Supplements to the European Guidelines on Prevention of Cervical Cancer

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1 Asturias, 23 October, 2011 Asturias, 23 October Supplements to the European Guidelines on Prevention of Cervical Cancer M. Arbyn Unit Cancer Epidemiology, IPH, Brussels, Belgium Rue Juliette Wytsmanstraat Brussels Belgium T F amidu.raifu@iph.fgov.be

2 LBC hrhpv testing: New methods for testing Triage ASC-US, LSIL Follow-up after treatment of hgcin 1ary screening QC of cytology Molecular markers HPV genotyping

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4 Siebers, Arbyn JAMA 2009, 302: Conclusion: This study indicates that liquid-based cytology does not perform better than conventional Pap tests in terms of relative sensitivity and PPV for detection of cervical cancer precursors.

5 New trials: Pap vs LBC Strander Eur J Cancer 2007 (Sweden) Sykes BJOG 2008 (New Zealand) Siebers, Arbyn JAMA 2009 (Netherlands) Adding newest trials conclusions of meta-analysis unchanged

6 LBC: logistical advantages Less unsatisfactory samples Microscopic screening is quicker (-1/3) Allows ancillary molecular testing: HPV testing Usable for biobanking

7 HPV testing in triage of ASCUS, LSIL

8 Triage with HPV testing from previous meta-analyses / ALTS Triage of ASCUS: HC2 more sensitive and similarly specific compared to repeat cytology for detection of underlying CIN2+ Triage of LSIL: LSIL is an expression of HPV infection, and therefore very often HPV positive. Might be useful in triage among older women (>40,>45, >50 years) Research needed to assess triage by biomarkers Arbyn et al, JNCI2004a &b, Gynecol Oncol 2005, Vaccine 2006; ALTS group AJOG2003a &b; Solomon Arch Pathol Lab Med 2009

9 HPV testing in follow-up after treatment of cervical precancer

10 Prediction of recurrent CIN after T of CIN with HPV or Cytology Se 0.94 ( ) Sp 0.80 ( ) DOR 65.7 ( ) Se 0.75 ( ) Sp 0.89 ( ) DOR 24.1 ( ) HPV Cytology Specificity.2 0

11 HPV testing after treatment of CIN hrhpv DNA testing after treatment predicts residual or recurrent CIN with higher sensitivity than cytology or histology of the section margins Specificity of hrhpv DNA does not differ significantly from histology of section margins but is lower than repeat cytology But: cave: heterogeneity of studies, methods, timing of follow-up visits Long term follow-up needed, since high sensitivity of HPV testing might be only valid to short term recurrent disease (Stander EJC 2007) Arbyn, Gynecol Oncol 2005, Vaccine 2006; Chan AJOG 2009

12 HPV testing in QA of cervical cytology

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14 ASCUS Manos, 1999 Bergeron, 2000 Lytwyn, 2000 Shlay, 2000 Morin, 2001 Solomon, 2001 Kulasingam, 2002 Pretorius, 2002 Guyot, 2003 Lonky, 2003 Wensveen, 2003 Rowe, 2004 Andersson, 2005 Carozzi, 2005 Dalla Palma, 2005 Giovannelli, 2005 Kendall, 2005 Nieh, 2005 Bergeron, 2006 Kiatpongsan, 2006 Monsonego, 2006 Ronco, 2007 Subtotal (I 2 = 96.7%, p < 0.001) ASC-US Bruner, 2004 Kelly, 2006 Ko, 2006 Selvaggi, 2006 Wright, 2006 You, 2007 Subtotal (I 2 = 93.2%, p < 0.001) BORDERLINE DYSKARYOSIS Rebello, 2001 Zielinski, 2001 Cuzick, 2003 Moss, 2006 Cuschieri, 2007 Subtotal (I 2 = 92.5%, p = 0.000). Overall (I 2 = 96.0%, p = 0.000) T+ rate (95% CI) 0.40 (0.36, 0.43) 0.43 (0.34, 0.52) 0.40 (0.28, 0.53) 0.31 (0.25, 0.38) 0.29 (0.24, 0.34) 0.57 (0.55, 0.59) 0.51 (0.45, 0.57) 0.32 (0.29, 0.35) 0.52 (0.32, 0.73) 0.46 (0.40, 0.52) 0.45 (0.37, 0.53) 0.44 (0.38, 0.50) 0.44 (0.31, 0.58) 0.49 (0.42, 0.56) 0.70 (0.63, 0.77) 0.23 (0.14, 0.31) 0.34 (0.33, 0.35) 0.74 (0.64, 0.85) 0.44 (0.42, 0.47) 0.39 (0.29, 0.49) 0.48 (0.36, 0.60) 0.31 (0.28, 0.35) 0.44 (0.39, 0.48) 0.27 (0.18, 0.36) 0.73 (0.60, 0.85) 0.40 (0.38, 0.42) 0.40 (0.36, 0.43) 0.34 (0.32, 0.37) 0.46 (0.43, 0.49) 0.42 (0.36, 0.47) 0.41 (0.30, 0.52) 0.35 (0.28, 0.41) 0.26 (0.18, 0.34) 0.46 (0.44, 0.47) 0.61 (0.54, 0.67) 0.42 (0.32, 0.51) 0.43 (0.40, 0.46) Proportion Triage of atypical cytology with HC2 T+ rate ASCUS (22 studies) 44% (CI: 39-48%) ASC-US (6) 42% (CI: 36-47%) Bordeline dyskaryosis (5) 42% (CI:32-51%) Overall: 43% (CI: 40-46%) Arbyn et al, J Cell Mol Med 2009

15 LSIL Bergeron, 2000 Lytwyn, 2000 Lee, 2001 Kulasingam, 2002 Pretorius, 2002 Sherman, 2002 Guyot, 2003 Rowe, 2004 Andersson, 2005 Carozzi, 2005 Ko, 2006 Monsonego, 2006 Ronco, 2007 You, 2007 Subtotal (I 2 = 94.2%, p< 0.001) MILD DYSKARYOSIS Rebello, 2001 Zielinski, 2001 Moss, 2006 Subtotal (I 2 = 42.5%, p= 0.176) T+ rate (95% CI) 0.58 (0.52, 0.64) 0.77 (0.62, 0.92) 0.67 (0.55, 0.78) 0.83 (0.77, 0.90) 0.76 (0.71, 0.81) 0.85 (0.82, 0.87) 0.73 (0.64, 0.81) 0.89 (0.82, 0.95) 0.74 (0.67, 0.82) 0.84 (0.78, 0.90) 0.78 (0.71, 0.85) 0.76 (0.70, 0.83) 0.55 (0.50, 0.59) 0.85 (0.82, 0.87) 0.76 (0.70, 0.82) 0.75 (0.67, 0.83) 0.80 (0.70, 0.90) 0.83 (0.81, 0.84) 0.81 (0.76, 0.85) Triage of LSIL/mild T+ rate of HC2 LSIL (14 studies) 76% (CI: 70-82%) Mild dyskaryosis (3) 81% (CI: 76-85%) Overall (I 2 = 93.3%, p < 0.001) (0.72, 0.81) Arbyn et al, J Cell Mol Med 2009

16 Conclusion: HPV testing could be used in quality control of cytology Arbyn, Gynecol Oncol 2005, Vaccine 2006; Chan AJOG 2009

17 HPV testing in 1ary screening: Accuracy to detect hgcin (cross-sectional studies)

18 Sensitivity of HC2 to detect CIN2+ in 1ary screening Study Sensitivity (95% CI) Weight % Developing countries Kuhn, 2000 Schiffman, 2000 Blumenthal, 2001 Salmeron, 2003 Sankaranarayanan, K1, 2004 Sankaranarayanan, M, 2004 Sankaranarayanan, T2, 2004 Sarian, 2005 Almonte, 2007 Subtotal (I2 = 85.8%, p = 0.000) Industrialised countries Ratnam, 2000 Clavel, 2001 Coste, 2003 Cuzick, 2003 Petry, 2003 Bigras, 2005 Inoue, 2006 Ronco, 2006 Mayrand, 2007 Cuzick, 2008 Kitchener, 2009 Subtotal (I2 = 60.7%, p = 0.005) 0.88 (0.82, 0.95) 0.89 (0.83, 0.94) 0.81 (0.75, 0.86) 0.93 (0.88, 0.98) 0.50 (0.37, 0.63) 0.70 (0.59, 0.82) 0.80 (0.70, 0.90) 0.83 (0.73, 0.92) 0.77 (0.71, 0.83) 0.80 (0.74, 0.87) 0.84 (0.68, 1.01) 1.00 (0.98, 1.02) 0.95 (0.88, 1.02) 0.97 (0.94, 1.00) 0.98 (0.94, 1.02) 0.98 (0.94, 1.01) 0.95 (0.93, 0.98) 0.98 (0.95, 1.00) 0.95 (0.86, 1.04) 0.86 (0.73, 0.99) 0.93 (0.91, 0.95) 0.96 (0.95, 0.98) China Belinson, 2001 Belinson, 2003 Qiao, 2008 Cagle, 2010 Subtotal (I2 = 0.0%, p = 0.906) 0.95 (0.91, 1.00) 0.97 (0.95, 0.99) 0.97 (0.93, 1.01) 0.96 (0.91, 1.00) 0.97 (0.95, 0.98) Overall (I2 = 87.9%, p = 0.000) 0.91 (0.89, 0.94) Sensitivity

19 Accuracy of HC2 to detect high-grade CIN 1. Absolute sensitivity: CIN2+: 91% (95% CI: %) [24 studies] CIN3+: 98% (95% CI: %) [7 studies] 2. Specificity: CIN2+: 88% (95% CI: %) [23 studies] 3. Relative sensitivity vs cytology 1.23 ( ) if ASCUS+; 1.38( ) if LSIL+ 4. Relative specificity vs cytology 0.97( ) if ASCUS+; 0.91( ) if LSIL+

20 Randomised trials

21 Study characteristics (2) Various follow-up protocols for screen+ Sometimes varying by age Different levels of blinding of gold standard verification For all trials: PPV, DR of CIN2, CIN3/AIS+ 4 trials: CIN3+ at 2 nd screening round 1 trial: I & M from cervical cancer

22 Baseline results: relative sensitivity for CIN2+ Cytology best HPV best RR (95% CI) Developing countries Sankar, (0.76, 1.03) Industrialised countries, CP Ronco, 2006* Bulkmans, 2007 Mayrand, 2007 Naucler, 2007 Ronco, 2008 Leinonen, 2009 Subtotal (I 2 = 0.0%, p = 0.910) 1.43 (1.00, 2.04) 1.64 (1.17, 2.31) 1.69 (0.83, 3.45) 1.42 (1.06, 1.91) 1.92 (1.28, 2.87) 1.43 (1.12, 1.84) 1.52 (1.33, 1.75) Industrialised countries, LBC Kitchener, (0.87, 1.28) Overall (I 2 = 75.0%, p = 0.000) Arbyn, Lancet Oncol Detection rate ratio *Age >=35 years

23 (HPV & cyto) vs HPV alone Detection of CIN2+, 1st screening round Study RR (95% CI) Ronco, 2006* HPV alone best Combination best 1.00 (0.72, 1.38) Bulkmans, (0.81, 1.44) Mayrand, (0.57, 1.93) Kitchener, (0.94, 1.22) Overall (I 2 = 0.0%, p = 0.983) 1.06 (0.95, 1.19) Relative sensitivity Arbyn, Lancet Oncol 2009 *Age >=35 years

24 HPV- vs cytology based screening CIN3+ in 2 nd round among in women with negative screen test at baseline RR (95% CI) Bulkmans, (0.28, 0.66) Naucler, (0.29, 0.96) Ronco, 2010* (Phase 1 &2) Kitchener, (0.21, 1.11) 0.52 (0.28, 0.97) Overall (I 2 =0.0%, p=0.93) 0.47 (0.35, 0.63) Arbyn, Lancet Oncol 2009 Ronco, Lancet Oncol Detection rate ratio *Age >=35 years

25 Longitudinal results RCTs: HPV vs cyto screening Incidence of cervical cancer Italian trial: HPV vs. Cyto group: 0 vs 9 cases Swedish RCT: 1 vs 5 cases Dutch trial: sign reduction in HPV arm Indian trial: -53% incidence (II+), -47% mortality Sankar 2009 NEJM; Ronco, Lancet Oncol 2010; Arbyn Lancet Oncol 2009; Naucler NEJM 2007;

26 Conclusion: hrhpv DNA testing More sensitive but less specific than cyto to detect CIN2+ & CIN3+ Accuracy estimates less variable than cytology Combined screening (cyto + HPV) does not increase sensitivity but decreases specificity and generates costs & adverse effects Less CIN3+, less invasive cancer among women with negative HPV test at base line Arbyn, Lancet Oncol 2009

27 Conclusion: hrhpv DNA testing HPV screening with validated tests: good reproducibility, less ~ skilled human resources HPV screening will allow extending intervals, but this will require a high level of organisation otherwise explosion of follow-up examinations Reduced specificity requires appropriate triage (cytology, typing 16/18, p16, RNA-5 types, persistent (type-specific) infection

28 Conclusion: hrhpv DNA testing Whatever the choice of future 1ary screening : the main factor of success will be the availability of a good organised and monitored system

29 Supplements to EU guidelines on HPV screening and vaccination Ready by end 2011

30 Acknowledgements European Commission: EUROCHIP-3, ECCG, EUROCOURSE, PREHDICT (FP7) Belgian Foundation Against Cancer Gynaecological Cancer Cochrane Review Collaboration (Bath, UK)