Prevention for cervial cancer

Prevention of Cervical cancer
Tevfik Yoldemir MD BSc MA PhD
tevfikyoldemir
profdrdrtevfikyoldemir

Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD, Cunningham FG, Calver LE. Chapter 29. Preinvasive Lesions of the Lower Genital Tract. In: Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM,
Bradshaw KD, Cunningham FG, Calver LE, eds. Williams Gynecology. 2nd ed. New York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=56710348. Accessed November 14, 2013.
Behavioral
interventions
Sexual abstinence
Delaying
coitarche
Limiting number
of sexual partners
HPVVaccines
Prophylactic
vaccines
Therapeutic
vaccines

•Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD, Cunningham FG, Calver LE. Chapter 29. Preinvasive Lesions of the Lower Genital Tract. In: Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM,
•Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines, 2010. MMWR 59(12):1, 2010b.
•Winer RL, Lee SK, Hughes JP, et al: Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 157(3):218, 2003
• Prevention of sexually transmitted infections (STIs) in
general
• Efficacy in preventing HPV transmission less certain
• No coverage of anogenital skin
• Less effective for spread skin-to-skin
• Reduction in HPV infection rates even if not
consistently used

Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD, Cunningham FG, Calver LE. Chapter 29. Preinvasive Lesions of the Lower Genital Tract. In: Hoffman BL, Schorge JO, Schaffer JI,
Halvorson LM, Bradshaw KD, Cunningham FG, Calver LE, eds. Williams Gynecology. 2nd ed. New York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=56710348. Accessed
November 14, 2013.
Protection by local and humoral immunity
against initial infection
Cell-mediated immunity in HPV
persistance and progression or regression
of lesions
Evasion of HPV from immune control by
avariety of mechanisms

Muñoz N, Castellsagué X, de Gonzales AM, Gissman L . HPV in the Etiology of Human Cancer Vaccine; 31 August 2006: 24(3): 1-10.

Chen XS, Garcea RL, Goldberg I, et al. Molecular Cell. 2000;5:557–567.

•Muñoz N, Castellsagué X, de Gonzales AM, Gissman L . HPV in the Etiology of Human Cancer Vaccine; 31 August 2006: 24(3): 1-10.
E6
P53
Proteolysis
Loss of
control of the
cell cycle
Regression of
keratinocyte
differantiation
Genomic
instability,Onkogenic
mutations
Loss of control of the cell
division
Viral
Proteins
CANCER
E7
PRB
E2
Transcription
FactorExpression of DNA
replication proteins

Moscicki AB, Schiffman M, Kjaer S, Villa LL. Updating the Natural History of HPV and Anogenital Cancer. Vaccine 31 August 2006; 24 (3): 42-51.

Lowy ve Schiller. J. Clin. Invest. 2006
Cytology
Histology
Very mild/
mild Dysplasia
Intermediate
Dysplasia
Severe
Dysplasia
In situ
Carcinoma
Invazive
Carcinoma
Normal

Cervical cancer: 0.493 million in 20021
High-grade precancerous lesions:
10 million2
Low-grade cervical lesions:
30 million2
Genital warts: 30 million3
HPV infection without
detectable abnormalities:
300 million2
• Parkin DM, Bray F, Ferlay J, Pisani P. CA Cancer J Clin. 2005;55:74–108. 2. World Health Organization. Geneva, Switzerland: World Health Organization; 1999:1–22. 3. World Health Organization. WHO
Office of Information. WHO Features. 1990;152:1–6.

•Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD, Cunningham FG, Calver LE. Chapter 29. Preinvasive Lesions of the Lower Genital Tract. In: Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw
KD, Cunningham FG, Calver LE, eds. Williams Gynecology. 2nd ed. New York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=56710348. Accessed November 14, 2013.
•Kanodia S, Fahey LM, Kast WM: Mechanisms used by human papillomaviruses to escape the host immune response. Curr Cancer Drug Targets 7:79, 2007.
Limitation of the infection to the epithelium
Absence of a viremic phase
Low-level expression of early genes
The nonlytic, non inflammatory nature of infection
Delayed production of highly immunogenic capsid
proteins

Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003; 157(3): 218-26.

•Christensen ND, Cladel NM, Reed CA, et al: Hybrid papillomavirus L1 molecules assemble into virus-like particles that reconstitute conformational epitopes and induce neutralizing antibodies to distinct HPV
types. Virology 291(2):324, 2001
Production of humoral antibodies neutralizing
HPV before the infection of the host cells
No prevention of transient HPV positivity or
resolution of preexisting infection
Prevention of establishment of new and
persistent infection and subsequent neoplasia

•Stanley M, Lowy DR, Frazer I: Chapter 12: Prophylactic HPV vaccines: underlying mechanisms. Vaccine 24S3:S3/106, 2006.
•Stanley M: Immune responses to human papillomavirus. Vaccine 24S1:S1/16, 2006.
•Villa LL, Ault KA, Giuliano AR, et al: Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine 24:5571, 2006.
Two FDA approved
vaccines for the
prevention of HPV
infection and cervical
neoplasia
Synthetic production
of the L1 capsid
proteins of each HPV
using recombinant
technologies
Highly immunogenic
but not infectious
resultant virus-like
particles lacking viral
DNA
Stronger immune
response by both
vaccines than
response to naturally
occuring infections

•Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD, Cunningham FG, Calver LE. Chapter 29. Preinvasive Lesions of the Lower Genital Tract. In: Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD,
Cunningham FG, Calver LE, eds. Williams Gynecology. 2nd ed. New York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=56710348. Accessed November 14, 2013.
•Harper DM, Franco EL, Wheeler CM, et al: Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet
367(9518):1247, 2006.
•Mao C, Koutsky LA, Ault KA, et al: Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol 107(1):18, 2006.
Gardasil (MSD)
Quadrivalent vaccine
Against HPV types 6,
11, 16, 18
Administration by IM
route
All previously
unvaccinate females
9-26 years
Vaccination schedule;
0,2,6 months
Cervarix (GSD)
Bivalent vaccine
Against HPV types 16,
18
Administration by IM
route
All previously
unvaccinate females
9-26 years
Vaccination schedule;
0,1,6 months

•American College of Obstetricians and Gynecologists: Human papillomavirus vaccination. Committee Opinion No. 467, September 2010.
•Centers for Disease Control and Prevention: FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee
on Immunization Practices (ACIP). MMWR 59(20):626, 2010.
• Administration prior to initiation of sexual activity with
the greatest potential benefit
• No contraindication of a history of previous sexual
intercourse or HPV-related disease
• No recommendation of HPV testing prior to vaccination
• Routine administration to girls aged 11-12 years ( as
early as age 9 years)
• Also recommended to girls aged 13-26 years before
sexual contact

•Centers for Disease Control and Prevention: FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee
on Immunization Practices (ACIP). MMWR 59(20):626, 2010.

• No
contraindication
Lactating
women
• Contraindication
during pregnancy
(Category B)
Pregnancy
• No
contraindication
but the titers
lower than
normal women
Immuno-
compromised
women

•Future II Study Group: Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 356(19):1915, 2007.
•Paavonen J, Naud P, Salmerón J, et al: Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a
double-blind, randomized study in young women. Lancet 374:301, 2009.
Prevention from cervical cancer~ 70%
No protection against infection caused by
other oncogenic HPV types 30%
Efficacy of the both vaccines in the prevention
of incident infection and high-grade cervical
neoplasia from types HPV 16 and 18 100%
Necessary for the continuation of cervical
cancer screening

The range of HPV
infections
• Clinical lesions
prevented
Cross-protection of
HPV types
• Not covered by the
vaccine
The strength and
duration of the
provoked response
•Bornstein J: The HPV vaccines—which to prefer? Obstet Gynecol Surv 64(5):345, 2009.

•Centers for Disease Control and Prevention: FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory
Committee on Immunization Practices (ACIP). MMWR 59(20):626, 2010.
Additional protection
of Gardasil against
HPVs 6 and 11
Protection of Gardasil
against significant
portion of low-grade
abnormalities
FDA approval for the
prevention of vaginal,
vulvar and anal
neoplasia
Approval of Gardasil
for the prevention
genital warts in both
males and females
Protection of Gardasil
against nearly all
genital warts

•Brown DR, Kjaer SK, Sigurddson K, et al: The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in
generally HPV-naïve women aged 16-26 years. J Infect Dis 199:926, 2009.
•Jenkins D: A review of cross-protection against oncogenic HPV by an HPV-16/18 ASO4-adjuvanted cervical cancer vaccine: importance of virological and clinical endpoints and implications for mass vaccination in cervical
cancer prevention. Gynecol Oncol 110:518, 2008.
•Huh WK, Kendrick JE, Alvarez RD: New advances in vaccine technology and improved cervical cancer prevention. Obstet Gynecol 109:1187, 2007.
Cross-protection of
Gardasil
against HPVs 31,45 and 52
Cross-reactivity of
Gardasil
for only HPV 31
HPV 45
significant cause of cervical
adenocarcinomas
Cervical
adenocarcinomas
more difficult to detect and
increasing in the incidence
Cross-coverage for HPV
types
additional 10-20 % potential
protection against cervical
cancer

•Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD, Cunningham FG, Calver LE. Chapter 29. Preinvasive Lesions of the Lower Genital Tract. In: Hoffman BL, Schorge JO, Schaffer JI,
Halvorson LM, Bradshaw KD, Cunningham FG, Calver LE, eds. Williams Gynecology. 2nd ed. New York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=56710348. Accessed
November 14, 2013.
•Bornstein J: The HPV vaccines—which to prefer? Obstet Gynecol Surv 64(5):345, 2009.
High
immunogenicity of
the two vaccines
Claim of Cervarix for the
induction of its adjuvant
higher and more
sustained antibody
levels
Excellent immune
memory provided by the
both vaccines
No correlation of antibody
levels with the duration of
clinical protection
Maintenance of of
protection for at least 5
years after vaccination

Evasion of
individual’s immune
responsiveness by
the host-HPV
interaction
Very limited
success rate
of therapeutic
vaccines
•Padilla-Paz LA: Human papillomavirus vaccine: history, immunology, current status, and future prospects. Clin Obstet Gynecol 48:226, 2005.

Holschneider CH. Chapter 48. Premalignant & Malignant Disorders of the Uterine Cervix. In: DeCherney AH, Nathan L, Laufer N, Roman AS, eds. CURRENT Diagnosis & Treatment: Obstetrics & Gynecology. 11th ed. New
York: McGraw-Hill; 2013. http://www.accessmedicine.com/content.aspx?aID=56975185. Accessed November 14, 2013.
Population based screening programs
& treatment of preinvasive and early
invasive disease 75 % reduction
in mortality
Women with cervical cancer who
never had cervical cytology, or
been sporadically screened, or
not been screened within the
previous 5 years > 50%
Follow current cervical screening
guidelines whether vaccinated or
not

Holschneider CH. Chapter 48. Premalignant & Malignant Disorders of the Uterine Cervix. In: DeCherney AH, Nathan L, Laufer N, Roman AS, eds. CURRENT Diagnosis & Treatment: Obstetrics & Gynecology. 11th ed.
New York: McGraw-Hill; 2013. http://www.accessmedicine.com/content.aspx?aID=56975185. Accessed November 14, 2013.
NO SCREENING BEFORE AGE 21 REGARDLESS OFTHE AGE AT
ONSET OF SEXUAL INTERCOURSE
Very rare incidence of cervical cancer in
women < 21 years of age
Significant potential for adverse effects such
as anxiety, cost, morbidity, long-term
consequences
High prevalence of transient HPV infections
after the onset of sexual intercourse
High spontaneous clearence rate of both HPV
infection and dysplasia

Holschneider CH. Chapter 48. Premalignant & Malignant Disorders of the Uterine Cervix. In: DeCherney AH, Nathan L, Laufer N, Roman AS, eds. CURRENT Diagnosis & Treatment: Obstetrics & Gynecology. 11th
ed. New York: McGraw-Hill; 2013. http://www.accessmedicine.com/content.aspx?aID=56975185. Accessed November 14, 2013.
EVERY 3 YEARS FOR WOMEN 21-29 YEARS OF AGE
No HPV testing in this age group
Screening of women ≥ 30 years with cytology
and HPV cotesting at every 5 years
Screening with cytology alone every 3 years

Holschneider CH. Chapter 48. Premalignant & Malignant Disorders of the Uterine Cervix. In: DeCherney AH, Nathan L, Laufer N, Roman AS, eds. CURRENT Diagnosis & Treatment: Obstetrics & Gynecology. 11th
ed. New York: McGraw-Hill; 2013. http://www.accessmedicine.com/content.aspx?aID=56975185. Accessed November 14, 2013.
No resumption of screening
for any reason
Post-treatment surveillance
for CIN 2/3 or worse,
continuation of screening for
at least 20 years even if it
extends over age 65
Discontinuation of screening
in women with hysterectomy
and no prior history of ≥ CIN
2/3
No requirement for evidence
of adequate prior negative
screening
DISCONTINUATION IN WOMEN <
65 YEARS WITH NEGATIVE
CONSECUTIVE SCREENING IN
THE PRECEDING 10 YEARS

HIV positive
women
• Twice in the first
year and then
annually
Immunosupressed
for other reasons
• Annually
In utero DES
exposure
• Annually

HPVTESTS FOR 13 0R 15 HIGH RISK HPVTYPES
Triage test for ASCUS in women ≥ 21 years with
reflex HPV testing
Triage test for LSIL in postmenopausal women
Follow-up test after CIN 1 lesions or negative
colposcopy with cytologic abnormalities
Follow-up after treatment for CIN 2/3
Adjunct to cytology for the primary screening
in women > 30 years

CONDITION RECOMMENDATION
Women ≥ 30 years, with uterus,
no immunosupression
HPV testing & cervical cytology
Both tests negative No repeat in the next 5 years
Both tests positive Triaging to colposcopy
Cytology normal, HPV test positive Repeat cytology and HPV testing in 6-
12 months
Either test abnormal after cotesting Colposcopy
Negative cytology & positive high risk
HPV
Type-specific testing for HPV 16 and 18

• Visual inspection of cervix screening tool in low-
resource settings
• Limited specificity, economical with immediate
results
• Direct visual inspection
• Cervicoscopy with using acetic acid, toluidine blue,
Lugol’s iodine

Prevention for cervial cancer

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