Primary and Secondary Prevention of Cervical
Cancer in Saudi Arabia
James Bentley
Professor Department of Obstetrics and
G...
Disclosure
•  Dr Bentley is involved in research for GSK and Merck
•  Dr Bentley has been a consultant for and is on speak...
Outline
•  Epidemiology of cervical cancer in Saudi Arabia
–  How does that compare with the world
•  What causes cervical...
Cervical Cancer in Saudi Arabia
•  Muslim country
population > 25
Million
•  2 million non Saudi
women
•  1.9 cases per
10...
Global Impact of Cervical Cancer
•  3rd commonest cancer
worldwide
•  510,000 new cases
per year
•  288,000 women die
each...
Canadian epidemiology of cervical cancer
•  Incidence of cervical cancer peaks among women in their 40s and
among women ≥ ...
Canadian Cervical Cancer
Mortality
Age standardised incidence of invasive cervical cancer and coverage of screening, England,
1971-95.
Quinn M et al. BMJ 199...
HPV
•  >100 types identified2
•  ~30–40 anogenital2,3
–  ~15–20 oncogenic*,2,3 types,
including 16, 18, 31, 33, 35, 39,
45...
Papillomavirus – phylogenetics
HPV18- Related
45, 39, 59, 51, 56
HPV16- Related
31, 33, 35, 52, 58
HPV types in cervical cancer
53.5
2.3
2.2
1.4
1.3
1.2
1.0
0.7
0.6
0.5
0.3
1.2
4.4
2.6
17.2
6.7
2.9
0 10 20 30 40 50 60 70 ...
HPV Transmission and Risk factors
•  Skin to skin sexual contact
–  Genital-genital, manual-genital, oral genital
–  May r...
Natural Course of Genital HPV Infection
First
Lesion
Immune
Response
CMI
Virological
clearance
DNA-ve
80% of cases
Viral
p...
Biology of HPV Infection: High-Grade
Lesions1–3
*CIN = cervical intraepithelial neoplasia; †ICC = invasive cervical cancer...
Normal
CIN 1
CIN 2
CIN 3
Cancer
Risk Factor
Cancer Precursor
Invasive Cancer
Death
Primary Prevention
Sexual Behaviour
HPV Infection and CIN
Incidence Rat...
Current Screening
Pap smear
•  MD/RN to collect
•  Supplies-low cost
•  Cytotech to process and read
•  Pathologist to confirm
•  Oversight ...
Current Recommendations
•  ACOG guidelines recommend
•  age 21
•  Discontinue screening in women at 65 to 70 years of age
...
Authora	
   Duration	
   Total no 	
   Abnormal
PAP 	
  
ASC-US	
   ASC-H	
   LSIL	
   HSIL	
   AGUS	
   CANCER	
  
Al-
Ja...
Limitations of Cytology
•  Sensitivity of pap test to detect CIN3+: 55%
•  Should be done in the context of an organized s...
Limitations of Cytology
•  Sensitivity of pap test to detect CIN3+: 55%
•  Should be done in the context of an organized s...
Limitations of Cytology
•  Sensitivity of pap test to detect CIN3+: 55%
•  Should be done in the context of an organized s...
Cervical Screening: Status and Challenges
•  Well established system of cytology screening with
colposcopy follow-up
•  Su...
Role of HPV testing
•  Triage equivocal or low grade cytology smears
(ALTS trial)
•  Follow-up of women with abnormal cyto...
CCCAST trial
PAPHPV
55.6%94.6%Sensitivity
96.8%94.1%Specificity
Mayrand et al.;
Ø compare the relative efficacy of HPV DN...
HPV Screening for Cervical Cancer in India
Sankaranarayanan,R:
–  RCT ,4 Arms of screening tool in India
–  HPV test vs. P...
HPV testing RCT
Ronco etal
•  Trial in Italy
•  94000 women 25-60 randomized in 2 phases
Ø  Cytology vs. HPV testing and ...
HR-HPV testing and Reflex PAP
HR-HPV DNA in women 30 + years old
Negative
Negative
Negative
Pap test
Positive
Positive
Col...
PRIMARY PREVENTION
Active protection via vaccination is mediated by
neutralizing antibodies at the cervix
HPV	
  
Cervical	
  canal	
  
Neutr...
HPV Vaccination Efficacy
Harper D; Expert Review Vaccines 2009
Effect on Treatments
Harper D; Expert Review Vaccines 2009
Early	
  effect	
  of	
  the	
  HPV	
  vaccinaKon	
  programme	
  on	
  cervical	
  
abnormaliKes	
  in	
  Victoria,	
  Aus...
Early	
  effect	
  of	
  the	
  HPV	
  vaccinaKon	
  programme	
  on	
  cervical	
  
abnormaliKes	
  in	
  Victoria,	
  Aus...
Early	
  effect	
  of	
  the	
  HPV	
  vaccinaKon	
  programme	
  on	
  cervical	
  
abnormaliKes	
  in	
  Victoria,	
  Aus...
HPV Vaccination: Summary
•  Safe, effective vaccines
•  In many societies has been shown to decrease HPV
effects, i.e. war...
Foreseeable Challenges:
•  To understand the prevalence of high-risk (HR)-HPV
infections and the prevalence of abnormal cy...
HR-HPV testing and Reflex PAP
HR-HPV DNA in women 30 + years old
Negative
Negative
Negative
Pap test
Positive
Positive
Col...
Conclusions
•  Introduction of a cervical cancer prevention program in
Saudi Arabia is possible
•  Vaccination has the pro...
Cervcal cancer prevention in sa
Cervcal cancer prevention in sa
Cervcal cancer prevention in sa
Cervcal cancer prevention in sa
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Transcript of "Cervcal cancer prevention in sa"

  1. 1. Primary and Secondary Prevention of Cervical Cancer in Saudi Arabia James Bentley Professor Department of Obstetrics and Gynecology Dalhousie University Halifax Canada
  2. 2. Disclosure •  Dr Bentley is involved in research for GSK and Merck •  Dr Bentley has been a consultant for and is on speakers bureau for both GSK and Merck
  3. 3. Outline •  Epidemiology of cervical cancer in Saudi Arabia –  How does that compare with the world •  What causes cervical cancer? •  Primary and Secondary Prevention •  Secondary Prevention: –  Is “pap” testing the best way to screen? –  What about HPV testing •  Primary Prevention –  Who/ when/ how •  Unanswered questions and solutions
  4. 4. Cervical Cancer in Saudi Arabia •  Muslim country population > 25 Million •  2 million non Saudi women •  1.9 cases per 100,000 women •  Currently no organized screening programs 0 1 2 15-19 20-24 25-29 30-34 35-39 40-44 2010 2005 Millions
  5. 5. Global Impact of Cervical Cancer •  3rd commonest cancer worldwide •  510,000 new cases per year •  288,000 women die each year, 80% of deaths occurring in developing countries
  6. 6. Canadian epidemiology of cervical cancer •  Incidence of cervical cancer peaks among women in their 40s and among women ≥ 70 years of age1 •  The median age at diagnosis of cervical cancer is 47; the median age at diagnosis for all types of cancer is between ages 60 and 692 1. TBD. 2. Cancer Care Ontario (Ontario Cancer Registry, 2005). Incidence and mortality rates of cervical cancer in Canada1 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ 0.0 5.0 10.0 15.0 20.0 Age Rate(per100,000) Incidence rate Mortality rate
  7. 7. Canadian Cervical Cancer Mortality
  8. 8. Age standardised incidence of invasive cervical cancer and coverage of screening, England, 1971-95. Quinn M et al. BMJ 1999;318:904 ©1999 by British Medical Journal Publishing Group
  9. 9. HPV •  >100 types identified2 •  ~30–40 anogenital2,3 –  ~15–20 oncogenic*,2,3 types, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 584 •  HPV 16 (54%) and HPV 18 (13%) accounted for the majority of worldwide cervical cancers.5 –  Nononcogenic** types include: 6, 11, 40, 42, 43, 44, 544 •  HPV 6 and 11 are most often associated with external genital warts.3 1. Howley PM. In: Fields Virology. Philadelphia, Pa: Lippincott-Raven; 1996:2045–2076. 2. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 4. Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518–527. 5. Clifford GM, Smith JS, Aguado T, Franceschi S. Br J Cancer. 2003:89;101–105. Nonenveloped double-stranded DNA virus1 *High risk; **low risk
  10. 10. Papillomavirus – phylogenetics HPV18- Related 45, 39, 59, 51, 56 HPV16- Related 31, 33, 35, 52, 58
  11. 11. HPV types in cervical cancer 53.5 2.3 2.2 1.4 1.3 1.2 1.0 0.7 0.6 0.5 0.3 1.2 4.4 2.6 17.2 6.7 2.9 0 10 20 30 40 50 60 70 80 90 100 X Other 82 73 68 39 51 56 59 35 58 52 33 31 45 18 16 53.5% 70.7% 77.4% 80.3% 82.9% 85.2% 87.4% 88.8% Munoz N et al. Int J Cancer 2004; 111: 278–85. Cervical cancer cases attributed to the most frequent HPV genotypes (%) HPVgenotype
  12. 12. HPV Transmission and Risk factors •  Skin to skin sexual contact –  Genital-genital, manual-genital, oral genital –  May result from non penetrative contact –  Condoms reduce risk but… are not fully protective –  Vertical transmission to newborn is rare (occurs with laryngeal papillomatosis) •  Risk factors –  Young age (peak age group 20–24 years of age) –  Lifetime number of sex partners –  Early age of first sexual intercourse –  Male partner sexual behavior –  Smoking –  Oral contraceptive use –  Uncircumcised male partners
  13. 13. Natural Course of Genital HPV Infection First Lesion Immune Response CMI Virological clearance DNA-ve 80% of cases Viral persistence DNA+ve LSIL/HSIL infection Seroconversion Antibody to L1 DNA-ve Productive viral infection, low grade lesions DNA+ve HrHPVs 12-18months LrHPVs 4-9months Time
  14. 14. Biology of HPV Infection: High-Grade Lesions1–3 *CIN = cervical intraepithelial neoplasia; †ICC = invasive cervical cancer 1. Goodman A, Wilbur DC. N Engl J Med. 2003;349:1555–1564. Adapted with permission from the Massachusetts Medical Society. 2. Doorbar J. J Clin Virol. 2005;32(suppl):S7–S15. 3. Bonnez W. In: Richman DD, Whitley RJ, Hayden FJ, eds. Clinical Virology. 2nd ed. Washington, DC: American Society for Microbiology Press; 2002:557–596. Normal Cervix HPV Infection (CIN* 2) (CIN* 3) Cervical Cancer (ICC†) Infectious Viral Particles Episome Perinuclear Clearing (Koilocytosis) Basal cell layer
  15. 15. Normal CIN 1 CIN 2 CIN 3 Cancer
  16. 16. Risk Factor Cancer Precursor Invasive Cancer Death Primary Prevention Sexual Behaviour HPV Infection and CIN Incidence Rate Mortality Rate Secondary Prevention Tertiary Prevention Franco et al., Vaccine,
  17. 17. Current Screening
  18. 18. Pap smear •  MD/RN to collect •  Supplies-low cost •  Cytotech to process and read •  Pathologist to confirm •  Oversight of the lab – Quality control due to this subjective test •  Weeks to report •  Notify woman •  Counsel woman •  Possible other assessments or treatment •  Expensive Sherris  J.  Intn  Persp  Sex  Reprod  Health  2009;35,3:147  
  19. 19. Current Recommendations •  ACOG guidelines recommend •  age 21 •  Discontinue screening in women at 65 to 70 years of age who have had three or more consecutive normal smears, and no abnormal results in the previous ten years. •  Women aged 30 and older who have had three consecutive normal Pap tests,every 2-3 years and if they also are tested for HPV DNA
  20. 20. Authora   Duration   Total no   Abnormal PAP   ASC-US   ASC-H   LSIL   HSIL   AGUS   CANCER   Al- Jaroudi (8)   2008- 2009   241   7   (2.9%)   3   (1.2%)   1   (0.4%)   2   (0.83%)   NR   1   (0.4%)   NR   Jamal   1984- 2000   22089   368   (1.66%)   88   (0.4%)   NR   81   (0.37%)   72   (0.32%)   36   (0.16%)   26   (0.1%)   Altaf   2001   3088   97   (3.14%)   14   (0.45%)   NR   29   (0.93%)   17   (0.55%)   4   (0.13%)   5   (0.16%)   Abdullah L (1)   1998 – 2005   5590   261   (4.7%)   103   (1.84%)   6   (0.10%)   5   (0.09%)   31   (0.55%)   30   (0.53%)   2   (0.04%)   Altaf   2000- 2004   5132   241   (4.7%)   124   (2.4%)   NR   31   (0.6%)   22   (0.4%)   58   (1.1%)   6   (0.1%)   Summary of reported data on Pap smear abnormalities in Saudi Arabia
  21. 21. Limitations of Cytology •  Sensitivity of pap test to detect CIN3+: 55% •  Should be done in the context of an organized screening program •  Quality assurance of cytology needs to be very good •  system of communication to the women screened so that they may receive sufficient treatment. •  Requires colposcopy and biopsy to confirm dysplasia •  The necessity for multiple visits with cytology based screening results in significant loss to follow-up
  22. 22. Limitations of Cytology •  Sensitivity of pap test to detect CIN3+: 55% •  Should be done in the context of an organized screening program •  Quality assurance of cytology needs to be very good •  system of communication to the women screened so that they may receive sufficient treatment. •  Requires colposcopy and biopsy to confirm dysplasia •  The necessity for multiple visits with cytology based screening results in significant loss to follow-up
  23. 23. Limitations of Cytology •  Sensitivity of pap test to detect CIN3+: 55% •  Should be done in the context of an organized screening program •  Quality assurance of cytology needs to be very good •  system of communication to the women screened so that they may receive sufficient treatment. •  Requires colposcopy and biopsy to confirm dysplasia •  The necessity for multiple visits with cytology based screening results in significant loss to follow-up
  24. 24. Cervical Screening: Status and Challenges •  Well established system of cytology screening with colposcopy follow-up •  Successful in reducing the incidence and mortality from cervical cancer However: •  Realistically in Canada , they have been unable to screen more than 70% of the population well •  How would a cytology based program work in Saudi Arabia? •  What effect will vaccination have?
  25. 25. Role of HPV testing •  Triage equivocal or low grade cytology smears (ALTS trial) •  Follow-up of women with abnormal cytology but normal colposcopy •  Predict outcome after treatment of high grade disease •  Primary Screening Cuzick  J.  Vaccine  2008  
  26. 26. CCCAST trial PAPHPV 55.6%94.6%Sensitivity 96.8%94.1%Specificity Mayrand et al.; Ø compare the relative efficacy of HPV DNA testing and Pap cytology in primary screening for cervical cancer and its high- grade precursors NEJM 2007 Ø women 30-69 Ø 9,667 women HPV testing is significantly more sensitive to detect CIN 2+
  27. 27. HPV Screening for Cervical Cancer in India Sankaranarayanan,R: –  RCT ,4 Arms of screening tool in India –  HPV test vs. Pap test vs. VIA vs. Observation •  Cervical cancer as an endpoint •  32000 women in each arm •  Screen positive received colposcopy and treatment •  Only significant screening method to reduce deaths from cervical cancer was HPV testing •  HPV testing versus standard care had a 50% reduction in stage II or higher cervical cancer (15 versus 33 / 100,000 person-year) and cervical cancer mortality (13 versus 26 per 100,000 person-year). •  Significant reduction in Ca Cervix in the HPV negative compared to negative Pap and VIA  NEJM  Apr2009  360(14)1385-­‐94  
  28. 28. HPV testing RCT Ronco etal •  Trial in Italy •  94000 women 25-60 randomized in 2 phases Ø  Cytology vs. HPV testing and cytology (phase 1) Ø  HPV testing alone (phase 2). –  Same rate of cancer in round one of testing –  Increased cancer in cytology group in round two •  HPV testing was more effective in preventing cancer by detecting high grade lesions earlier. •  However: HPV testing leads to over diagnosis of CIN 2 which is likely to resolve Ronco G; Lancet March 2010
  29. 29. HR-HPV testing and Reflex PAP HR-HPV DNA in women 30 + years old Negative Negative Negative Pap test Positive Positive Colposcopy Positive Repeat HR-DNA testing @ 5 year intervals till age 65 Repeat HR- HPV testing at 12 months
  30. 30. PRIMARY PREVENTION
  31. 31. Active protection via vaccination is mediated by neutralizing antibodies at the cervix HPV   Cervical  canal   Neutralizing  anKbodies   Blood  vessel   Epithelial  tear   Basement  membrane   Cervical   epithelium   1.  Stanley  M.  Vaccine  2006;  24:S16–S22;     2.  Giannini  S,  et  al.  Vaccine  2006;  24:5937–5949;     3.  Nardelli-­‐Haefliger  D,  et  al.  J  Natl  Cancer  Inst  2003;  95:1128–1137;     4.  Poncelet  S,  et  al.  IPC  2007(poster).  
  32. 32. HPV Vaccination Efficacy Harper D; Expert Review Vaccines 2009
  33. 33. Effect on Treatments Harper D; Expert Review Vaccines 2009
  34. 34. Early  effect  of  the  HPV  vaccinaKon  programme  on  cervical   abnormaliKes  in  Victoria,  Australia:  an  ecological  Study   – Australian  Data   – All  women  12-­‐26  were  offered  vaccinaKon  with   Gardasil   – Using  State  based  Pap  Test  Registers   – VaccinaKon  rates:   •   71-­‐79%  in  the  school  based  program   •  74%  I  dose,  69%  2  doses,  56%  3  doses  in  18-­‐28  year   olds   – Screening  starts  at  age  18  or  2  years  aaer  sexual   acKvity   Brotherton  JM  et  al  Lancet  (2011)  Vol  337  June   18    2085-­‐2091  
  35. 35. Early  effect  of  the  HPV  vaccinaKon  programme  on  cervical   abnormaliKes  in  Victoria,  Australia:  Low  Grade  effect  by  age   Brotherton  JM  et  al  Lancet  (2011)  Vol  337  June   18    2085-­‐2091  
  36. 36. Early  effect  of  the  HPV  vaccinaKon  programme  on  cervical   abnormaliKes  in  Victoria,  Australia:  High  Grade  effect  by  stage   Brotherton  JM  et  al  Lancet  (2011)  Vol  337  June   18    2085-­‐2091  
  37. 37. HPV Vaccination: Summary •  Safe, effective vaccines •  In many societies has been shown to decrease HPV effects, i.e. warts and cervical cancer precursors •  Best given in school based programs: –  Ensures maximal coverage with all 3 doses –  Able to give before any sexual activity •  But….. •  Costly •  Does it make economic sense in SA? •  Is it necessary in SA? •  However no significant harm from vaccination
  38. 38. Foreseeable Challenges: •  To understand the prevalence of high-risk (HR)-HPV infections and the prevalence of abnormal cytology findings in general population. •  To understand the sexual practices of the population. –  By region and population group. •  Implementation of any screening program, either primary or secondary, will be difficult in patients with a sexually transmitted infection. •  Vaccination – is it cost-effective given the low rates of cervical cancer? •  Introduction of quality assurance in screening and colposcopy. •  Which screening method should be used and how does one triage the patients?
  39. 39. HR-HPV testing and Reflex PAP HR-HPV DNA in women 30 + years old Negative Negative Negative Pap test Positive Positive Colposcopy Positive Repeat HR-DNA testing @ 5 year intervals till age 65 Repeat HR- HPV testing at 12 months
  40. 40. Conclusions •  Introduction of a cervical cancer prevention program in Saudi Arabia is possible •  Vaccination has the promise to prevent cervical cancer in a large group of women •  Screening should be done using HPV testing as the initial method •  All aspects, i.e. Screening, colposcopy, treatment and invasive cancer surveillance require very careful quality assurance processes.

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