To do or not to do; the choice is yours!

Zainal Abidin Hanafiah 16.2.2011

World Cancer burden for female

EUROPE 59,931

N. AMERICA 14,670
Malaysia : 16.1

C-S. AMERICA 71,862

AFRICA 78,897

ASIA 265,884

Age standardized incidence

< 87.3 < 16.2 < 32.6 < 9.3 < 26.2

Globocan 2002

Year 2006 Estimation

Total newly diagnosed Ca Cervix : ~ 500,000 cases (WHO). 12% of all cancers in women. 80% from Developing countries. Total death : 280,000 (WHO)

1. Jemal A et al. Cancer Statistic,2006.CA Cancer J Clin 2006:56;1006-30.

Most Common Female Cancer in Malaysia : NCR 2005

Cervical Cancer Incidence By Age, Peninsular Malaysia (Per 100,000)

Source: National Cancer Registry (2005)

Risk Factors for Cervical Cancer Persistent high risk HPV infection Little or no history of Pap screening History of cervical dysplasia Smoking Parity Increasing age Immunosuppression Other sexually transmitted infections Failure to use condoms?

Role of HPV in Cervical Cancer

Nearly 100% of cervical cancer is due to HPV Infection Specifically, it is due to persistent high risk HPV infection Infections are sexually acquired in teens, twenties (40% prevalence within 2 yrs of sex) Most HPV infections are transient (<2 yrs) In most cases, the bodys immune system eliminates HPV infection; rarely do symptoms occur

HPV is the necessary cause of cervical cancer

RR/OR

> 500

HPV 18 and cervical adenocarcinoma in the Philippines Oncogenic HPV DNA and cervical cancer in Costa Rica HPV DNA and cervical cancer in Bangkok

100 50 20
1

Hepatitis B virus and liver cancer in Taiwan Hepatitis B virus and liver cancer in Greece Hepatitis C virus and liver cancer in Italy Cigarette smoking and lung cancer BASELINE REFERENCE Smoking cessation before middle age and lung cancer in UK Adult HBV vaccination and liver cancer in Korea Newborn HBV vaccination and liver cancer in Taiwan

10 0.1 0.6 0.1

Cervical Cancer Prevention Strategy

Overview cervical cancer prevention

Avoidance of Human Papillomavirus Infection. How??? a) Abstinence from sexual activity; abstinence
prevents HPV infection.

b) Barrier protection and/or spermicidal gel during sexual intercourse; Total use of barrier
protection decreases cancer incidence, relative risk of 0.4 (95% confidence interval [CI], 0.20.9).

3) Based on fair evidence, vaccination against HPV-16/HPV-18 is effective to avoid HPV infection, and thus cervical cancer; Vaccination against HPV-16 and HPV-18 reduces
incident and persistent infections with efficacy of 91.6% (95% CI, 64.598.0) and 100% (95% CI, 45100), respectively. Efficacy beyond 6 to 8 years is not known.

 Screening via Gynecologic Examinations and Pap smear,

Based on solid evidence, screening via regular gynecologic examinations and cytologic test (Pap smear) with treatment of precancerous abnormalities decreases the incidence and mortality of cervical cancer. Screening is not beneficial in detecting invasive cancer in women younger than 25 years because of the low prevalence of invasive disease, and the harms outweigh the benefits. Screening is not beneficial in women older than 60 years if they have had a history of recent negative tests;
Estimates from population studies suggest that screening may decrease cancer incidence and mortality by more than 80%.

 Cigarette Smoke
Based on solid evidence, cigarette smoking, both active and passive, increases the risk of cervical cancer; Among HPV-infected women, current and
former smokers have approximately two to three times the incidence of high-grade cervical intraepithelial neoplasia or invasive cancer. Passive smoking is also associated with increased risk, but to a lesser extent.

 High parity ; Based on solid evidence, high

parity is associated with increased risk of cervical cancer; Among HPV-infected women,
those who have had seven or more full-term pregnancies have approximately four times the risk of squamous cell cancer compared with nulliparous women, and two to three times the risk of women who have had one or two full-term pregnancies.

 Long-term use of oral contraceptives;

Based on solid evidence, long-term use of oral contraceptives is associated with increased risk of cervical cancer; Among HPV-infected women,
those who used oral contraceptives for 5 to 9 years have approximately three times the incidence of invasive cancer, and those who used them for 10 years or longer have approximately four times the risk.

High Risk HPV

Co-Factors: 1. Smoking 2. Unhealthy sexual practises 3. Immune deficency 4. STDs 5. Environmental factors

Cervical cells

CIN

Invasive Cancer

Genetic

Primary Prevention
Lifestyle modification HPV Vaccine Sexual abstinence

Secondary Prevention
Pap Smear HPV Typing VIA etc
Treatment of CIN

Tertiary Prevention

Secondary prevention
Pap smear

Pre-requisite for successful secondary prevention of Cervical Cancer

Coordinated and well organized program Adequate resources (financial,infrastructure and manpower) Appropriate screening test ( Pap Smear/VIA/HPV testing etc) Good coverage at least 75% of targeted population Appropriate treatment for positive screening test and accurate diagnosis of pre-invasive lesion Appropriate treatment for pre-invasive lesion Screening / Cancer registry and quality-control

Implementation of Secondary Prevention : Most important questions to answer

Who : Who is going to coordinate the program Who is going to participate Who are the target population How : What are the most appropriate screening modalities When : When to start and when to stop

Interval of screening

Cervical Screening Benefits (conventional pap smear)

1. REDUCTION IN INCIDENCE OF CERVICAL CARCINOMA.(WHO.Control of
Cancer of Uterine Cervix.Bulletin World Health Organ.1986;64:607-18)

2.

REDUCTION IN MORTALITY RATE

- Depending of coverage ( Iceland 80% reduction with 100% coverage)

Secondary prevention
Pap smear screening cytology screening Virus causes cellular changes that can be detected early Whole populations need to be screened to be effective Expensive and timeconsuming for healthcare professionals and individuals Abnormal Pap smear results cause significant distress and uncertainty to women1,2

Dr Papanicolaou
1. Bell S et al. Prev Med 1995; 24: 6106; 2. Lerman C et al. Am J Obstet Gynecol 1991; 165: 658 62.

Collection of Pap Smear Slides among all states in 2004

State Perlis Kedah P.Pinang Pahang Terengganu Kelantan Sabah Sarawak Perak Melaka Johor N.Sembilan Selangor Wilayah Jumlah MOH Laboratory 442 13786 15545 18341 15211 19074 16074 24569 14195 5414 32547 12840 19482 12560 208785 Private Laboratory 504 17215 17093 5337 1416 20191 57309 19015 18761 7790 29229 1814 38675 ? 234349 Total Collected 946 31001 32638 23678 16627 39265 73383 43584 32956 13204 51774 14654 58157 1256 No of screener required 6 7 5 3 8 15 9 7 3 10 3 12 0 89

443134

Expected total number of pap smear :1,066,700/year Total slides collected in 2004 : 443,134 Pap smear coverage : At most is 40%

Problem with cytology

Subjective test with variable accuracy because results are dependent on a high quality sample. Reproducibility varies widely in different centers and often very poor in developing country with low sensitivity. Stringent on-going quality control and training staff is essential to maintain standards. Involved many procedures Results is late Time consuming and labour intensive

SECONDARY PREVENTION : OPTIONS OTHER THAN PAP SMEAR

1. Cheaper 2. Less procedures and less labor intensive 3. Faster result 4. More Practical and easy to learn 5. Reproducible 6. At least same efficacy

1. VISUAL INSPECTION

2. NEW HPV TESTING

Visual Inspection by Acetic Acid (VIA)

HPV DNA TESTING

In 2005, the International Agency for Research on Cancer (IARC)/World Health Organization (WHO) recommended that HPVDNA testing can be used for primary screening instead of cytology.1 HPV testing is consistently very sensitive in all studies with the sensitivity for CIN 2+ and CIN3+ both being 96.1%.
Specificity of HR HPV testing ( CIN 2) range from 76.5%-95.5%. Lower specificity in women < 35.

Women with concurrent negative test for pap and HPV test can be reassured that their risk of unidentified CIN 2 is only 0.1%.

HPV DNA Test

Comparative efficacy of VIA, HPV Testing and Conventional Cytology in Cervical Cancer Screening: A Randomized Intervention Trial in Osmanabad
District, Maharashtra State, India
Collaborative project of Nargis Dutt Memorial Cancer Hospital, Barshi, India, Tata Memorial Centre (TMC) Mumbai, India and IARC

1. To evaluate the reduction in cervical cancer incidence and mortality associated with a single round of screening with VIA or cytology or HPV testing, as compared to a control group with no screening. 2. To evaluate the cost-effectiveness of the above three approaches
N : 131,746 ( Cyto :32,050, VIA : 34,074, HPV : 34,126, Control :31,488) Age : 30-59

Primary prevention

HPV vaccination

What is HPV?

Human papillomavirus
HPV is one of several species of the genus Papillomavirus in the Papovaviridae family There are more than 100 types of HPV HPV is a relatively small virus containing two strands of DNA within a spherical shell (capsid)

HPV capsids, approximately 55 nm in diameter

Image source: GSK Biologicals

Oncogenic and low-risk HPV types

At least 30 HPV types target the genital mucosa Some 15 types were classified as oncogenic Globally, types 16 and 18 together account for more than 70% of cervical cancer cases
Other oncogenic types (in descending order of global prevalence) include 45, 31, 33, 52, 58, 35, 59, 56, 51, 39, 68, 73 and 82

Low-risk types cause benign genital warts

90% of genital warts are due to types HPV 6 and 11
Other low-risk types include 42, 43, and 44

oz N et al. N Engl J Med 2003; 348: 51827.

HPV types in cervical cancer

53.5% 70.7% 77.4% 80.3% 82.9% 85.2% 87.4% 88.8%

HPV genotype

Cervical cancer cases attributed to the most frequent HPV genotypes (%)

oz N et al. Int J Cancer 2004; 111: 27885.

How do HPV virus get transmitted?

Acquiring HPV infections

HPV infection is easily transmitted1 Acquisition is by skin-to-skin genital contact penetrative intercourse is not necessary to become infected1 Approximately 50% of sexually active women will be infected with oncogenic HPV at some point, usually soon after sexual debut1 Every sexually active woman is at risk of oncogenic HPV infection, which may cause cervical cancer2,3
1. McIntosh N. Human papillomavirus and cervical cancer. JHPIEGO 2000; 2. Gravitt PE et al. Infect Dis Clin North Am 2005; 19: 43958; 3. Bosch FX et al. J Clin Pathol 2002; 55: 24465.

Acquiring HPV infections

Prevalence is greatest (approximately 20%) in women aged less than 25 years1 The risk starts right from sexual debut2 Condoms reduce the risk but are not fully effective3 It can be transmitted by contact with infected labial, scrotal, or anal tissues. Even dead cells shed during intercourse can contain virus and remain infective for days.
1. Ferlay J et al. Globocan 2002. IARCPress 2004; 2. Burk RD. Hosp Pract (Off Ed) 1999; 34: 103 11.; 3. McIntosh N. Human papillomavirus and cervical cancer. JHPIEGO 2000; 4. Gravitt PE et al. Infect Dis Clin North Am 2005; 19: 43958.

Outcomes of HPV infection

HPV infection Low-risk types 6, 11, others Genital warts Oncogenic types 16, 18, others Cervical infection

Therapy
Regression

CIN I/II Regression

CIN II/III Cervical cancer

Prevalence of high risk HPV among women in Malaysia

3 studies show similar pattern of HPV types in CaCx HPV type16 - 47%, type 18 41% 1 HPV type 16/18 74% 2 HPV 16 (43%), HPV 18 (13%), HPV 33 (12.6% ), HPV 45 (8.5%) 4 HPV types 16/18 comprised at least 50% of HPV detected in high and low risk women3
Cheah PL,HPV related diseases in Malaysians, Malays J Pathol,1994 2 M Yadav, Z.A Nurhayati, A.Padmanathan, Y.Abdul Aziz and A.W.Norhanom, Polymerase Chain Reaction Detection and Restriction Enzyme Typing of Human Papillomavirus in Cervical Carcinoma,1995) 3 YP Tiang, CH Tan, YF Ngeow, S Ramachandran, HK Doshi, Detection of HPV in Papanicolaou smears from women attending STD and District health clinics in Msia, 2005) 4. Prof Sharifah Nor Akmal (HUKM) 140 cases review (unpublished)
1

 HPV has been identified as the necessary cause of cervical cancer Infection with oncogenic HPV can lead to the development of cervical cancer HPV is sexually transmitted via skin-to-skin contact and penetrative sex is not necessary for transmission Screening is important, but it does not detect all precancerous lesions or cancer

HPV vaccine
Its role : prevent cervical cancer by inducing immunity against high risk HPV types Type of vaccine: prophylactic not therapeutic