Slide 1: Biophotonic Detection of Cervical Dysplasia: The Transition from Clinical Trials to Real World Use
Biophotonic Detection of Cervical Dysplasia: The Transition from Clinical Trials to Real World Use Leo B. Twiggs MD Professor Emeritus University of Miami Miller School of Medicine Miami Florida USA
Slide 2: Acknowledgements and Disclaimer
Acknowledgements and Disclaimer US and Canadian Clinical Trials partially supported by US National Cancer Institute Presenter and Principal Investigators do not have a financial interest in this project
Slide 3: Presentation Outline
Presentation Outline • Brief history of biophotonics (spectroscopy) for cancer detection • Clinical trial history and study results • Current evaluations of commercial systems • Conclusions
Slide 4: Brief History of Biophotonics
Brief History of Biophotonics • 1990’s – Mostly academic research projects – City University of New York, MIT, University of Texas, British Columbia • 2000’s – Commercialization of specific applications for: – Lung cancer – Colorectal cancer – Cervical cancer • Most of these companies did not surviv
Slide 5: Biophotonics and Cervical Dysplasia
Biophotonics and Cervical Dysplasia • Initial application was to assist colposcopists in identifying lesions to biopsy (e.g., Medispectra (defunct) and Dysis) – Mostly due to cost and complexity of these systems • Some companies chose to develop lower cost systems – Polartechnics – Guided Therapeuti
Slide 6: Cancer Markers Identified by Spectroscopy
Cancer Markers Identified by Spectroscopy • Biochemistry: Fluorescence 300-500 nm excitation – NADH, FAD, Tryptophan – Collagen, Elastin – Porphyrin • Morphology: Reflectance 350-900 nm – Increase in Nuclear/Cytoplasmic ratio – Hyperchromasia – Loss of cellular differentiation – Angiogenesis
Slide 7: Clinical Rationale
Clinical Rationale Pre-colposcopy triage techniques need high negative predictive value and specificity • ALTS 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 • ALTS Trial-Only about 5% of ASCUS Pap t
Slide 8: Precursors to Invasive Cervical Cancer
Precursors to Invasive Cervical Cancer Spectroscopy light penetrates below surface layer
Slide 9: Potential Solution: Better Technology
Potential Solution: Better Technology 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
Slide 10: Spectral Output of Cervical Tissue
Spectral Output of Cervical Tissue Squamous Normal (SN) = Blue Squamocolumnar junction (TZ) = Green High Grade Dysplasia (HG) = Red
Slide 11: Clinical Rationale For Better Triage
Clinical Rationale For Better Triage Countries with established screening programs, e.g., US, Canada and Western Europe, have seen dramatic reductions in mortality due to cervical cancer However… • Significant disease is not detected (false negatives) • Many women without disease are referred to exp
Slide 12: US Pivotal Study Group
US Pivotal Study Group • 1607 total enrolled • 195 excluded (mostly training cases or women with discordant or insufficient histopathology) • 1447 analyzed for sensitivity and specificity • 804 subjects with two year follow up • Study published in Gynecologic Oncology, April 2013
Slide 13: Multimodal Spectroscopy as a Triage Test: Results of a 1,607 Subject Pivotal Trial
Multimodal Spectroscopy as a Triage Test For Women at Risk For Cervical Neoplasia: Results of a 1,607 Subject Pivotal Trial Funding in part by The National Cancer Institute The Georgia Research Alliance Leo Twiggs, Nahida Chakhtoura University of Miami Women’s Hospital Center Claudia Werner, William
Slide 14: US Pivotal Study Design
US Pivotal Study Design • Each subject served as own control • Referral Pap/HPV or other risk factor to qualify for study • Day of study, each subject had endocervical samples taken for Pap and HPV, followed by colposcopy and biopsy • Histology QA procedure used to reach diagnosis for each subject •
Slide 15: Study Design Flow Chart
Study Design Flow Chart Subject Had Referral Pap and was Scheduled for Colposcopy Dysplasia Pap •ASC-H •LSIL ASC-US Pap •HSIL Other Factors •Repeat ASC-US •Previous CIN •HPV Positive •Recurrent Changes •W/Risk Factors •Other Risk Factors Study Procedure 1) Cervical Spectroscopy 2) Sample taken for P
Slide 16: US Patient Demographics
US Patient Demographics Total Age Non-Hispanic Hispanic Enrolled Asian American African African Pacific White White Indian American American Islander 16-20 1 2 182 36 6 63 290 21-30 2 13 383 101 6 178 683 31-over 0 5 303 113 2 211 634 TOTAL 1,607
Slide 17: Definitions
Definitions • Final histology – Pathology QA review involved blinded review by two independent expert pathologists – Up to two year histopathology follow-up after study • Standard of Care Includes: Pap cytology, HPV testing and colposcopic impression • Sensitivity - Ability of test to correctly iden
Slide 18: Study Results
Study Results % Sensitivity % Specificity % Specificity Modality CIN2+ (n = 276) CIN1 (n = 570) Normal (601) Standard of Care N/A N/A 76** for referral* (all referred to biopsy) (all referred to biopsy) LuViva® 91 30 39 * Includes Pap cytology, HPV and colposcopy impression ** As determined by up to
Slide 19: Rationale as Rule In Test to Find Cervical Cancer Earlier
Rationale as Rule In Test to Find Cervical Cancer Earlier Modality Sensitivity Specificity Sensitivity P value vs. (95% CI) (95% CI) LuViva 72.2% 50.4% Pap Cytology 0.0016 (65.9,78.5) (46.3,54.6) 21.1% 97.5% Colposcopy* <0.0001 (15.4,26.9) (96.2,98.8) 74.2% Standard of Care** 0% 0.0018 (68.1,80.4) 8
Slide 20: LuViva Triage Test: Reduction of Unnecessary Colposcopy and Biopsy
LuViva Triage Test: Reduction of Unnecessary Colposcopy and Biopsy • Using the results of LuViva • Normals - 222/570 (39%) would not need further evaluation • CIN1 - 182/601 (30%) would not need further evaluation • Significant cost savings • Reduced anxiety and complications from overtreatment
Slide 21: US Study Conclusions
US Study Conclusions LuViva detected 91% of CIN2+ compared with 76% sensitivity for the current standard of care consisting of Pap, HPV and colposcopically directed biopsy • Data support use of LuViva to find cervical dysplasia earlier than standard of care LuViva would have reduced the number of fa
Slide 22: LuViva Advanced Cervical Scan
LuViva® Advanced Cervical Scan
Slide 23: LuViva Advanced Cervical Scan
LuViva® Advanced Cervical Scan • Measures fluorescence and reflectance spectra in one minute • Easy to operate with immediate result • Single patient use disposable • Built in video colposcope • LuViva developed by Guided Therapeutics, Inc. Norcross, Georgia, USA
Slide 24: LuViva Cervical Guide
LuViva® Cervical Guide RFID Chip Calibration cap • Single-use patient interface • Attaches to Handheld Unit • Calibrates spectrograph prior to each test • Maintains optical distance and blocks ambient light • RFID Chip assures patient protection by prohibiting use on next patient
Slide 25: Scan Procedure
Scan Procedure • Prep subject for gynecological exam • Remove excessive blood or mucus, nothing is applied • Activate calibration and internal quality checks (1 minute) • Insert Cervical Guide(CG) until contact is made with cervix and it is in focus with os centered (15-20 seconds) • Initiate scan –
Slide 26: LuViva Triage Results Screen
LuViva Triage Results Screen LOW RESULT MEANS: • 99% Confidence (NPV) patient does not have CIN3 or cancer • 40% without dysplasia or cancer • Patient return to normal screening MODERATE RESULT MEANS: • Moderate Risk of CIN1 or CIN2 • Doctor should consider colposcopy or close follow up based on his
Slide 27: LuViva Triage
LuViva Triage For triage, LuViva is intended for use after abnormal cytology and/or positive HPV findings and/or other risk factors to triage women aged 16+ for additional evaluation prior to colposcopy and biopsy
Slide 28: Results of Commercial Evaluations
Results of Commercial Evaluations Number Study Sensitivity Specificity** Researchers Tested IFCPC* 100% 44% 55 Bentley and Zane London, UK 2014 Nigerian Ministry of 100% 33% 100 Adewole et al Health - 2014 Other International 91% 46% 132 Various Evaluations (n = 3) * International Federation of Cerv
Slide 29: Results of Commercial Evaluations
Results of Commercial Evaluations Conclusion: Results of commercial evaluations are consistent with US pivotal study results • High sensitivity (>90%) • 30% to 50% of unnecessary colposcopies and biopsies avoided • LuViva is accepted by physicians and their patients
Slide 30: Cervical Spectroscopy Conclusions
Cervical Spectroscopy Conclusions • Improves detection of high-grade dysplasia • Eliminates unnecessary colposcopy & biopsy • The test is relatively simple o Less discomfort o Well accepted by patients • Provides immediate and more accurate results • May reduce cost to patients and healthcare system
Slide 31: Thank You
Thank You WJ Health | sater scrico: UNIVERSITY OF MIAMI HEALTH SYSTEM. of MEDICINE
Slide 32: Areas of Focus Learned from Commercial Evaluations
Areas of Focus Learned from Commercial Evaluations • The following rules will help avoid false positive and false negative results • Do make sure the os can be clearly seen and is centered in both the pre- and post-spectroscopy video images • Do make sure the both the pre- and post-spectroscopy imag
Slide 33: Technology Advancement
Technology Advancement • Advances in the electro-optics, illumination sources and sensors • Efficiencies in performance and cost of multimodal hyperspectroscopy (MHS) • Development of clinically relevant and convenient devices for the detection of cervical neoplasia
Slide 34: Pivotal Trial Study Accrual Targets
Pivotal Trial Study Accrual Targets Estimated Number of Number of Total Prevalence of CIN2+ Cases Benign Cases Cases CIN 2+ (%) Required Required 20.0 165 - 213 414 - 1031 1600-1650 • Enrollment from June 2004 to September 2008 at seven diverse clinical sites • Follow up data integration starting Ju
Slide 35: Subject Accountability Tree
Subject Accountability Tree 2079 (Total number of subjects enrolled) – 70 withdrawn 2009 “Spectroscopic Evaluation of Cervical Neoplasia” 2004 - 2008 418 enrolled – 16 withdrawn 1661 enrolled – 54 withdrawn 402 1607 Beta Interim and Threshold (BIT) arm Primary Efficacy and Performance (PEP) arm Alph
Slide 36: Up to Two Year Follow Up Results
Up to Two Year Follow Up Results Clinical Site Enrolled Follow up Data Not Yet Lost to Follow Follow up Data Made Available Up University of Texas Southwest 234 64 125 45 Emory University/Grady Hospital 348 48 81 219 University of Miami 313 0 116 197 University of Connecticut 394 0 164 230 Saint Fra
Slide 37: Clinical Rationale Cervical Cancer Screening
Clinical Rationale Cervical Cancer Screening Current screening and triage methods cause: •Delays in diagnosing significant disease •Excessive false positive rate •Expensive billions of dollars of unnecessary cost
Slide 38: Patient Referral and Histopathology Results
Patient Referral and Histopathology Results Cases with no or indeterminate histopathology excluded (n=74) Reason for Prevalence Prevalence Normal CIN 1 CIN 2+ TOTAL Referral CIN 1 (%) CIN 2+ (%) Negative Pap 23 12 2 37 32.4 5.5 ASC/HPV+** 325 272 71 668 40.7 10.6 LSIL 245 330 134 709 46.5 18.9 HSIL
Slide 39: LuViva Triage
LuViva Triage For triage, LuViva is intended for use after abnormal cytology and/or positive HPV findings and/or other risk factors to triage women aged 16+ for additional evaluation prior to colposcopy and biopsy
Slide 40: Study Clinical Sites
Study Clinical Sites University of Texas Southwest – Dallas, Texas Principal Investigator – Claudia Werner, MD Emory University School of Medicine – Atlanta, Georgia Principal Investigator – Lisa C. Flowers, MD University of Miami – Miami, Florida Principal Investigator – Leo B. Twiggs, MD / Co PI –