Luciano Mariani Istituto Nazionale Tumori Regina Elena, Roma

Luciano Mariani Istituto Nazionale Tumori Regina Elena, Roma SANIT 2008 PREVENZIONE SECONDARIA DEI TUMORI DELLA MAMMELLA, CERVICE UTERINA E COLONRETTO Roma, 24 giugno 2008

1. Vaccination and cytologic screening are complementary strategies... we will need both (X. Bosch Br J Cancer 2008) 2. An effective screening program will be a prerequisite for the evaluation of hpv vaccines (S.Franceschi, 2000)

1. Vaccination and cytologic screening are complementary strategies... we will need both (X. Bosch Br J Cancer 2008) 2. An effective screening program will be a prerequisite for the evaluation of hpv vaccines (S.Franceschi, 2000) 3. How to most efficiently carry out cervical cancer screening in the era of vaccination is unclear (N.Kiviat, 2008) 4. The best blend of vaccination and screening/management tools is not obvious (M.Schiffman, 2007)

SHOULD WE CONTINUE THE CYTOLOGIC SCREENING PROGRAMS? 1. HPV vaccines are prophylactic and protection is type-specific: fully effective as pre-exposure prophylaxis; lower efficacy in women previously exposed to vaccine-targeted HPV types at the time of vaccination; no benefit in currently infected women no therapeutic effect. 2. They do not include all oncogenic HPV types. 3. The goal of HPV vaccination is containment, rather than eradication of infection. 4. Long-term effectiveness of vaccination to be value. 5. The observable impact on cancer incidence will trend only after 20 or 30 years (Arbyn J Clin Virol 2007) 6. The non-vaccinated population needs to be protected ( For most living women today, screening remains their primary option for cervical cancer prevention X. Bosch, 2008) YES

SHOULD WE MODIFY THE CYTOLOGIC SCREENING PROGRAMS? 1. Should we separate algorithms for unvaccinated and vaccinated women?

SHOULD WE MODIFY THE CYTOLOGIC SCREENING PROGRAMS? 1. Should we separate algorithms for unvaccinated and vaccinated women? a) should we plan a traditional cytologic screening or the combined HPV-Pap algorithm? b) should we reconsider the age of starting? c) should we reconsider the interval? 2. Have we time enough to plan such modifications? Presently no change is recommended, but future change is likely.

The paradigm is changing We are moving from a morphologic prevention model based on cytology-colposcopy-histology to a biomolecular model based on virologic view of HPV and its molecular interaction with the human host.

The paradigm is changing We are moving from a morphologic prevention model based on cytology-colposcopy-histology to a biomolecular model based on virologic view of HPV and its molecular interaction with the human host.

MSD/SPMSD Gardasil L. Villa et al. Br J Cancer 95:1459-66. 2006 S. Garland et al. N Engl J Med356:1928-1943, 2007 FUTURE Study Group Lancet 369: 1861-1868, 2007 FUTURE Study Group JID 196:1438-46, 2007 GSK Cervarix D. Harper et al. Lancet 364:1757-65, 2004 D. Harper et al. Lancet 367:1247-55, 2006 J. Paavonen et al. Lancet 369:2161-70, 2007 A.Hildesheim et al JAMA 298(7):743-753, 2007

1 Vaccine-HPV type QUADRIVALENT Efficacy (95% CI) CIN2+ or AIS CIN2 CIN3 AIS 99% (93, 100) 100% (93, 100) 98% (89, 100) 100% (31,100) QUADRIVALENT Efficacy (95% CI) CIN2+ or AIS CIN2 CIN3 AIS 99% (93, 100) 99% (93, 100) 97% (90, 100) 100% (55,100) BIVALENT Efficacy (95% CI) CIN2+ QUADRIVALENT CIN2+ or AIS CIN2 CIN3 AIS 90.4% (53, 99) Efficacy (95% CI) 44% 50% 39% 54% (31, 55) (34, 62) (21, 53) (-30,86)

1 TIME TO EVENTS: CIN 1-2-3 for vaccine-type HPV The protection in intent-to-treat vaccinated population would be expected to increase over time as women in the placebo group continue to become infected with vaccinetargeted types of HPV and develop CIN2,3 lesions (Thomas C. Wright Jr., F. Xavier Bosch, 2008)

1 Any-HPV type QUADRIVALENT Efficacy (95% CI) CIN2+ or AIS CIN2 CIN3 AIS 99% (93, 100) 100% (93, 100) 98% (89, 100) 100% (31,100) QUADRIVALENT Efficacy (95% CI) CIN2+ or AIS CIN2 CIN3 AIS 99% (93, 100) 99% (93, 100) 97% (90, 100) 100% (55,100) BIVALENT Efficacy (95% CI) CIN2+ 90.4% (53, 99) QUADRIVALENT Efficacy (95% CI) CIN2+ or AIS CIN2 CIN3 AIS 17% (1, 31) 22% (3, 38) 21% (<0,38) 37% (<0,84)

1 TIME TO EVENTS: CIN 1-2-3 for any type HPV The current genital HPV continue vaccines include only two of the 15 types. Therefore screening will (Margaret Stanley, 2008) oncogenic have to

2 (AIFA, Agenzia Italiana del Farmaco, 2007) LONG-TERM SAFETY? Time is needed to answer this issue.

3

3 SEROCONVERSION IMMUNOGENICITY (GMT neutralizing IgG) ANAMNESTIC IMMUNE-RESPONSE MEMORY immunity following vaccination exceeds 5 years and appears to be sustained. (Sven-Eric Olsson, Vaccine 2007)

3 SEROCONVERSION IMMUNOGENICITY (GMT neutralizing IgG) ANAMNESTIC IMMUNE-RESPONSE MEMORY It is possible that re-infection will provide a means of naturally sustaining immunity in the absence of vaccine boosting. (Sven-Eric Olsson, Vaccine 2007)

4 At licensing, vaccines are typically used broadly without full knowledge of their duration of protection. CLINICAL TRIALS: protection up to 5 years. Need for further boost? Sourveillance screening program Uselessness of specific IgG antibodies LONG-TERM PROTECTION? Time is needed to answer this issue.

4 Anti-HBs levels disappear in 10-50% of vaccinees after 45 years (Bauer T and Jilg W. Vaccine. 2006;24:572-577) Protection against Hepatitis B infection/disease remains high. No booster has been recommended (Mast E, 2004) 6 12 24 36 48 Months After First Vaccine Dose 6 0

5 Already to be value post-marketing studies Reported positive, but transitory crossimmune reaction (antibody response) to bivalent vaccine against HPV-45 and HPV-31. (Paavonen J, Lancet 369:2161-70, 2007) Reported partial clinical cross-protection (CIN2-3 or AIS) against HPV-45 and HPV-31 (Int.Papillomavirus Conference, Bejing 2007) CROSS-PROTECTION? Time is needed to answer this issue.

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VARIABLES INVOLVED? 1. VACCINES: efficacy, duration of protection, crossprotection, type-replacement. 2. LOCAL VARIABLES: HPV-prevalence, age-incidence, sexual behaviour, acceptability, awareness of HPV/cervical cancer. 3. ORGANIZED PROGRAM: cohort selection and catch-up, achievable coverage and adhesion, continuity of funding over time 4. MONITORING SYSTEM: linkage with screening programs cancer registries. 5. and NATURAL HISTORY OF CERVICAL LESIONS IN VACCINATED WOMEN :?? 6. IMPACT OF OPPORTUNISTIC VACCINATION:?? BENEFITS FOR COMMUNITY? Time is needed to answer this issue.

The power of screening tools (cytology, HPV-test, colposcopy) is largely related to detection of HPV-16 and 18 Assuming that HPV vaccination: will became an accepted primary prevention approach, will display a high clinical efficacy against HPV-16 and HPV-18, how will change the performance of screening tools in a condition of lower HPV prevalence?

REDUCTION OF HPV PREVALENCE BY 40-60% (Clifford GM, Cancer Epidemiol Biomarkers Prev 2005)

REDUCTION OF HPV PREVALENCE BY 40-60% (Clifford GM, Cancer Epidemiol Biomarkers Prev 2005) Reduction of PPV of cervical screening screening performance in high lesion prevalence or in artificial situation of cytologic triage of HPV-positive women. (Sensitivity 70%; Specificity 98%) decreased sensitivity (40%) and specificity (90%) expected in conditions of decreased lesion prevalence following vaccination. Eduardo L. Franco, Jack Cuzick, 2008

Cytologic PPV decreases with reductions in prevalence: increasingly false-positive diagnosis, unnecessary worry and medical interventions, higher costs. FURTHER DEGRADATION OF THE CYTOLOGIC PPV 1.change in the signal (squamous abnormalities) -tonoise (inflammatory changes) ratio in the pleomorphic cellular abnormalities that cytotechnicians differentiate on a routine basis. 2.Cytology laboratories in litigation-prone countries will tend to err on the side of conservatism to decrease the risk of malpractice suits. 3.Maintaining unnecessarily frequent screening visits as policy to provide protection against false-negative diagnoses. (E.Franco, 2008)

HPV ASC 8.0 ASC ASC 86.1 ASC LSIL 10.9 ASC HSIL 2.9 Negative 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) 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 COLPOSCOPY

REDUCTION OF REFERRAL TO COLPOSCOPY HPV Agreement Equivocal on normal Agreement on 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 The removal of HPV-16 by vaccination would leave an even Am J Obstet Gynecol 2007) more difficult task(j Jeronimo, of targeting lesion for biopsy diagnosis (M. Schiffman, 2007)

1.Is not prone to subjective interpretation and will maintain its performance characteristics under low-lesion prevalence conditions. 2.The PPV of HPV testing may be proportionally higher than that of cytology as lesion rates decrease in response to vaccination. 3.In screening programs it is reasonable to use the most sensitive test as up-front (to identify all women at risk for high-grade cervical lesions), followed by a more specific test as triage (to avoid unnecessary referral).

Prediction of risk of CIN3+ by a single HPV-test at baseline in women >30 yrs (Khan MJ 2005)

The positive predictive value of HPV-testing would dropt along with the cost-effectiveness of Prediction of risk of CIN3+ by a single HPV-test at each HPV-screen. baseline in women >30 yrs (Khan MJ 2005) (M. Schiffman, 2007)