Luciano MarianiLuciano MarianiIstituto Nazionale Tumori Regina Elena, RomaIstituto Nazionale Tumori Regina Elena, Roma
SANIT 2008SANIT 2008
PREVENZIONE SECONDARIA DEI TUMORI DELLA MAMMELLA, PREVENZIONE SECONDARIA DEI TUMORI DELLA MAMMELLA,
CERVICE CERVICE UTERINA E COLONRETTOUTERINA E COLONRETTO
Roma, 24 giugno 2008Roma, 24 giugno 2008
1.1. ““Vaccination and cytologic screening are Vaccination and cytologic screening are complementary strategies complementary strategies ...... we will need we will need bothboth”” (X. Bosch Br J Cancer 2008)(X. Bosch Br J Cancer 2008)
2.2. ““An effective screening program will be a An effective screening program will be a prerequisiteprerequisite for the evaluation of hpv for the evaluation of hpv vaccinesvaccines”” (S.Franceschi, 2000)(S.Franceschi, 2000)
1.1. ““Vaccination and cytologic screening are Vaccination and cytologic screening are complementary strategies complementary strategies ...... we will need we will need bothboth”” (X. Bosch Br J Cancer 2008)(X. Bosch Br J Cancer 2008)
2.2. ““An effective screening program will be a An effective screening program will be a prerequisiteprerequisite for the evaluation of hpv for the evaluation of hpv vaccinesvaccines”” (S.Franceschi, 2000)(S.Franceschi, 2000)
3.3. ““How to most efficiently carry out cervical How to most efficiently carry out cervical cancer screening in the era of vaccination cancer screening in the era of vaccination isisunclearunclear”” (N.Kiviat, 2008)(N.Kiviat, 2008)
4.4. ““The best blend of vaccination and The best blend of vaccination and screening/management tools is screening/management tools is not obviousnot obvious””((M.Schiffman, 2007)M.Schiffman, 2007)
1.1. HPV vaccines are prophylactic and protection is typeHPV vaccines are prophylactic and protection is type--specific:specific:
•• fully effective as prefully effective as pre--exposure prophylaxis;exposure prophylaxis;
•• lower efficacy in women previously exposed to vaccinelower efficacy in women previously exposed to vaccine--targeted targeted HPV types at the time of vaccination;HPV types at the time of vaccination;
•• no benefit in currently infected women no benefit in currently infected women �� no therapeutic no therapeutic effecteffect..
2.2. They do notThey do not include all oncogenic HPV types.include all oncogenic HPV types.
3.3. The goal of HPV vaccination is The goal of HPV vaccination is ““containmentcontainment””, rather than , rather than ““eradicationeradication”” of infection.of infection.
4.4. LongLong--term effectiveness of vaccination to be valueterm effectiveness of vaccination to be value..
5.5. The observable impact on cancer incidence will trend only The observable impact on cancer incidence will trend only after 20 or 30 years after 20 or 30 years (Arbyn J Clin Virol 2007)(Arbyn J Clin Virol 2007)
6.6. The nonThe non--vaccinated population needs to be protected vaccinated population needs to be protected ((““For For most most living women today, screening remains their primary option for living women today, screening remains their primary option for cervical cancer preventioncervical cancer prevention”” X. Bosch, 2008)X. Bosch, 2008)
SHOULD WE CONTINUE SHOULD WE CONTINUE
THE CYTOLOGIC SCREENING PROGRAMS ?THE CYTOLOGIC SCREENING PROGRAMS ?
YES
1.1. Should we separate algorithms for Should we separate algorithms for unvaccinated unvaccinated and and vaccinated vaccinated women?women?
SHOULD WE MODIFYSHOULD WE MODIFY
THE CYTOLOGIC SCREENING PROGRAMS ?THE CYTOLOGIC SCREENING PROGRAMS ?
1.1. Should we separate algorithms for Should we separate algorithms for unvaccinated unvaccinated and and vaccinated vaccinated women?women?
a)a) should we plan a should we plan a traditional cytologic traditional cytologic screening or the screening or the combined HPVcombined HPV--Pap Pap algorithmalgorithm??
b)b) should we reconsider the should we reconsider the age of starting age of starting ??c)c) should we reconsider the should we reconsider the intervalinterval ??
2.2.Have we time enough to plan such modifications ?Have we time enough to plan such modifications ?
Presently no change is recommended,but future change is likely.
SHOULD WE MODIFYSHOULD WE MODIFY
THE CYTOLOGIC SCREENING PROGRAMS ?THE CYTOLOGIC SCREENING PROGRAMS ?
We are moving from a We are moving from a morphologic prevention morphologic prevention
modelmodel based on cytologybased on cytology--colposcopycolposcopy--histology to a histology to a
biomolecular model biomolecular model based on virologic view of HPV based on virologic view of HPV
and its molecular interaction with the human host.and its molecular interaction with the human host.
The paradigm is changingThe paradigm is changing……
We are moving from a We are moving from a morphologic prevention morphologic prevention
modelmodel based on cytologybased on cytology--colposcopycolposcopy--histology to a histology to a
biomolecular model biomolecular model based on virologic view of HPV based on virologic view of HPV
and its molecular interaction with the human host.and its molecular interaction with the human host.
The paradigm is changingThe paradigm is changing……
L. Villa et al. L. Villa et al. Br J Cancer 95:1459Br J Cancer 95:1459--66. 200666. 2006
S. Garland et al. S. Garland et al. N Engl J Med356:1928N Engl J Med356:1928--1943, 20071943, 2007
FUTURE Study Group FUTURE Study Group Lancet 369: 1861Lancet 369: 1861--1868, 20071868, 2007
FUTURE Study Group FUTURE Study Group JID 196:1438JID 196:1438--46, 200746, 2007
GSKCervarix ®
MSD/SPMSDGardasil ®
D. Harper et al. D. Harper et al. Lancet 364:1757Lancet 364:1757--65, 200465, 2004
D. Harper et al. D. Harper et al. Lancet Lancet 367:1247367:1247--55, 200655, 2006
J. Paavonen et al. J. Paavonen et al.
LancetLancet 369:2161369:2161--70, 200770, 2007
A.Hildesheim et al A.Hildesheim et al JAMA JAMA 298(7):743298(7):743--753, 2007753, 2007
QUADRIVALENT Efficacy (95% CI)
CIN2+ or AISCIN2+ or AIS
CIN2 CIN2
CIN3CIN3
AISAIS
99% 99% (93, 100)(93, 100)
100% 100% (93, 100)(93, 100)
98% 98% (89, 100)(89, 100)
100% 100% (31,100)(31,100)
BIVALENT Efficacy (95% CI)
CIN2+CIN2+ 90.4% 90.4% (53 , 99)(53 , 99)
QUADRIVALENT Efficacy (95% CI)
CIN2+ or AISCIN2+ or AIS
CIN2 CIN2
CIN3CIN3
AISAIS
99% 99% (93, 100)(93, 100)
99% 99% (93, 100)(93, 100)
97% 97% (90, 100)(90, 100)
100% 100% (55,100)(55,100)
QUADRIVALENT Efficacy (95% CI)
CIN2+ or AISCIN2+ or AIS
CIN2 CIN2
CIN3CIN3
AISAIS
44% 44% (31, 55)(31, 55)
50% 50% (34, 62)(34, 62)
39% 39% (21, 53)(21, 53)
54% 54% ((--30,86)30,86)
Vaccine-HPV type
1
TIME TO EVENTS: TIME TO EVENTS: CIN 1CIN 1--22--3 for vaccine3 for vaccine--type HPVtype HPV
The protection in The protection in ‘‘‘‘intentintent--toto--treattreat’’’’ vaccinated population vaccinated population
would be expected to increase over time would be expected to increase over time as women in the as women in the
placebo group continue to become infected with vaccineplacebo group continue to become infected with vaccine--
targeted types of HPV and develop CIN2,3 lesions targeted types of HPV and develop CIN2,3 lesions
(Thomas C. Wright Jr., F. Xavier Bosch, 2008)(Thomas C. Wright Jr., F. Xavier Bosch, 2008)
1
QUADRIVALENT Efficacy (95% CI)
CIN2+ or AISCIN2+ or AIS
CIN2 CIN2
CIN3CIN3
AISAIS
99% 99% (93, 100)(93, 100)
100% 100% (93, 100)(93, 100)
98% 98% (89, 100)(89, 100)
100% 100% (31,100)(31,100)
BIVALENT Efficacy (95% CI)
CIN2+CIN2+ 90.4% 90.4% (53 , 99)(53 , 99)
QUADRIVALENT Efficacy (95% CI)
CIN2+ or AISCIN2+ or AIS
CIN2 CIN2
CIN3CIN3
AISAIS
99% 99% (93, 100)(93, 100)
99% 99% (93, 100)(93, 100)
97% 97% (90, 100)(90, 100)
100% 100% (55,100)(55,100)
QUADRIVALENT Efficacy (95% CI)
CIN2+ or AISCIN2+ or AIS
CIN2 CIN2
CIN3CIN3
AISAIS
17% 17% (1, 31)(1, 31)
22% 22% (3, 38)(3, 38)
21% 21% (<0,38)(<0,38)
37% 37% (<0,84)(<0,84)
Any-HPV type
1
1
TIME TO EVENTS: TIME TO EVENTS: CIN 1CIN 1--22--3 for any type HPV3 for any type HPV
““The current vaccines include The current vaccines include only two of the 15 oncogenic only two of the 15 oncogenic
genital HPV typesgenital HPV types. Therefore screening will have to . Therefore screening will have to
continuecontinue”” (Margaret Stanley, 2008)(Margaret Stanley, 2008)
(AIFA, Agenzia Italiana del Farmaco, 2007)(AIFA, Agenzia Italiana del Farmaco, 2007)
2
LONGLONG--TERM SAFETY ?TERM SAFETY ?Time is needed to answer this issue.Time is needed to answer this issue.
3
SEROCONVERSIONSEROCONVERSIONIMMUNOGENICITY IMMUNOGENICITY (GMT neutralizing IgG)(GMT neutralizing IgG)
ANAMNESTIC IMMUNEANAMNESTIC IMMUNE--RESPONSE RESPONSE MEMORYMEMORY
(Sven(Sven--Eric Olsson, Eric Olsson,
Vaccine 2007)Vaccine 2007)
immunity following vaccination exceeds 5 years and appears to be sustained.
3
SEROCONVERSIONSEROCONVERSIONIMMUNOGENICITY IMMUNOGENICITY (GMT neutralizing IgG)(GMT neutralizing IgG)
ANAMNESTIC IMMUNEANAMNESTIC IMMUNE--RESPONSE RESPONSE MEMORYMEMORY
(Sven(Sven--Eric Olsson, Eric Olsson,
Vaccine 2007)Vaccine 2007)
It is possible that re-infection will provide a means of naturally sustaining immunity in the absence of vaccineboosting.
3
4•• At licensing, vaccines are typically used At licensing, vaccines are typically used
broadly without full knowledge of their broadly without full knowledge of their
duration of protection.duration of protection.
•• CLINICAL TRIALS:CLINICAL TRIALS: protection up to 5 years.protection up to 5 years.
•• Need for further boost?Need for further boost?
•• Sourveillance Sourveillance �� screening programscreening program
•• Uselessness of specific IgG antibodiesUselessness of specific IgG antibodies
LONGLONG--TERM PROTECTION?TERM PROTECTION?Time is needed to answer this issue.Time is needed to answer this issue.
•• AntiAnti--HBs levels disappear in 10HBs levels disappear in 10--50% of vaccinees after 450% of vaccinees after 4--5 years 5 years (Bauer T and Jilg W. Vaccine. 2006;24:572(Bauer T and Jilg W. Vaccine. 2006;24:572--577)577)
•• Protection against Hepatitis B infection/disease remains Protection against Hepatitis B infection/disease remains high.high.
•• No booster has been recommended No booster has been recommended (Mast E, 2004)(Mast E, 2004)
66 2424 3636 4848 66
001212
Months After First Vaccine DoseMonths After First Vaccine Dose
4
5•• Already to be valueAlready to be value�������� postpost--marketing marketing
studiesstudies
•• Reported positive, but transitory crossReported positive, but transitory cross--
immune reaction (antibody response) to immune reaction (antibody response) to
bivalent vaccine against HPVbivalent vaccine against HPV--45 and HPV45 and HPV--31. 31.
(Paavonen J, (Paavonen J, LancetLancet 369:2161369:2161--70, 2007)70, 2007)
•• Reported partial clinical crossReported partial clinical cross--protection protection
(CIN2(CIN2--3 or AIS) against HPV3 or AIS) against HPV--45 and HPV45 and HPV--31 31
(Int.Papillomavirus Conference, Bejing 2007)(Int.Papillomavirus Conference, Bejing 2007)
CROSSCROSS--PROTECTION ?PROTECTION ?Time is needed to answer this issue.Time is needed to answer this issue.
?
?
5.5. NATURAL HISTORY OF CERVICAL LESIONS NATURAL HISTORY OF CERVICAL LESIONS IN IN
VACCINATED WOMEN VACCINATED WOMEN :? ?:? ?
6.6. IMPACT OF OPPORTUNISTIC VACCINATION: IMPACT OF OPPORTUNISTIC VACCINATION: ? ?? ?
VARIABLES INVOLVEDVARIABLES INVOLVED
1.1. VACCINESVACCINES: : efficacy, duration of protection, crossefficacy, duration of protection, cross--
protection, typeprotection, type--replacement.replacement.
2.2. LOCAL VARIABLESLOCAL VARIABLES: : HPVHPV--prevalence, ageprevalence, age--incidence, sexual incidence, sexual
behaviour, acceptability, awareness of HPV/cervical behaviour, acceptability, awareness of HPV/cervical
cancer.cancer.
3.3. ORGANIZED PROGRAMORGANIZED PROGRAM: : cohort selection and catchcohort selection and catch--up, up,
achievable coverage achievable coverage and adhesion, continuity of funding and adhesion, continuity of funding
over timeover time
4.4. MONITORING SYSTEMMONITORING SYSTEM: : llinkage with screening inkage with screening programs programs
and cancer registries. and cancer registries.
BENEFITS FOR COMMUNITY ?BENEFITS FOR COMMUNITY ?Time is needed to answer this issue.Time is needed to answer this issue.
The power of screening tools The power of screening tools
(cytology, HPV(cytology, HPV--test, colposcopy) test, colposcopy)
is largely related to detection of HPVis largely related to detection of HPV--16 and 1816 and 18
AAssuming that HPV vaccination: ssuming that HPV vaccination: ••will became an will became an accepted primary prevention accepted primary prevention approach,approach,••will display a high clinical efficacy against HPVwill display a high clinical efficacy against HPV--16 16 and HPVand HPV--18,18,……how will change how will change the performance of screening the performance of screening toolstoolsin a condition of in a condition of lower HPV prevalencelower HPV prevalence??
REDUCTION OF HPV PREVALENCE BY 40REDUCTION OF HPV PREVALENCE BY 40--60% 60% ((Clifford GM , Cancer Epidemiol Biomarkers Prev 2005)Clifford GM , Cancer Epidemiol Biomarkers Prev 2005)
REDUCTION OF HPV PREVALENCE BY 40REDUCTION OF HPV PREVALENCE BY 40--60% 60% ((Clifford GM , Cancer Epidemiol Biomarkers Prev 2005)Clifford GM , Cancer Epidemiol Biomarkers Prev 2005)
��������Reduction of PPV of cervical screening Reduction of PPV of cervical screening
Eduardo L. Franco, Jack Cuzick, 2008Eduardo L. Franco, Jack Cuzick, 2008
decreased sensitivity (40%) and decreased sensitivity (40%) and
specificity (90%) expected in conditions specificity (90%) expected in conditions
of decreased lesion prevalence following of decreased lesion prevalence following
vaccination.vaccination.
screening performance in high lesion
prevalence or in artificial situation of
cytologic triage of HPV-positive women.
(Sensitivity 70%; Specificity 98%)
Cytologic PPV decreases with reductions in prevalence: Cytologic PPV decreases with reductions in prevalence:
��increasingly falseincreasingly false--positive diagnosis, positive diagnosis,
��unnecessary worry and medical interventions, unnecessary worry and medical interventions,
��higher higher costs.costs.
FURTHER DEGRADATION OF THE CYTOLOGIC PPVFURTHER DEGRADATION OF THE CYTOLOGIC PPV
1.1.change in the change in the signalsignal ((squamous abnormalities) squamous abnormalities) --toto--
noisenoise ((inflammatory changesinflammatory changes) ) ratioratio in the pleomorphic in the pleomorphic cellular abnormalities that cytotechnicians cellular abnormalities that cytotechnicians
differentiate on a routine basis.differentiate on a routine basis.
2.2.Cytology laboratories in litigationCytology laboratories in litigation--prone prone countries countries
will tend will tend to err on the side of conservatism to err on the side of conservatism to to
decrease the risk of malpractice decrease the risk of malpractice suits.suits.
3.3.Maintaining Maintaining unnecessarily frequent screening visits unnecessarily frequent screening visits
as policy to provide protection as policy to provide protection against falseagainst false--negative negative diagnoses diagnoses . . (E.Franco, 2008)(E.Franco, 2008)
HPVHPV ASCASC ASC ASC
��������ASCASCASC ASC
��������LSILLSILASC ASC
��������HSILHSIL
Negative 8.0 86.1 10.9 2.9
Low Risk 16.4 63.6 29.0 7.5
HPV-16 38.5 21.7 18.3 60.0
HPV-18 30.8 58.3 25.0 16.7
(M Kovacic, Cancer Res 2006)(M Kovacic, Cancer Res 2006)Removing HPV-16 and 18 by vaccination would leave many ASCUS and LSIL diagnoses but depleted number of HSIL.
(M. Schiffman, 2007)
The lower PPV for cytology will require greater expertise
to maintain good quality
REDUCTION OF REFERRAL TO COLPOSCOPYREDUCTION OF REFERRAL TO COLPOSCOPY
HPVHPV Agreement Agreement
on normalon normalEquivocalEquivocal Agreement Agreement
on lesionon lesion
Negative 42.9 29.7 27.4
Low Risk 31.3 19.1 49.6
High Risk
(non16)
27.1 27.9 45.1
HPV-16 11.1 19.8 69.1
(J Jeronimo, Am J Obstet Gynecol 2007)(J Jeronimo, Am J Obstet Gynecol 2007)
The removal of HPV-16 by vaccination would leave an even more difficult task of targeting lesion for biopsy diagnosis
(M. Schiffman, 2007)
REDUCTION OF REFERRAL TO COLPOSCOPYREDUCTION OF REFERRAL TO COLPOSCOPY
1.1.Is not Is not prone to subjective interpretation and will prone to subjective interpretation and will maintain maintain
its performance its performance characteristics under lowcharacteristics under low--lesion prevalence lesion prevalence
conditions.conditions.
2.2.The The PPVPPV of HPV testing may be proportionally higher than of HPV testing may be proportionally higher than
that of cytology as lesion rates decrease in that of cytology as lesion rates decrease in response to response to
vaccination.vaccination.
3.3.In screening programs it is reasonable to use the In screening programs it is reasonable to use the most most
sensitive sensitive test as uptest as up--front front (to identify all women at risk for (to identify all women at risk for
highhigh--grade cervical lesions), grade cervical lesions), followed by a followed by a more specific more specific test test
as triage as triage (to avoid unnecessary referral(to avoid unnecessary referral))..
Prediction of risk of CIN3+ by a single HPVPrediction of risk of CIN3+ by a single HPV--test at test at
baseline in women >30 yrs baseline in women >30 yrs (Khan MJ 2005)(Khan MJ 2005)
Prediction of risk of CIN3+ by a single HPVPrediction of risk of CIN3+ by a single HPV--test at test at
baseline in women >30 yrs baseline in women >30 yrs (Khan MJ 2005)(Khan MJ 2005)
The positive predictive value of HPV-testing would dropt along with the cost-effectiveness of each HPV-screen.
(M. Schiffman, 2007)
