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Presentation study protocol
Presentation study protocol
Presentation study protocol
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Presentation study protocol
Presentation study protocol
Presentation study protocol
Presentation study protocol
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Presentation study protocol
Presentation study protocol
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Presentation study protocol
Presentation study protocol
Presentation study protocol
Presentation study protocol
Presentation study protocol
Presentation study protocol
Presentation study protocol
Presentation study protocol
Presentation study protocol
Presentation study protocol
Presentation study protocol
Presentation study protocol
Presentation study protocol
Presentation study protocol
Presentation study protocol
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Presentation study protocol
Presentation study protocol
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Presentation study protocol
Presentation study protocol
Presentation study protocol
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Presentation study protocol

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enrouteplus

enrouteplus

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  • 1. RATIONALE AND PROTOCOL
  • 2. RATIONALE OF THE STUDY INTRODUCTION • high disease recurrence in pN0 colon cancer patients. • epidemiology pN0 – stage I: 16% – stage II: 38%
  • 3. RATIONALE OF THE STUDY INTRODUCTION • high disease recurrence in pN0 colon cancer patients. • epidemiology pN0 ~ 10.000 new CC pts – stage I: 16% ~ 5.400 stage I-II – stage II: 38% in the Netherlands
  • 4. RATIONALE OF THE STUDY INTRODUCTION • high disease recurrence in pN0 colon cancer patients. • 5-yr disease recurrence 5yr OS stage I 10% 90% stage II 15-30% 75% ~ 1620 pts yearly in the Netherlands
  • 5. RATIONALE OF THE STUDY INTRODUCTION • high disease recurrence in pN0 colon cancer patients. • yearly estimates USA • 148.000 new cases • 58.000 stage I/II • 30% recurrence and death
  • 6. RATIONALE OF THE STUDY INTRODUCTION • high disease recurrence in pN0 colon cancer patients. • need for 1.) improvement and 2.) study EnRoute study
  • 7. Medisch Contact 2010 RATIONALE OF THE STUDY
  • 8. Steenbergen, EJSO 2009 RATIONALE OF THE STUDY
  • 9. Van der Zaag, EJSO 2009 RATIONALE OF THE STUDY
  • 10. Van der Zaag, EJSO 2009 RATIONALE OF THE STUDY
  • 11. RATIONALE OF THE STUDY INTRODUCTION • high disease recurrence ? • high-risk pN0 group – <10LNN, T4, perforation, obstruction, angioinvasi on – micrometastases (MM)
  • 12. RATIONALE OF THE STUDY MICROMETASTASES • a marker of tumor biology? • relevant in pN0 colon cancer? • treatment options?
  • 13. Van Schaik, EJSO 2008 RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • Van Schaik, EJSO 2008 – retrospective study cohort 2000 – 2002 – 137 consecutive Dukes A/B CC patients – serial sectioning & IHC (cytokeratin) of all lymph nodes – aim: relation pN0micro+ and DFS/OS
  • 14. Van Schaik, EJSO 2008 RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • Van Schaik, EJSO 2008 – retrospective study cohort 2000 – 2002 – median FU: 53 months – recurrence vs no recurrence: 41% vs 16% MM
  • 15. Van Schaik, EJSO 2008 RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • Van Schaik, EJSO 2008 – retrospective study cohort 2000 – 2002 – median FU: 53 months – 5-yr OS N0micro+ vs N0 62 vs 79% – DFS N0micro+ vs N0 51 vs 72%
  • 16. Van Schaik, EJSO 2008 RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • Van Schaik, EJSO 2008
  • 17. Koyanagi, Clin Cancer Res 2008 RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • Koyanagi, Clin Cancer Res 2008 – prospective multicenter trial – 67 patients with colorectal cancer; T1-3 – SLNM in 99% and MM detection by RT-PCR
  • 18. Koyanagi, Clin Cancer Res 2008 RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • Koyanagi, Clin Cancer Res 2008
  • 19. Iddings, Ann Surg Oncol 2006 RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • Iddings, Ann Surg Oncol 2006, meta-analysis – 25 articles reviewed, 10 met inclusion criteria – aim: relation pN0micro+ and DFS/OS • 4x > IHC and DFS • 5x > IHC and OS • 3x > RT-PCR and OS • 1x > IHC / RT-PCR and DFS / OS
  • 20. Iddings, Ann Surg Oncol 2006 RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • Iddings et al. – RT-PCR-studies: n = 173 – Noura, Rosenberg and Liefers – upstaging RT-PCR 37% N0 to Nmicro+ – absolute survival difference 18.7% at 3 yrs
  • 21. Iddings, Ann Surg Oncol 2006 RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • Iddings et al. – upstaging IHC 32% N0 to Nmicro+ – DFS difference tended to be shorter (76% vs 80%, NS, great variation between small studies) – OS tended to be shorter also (81 vs 83%) 3 yrs
  • 22. Iddings, Ann Surg Oncol 2006 RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • Iddings et al.: A large multicenter controlled trial with standardized lymph node harvesting and processing methodologies would be pivotal in determining which N0 patients would benefit most from adjuvant therapy
  • 23. Cahill, BMC Surg 2008 RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • Cahill, BMC Surg 2008 – meta-analysis – 63 studies reviewed – 52 studies included – aim: accuracy SLNM
  • 24. Cahill, BMC Surg 2008 RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • Cahill, BMC Surg 2008 – meta-analysis – 63 studies reviewed – 52 studies included – aim: accuracy SLNM
  • 25. Clinicaltrials.gov RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • current recruiting studies
  • 26. RATIONALE OF THE STUDY MICROMETASTASES • probable clinical relevance • treatment options?
  • 27. Oncoline.nl RATIONALE OF THE STUDY MICROMETASTASES • treatment options? • guideline: adjuvant chemotherapy not beneficial in stage II colon cancer – IMPACT-B2 study – Figueredo, et al. J Clin Oncol 2004 – Gill, et al. J Clin Oncol 2004
  • 28. Oncoline.nl RATIONALE OF THE STUDY MICROMETASTASES • treatment options? • guideline: adjuvant chemotherapy not beneficial in stage II colon cancer • guideline: adjuvant chemotherapy beneficial in high-risk stage II colon cancer patients
  • 29. Cochrane.org RATIONALE OF THE STUDY MICROMETASTASES Cochrane Review Adjuvant therapy for completely resected stage II colon cancer – DFS benefit with adjuvant chemotherapy – discuss adjuvant chemotherapy in high risk pN0 patients – need to further define high risk features – randomization to observational arms still ethical
  • 30. EnRoute PROTOCOL
  • 31. RATIONALE OF THE STUDY
  • 32. Cochrane.org RATIONALE OF THE STUDY
  • 33. EnRoute PROTOCOL HYPOTHESES 1. The high recurrence rate in pN0 colon cancer patients (up to 30% in 5 year) is due to conventional risk factors (tumor obstruction/perforation, T4, LNN < 10, and/or lymphangioinvasion) and to currently unknown risk factors (isolated tumor cells/micrometastases)
  • 34. EnRoute PROTOCOL HYPOTHESES 2. Ex vivo SLNM procedure and focussed examination of sentinel nodes by using serial sectioning and immunohistochemical methods detect ITCs/MMs in pN0 colon cancer patients.
  • 35. EnRoute PROTOCOL HYPOTHESES 3. The presence of nodal ITC/MMs in pN0 colon cancer patients significantly influences prognosis negatively.
  • 36. EnRoute PROTOCOL HYPOTHESES 4. Treatment with adjuvant chemotherapy of pN0micro+ colon cancer patients results in better 3-year disease free and overall survival of stage II colon cancer patients.
  • 37. EnRoute PROTOCOL STUDY DESIGN • multicenter, open label, randomized clinical trial. – run-in phase
  • 38. EnRoute PROTOCOL STUDY DESIGN flow chart
  • 39. EnRoute PROTOCOL PRIMARY END-POINT - 3-year disease free survival (DFS) in study groups (proportion of patients without local or distant recurrence, or second primary colorectal cancer, during the defined period of time)
  • 40. EnRoute PROTOCOL INCLUSION CRITERIA Registration - histological proven colon cancer, clinically localized, judged potentially resectable for cure, without intraoperatively gross nodal involvement - radiological suspicion of colon cancer, clinically localized, judged potentially resectable for cure, without intraoperatively gross nodal involvement - written informed consent
  • 41. EnRoute PROTOCOL EXCLUSION CRITERIA Registration - age < 18 years - previous colorectal surgery - clinical tumor perforation or obstruction
  • 42. EnRoute PROTOCOL INCLUSION CRITERIA Randomization - pN0micro+ colon cancer patients (stage I/II, Dukes A/B) - patients deemed to be fit for chemotherapy treatment (WHO classification ≤ 1; ASA classification ≤ 2)
  • 43. EnRoute PROTOCOL EXCLUSION CRITERIA Randomization - high risk pN0 according to: LNN < 10, T4, perforation/obstruction, lymphangioinvasion - chemotherapy-related exclusion criteria
  • 44. EnRoute PROTOCOL CONSORT STATEMENT
  • 45. EnRoute PROTOCOL RANDOMIZATION • centrally-performed, computer-generated • Datacenter Heelkunde LUMC • 1:1 ratio • block-randomization per center
  • 46. EnRoute PROTOCOL CHEMOTHERAPY TREATMENT • CAPOX • 8 cycles of 2 weeks; 1 week interval
  • 47. EnRoute PROTOCOL FOLLOW UP
  • 48. EnRoute PROTOCOL CONCLUSION • high disease recurrence in pN0 colon • delineation high risk pN0 patientgroup – micrometastases • enforcement quality colon cancer treatment – standardized surgery – standardized pathological examination
  • 49. PATHOLOGY PROTOCOL ACKNOWLEDGEMENTS Steering investigators – K. (Koop) Bosscha (JBZ) Principal Investigator – D.J. (Daan) Lips (JBZ) Study coordinator – B. (Boukje) Koebrugge (JBZ) PhD student – P. (Peet) Nooijen (JBZ) – H.J. (Hans) van de Linden (JBZ) – H.F. (Hans) Pruijt (JBZ) – V.T.H.B.M. (Vincent) Smit (LUMC) – H. (Hein) Putter (LUMC) – G.J. (Gerrit-Jan) Liefers (LUMC) – C.J.H. (Cock) van de Velde (LUMC) Co-Principal Investigator Educational Grant:
  • 50. PARTICIPATE IN www.enrouteplus.nl

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