The China Studies: A Decade of Science and Service

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The China StudiesA Decade of Science and
Service
Jerome L. Belinson, M.D. Professor of Surgery
Lerner College of Medicine Department of
Obstetrics Gynecology Preventive Oncology
International? Cleveland Clinic
Foundation Cleveland, Ohio, U.S.A.
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The Signing of the Memorandum of Understanding-
1997
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Global Burden of Cervical Cancer in 2002
Cervical cancer is the second most common cancer
of women worldwide
Incident cases

• Developed Countries

83,810

• Developing Countries

409,190

• World

493,000
Deaths
274,000
Prevalent cases
1,400,000
GLOBOCAN 2002 (Parkin DM et al. CA Cancer J Clin
20055574-108)
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ESTIMATED NUMBER OF NEW CERVICAL CANCER CASES PER
YEAR 2000
Worldwide
Developing Countries 379,153
Developed Countries 91,451
IARC, 2001
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PREVENTIVE ONCOLOGY INTERNATIONAL
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Study Sites

• Xiangyuan, 98,99,03,06 Shanxi Province
  (SPOCCS I, II, and III)
• Yangcheng, 98,99,03 Shanxi Province (SPOCCS I
  and II )
• Mixian, ,07 Henan Province (SPOCCS III)
• Yutian, ,07 Xingjiang Province (SPOCCS III)
• Beijing 06 A community hospital (SPOCCS III)
• Shanghai 07 a community hospital (SPOCCS III)
• Shenzhen 07,08 Peking Univ Shenzhen Hosp
  (PUSH-OCT)
• Wengan, 08 Guizhou Province (GUPOCT)
• Sandu, 08 Guizhou Province (GUPOCT)
• Libo, 08 Guizhou Province (GUPOCT)
• Duyun, 08 Guizhou Province (GUPOCT)

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SCREEN THE UNSCREENED rather than OVER-SCREEN
THE OVER-SCREENED
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The Screening Program Must Be Specific To The
Target Population

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Determinants of Screening Algorithms
Sensitivity and specificity of screening tests
Health care infrastructure

• Human resources

Financial resources
Age cancers develop
Prevalence of disease
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Objective

• To develop a screening test that is sensitive
  for
• CIN II, III, or cancer and specific enough for
  CIN
• II, III to allow treatment by destruction of
  the T-
• zone without histologic confirmation.

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SPOCCS STUDY
SPOCCS Protocol
HPV Self-Test
Fluorescent Spectroscopy
ThinPrep Pap
HPV Direct Test
VIA
Colposcopy Biopsy
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I
IV
II
III
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• Prevalence of cervical cancer and feasibility of
  screening in rural China a pilot study for the
  Shanxi Province Cervical Cancer
  Screening Study
• Belinson JL, Qiao YL, Pretorius RG, et al.
• Int J Gyn Oncol 2411-7, 1999

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Shanxi Province Cervical Cancer Screening Study A
CROSS-SECTIONAL COMPARATIVE TRIAL OF MULTIPLE
TECHNIQUES TO DETECT CERVICAL INTRAEPITHELIAL
NEOPLASIA   J.Belinson1, YL.Qiao2, R.Pretorius3,
WH. Zhang2, P. Elson1 , QJ.Pan2, K Keaton1,
L.Li2 , C Biscotti1, SD Rong 2 , A Dawson1,
LY.Wu2, C. Fischer4, AL.Lee2, A.Lorincz5, L Yang
2 , D. Zahniser6 , SD Ren 7  The Departments of
Gynecology, Pathology and Biostatistics from 1The
Cleveland Clinic Foundation Cleveland Ohio and
2The Cancer/Institute Hospital Chinese Academy of
Medical Sciences Beijing China. 3Department of
Gynecologic Oncology and Pelvic Surgery Kaiser
Permanente Fontana California. 4Optical Biopsy
Tech. LLC. Knoxville, Tennessee. 5Digene Corp.,
Silver Spring, Maryland, 6Cytyc Corp.,
Boxborough, Mass. 7Women and Children Clinic,
Xiangyuan County, Shanxi Province, China.  
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• SPOCCS I demonstrated with minimal verification
  bias,
• The sensitivity and specificity of HPV self and
  direct tests, liquid based cytology, VIA, and
  fluorescent spectroscopy.
• In addition
• Colposcopy is not as accurate as we believed.
• All of the women with gtCIN 2 are either
  HR-HPV positive or gtASCUS on cytology.

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SPOCCS STUDY
Liquid Based Cytology HPV
NPV
99.6 224/225
ASCUS / HPV negative

99.3 283/285
gtASCUS / HPV negative
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• Cervical cancer screening by simple visual
  inspection after acetic acid. Obstet Gynecol
  98441-1, 2001.
• Belinson JL, Pretorius, RG, Zhang WH, Wu LY, Qiao
  YL, Elson P.

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VIA Technique

• Place Speculum
• Apply 5 Acetic Acid
• Wait at least 1 Minute
• Record Observations

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• This study reported on VIA in SPOCCS I. The take
  home message was that VIA is not very sensitive
  and that the sensitivity of VIA is a function of
  lesion size.
• However the absence of verification bias made
  this study unique in the VIA literature at that
  time

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Test Qualities of VIA When Performed as Primary
Screening in Low-Resource Settings
Study Country Cases
Detection of HGSIL Cancer
Sensitivity a Specificity a Megevand
et al (1996) South Africa 2,426
65 98 Sankaranarayanan et al (1998)
India 2,935 90 92 Sankaranarayana
n et al (1999) India 1,351
96 68 University of Zimbabwe
2,148 77 64 Zimbabwe/JHPIEGO
(1999) Belinson (2001) China
1,997 71 74 Denny et al (2002 )
South Africa 2,754
70 79 Sankaranarayanan Wesley India
4444 83 87 (2003)
aEstimated from the number provided in the
manuscript and does not reflect adjustment(s) for
verification bias.
Modified from JHPIEGO Corporation
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• Primary Screening with Liquid Based Cytology in a
  High Risk Unscreened Population
• Belinson JL, Pan QJ, Biscotti C, Pretorius RG,
  Elson P, Qiao YL. ACTA Cytologica,May/June 2002
  46(3) 470-474.
• A Thin-Layer Liquid-Based Pap Test for Mass
  Screening in an Area of China with a High
  Incidence of Cervical Carcinoma A
  Cross-Sectional Comparative Study
• Pan QJ, Belinson JL, Li L, Pretorius RG, Qiao
  YL, Zhang WH, Zhang X, Wu LY, Rong SD, Sun YT.
  ACTA Cytol. 2003 4745-50.

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• These papers demonstrated the high sensitivity of
  liquid based cytology and led to the approval of
  its use in China
• The papers in addition exposed one of the
  difficulties with the ThinPrep LBC especially in
  underserved environments. The filter became
  clogged due to blood and mucous which increased
  the rate of unsatisfactory cytology without
  re-processing.

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• The colposcopic impression Is it influenced by
  the colposcopists knowledge of the findings on
  the referral Papanicolaou smear? J Repod
  Medicine 46724-8, 2001.
• Pretorius RG, Belinson JL, Zhang WH, Burchette
  RJ, Elson P, Qiao YL.

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• Sensitivity of Colposcopy for gt CIN II is lower
  for women with LGSIL than HGSIL at Kaiser Fontana
• Hypothesis This was due to the influence of the
  cytology report on the colposcopic.
• SPOCCS I proved hypothesis wrong , the result
  was primarily a function of lesion size.

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Cervico-Vaginal Self-Sampling

• Investigation of Devices
• Investigation of Patient Acceptance
• Barriers
• Cultural Differences
• Investigation of Effectiveness
• Sensitivity
• Specificity

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• Patient Acceptance of Self-Sampling for Human
  Papillomavirus in Rural China
• Tisci SE, Shen YH, Fife D, Goycoolea JM, Ma CP,
  Qiao YL, Belinson JL. J Lower Genital Tract Dis.
  2003 7(2) 107-116.

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• Shanxi Province cervical cancer screening study
  II Self-sampling for high-risk human
  papillomavirus compared to direct sampling for
  human papillomavirus and liquid based cervical
  cytology
• Belinson JL, Qiao YL, Pretorius RG, Zhang WH,
  Rong SD, Huang MN, Zhao FH, Wu LY, Ren SD, Huang
  RG, Washington MF, Pan QJ, Li L, Fife D.. Int J
  Gynecol Cancer 200313(6)819-26

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• The object of SPOCCS II was to determine the
  sensitivity and specificity of a new, improved
  self-test for HPV and to compare this self-test
  to the endocervical test for HC 2
• The tests (self and direct) were on different ROC
  curves.
• One of the first large samples to suggest primary
  HPV screening could replace cytology.

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Sensitivity and Specificity of Screening Tests in
SPOCCS II
1 98.6 vs. 88.3, plt.001, 98.6 vs. 87.5,
plt.001 2 88.3 vs. 87.5, p0.815 3 81.2 vs.
79.7, p.002, 81.2 vs. 77.2, plt.001 4 79.7
vs. 77.2, plt.001
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1 87.7 vs. 85.6, Chi Square 0.74, 0.5
ltplt0.75 2 89.4 vs. 90.9, Chi Square10.0,
plt.005
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Proportion of Subjects with gtCIN II for
Combinations of Direct Self Tests for HPV in
SPOCCS II
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Proportion of Subjects with gtCIN II for
Combinations of Direct Self Tests for HPV in
SPOCCS I
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SPOCCS III Detection of a Broad Spectrum of
HPV Types and Associated Cervical Cancer and
Intraepithelial Neoplasia in Chinese Women
Between the Ages of 16-54 in 5 Sites in China A
Community Based Epidemiologic Study   China
Cancer Research Foundation The Cleveland Clinic
Foundation  
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Objectives of SPOCCS III
DETERMINE THE TYPE-SPECIFIC PREVALENCE OF HPV,
CIN 2 , AND GENITAL WARTS IN CHINESE WOMEN AGE
16-54 YEARS. DETERMINE SPECIFIC TYPE OF HPV
IN THE UPPER AND LOWER VAGINA , ENDOCERVIX, AND
ANUS IN WOMEN WITH AND WITHOUT CIN 2 .
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• The relative importance of colposcopically
  directed biopsy, random cervical biopsy, and
  endocervical curettage in the diagnosis of
  cervical intraepithelial neoplasia II or worse
• Pretorius RG, Zhang WH, Belinson JL, Man-Ni H,
  Ling-Ying W, Zhang X, Qiao YL.. Am J Obstet
  Gynecol 2004191(2)440-4.

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• Sensitivity of Colposcopy for gtCIN II 57
• Yield of Random Biopsy is a strong function of
  the cytology. (17.6 - HGSIL 3.6 - LGSIL and
  1.7 - ASCUS/HPV)
• Random biopsies showing gtCIN II came from
  smaller, lower grade lesions
• 5.5 of gtCIN II diagnosed only on ECC

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• Inflation of sensitivity of cervical cancer
  screening tests secondary to correlated error in
  colposcopy
• Pretorius RG, Kim RJ, Belinson JL, Elson P, and
  Qiao YL.. J Lower Genital Tract Disease
  2006105-9.

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• Inappropriate gold standard bias in cervical
  cancer screening studies
• Pretorius RG, Bao YP, Belinson JL, Burchette RJ,
  Smith JS, Qiao YL.. Int J Cancer
  2007121(10)2218-24.

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SENSITIVITY AND SPECIFICITY OF VISUAL INSPECTION
IN DETECTION OF ?CIN II IN SPOCCS I CALCULATED
WITH THREE DIFFERENT GOLD-STANDARDS
Standard 1
Standard 2 Standard 3 Sensitivity
61/86 51/65
51/58
71 78
88 Specificity 1420/1911
1431/1932
1431/1939
74 74 72
Standard 1 Five biopsies on all subjects,
insufficient specimens considered negative
(Belinson, Gynecol. Oncol, 200183439-44. Standar
d 2 Colposcopy on all patients, ectocervical
biopsy only if colposcopy detects lesions of low,
high, or cancer. No ECC Standard 3 Colposcopy
only if VIA, or self-test for HPV, and biopsy
only if colposcopy (low,high, or cancer). No
ECC (Sankar, Cancer 1998832150-6)

• Franco EL Statistical Issues in Human
  Papillomavirus Testing and Screening. Clinics in
  Laboratory Medicine 200020345-67

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• This paper shows that VIA and colposcopy are
  correlated and that there is inflation of
  sensitivity of VIA when colposcopy is used as the
  gold standard for CIN 2 or worse.
• The critical issue is NOT lesion size but Kappa.
  The two techniques miss the SAME lesions.
• This paper has had a major influence on the
  evaluation of studies using visual diagnostic
  modalities.

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• Distribution of cervical intraepithelial
  neoplasia 2, 3, and cancer on the uterine cervix
• Pretorius RG, Zhang X, Belinson JL, Zhang W, Ren
  S, Bao Y, Qiao YL.. J Lower Genital Tract
  Disease 20061045-50.

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• Shows that CIN 2 or worse is randomly distributed
  on the cervix.
• (prior literature had reported anterior gt
  posterior)
• It also shows that there are more
  colposcopic-detected lesions on the anterior
  cervix than on the posterior cervix.

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• Risk factors for HPV infection and cervical
  cancer among unscreened women in a high-risk
  rural area of China
• Zhao FH, Forman MR, Belinson J, Shen YH, Graubard
  BI, Patel AC, Rong SD, Pretorius RG, Qiao YL.
  Int J Cancer. 2006 Jan 15 118(2) 442-8.

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• SPOCCS I Follow-up Study
• (unpublished)

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• The Result
• Colposcopic Diagnosis Known for gt20,000 Quadrants
• Biopsy Diagnosis Known for gt20,000 Quadrants
• Quadrant Matched Analysis Feasible (minimum 5Bxs
  / Pt.)
• Tissue Samples Analyzed to Understand Diagnostic
  Errors

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I
IV
II
III
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• FALSE NEGATIVE COLPOSCOPY IS ASSOCIATED WITH
  THINNER CERVICAL INTRAEPITHELIAL NEOPLASIA 2 AND
  3
• Bin Yang, MD, Robert G. Pretorius, MD, Jerome L.
  Belinson, Xun Zhang, MD, Raoul Burchette, M.P.H.,
  You-Lin Qiao, MD, PhD.
• In Press Gynecologic Oncology

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AVERAGE EPITHELIAL THICKNESS (MICRONS) BY
COLPOSCOPIC IMPRESSION AND HISTOLOGY
HISTOLOGY COLPO IMP NORMAL COLPO IMP LOW COLPO IMP HIGH COLPO IMP CANCER
NORMAL 3781 3701 4821
CIN 1 3552 3462 4182 310
CIN 2 1853 2583 3343 346
CIN 3 1814 2304 3724 4264

• 1378 and 370 vs. 482, plt.001
  only one slide in this cell
• 2355 and 346 vs. 418, plt.001
• 3185 vs. 258 vs. 334, plt.001
• 4181 vs. 230 vs. 372 vs. 426, plt.001

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SENSITIVITY OF COLPOSCOPY FOR CIN 2 3 AS A
FUNCTION OF EPITHELIAL THICKNESS

• Epithelial Thickness (mµ) Sensitivity of
  Colposcopy
• for CIN 2 3

0-139 140-290 291-441 gt441 TOTAL
31.3 (5/16) 75.8 (50/66) 88.6 (39/44) 94.4
(17/18) 77.1 (111/144)
31.3 vs. 75.8 vs. 88.6 vs. 94.4 plt.001
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Colposcopy Based on SPOCCS Data, Represents A New
Paradigm
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Colposcopy Based on SPOCCS Data

• With the proper biopsy instrument to use, it is
  better to take more biopsies than be selective.
• Random biopsies are the great equalizer, when
  individuals of varying skills are doing
  colposcopy
• Better to take more time taking biopsies then
  trying to decide whether a white lesion is low
  grade or high grade.
• We believe doing the evaluation by quadrant adds
  structure to the examination. Therefore do the
  colposcopy by quadrant.
• Biopsy any areas in each quadrant that are
  abnormal.
• A biopsy must come from the region of the SCJ in
  every quadrant.
• All patients should have an ECC

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PUSH-OCT STUDY OF THE DIAGNOSTIC EFFICACY OF
REAL TIME OPTICAL COHERENCE TOMOGRAPHY (OCT)
IN THE MANAGEMENT OF PRE-INVASIVE AND INVASIVE
NEOPLASIA OF THE UTERINE CERVIX (Adjunct to
Colposcopy) ?
Wulan N, Belinson JL, Belinson,SE, Rong X, Zhang
W,Zhu YS,Wang C, Yang B, Tresser NJ, Mohr M, Wu
RF.
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GUPOCT GUIZHOU PROVINCE STUDY OF THE DIAGNOSTIC
EFFICACY OF REAL TIMEOPTICAL COHERENCE
TOMOGRAPHY (OCT) IN THE MANAGEMENT OF
PRE-INVASIVE AND INVASIVE NEOPLASIA OF THE
UTERINE CERVIX (Adjunct to Unmagnified Visual
Inspection - VIA) ?
Wulan N, Rasool N, Belinson SE, Rong X, Belinson
JL, Zhang W, Yang B, Zhu YS, Wang C, Tresser NJ,
Mohr M, Wu RF.
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Imalux OCT Imaging System
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OCT

• Imaging Modality
• Non-Invasive , Harmless, Infrared Light
• Tissues Illuminated and Backscattered Light
  Collected
• Creates High Resolution Real Time Images In Vivo
• Similar to B-mode Ultrasound with Better
  Resolution in the Superficial Layers
• Provides Structural Information of Internal
  Tissue Microstructure

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Normal
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CIN III
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• CONCLUSIONS
• Over 20,000 women educated about HPV and screened
  in our studies
• Weve contributed to the development of the
  cervical cancer consortium in China
• Liquid based cytology and Hybrid Capture HPV
  testing were approved in China after our clinical
  trials
• Numerous physicians, nurses and other healthcare
  workers have attended our educational sessions
• Many other successful collaborations for cervical
  cancer studies developed after the success of our
  collaboration

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• And ----- on a personal level
• The opportunity to do this research with a truly
  remarkable international research team is indeed
  a gift and a highlight of my life. Young women
  with young families should live normal lives
  because our team detected their cancers and
  high-grade pre-cancers. They have come from
  their remote villages because we were there doing
  this work. We look forward to our work spawning
  innovative screening solutions and other
  preventive strategies in the future.
• JLB,
  5/14/2008