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1 Crespi Screening Rettocolon Presentation Transcript

  • 1. Lo stato dell’arte nello screening del CRC Roma – 28 Novembre 2009 Massimo CRESPI, Daniele LISI Istituto “Regina Elena” – Roma ASL RmB Poliamb. Don Bosco - Roma
  • 2. Possible actions for CRC Prevention Level II: Obtained from at least one properly designed RCT Level III: Obtained from a control trial without randomisation, “ “ cohort or case-control analytic studies, “ “ multiple time-series with/without the intervention Physical activity Energy intake Fresh fruit and vegetable Dietary fat Calcium Fiber Anti-oxidant vitamines Selenium SCREENING Anti-inflammatory drugs Summary of action with level II or III of evidence
  • 3.
    • Screening is a mean to accomplish early detection
    • Target disease has to be prevalent
    • Earlier diagnosis has to improve outcome
    • Test (s) have to be sensitive, specific, acceptable, affordable.
    Rationale of screening The concepts of screening in 4 sentences
  • 4. Established concepts FOBTs For early detection only of CRC Colonoscopy For early detection and prevention of CRC and polyps
  • 5. Results of European / USA RCTs based on FOBT
    • Europe (4 studies - biennial FOBT - 320,000 subjects) 15 – 18 % reduction in mortality
    • In subjects complying to all periodic recalls, reduction was 43 %
    • Early stage were 41 % in intervention arm vs 11% in controls
    • USA (Minnesota), annual FOBT, reduction in mortality in participating subjects was 55 %
    G-FOBT was the method of choice worldwide
  • 6. GUAIAC TEST ON 3 FECAL SAMPLES CHEAP AND SIMPLE TO USE !
  • 7. Mortality reduction in the active participating population - Funen : - 33 % - Nottingham : - 39% - Burgundy : - 33% - Minnesota : - 55 %
  • 8. FOBT long-term results The Danish RCT study
    • Biennial guaiac-FOBT on 3 fecal samples
    • 9-rounds of screening completed
    • Compliance 1st invitation 67 %
    • “ to re-testing 90 %
    • Overall colonoscopy rate 5.3 %
    • Dukes A in screened 36 % ( 11 % controls)
    • Overall reduction in mortality 11 %
    • Reduction in mortality in those attending all 9-rounds 43 %
    Kronborg O. 2004
  • 9. Proportion of TNM stage 1 cancer in the screened and control population Downstaging 20% 16% 40% Burgundy 12% 11% 44% Nottingham 11% 9% 40% Funen Control population Test not done Positive test
  • 10. RESULTS OF A CRUCIAL COHORT STUDY (JPHC) ON CRC SCREENING IN JAPAN 42,150 subject – 551,459 person/years f.u. (13 years) RR death from CRC in screened 0.28 (0.13 - 0.61) a 70% reduction RR death from all causes 0.70 (0.61 - 0.79) a 30% reduction Incidence of CRC similar but RR 0.41 for advanced CRC Conclusions: no need for RCTs to implement screening (not ethical) KJ Lee et al, 2007
  • 11. Reduction in mortality beyond lead time and delay time bias     Summary: effects of CRC screening as shown by RCTs achieved: -15 to -55 % Improved survival (down-staging) Reduction in incidence by removals of precancerous lesions (polyps) achieved: up to 65% achieved: up to 70%
  • 12. Meinhard Classen THE STATUS QUO OF COLORECTAL CANCER SCREENING IN EUROPE A Pan - European Survey between November 2004 and March 2007 with support of René Lambert NETZWERK gegen Darmkrebs
  • 13. France Germany United Kingdom Bulgaria Poland Czech Republic Slovakia Romania Hungary Austria Italy Albania (red background: countries with national CRC screening program) Luxembourg Is CRC screening established in your country? QUESTION: ANSWER: Finland United Kingdom Germany Iceland 15 / 39 countries (38 %) established CRC screening EU members: 13 / 27 (48 %) Courtesy of M. Classen daa2map.de
  • 14. Ongoing CRC screening activities in Italy M. Zorzi et al 2006 survey - National Centre for Screening Monitoring I 5.3 – II 3.9 I 5.8 – II 4.1 I-Fobt + 46.5 % (4.8 – 81 %) 47.1% (6.7–78.1%) Compliance CRC 0.31 % AA 1.46 % CRC 0.37 % AA 1.68 % 1 st screen 81.2% (69.2 – 90.7%) 82 % (56 – 100 %) OC adherence CRC 0.13 % AA 0.77 % CRC 0.11 % AA 0.49 % 2 nd screen 56 % 55 % TNM I or II 2,107,000 827,473 Invited 69 52 Programs 2006 2005
  • 15. Ongoing CRC screening activities in Italy 2006 Regional variations M. Zorzi et al 2006 survey - National Centre for Screening Monitoring # Population covered by organized screening programs 4.8 10.0 % South 22.8 48.5 % Center 50.2 66.1 % North Actual extension (invited) Theoretical extention #
  • 16. Screening programs by PHS
    • National Law 388/2000
    • Screening Colonoscopy free of charge after 45 y of age
    • National Law 138/2004
    • Acknowledges the EU directive for cancer screenings and introduces the right for all citizens to get oncological screening free of charge
    • Allocates € 52million for 3y to implement screening of CRC and to further support cervical and breast cancer screening
  • 17. Italy 2002 Scaduto 2004 !! WWW.CANCROCOLON.IT
  • 18. Sampdoria - Parma (21 Feb 04) Scaduto 2004 !! Italy 2002 Scaduto 2004 !!
  • 19. Italy 2002 Scaduto 2004 !!
  • 20. CRC screening is feasible: by historical methods of proven efficacy and efficiency ( G-FOBT ) by actual methods I-FOBT or HeSENSA Endoscopy (invasive, costly, but highly efficient in reducing also incidence by polypectomy) by methods in development Virtual Colonoscopy Pill cam Stool-DNA
  • 21. Stool Tests G-FOBT Immuno FOBT sDNA
  • 22. Relative efficiency of G-FOBT and I-FOBT for CRC and AA (330 subj. undergoing OC) Rozen P. et al. 2009 # mostly flat lesions in right colon 68.8 53.1 53.1 Sensitivity % 2.1 91.9 I-FOBT (2 samples) 2.1 94.0 I-FOBT (1 sample) 8.1 59.4 G-FOBT (3samples) No. of OC / Neoplasia Specificity % 7 8 15 AA not identified # both I-FOBT G-FOBT
  • 23. Performance Characteristics of Stool DNA in the detection of CRC
    • No dietary restrictions
    • No stool sampling (utilizes the entire stool !?!)
    • Several studies suggesting strong patient acceptance
    • Testing interval uncertain
    • Uncertainty about the meaning of false positives
    46% Chen, et al JNCI, 2005 (2) 63% Syngal, et. al Cancer, 2006 (1) 70% Whitney, et al J Mol Diagn, 2004 (1.1) 88% Itzkowitz, et al DDW-AB, 2006 (2) 51.6% Imperiale, et al NEJM, 2004 (1) 91% Ahlquist, et al Gastro, 2000 (1) Sensitivity for Cancer Study with One-Time Testing (v)
  • 24. sDNA - Sample Collection Collection bucket inserted into bracket and installed under toilet seat Patient supplies whole stool sample; no diet or medication restrictions Patient seals sample in outer container and freezer pack Patient seals container and ships back to designated lab (all packing materials and labels supplied)
  • 25. Stool DNA
    • Limitations
    • Misses some cancers
    • Sensitivity for adenomas with current commercial version of test is low
    • Technology (and test versions) are in transition
    • Appropriate re-screening interval is not known
    • Cost is a problem
    • Not clear how to manage positive stool DNA test if colonoscopy is negative (Real False positive ??)
  • 26. CRC stool screening tests Imperiale TF et al, NEJM (2008) 351:274-14 5 400 to 800 Cost (USD) 12.9 13.0 15.0 10.8
    • 51.6
    • 56.0
      • 32.5
      • 18.2
    Sensitivity Adc Adc N-Adenom-HGD Adv.ad+ ADC Hemoccult II (guaiac) DNA
  • 27. Endoscopy
  • 28. Endoscopic screening of CRC Colonoscopy Flexible sigmoidoscopy
  • 29. Miss rate of Flexible Sigmoidoscopy for proximal lesions in subjects with no-distal lesions Range from 22.8 % to 65 % (results of more than 50 studies)
  • 30. Efficacy of colonoscopy in reducing incidence of CRC
    • Results of two multi-center studies based on long-term follow-up of asymptomatic subjects after a colonoscopy with polypectomy
    • US National Polyp Study (prospective) - 76 %
    • Italian Multicenter Study (retrospective) - 66 %
    An alternative screening method But COMPLIANCE in general population is low
  • 31. Screening Colonoscopy (OC) in asymptomatic subjects Meta-analysis of 10 studies, 68,324 participants Niv Y et al, 2007 Perforation 0.01 % Bleeding 0.05 % Complication 5 % (4 – 6 %) Advanced Aden. 19 % (15 - 23 %) Adenoma 0.78 % (0.13 – 2.97 %) Stage I or II 77 % CRC 97 % (94 – 98 %) Complete (OC)
  • 32. Bowles CJA, Gut 2004 Colonoscopy Complications
  • 33. Risk of CRC after negative colonoscopy Geul K et al, 2007 About 80% subjects with CRC between 50 – 58y have already one adenoma at 50y Singh et al, 2009 Right colon Left colon Overall 0.67 0.16 0.55 RR
  • 34. Repeated screen colonoscopy after 5y Chinese average risk Leung WK et al, 2009 RR 19.6 --- 24.6 % Any polyp Advanced Ad. No polyp Baseline findings 20.7 % 1.4 % Advanced Adenomas After 5y
  • 35. Advanced Colorectal Neoplasia after Polypectomy (pooled 9,167 subjects - mean age 62y - follow-up 47,2 months) Martinez ME et al, 2009 AA 11.2 % (1 out of 10) – Invasive CRC 0.6 % (missed or incompletely excised lesions at baseline ?) RR 1.68 Proximal adenoma from 1.39 to 2.70 (60y or more) Older age RR 1.40 Male sex Family history High grade dysplasia No. of adenomas and size Risk factors at baseline for AA and CRC at follow-up (not significant) RR 1.08 (not significant) RR 1.32 (size RR 1.56)
  • 36. Sex and Advanced Neoplasia Meta-analysis of 17 studies, 924,932 participants Nguyen Y et al, 2009 Women are protected until menopause and by HRT (tumor suppressor role of estrogen receptor beta) 1.53 ≥ 70 1.78 60 – 69 1.86 50 – 59 1.53 40 – 49 RR men vs women Age group
  • 37. Virtual Colonoscopy (CTC)
  • 38. Possible impact of Virtual Colonography
    • Mixed results: Pickhardt (+), Johnson (-), Cotton (-), Rockey (-)
    • No therapeutic potential
    • Radiation risk
    • High up front costs
  • 39. What about diminutive polips ≤ 9 mm ?
    • Rate of cancerization at f.u. ?
    • Pickhardt < 0.1%
    • From literature ≈ 3 – 5 % ?
    • Preference for OC polipectomy after CTC
    • Pickhardt 60 % NO 3y f.u. CTC
    • Shah 85 % YES (same by GPs)
    Pickhardt RJ 2009 Shah JP 2009
  • 40. Distribution of advanced neoplasia according to polyp size at screening colonoscopy (data from 4 studies with 20,562 subjects) Advanced adenomas detected in 1155 subjects (5.6% overall) of these in diminutive polyps ( ≤ 5mm) 4.6% in small polyps (6-9mm) 7.9% in large polyps ( ≥ 10mm) 87.5% Hassan C et al, 2009
  • 41. Colon capsule (CE) Ø11 mm 31 mm
  • 42. Any method . . . but compliance ??
  • 43. Compliance to screening tests in the two Italian studies
    • FOBT / Colonoscopy screening in North/Center/South Italy
    • (AMOD multicenter RCT) FOBT 27.1%
    • CS 10.0%
    • (Lisi, Hassan, Crespi et al. 2009)
    • FOBT / Colonoscopy screening in Northern Italy
    • (SCORE3) FOBT 32.3%
    • CS 26.5%
    • (Segnan N, et al. 2007)
  • 44. Compliance to screening tests in average practice (in the real world !!)
    • Population based extent of CRC screening
    • in Ontario (Canada)
    • <20%
    • (Rabeneck L. et al. 2004)
    • Participation in colonoscopy population
    • screening in Australia
            • 18.2%
            • (Scott RG et al. 2004)
  • 45. In the real world….
        • Uptake of screening opportunities is not exceeding 40 to 50% even in the more developed, wealthy nations
        • In unselected general population it is as low as 20% (Australia, Canada)
        • The scarce convincememnt of GPs in advising CRC screening and the embarassment to discuss bowel matters are problems that only a strong action towards increased awareness may overcome
  • 46. Important factors to improve compliance to screening Awareness !! The data from US and Europe show substantial differences
  • 47. ? How to increase compliance ? The problem is: compliance to any screening test … …
  • 48.  
  • 49.  
  • 50. Brazil 2004 !!
  • 51. Most efficient CRC screen strategies by mathem. models (starting age 50y) in term of life-years gained and mortality reduction These tests provide similar life-years gained, but only if OC adherence is 50% or more. Zauber A et al, 2008 65.7 % HeSENSA annually + Flex.S. every 5y 66.0 % Hemoccult SENSA annually 64.6 % Colonoscopy (OC) every 10y 64.6 % I-FOBT (max sensitivity) every 2 – 3 y 65.7 % Mortality reduction I-FOBT every 2 – 3 y + Flex.S. every 5y
  • 52. How identify High Risk subjects ? 25% COLONOSCOPY
  • 53. A bit of culture, a minimal effort, a great yield! HOW identify them ?? … by a simple question Accuracy 80 % Church, Dis Colon Rectum, 2000 A specific dedication by General Practitioners is suggested being crucial in selecting subjects , by simple questions , for:  Genetic syndromes  Familiar risk These patients NEED COLONOSCOPY
  • 54. Open questions
    • Still debatable:
    • Colonoscopy as preferred strategy (ACG 2009, ASGE, ecc.), but compliance >50% needed (Zauber)
    • IS THAT THE CASE?
    • - FOBTs high specificity means lower sensitivity and less colonoscopies
    • IS THAT ADVISABLE ?
    • Is CTC in skilled hands an alternative strategy?
    • What about “ capsule ”?
    • Is DNA fecal testing affordable, effective and practicable?
  • 55. Conclusions: some already established concepts Any test is better than NO-test In the US 1990 – 2005 CRC Mortality Males -31.8 % Females -28.0 % FOBTs For early detection only of CRC Colonoscopy For early detection and prevention of CRC and polyps
  • 56. CONCLUSIONS Colonoscopy is the test of choice in high risk subjects S creening c olonoscopy may be proposed today as an option in average risk subjects in the frame of a direct doctor / patient relationship Crucial to the selection of high risk subjects is the informed and conscious involvement of GPs
  • 57. South Center North FOBT programs: adjusted compliance of single program by Region
  • 58. AMOD study Variability of compliance to FOBT Mean 27.1 % (range 7.9 – 90.9 %) North 26.7 % South 29.9 % Center 26.1 % % GPs North 26.7 % Center 26.1 % North 26.7 % Center 26.1 % North 26.7 % South 29.9 % Center 26.1 % North 26.7 % South 29.9 % Center 26.1 % North 26.7 % Lisi D. et al, DLD 2009
  • 59. AMOD study Variability of compliance to OC Mean 10.0 % (range 0.8 – 54.9 %) North 10.7 % South 2.8 % Center 13.3 % % GPs Lisi D. et al, DLD 2009
  • 60. The ultimate efficiency indicator of preventive diagnostic therapeutic strategies and the frame for evaluation of Health Systems Survival of Cancer Patients
  • 61. Colorectal Cancer (Males) 5y Survival (%) EPICENTRO.ISS.IT EUROCARE.IT Eurocare-3 study Annals of Oncology 2003 (Suppl. 5) vol. 14
  • 62. EPICENTRO.ISS.IT EUROCARE.IT Eurocare-3 study Annals of Oncology 2003 (Suppl. 5) vol. 14 (Not EU) (Not EU) (Not EU) England Scotland Wales 5y survival of CRC from Cancer Registries
  • 63. CRC survival in Italy
  • 64. D.K. Podolsky (NEJM, 2000) : “ The barrier to reducing the numbers of deaths from Colorectal Cancer is not a lack of scientific data but a lack of organization, financial and societal commitment!” After 9 years barriers are still barriers!
  • 65. Low public compliance to screening colonoscopy (from Jack Tippit, Saturday Evening Post)