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Marc Arbyn - Standards for colposcopy

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Marc Arbyn - Standards for colposcopy

  1. 1. Marc Arbyn Coordinator of the Unit of Cancer Epidemiology
  2. 2. Rue Juliette Wytsmanstraat 14 | 1050 Brussels | Belgium T +32 2 642 50 73 | F +32 2 642 54 10 | email: amidu.raifu@iph.fgov.be | http://www.iph.fgov.be M Arbyn1 (1) Unit of Cancer Epidemiology, Belgian Cancer Centre Scientific Institute of Public Health, Brussels, Belgium; Standards for Colpscopy: Evidence for the margin status as indicator for good clinical practice
  3. 3. 4
  4. 4. History of meta-analysis: margin status & treatment failure  Surgical treatment of cervical precancer (CIN2/3): acceptance for positive margins ≤ 20% (= EFC quality indicator: Moss et al, EJOGRB 2014)  Meta-analyses  Ghaem-Maghami, Lancet Onol 2007: significant ↑ risk of residual/recurrent CIN2+  Arbyn, BMJ 2008; Kyrgiou, BMJ 2016: risk of preterm delivery (PTD), associated with surgical treatment of CIN, ↑ with ↑ depth 5
  5. 5. History of meta-analysis: margin status & treatment failure  Prior meta-analyses  Arbyn, Vaccine 2012: post-treatment HPV testing, accurate predictor of residual CIN2+  Current  % + margins, % failure & association with margin  Accuracy of margin status  Accuracy of post-treatment HPV  Relative accuracy: margins vs HPV vs both  Margin status a good quality indicator? 6
  6. 6. Meta-analysis: margins & treatment failure (inclusion criteria) 7  Restrictions:  Histological verification of CIN2+ at treatment  Histological verification of failing cases: CIN2+  HPV testing between 3-9 months post-treatment  Follow-up of at least 18 month  Covariates:  Treatment procedure  Grade treated CIN  Location of involved margins: ecto-cervical, endo-cervical or both  Year of publication
  7. 7. Meta-analysis: margins & treatment failure 8 Total 97 studies Risk of treatment failure associated with margin status 93 studies Accuracy studies margin status 25 studies • Only margin status: 7 studies • Also post-treatment HPV: 18 studies • Joint accuracy of margin status & post-treatment HPV: 5 studies 1. Meta-analysis Ghaem-Maghani, 2007 [residual CIN2+ ~ margins]: 65 studies 2. Meta-analyses Arbyn, Vaccine2006/12 & update [post-treatment HPV]: 15 studies 3. New searches (2006-16): 16 studies Excluded:  Double reporting: 1  Case-control studies: 3
  8. 8. Subtotal (I2 = 95.4%, p< 0.001) Andersen, 1994 Kong, 2014 Mazouni, 2005 Bandieramonte, 1998 Maluf, 2004 Ueda, 2006 Fambrini, 2008 Vedel, 1993 Vergote, 1992 Mohamed-Noor, 1997 Reich, 2002 Skjeldestad, 1997 Orbo, 2004 Grundsell, 1983 LC Subtotal (I2 = 98.3%, p< 0.001) Izumi, 2000 Stamatopoulos, 2001 Lopes, 1993 Moore, 1992 Ahlgren, 1975 Bertelsen, 1999 Murta, 1999 Milojkovic, 2002 White, 1993 Murta, 2004 Demopoulos, 1991 Riethmuller, 2008 Paterson-Brown, 1992 Larsson, 1981 Orbo, 2004 Bjerre, 1976 CKC Study 16.9 (13.8, 20.6) 13.3 (11.0, 16.1) 15.2 (12.2, 18.8) 2.8 (1.1, 6.9) 46.6 (34.3, 59.2) 12.3 (10.9, 13.8) 15.4 (8.0, 27.5) 19.2 (15.6, 23.5) 26.5 (18.8, 36.0) 18.2 (15.5, 21.2) 8.1 (7.4, 8.9) 23.4 (20.9, 26.0) 27.3 (19.1, 37.4) 7.1 (4.7, 10.7) 17.8 (12.9, 23.2) 20.8 (13.1, 31.6) 12.4 (8.1, 18.6) 42.7 (37.3, 48.3) 19.8 (15.7, 24.7) 13.5 (11.0, 16.6) 35.1 (27.5, 43.6) 4.1 (3.0, 5.5) 18.8 (13.3, 25.8) 41.4 (33.7, 49.5) 16.7 (12.6, 21.9) 24.6 (20.6, 29.1) 40.3 (34.6, 46.2) 6.1 (4.5, 8.0) 36.1 (33.6, 38.7) ES (95% CI) 20.2 (14.3, 26.7) 21.4 (14.8, 29.9) 11.9 (9.0, 15.5) 0 20 40 60 80 100 % positive margins Overall (I2 = 95.8%, p< 0.001) Dobbs, 2000 Ang, 2011 Alonso, 2006 Ribaldone, 2010 Kang, 2010 Wu, 2016 Mints, 2006 Gardeil, 1997 Herfs, 2015 Bodner, 2002 Robinson, 1998 Aerssens, 2009 Fuste, 2009 Prato, 2008 Verguts, 2006 Goff, 1994 Gonzalez, 2001 Bae, 2007 Skinner, 2004 Hulman, 1998 Johnson, 2003 Felix, 1994 Nagai, 2004 de Cabezon, 1998 Jain, 2001 Kucera, 2001 Flannelly, 2001 Zaitoun, 2000 Brismar, 2009 Lu, 2006 Shafi, 1993 Livasy, 1999 Kang, 2016 Houfflin, 2003 Baldauf, 1998 Ryu, 2012 Spitzer, 1993 Gosvig, 2015 Bar-Am, 2000 Torne, 2013 Hanau, 1997 Hallam, 1993 Study 25.9 (22.3, 29.6) 23.4 (19.1, 28.3) 47.3 (44.8, 49.8) 32.8 (26.7, 39.6) 10.3 (5.3, 19.0) 16.5 (13.9, 19.5) 13.2 (11.1, 15.7) 8.8 (5.2, 14.4) 47.5 (40.8, 54.4) 26.0 (19.2, 34.1) 16.2 (7.7, 31.1) 46.7 (38.1, 55.5) 16.4 (10.9, 24.0) 29.6 (22.0, 38.5) 19.4 (12.0, 30.0) 16.7 (10.7, 25.1) 31.7 (25.0, 39.2) 21.1 (14.6, 29.4) 39.5 (35.1, 44.0) 31.4 (27.5, 35.6) 32.0 (28.6, 35.6) 28.1 (18.1, 40.8) 5.6 (2.9, 10.7) 27.1 (18.1, 38.5) 59.5 (48.5, 69.6) 12.7 (8.2, 19.1) 30.1 (28.3, 31.9) 41.2 (38.3, 44.2) 28.2 (19.8, 38.6) 30.1 (26.0, 34.5) 20.9 (15.2, 28.0) 53.0 (46.1, 59.8) 10.7 (7.2, 15.6) 36.1 (29.8, 42.9) 16.5 (12.5, 21.4) 26.2 (20.4, 33.0) 17.4 (12.5, 23.8) 23.1 (19.8, 26.8) 9.5 (5.6, 15.6) 22.7 (16.4, 30.6) 25.3 (17.3, 35.3) 28.4 (25.6, 31.5) 42.9 (33.8, 52.4) 30.1 17.4 (12.5, 23.8) ES (95% CI) 0 20 40 60 80 100 % positive margins Proportion of involved margins (%) CKC: 20.2% LC: 17.8% LLETZ: 25.9%
  9. 9. Trend in % positive margins (by treatment procedure)
  10. 10. Heterogeneity between groups: p < 0.001 Overall (I2 = 92.3%, p<0.0001) Brismar, 2009 Subtotal (I2 = 90.1%, p<0.0001) Herfs, 2015 Nagai, 2004 Study Alonso, 2006 Zhao, 2014 Guerra, 1996 Reich, 2002 Gallwas, 2010 LLETZ Torne, 2013 Ang, 2011 LC Subtotal (I2 = 35.7%, p=0.17) Chao, 2004 Verguts, 2006 Kang, 2010 Trope, 2011 Kang, 2016 Aerssens, 2009 Skinner, 2004 Orbo, 2004 Gosvig, 2015 Subtotal (I2 = 99.7%, p<0.0001) Fambrini, 2008 Ryu, 2012 Bandieramonte, 1998 Murta, 1999 Wu, 2016 Subtotal (I2 = 99.7%, p<0.0001) CKC Mixed 6.6 (4.9, 8.4) 5.9 (2.5, 13.0) 6.7 (4.6, 9.3) 3.1 (1.2, 7.6) ES (95% CI) 11.9 (8.2, 17.2) 6.8 (5.4, 8.5) 2.1 (1.7, 2.5) 10.3 (5.8, 17.5) 9.1 (5.3, 15.2) 3.7 (2.8, 4.7) 6.8 (5.7, 8.1) 6.0 (4.5, 7.9) 9.7 (4.8, 18.7) 5.5 (4.0, 7.5) 6.4 (4.3, 9.5) 12.6 (8.8, 17.9) 9.8 (5.7, 16.4) 15.4 (12.3, 18.9) 9.2 (6.8, 12.1) 2.9 (1.8, 4.7) 2.1 (0.4, 4.9) 5.8 (2.0, 15.6) 6.6 (3.8, 11.1) 2.2 (1.4, 3.4) 2.2 (1.8, 2.6) 4.9 (2.4, 9.8) 5.2 (3.2, 8.1) 1.4 (0.4, 4.9) 18.3 (12.6, 25.8) 0 10 20 30 40 50 Residual/recurrent CIN2+ (%) Occurrence of residual/recurrent CIN2+ (=treatment failure) % Failure: 6.6% (95% CI: 4.9-8.4)
  11. 11. 0.5 1 2 10 100 Risk CIN2+ ~ margin status Heterogeneity between groups: p = 0.002 Overall (I2 = 89.3%, p<0.001); Study Orbo, 2004 Subtotal (I^2 = 0.0%, p = 0.5) Aerssens, 2009 LC Brismar, 2009 Zhao, 2014 Subtotal (I^2 = 73.6%, p = 0.0) LLETZ Herfs, 2015 Mixed Ryu, 2012 Skinner, 2004 Alonso, 2006 Subtotal (I^2 = 91.0%, p = 0.0) Subtotal (I^2 = 0.0%, p = 0.5) Ahlgren, 1975 Torne, 2013 Trope, 2011 Nagai, 2004 Reich, 2002 Kang, 2010 Fambrini, 2008 Orbo, 2004 Bandieramonte, 1998 Chao, 2004 Ang, 2011 CKC Gallwas, 2010 Dobbs, 2000 Larsson, 1981 Bjerre, 1976 Verguts, 2006 Orbo, 2004 Murta, 1999 17.5 (12.8, 22.7) ES (95% CI) 11.8 (6.1, 21.5) 12.6 (10.0, 15.4) 15.0 (5.2, 36.0) 8.3 (2.3, 25.8) 14.7 (10.7, 19.9) 25.6 (19.6, 32.2) 8.8 (3.0, 23.0) 20.8 (11.7, 34.3) 28.3 (22.3, 35.3) 27.3 (18.0, 39.0) 15.9 (8.3, 25.2) 14.1 (3.0, 29.5) 30.0 (19.9, 42.5) 33.3 (19.2, 51.2) 19.7 (11.6, 31.3) 12.5 (2.2, 47.1) 21.5 (17.7, 25.9) 17.1 (11.2, 25.2) 25.0 (7.1, 59.1) 16.7 (6.7, 35.9) 0.0 (0.0, 49.0) 11.5 (8.2, 15.7) 3.9 (2.8, 5.6) 10.0 (1.8, 40.4) 12.0 (6.4, 21.3) 40.9 (27.7, 55.6) 24.6 (21.0, 28.6) 14.3 (4.0, 39.9) 9.1 (3.6, 21.2) 37.0 (24.5, 51.4) ES (95% CI) 11.8 (6.1, 21.5) 12.6 (10.0, 15.4) 15.0 (5.2, 36.0) 8.3 (2.3, 25.8) 14.7 (10.7, 19.9) 25.6 (19.6, 32.2) 8.8 (3.0, 23.0) 20.8 (11.7, 34.3) 28.3 (22.3, 35.3) 27.3 (18.0, 39.0) 15.9 (8.3, 25.2) 14.1 (3.0, 29.5) 30.0 (19.9, 42.5) 33.3 (19.2, 51.2) 19.7 (11.6, 31.3) 12.5 (2.2, 47.1) 21.5 (17.7, 25.9) 17.1 (11.2, 25.2) 25.0 (7.1, 59.1) 16.7 (6.7, 35.9) 0.0 (0.0, 49.0) 11.5 (8.2, 15.7) 3.9 (2.8, 5.6) 10.0 (1.8, 40.4) 12.0 (6.4, 21.3) 40.9 (27.7, 55.6) 24.6 (21.0, 28.6) 14.3 (4.0, 39.9) 9.1 (3.6, 21.2) 37.0 (24.5, 51.4) 0 20 40 60 80 100 PPV (%) Margin+ Heterogeneity between groups: p = 0.319 Overall (I2 = 92.3%, p<0.001) Brismar, 2009 Bjerre, 1976 Alonso, 2006 Kang, 2010 Verguts, 2006 Subtotal (I^2 = 97.1%, p = 0.0) Gallwas, 2010 Subtotal (I^2 = 62.7%, p = 0.0) Subtotal (I^2 = 0.0%, p = 0.7) LC Mixed Torne, 2013 Ryu, 2012 Zhao, 2014 Subtotal (I^2 = 80.5%, p = 0.0) Aerssens, 2009 Ang, 2011 Nagai, 2004 Ahlgren, 1975 Trope, 2011 Dobbs, 2000 Orbo, 2004 LLETZ Orbo, 2004 Murta, 1999 Fambrini, 2008 Chao, 2004 Skinner, 2004 Bandieramonte, 1998 Orbo, 2004 Herfs, 2015 Larsson, 1981 Reich, 2002 CKC Study 3.8 (2.4, 5.4) 4.9 (1.7, 13.5) 3.0 (2.1, 4.4) 4.4 (2.1, 9.4) 3.2 (2.0, 5.0) 8.6 (3.7, 18.6) 3.5 (0.9, 7.7) 10.3 (5.7, 17.9) 3.5 (2.3, 4.9) 1.8 (0.3, 4.1) 2.0 (0.5, 6.9) 1.5 (0.4, 5.2) 4.4 (3.1, 6.1) 5.3 (3.1, 7.9) 8.8 (4.7, 15.9) 3.4 (2.4, 4.9) 4.4 (2.1, 9.4) 0.4 (0.1, 2.3) 3.5 (1.9, 6.4) 0.8 (0.2, 2.9) 3.1 (0.9, 10.7) 8.7 (6.3, 11.9) 8.2 (4.0, 16.0) 2.3 (0.4, 11.8) 2.9 (1.7, 4.8) 6.9 (4.5, 10.5) 1.4 (0.4, 5.1) 9.8 (7.0, 13.5) 1.0 (0.2, 5.6) 5.7 (4.2, 7.7) 0.4 (0.2, 0.6) ES (95% CI) 4.9 (1.7, 13.5) 3.0 (2.1, 4.4) 4.4 (2.1, 9.4) 3.2 (2.0, 5.0) 8.6 (3.7, 18.6) 3.5 (0.9, 7.7) 10.3 (5.7, 17.9) 3.5 (2.3, 4.9) 1.8 (0.3, 4.1) 2.0 (0.5, 6.9) 1.5 (0.4, 5.2) 4.4 (3.1, 6.1) 5.3 (3.1, 7.9) 8.8 (4.7, 15.9) 3.4 (2.4, 4.9) 4.4 (2.1, 9.4) 0.4 (0.1, 2.3) 3.5 (1.9, 6.4) 0.8 (0.2, 2.9) 3.1 (0.9, 10.7) 8.7 (6.3, 11.9) 8.2 (4.0, 16.0) 2.3 (0.4, 11.8) 2.9 (1.7, 4.8) 6.9 (4.5, 10.5) 1.4 (0.4, 5.1) 9.8 (7.0, 13.5) 1.0 (0.2, 5.6) 5.7 (4.2, 7.7) 0.4 (0.2, 0.6) ES (95% CI) 0 20 40 60 80 100 cNPV (%) Margin- . . . . Overall (I2 = 85.9%, p=0.000) Bandieramonte, 1998 Mixed Subtotal (I-squared = 70.2%, p = 0.000) CKC Orbo, 2004 Alonso, 2006 Subtotal (I-squared = 56.8%, p = 0.055) Verguts, 2006 Kang, 2010 Torne, 2013 ID Ryu, 2012 Study Ang, 2011 Trope, 2011 Nagai, 2004 LC Murta, 1999 Gallwas, 2010 Aerssens, 2009 Larsson, 1981 Dobbs, 2000 Subtotal (I-squared = 0.0%, p = 0.873) Herfs, 2015 Orbo, 2004 LLETZ Zhao, 2014 Chao, 2004 Skinner, 2004 Subtotal (I-squared = 93.4%, p = 0.000) Brismar, 2009 Orbo, 2004 Bjerre, 1976 Fambrini, 2008 Ahlgren, 1975 Reich, 2002 4.9 (3.1, 7.6) 5.6 (0.3, 102.7) 4.2 (2.4, 7.2) 0.9 (0.3, 2.5) 6.1 (2.6, 14.7) 3.0 (1.8, 4.9) 1.7 (0.4, 7.7) 5.3 (2.9, 9.8) 17.0 (3.9, 73.4) ratio (95% CI) 14.1 (3.2, 61.9) 1.2 (0.7, 1.9) 5.6 (2.5, 12.3) 2.8 (0.4, 20.6) 4.5 (2.0, 10.0) 1.0 (0.1, 6.8) 1.7 (0.5, 5.7) 7.2 (4.5, 11.4) 14.8 (3.3, 66.8) 6.6 (2.0, 22.0) 8.6 (0.9, 79.5) 1.4 (0.7, 2.8) 3.4 (2.1, 5.3) 4.0 (2.2, 7.3) 4.1 (2.5, 6.7) 9.2 (3.3, 25.7) 1.7 (0.3, 9.5) 5.3 (1.0, 27.3) 8.1 (5.4, 12.2) 11.0 (1.1, 107.5) 72.9 (9.9, 535.3) 56.0 (33.6, 93.3) 5.6 (0.3, 102.7) 4.2 (2.4, 7.2) 0.9 (0.3, 2.5) 6.1 (2.6, 14.7) 3.0 (1.8, 4.9) 1.7 (0.4, 7.7) 5.3 (2.9, 9.8) 17.0 (3.9, 73.4) ratio (95% CI) 14.1 (3.2, 61.9) 1.2 (0.7, 1.9) 5.6 (2.5, 12.3) 2.8 (0.4, 20.6) 4.5 (2.0, 10.0) 1.0 (0.1, 6.8) 1.7 (0.5, 5.7) 7.2 (4.5, 11.4) 14.8 (3.3, 66.8) 6.6 (2.0, 22.0) 8.6 (0.9, 79.5) 1.4 (0.7, 2.8) 3.4 (2.1, 5.3) 4.0 (2.2, 7.3) 4.1 (2.5, 6.7) 9.2 (3.3, 25.7) 1.7 (0.3, 9.5) 5.3 (1.0, 27.3) 8.1 (5.4, 12.2) 11.0 (1.1, 107.5) 72.9 (9.9, 535.3) 56.0 (33.6, 93.3) RR Relative risk 17.5% 3.8% 4.9
  12. 12. Location of margin involvement 13  Positivity rate:  Unspecified: 23.1%  Ectocervical: 10.4%  Endocervical: 11.0%  Endo- & ecto-cervical: 2.9%  Occurrence of residual/recurrent CIN2+:  Ectocervical: 7.2% (95% CI 0.0-23.6%)  Endocervical: 16.3% (95% CI 5.9-29.9%)  Endo- & ecto-cervical: 18.9% (95% CI 0.0-62.9%)
  13. 13. Accuracy to predict residual or recurrent CIN2+ 14 Margin status vs post-treatment HPV testing
  14. 14. Quality of diagnostic test accuracy studies (QUADAS tool) Marginal & HPV post-treatment status to predict treatment outcome (18 studies) P1 P2 P3 T1 T2 R1 R2 R3 F1 F2 F3 F4 F5 F6 Chua,199726 Y Y Y Y Y Y U Y Y Y U Y Y Y Chao,2004 61 Y Y Y Y U Y N Y Y Y N Y U U Nagai, 2004 65 Y Y Y Y Y Y N Y Y N N Y Y U Alonso, 200670 Y Y Y Y Y Y U Y Y Y N Y Y U Verguts,200676 Y Y Y Y Y Y N Y Y Y Y Y Y Y Fambrini,200878 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Aerssens,200981 Y Y Y Y Y Y N Y Y Y Y Y Y Y Brismar, 200982 Y Y N Y Y ? Y Y N U U Y Y Y Kang, 201087 Y Y Y Y Y Y N Y Y N N Y U U Trope,201192 Y Y U Y Y Y N Y Y Y Y Y Y Ryu,201294 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Torne,201396 Y Y Y Y Y Y N Y Y Y ? Y Y Y Kong, 201497 Y Y Y Y Y Y U Y N N N Y U U Zhao, 201498 Y Y Y Y Y Y Y Y Y Y Y Y U U Gosvig, 201599 Y Y Y Y Y Y U Y Y Y U Y Y Y Herfs, 2015100 Y Y Y Y U Y Y Y Y Y Y Y Y Y Kang, 2016101 Y Y Y Y U Y N Y Y Y Y U U U Wu, 2016102 Y Y Y Y U Y U Y Y U Y N U N % yes 100 100 88 100 78 94 28 100 89 72 50 88 67 55 % unclear 0 0 6 0 22 6 28 0 0 11 22 6 33 39 % no 0 0 6 0 0 0 44 0 11 17 28 6 0 6 Author, Year Risk of Bias Patient Selection Compared tests Reference Test Flow & Timing
  15. 15. 020.406080100 Sensitivity(%) 020406080100 Specificity (%) hrHPV margin status Accuracy of margin status and post-treatment HPV testing to predict treatment failure Sensi Speci Margins 55.8% 84.4% HPV 91.0% 83.8%
  16. 16. Accuracy of margin status and post-treatment HPV testing to predict treatment failure Absolute Absolute sensitivity (95% CI) specificity (95% CI) Margins 55.8%(45.8-65.5%) 84.4%(79.5-88.4%) hrHPV 91.0%(82.3-95.5%) 83.8%(77.7-88.7%) margins Relative sensitivity Relative specificity vs HPV 0.62 (0.53-0.72) 1.01 (0.97-1.06)
  17. 17. 0.01 0.05 0.1 0.5 1 5 10 20 50 80 90 95 99 99.5 99.9 Post-testProbability(%) 0.01 0.05 0.1 0.5 1 5 10 20 50 80 90 95 99 99.5 99.9 Pre-testProbability(%) Pre (6.6%) Post(+) (28.4%) Post(-) (0.8%) 0.01 0.05 0.1 0.5 1 5 10 20 50 80 90 95 99 99.5 99.9 Post-testProbability(%) 20 0.01 0.05 0.1 0.5 1 5 10 50 80 90 95 99 99.5 99.9 Pre-testProbability(%) Pre (6.6%) Post(+) (17.1%) Post(-) (3.7%) Margin status hrHPV Clinical utility of a test: PPP plot (pretest-posttest probability)
  18. 18. 020406080 Positivemargin(%) CKC LC LLETZ MIX <20% + margin status
  19. 19. Margin status as quality indicator of good clinical practice 05101520 %ofstudies 0 20 40 60 80 Proportion involved margins (%)
  20. 20. 21 Conclusion: prediction of cure/failure  Women with positive margins show increased risk of treatment failure  Post-treatment HPV testing: more accurate than margin status  Margin status is not an accurate quality indicator in colposcopy practice  Not even one study addresses both outcomes (obstetrical oncological safety) => object for new research)  Update of EU guidelines on management of screen+ women needed
  21. 21. 22 Margin status a good quality indicator for clinical practice?  Pertinent: (+++) RR  Reproducible: (-/+) broad  Accurate: (+)  Actionable: (+), may induce obstetrical harm  Conclusion: poor to moderate evidence
  22. 22. 23 Acknowledgements  European Federation of Colposcopy  Institut national du Cancer  European Commission: CoHear(FP7)

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