIVERSITY OF
Slide 21: Study Inclusion Criteria
Study Inclusion Criteria • Age 18 or above • Able to read or understand and give informed consent • Scheduled for colposcopy • Pap test within 120 days • Had a referral Pap test or willing to undergo a Pap test on day of study LuViva Advanced Cervical Scan Miami UNIVERSITY OF
Slide 22: Study Exclusion Criteria
Study Exclusion Criteria • Pregnancy • Menstruating on the day of study • Radiation to genitourinary system within 1 year • Prior hysterectomy • Congenital anatomical cervical variant (e.g., double cervix) LuViva Advanced Cervical Scan Miami UNIVERSITY OF
Slide 23: Study Design Flow Chart
Study Design Flow Chart Subject Had Referral Pap and was Scheduled for Colposcopy ASCUS Pap Dysplasia Pap Other Factors •Repeat ASCUS •ASCH •Previous CIN •HPV Positive •LSIL •Recurrent Changes •W/Risk Factors •HSIL •Other Risk Factors Study Procedure 1) Cervical Spectroscopy 2) Sample taken for P
Slide 24: Clinical Trial Objectives
Clinical Trial Objectives • Evaluate Multimodal Spectroscopy at five U.S. centers with diverse population – 648 subjects enrolled, 574 evaluable with valid cytology and QA pathology – Age Range: 18 – 73 • Additional goals: – Further evaluate patient acceptability for procedure – Estimate spectroscop
Slide 25: Quality Assurance (QA) Histopathology Procedure
Quality Assurance (QA) Histopathology Procedure • Site pathology renders diagnosis which is assigned to one of three categories – Normal – CIN1 – CIN2+ • Site pathology sends original or representative slide to QA 1 – If QA 1 agrees with site, diagnosis confirmed – If QA 1 disagrees with site diagno
Slide 26: Algorithm Performance
Algorithm Performance Sensitivity and Specificity of Spectroscopy by Disease Category for All 572 Evaluable Subjects ALL CASES (N=572) SENSITIVITY SPECIFICITY DISEASE CIN2+ CIN1 No CIN NUMBER TESTED 142 180 250 NUMBER CORRECT 135 135 138 PERCENT CORRECT 95.1 75.0 55.2 95% CONFIDENCE 91.55, 68.67, 49
Slide 27: University of Miami Algorithm Performance
University of Miami Algorithm Performance Sensitivity and Specificity of Spectroscopy by Disease Category for 151 Evaluable Subjects enrolled at the University of Miami Miami CASES (N=151) SENSITIVITY SPECIFICITY DISEASE CIN2+ CIN1 No CIN NUMBER TESTED 48 50 53 NUMBER CORRECT 45 43 34 PERCENT CORREC
Slide 28: Histopathology Agreement Analysis
Histopathology Agreement Analysis Site / QA 1 Site / QA 2 QA 1 / QA 2 NUMBER OF SUBJECTS 424 213 213 AGREE (both positive) 101 59 56 AGREE (both negative) 260 105 106 PERCENT AGREEMENT 85% 77% 76% KAPPA STATISTIC* 0.65 0.52 0.50 *Kappa value of at 0.41 to 0.60 indicates moderate agreement, above 0.6
Slide 29: Algorithm Performance Without Interferences
Algorithm PerformanceWithout 6 Interferences “Clean Cases” ALL CASES (N=510) SENSITIVITY SPECIFICITY DISEASE CIN2+ CIN1 No CIN NUMBER TESTED 133 151 226 NUMBER CORRECT 127 119 128 PERCENT CORRECT 95.5 78.8 56.6 95% CONFIDENCE 91.98, 72.28, 50.14, INTERVAL 99.02 85.32 63.06 These results suggesting
Slide 30: University of Texas Southwest Clinical Trial
University of Texas Southwest Clinical Trial • UTSW one of largest clinics in US – Over 90,000 Paps handled each year • Trial, completed in 2004, nearly identical to current FDA pivotal trial • 113 Subjects scheduled for colposcopy: 18 CIN2+ and 84 subCIN2 cases • Study compared Pap+HPV and Pap+Cer
Slide 31: CNDS Ability to Detect Cases Missed by Pap and Site Histopathology
CNDS Ability to Detect Cases Missed by Pap and Site Histopathology • 19 cases that were missed or misclassified by Pap – All 19 detected by CNDS (100% sensitivity) • 18 cases that were misclassified as low grade or normal by colposcopicallydirected site biopsy – QA histopathology (two independent
Slide 32: Clinical Benefits of Cervical Spectroscopy Compared with Standard of Care
Clinical Benefits of Cervical Spectroscopy Compared with Current Standard of Care Triage Sensitivity Specificity Immediate Time to Lab All Easy to Modality Result Acquire Turn Ages Train and Data around Use HPV/ 65% 26% NO < 1 min 24 NO YES Colposcopy (combined) (combined) YES 15 min weeks YES NO
Slide 33: Conclusions
Conclusions Cervical Spectroscopy • Improves detection of highgrade dysplasia • Eliminates unnecessary colposcopy & biopsy • The test is relatively simple – Less discomfort – Well accepted by subjects • Provides immediate and more accurate results • Reduces cost to patients and healthcare system Lu
Slide 34: Thank You
Thank You The National Cancer Institute The Georgia Research Alliance LuViva Advanced Cervical Scan Miami UNIVERSITY OF
Slide 35: LuViva Advanced Cervical Scan
LuViva Advanced Cervical Scan