78strategiesn in ksa

Dr.Nisrin Anfinan Consultant Gynecology Oncology King Abdulaziz University Hospital

64,928 Europe

67,078 Africa

49,025 South America

14,845 United States/

Canada

1,077 Australia/

New Zealand

39,648 Southeast

Asia

51,266

Eastern Asia 21,596

Central America

151,297 Southcentral

Asia

Cervical Cancer: Worldwide Prevalence, Incidence, and Mortality Es8mates

Prevalence: 2,274,000 women have cervical cancer1 Incidence: 510,000 new cases each year1

Mortality: Second leading cause of female cancer-‐related deaths (288,000 annually)1

1. World Health Organization. Geneva, Switzerland: World Health Organization; 2003:1–74. 2. Bosch FX, de Sanjosé S.

J Natl Cancer Inst Monogr. 2003;31:3–13.

2000 estimated incidence of invasive cervical cancer !by selected region2:

Saudi Arabia

Cervical Cancer: In Saudi Arabia , Incidence, and Mortality Es8mates

1.9 cases per 100,000 women, accounting for 2.6% of diagnosed cancer cases in women

Every year, 152 women are diagnosed with cervical cancer and 55 die from the disease. new cervical cancer cases and deaths in 2025 are 309

Cancer Incidence Report Saudi Arabia 2007. Available at www.scr.org.sa/reports/SCR2007.pdf Accessed on June 26, 2011

Cervical Cancer: Global Stats Age Standardized Incidence rate/100000 women

Total Cases

Deaths

World 15.3 530232 275008

Saudi Arabia 1.9 152 55

Western Asia 39.18 4.5 2.1

Canada 6.6 1419 544

Globocan 2008 IARC

Cervical Cancer: Saudi Arabia � Very low incidence, 1.9/100,000 women �  ? Any demographic data on “high risk groups”? � Very little known about HPV incidence and transmission

� Data on conventional pap triage is poor � Hospital based � No population based data

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?


�  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.





�  Implementation of any screening program, either primary or secondary, will be difficult in patients with a sexually transmitted infection.


Introduction of quality assurance in screening and colposcopy. Which screening method should be used and how does one triage the patients




�  Vaccination – is it cost-‐effective given the low rates of cervical cancer?






�  Introduction of quality assurance in screening and colposcopy.





�  Introduction of quality assurance in screening and colposcopy. �  Which screening method should be used and how does one triage the patients?

Cervical Cancer Preven8on

Normal Cervix

HPV Infection

Cervical Dysplasia

Cervical Cancer

Primary Prevention: Vaccination

Secondary Prevention: Screening

PRIMERY PREVENSION

Transmission of HPV

� Prevalence in asymptomatic North American women is 2-‐40 % mean 10.41% � Highest in young women

� Sexual contact primary route of transit, important factors �  Earlier age at sexual debut �  Increased number of partners

� More transmissible than any virus but less than bacterial infections

Burchell et al Vaccine 24S3 (2006)

Ac8ve protec8on via vaccina8on is mediated by neutralizing an8bodies at the cervix

HPV

Cervical canal

Neutralizing an8bodies

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).

Product characteristics – prophylactic HPV vaccines

CervarixTM1 Gardasil®2

Antigen VLPs of HPV 16 & 18 VLPs of HPV 16, 18, 6 & 11

Administration

0, 1 & 6 months by intramuscular injection

0, 2 & 6 months by intramuscular injection

1. CervarixTM. European Summary of Product Characteris8cs, 2007; 2. Gardasil®. European Summary of Product Characteris8cs, 2008.

HPV Vaccines: Cross Protec8on

Gardasil(Merck) Quadrivalent

Cervarix (GSK) Bivalent

HPV 45 (related to 18)

V/P 3/2

V/P 1/17 Reduction 94%

HPV 31 (related to 16)



HPV Vaccines: Published data

Gardasil(Merck) Cervarix (GSK)

Dose and administration

0.5 ml IM 0.5 ml IM

Schedule 0,2,6 months 0,1,6 months

Trial size 17622 18644

comparator Placebo with alum Hepatitis A Site Up to 16 countries 14 countries

Age range 16-24; 15-26 15-25

eligibility < 4 sexual partners ( median 2)

< 6 sexual partners

exclusion Hx of abnormal pap smears; pregnancy

Hx of colposcopy, immunocompromised or pregnant

duration 48 month study, 3 year data

Mean 14.8 months

HPV Vaccina8on Efficacy

Harper D; Expert Review Vaccines 2009

Vaccine efficacy

�  Safe effective vaccines � Trials show a reduction in CIN and treatment � Other trials have shown safety and immunogenicity in women 9-‐15 years old

Safety/Adverse Events GARDASIL Quadravalent CERVARIX Bivalent

14 days after injection

Gardasil (14 days after injection) (n=5088)%

Alum Placebo (n=3470)%

Saline Placebo (n=320)%

Cervarix (7 days after injection) (n=22806)%

Alum Placebo (n=4485)%

HAV 720 (n=8750)%

Injection site

Pain 83.9 75.4 48.6 78 52.5 58.9 Swelling 25.4 15.8 7.3 25.8 8.2 10.1 Erythema 24.6 18.4 12.1 29.6 10.6 16.1 Puritis 3.1 2.8 0.6 Not noted Not noted Not noted

Systemic

Fever(>37.8oC)

10.3 8.6 5.1 5.2 4.6

Nausea 4.2 4.1 12.9 11.6 14.0 Diarrhea 1.2 1.5

Dizziness 2.8 2.6

Data taken from product monograph Canada and Australia

When to vaccinate?

�  Should vaccinate before sexual activity � Works best in a school based program

� High rates of vaccination in UK, Canada Australia etc; where school based programs are used

Dura8on and Safety � Both vaccines have demonstrated efficacy beyond 7 years

� Antibody levels vary, but there has been no evidence of breakthrough infections thus far

� All evidence from the millions of doses given confirms that they are very safe vaccines

HPV vaccine in Saudi Arabia Statement

Saudi Gynecology Oncology Group( SGOG) statement �  Health care providers should be encouraged to discuss HPV vaccine for women who wish to be vaccinated and help them in the decision making.

Primary Vaccination with three doses of cancer cervix vaccine should be given for females 15 to 26 years of age to decrease the risk of HPV infection and subsequently prevent cervical cancer. In addition catch-‐up immunization for women above age 26 years could be done .

Women who received the HPV vaccine should continue to follow the existing cervical cancer screening programs.


�  Primary Vaccination with three doses of cancer cervix vaccine should be given for females 15 to 26 years of age to decrease the risk of HPV infection and subsequently prevent cervical cancer. In addition catch-‐up immunization for women above age 26 years could be done .

�  Women who received the HPV vaccine should continue to follow the existing cervical cancer screening programs.


�  Primary Vaccination with three doses of cancer cervix vaccine should be given for females 15 to 26 years of age to decrease the risk of HPV infection and subsequently prevent cervical cancer. In addition catch-‐up immunization for women above age 26 years could be done .

�  Women who received the HPV vaccine should continue to follow the existing cervical cancer screening programs.

Cervical Cancer Preven8on

Normal Cervix

HPV Infection

Cervical Dysplasia

Cervical Cancer

Primary Prevention: Vaccination

Secondary Prevention: Screening

Op8ons in screening � PAP smear � VIA � HPV testing

Collec8on methods

Physician / nurse collection Patient self collection

Cervical cancer decrease with PAP smear

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?

Limita8ons 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













Authora Duration Total no Abnormal PAP

smear ASC-US ASC-H LSIL HSIL AGUS INVASIVE

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

Visual Inspec8on with Ace8c Acid (VIA)

Op8ons in Screening

� VIA: Visual inspection with acetic acid � VILI: Visual inspection with Lugols iodine

�  Both Low tech can be done by nurses � May need to utilize colposcopy to triage post positive test to rule out cancer

Test Quali8es of VIA in Primary Healthcare Sefng (Phase 2)

TEST SENSITIVITY

(%)

SPECIFICITY (%)*

POSITIVE PREDICTIVE VALUE (%)*

NEGATIVE PREDICTIVE VALUE (%)*

VIA (n = 2,130)

77 (70–82)

64 (62–66)

19 96

Pap smear (n = 2,092)

44 (35–51)

91 (37–51)

33 94

95% Confidence Interval University of Zimbabwe/JHPIEGO Cervical Cancer Project 1999.

HPV tes8ng in cervical cancer screening Approaches already implemented or being examined: Ø  Serial: Cytology screening followed by HPV testing to

triage ASC-‐US (USA, Nfld) Ø  Parallel: Cytology and HPV cotesting (approved in USA,

implemented in California(Kaiser),Quebec) Ø  Serial: HPV testing followed by cytologic triage (being

examined in the Finnish trial, BC RCT, a.k.a., HPV FOCAL Study)

HPV Tes8ng ADVANTAGES �  Very sensitive �  Better quality control �  Decreases the number of cytologists needed

�  Increase screening interval which decreases cost and improves convenience

DISADVANTAGES

�  Need a second test due to lower specificity

Role of HPV tes8ng •  Triage equivocal or low grade cytology smears

(ALTS trial)

•  FUP of women with abnormal cytology but normal

colposcopy

•  Predict outcome after treatment of high grade disease

•  Primary Screening

Cuzick J. Vaccine 2008

CCCAST trial

PAP HPV 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 Pap screening followed by HPV (hc 2) vs hc2 testing followed by HPV in women 30-‐69 Ø  9,667 women

HPV testing is significantly more sensitive to detect CIN 2+

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

�  Significant reduction in Ca Cervix in the HPV negative compared to negative Pap and VIA

NEJM Apr2009 360(14)1385-‐94

HPV tes8ng 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

Cost Effec8veness Several studies proved the cost effectiveness of HPV testing as screening test for Cervical cancer

�  In developing countries �  Screening program not well established � Middle income

Br J Cancer.2010 Dec 7;103(12):1773-‐82. Cancer Causes Control.2011 Feb;22(2):261-‐72. Eur J Cancer. 2011 Jul;47(11):1633-‐46

Screening program in Saudi Arabia

Suggested Screening Strategy � Use the high sensitivity of HPV test initially

�  Digene Hybrid capture 2 test is suitable

� Positive HPV test has reflex pap testing �  If both positive colposcopy is performed �  If HPV neg repeat screen in 5 years �  If HPV +ve and pap neg, repeat HPV and pap in 1 year

HR-‐HPV tes8ng 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

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.

Thank you

Health & Medicine

78strategiesn in ksa