Presentation study protocol
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The document outlines the rationale and protocol for a study investigating micrometastases in pN0 colon cancer patients. It notes high recurrence rates in this group and aims to 1) improve risk stratification and 2) study the impact of adjuvant chemotherapy for pN0micro+ patients. The proposed study is a multicenter, randomized clinical trial that will examine lymph nodes from pN0 colon cancer patients using serial sectioning and immunohistochemistry to detect micrometastases, and randomize pN0micro+ patients to observation or adjuvant chemotherapy to evaluate 3-year disease-free survival.
Presentation study protocol
- 2. INTRODUCTION high disease recurrence in pN0 colon cancer patients. epidemiology pN0 stage I: 16% stage II: 38% RATIONALE OF THE STUDY
- 3. 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 RATIONALE OF THE STUDY
- 4. 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 RATIONALE OF THE STUDY
- 5. 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 RATIONALE OF THE STUDY
- 6. INTRODUCTION high disease recurrence in pN0 colon cancer patients. need for 1.) improvement and 2.) study EnRoute study RATIONALE OF THE STUDY
- 7. RATIONALE OF THE STUDY Medisch Contact 2010
- 8. RATIONALE OF THE STUDY Steenbergen, EJSO 2009
- 9. RATIONALE OF THE STUDY Van der Zaag, EJSO 2009
- 10. RATIONALE OF THE STUDY Van der Zaag, EJSO 2009
- 11. INTRODUCTION high disease recurrence ? high-risk pN0 group <10LNN, T4, perforation, obstruction, angioinvasion micrometastases (MM) RATIONALE OF THE STUDY
- 12. MICROMETASTASES a marker of tumor biology? relevant in pN0 colon cancer? treatment options? RATIONALE OF THE STUDY
- 13. 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 pN0 micro+ and DFS/OS RATIONALE OF THE STUDY Van Schaik, EJSO 2008
- 14. 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 RATIONALE OF THE STUDY Van Schaik, EJSO 2008
- 15. MICROMETASTASES clinical relevance of MM: worse prognosis? Van Schaik, EJSO 2008 retrospective study cohort 2000 – 2002 median FU: 53 months 5-yr OS N0 micro+ vs N0 62 vs 79% DFS N0 micro+ vs N0 51 vs 72% RATIONALE OF THE STUDY Van Schaik, EJSO 2008
- 16. MICROMETASTASES clinical relevance of MM: worse prognosis? Van Schaik, EJSO 2008 RATIONALE OF THE STUDY Van Schaik, EJSO 2008
- 17. 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 RATIONALE OF THE STUDY Koyanagi, Clin Cancer Res 2008
- 18. MICROMETASTASES clinical relevance of MM: worse prognosis? Koyanagi, Clin Cancer Res 2008 RATIONALE OF THE STUDY Koyanagi, Clin Cancer Res 2008
- 19. 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 RATIONALE OF THE STUDY Iddings, Ann Surg Oncol 2006
- 20. 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 N micro+ absolute survival difference 18.7% at 3 yrs RATIONALE OF THE STUDY Iddings, Ann Surg Oncol 2006
- 21. MICROMETASTASES clinical relevance of MM: worse prognosis? Iddings et al. upstaging IHC 32% N0 to N micro+ 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 RATIONALE OF THE STUDY Iddings, Ann Surg Oncol 2006
- 22. 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 RATIONALE OF THE STUDY Iddings, Ann Surg Oncol 2006
- 23. MICROMETASTASES clinical relevance of MM: worse prognosis? Cahill, BMC Surg 2008 meta-analysis 63 studies reviewed 52 studies included aim: accuracy SLNM RATIONALE OF THE STUDY Cahill, BMC Surg 2008
- 24. MICROMETASTASES clinical relevance of MM: worse prognosis? Cahill, BMC Surg 2008 meta-analysis 63 studies reviewed 52 studies included aim: accuracy SLNM RATIONALE OF THE STUDY Cahill, BMC Surg 2008
- 25. MICROMETASTASES clinical relevance of MM: worse prognosis? current recruiting studies RATIONALE OF THE STUDY Clinicaltrials.gov
- 26. MICROMETASTASES probable clinical relevance treatment options? RATIONALE OF THE STUDY
- 27. 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 RATIONALE OF THE STUDY Oncoline.nl
- 28. 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 RATIONALE OF THE STUDY Oncoline.nl
- 29. 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 RATIONALE OF THE STUDY Cochrane.org
- 30. EnRoute PROTOCOL
- 31. RATIONALE OF THE STUDY
- 32. RATIONALE OF THE STUDY Cochrane.org
- 33. EnRoute PROTOCOL HYPOTHESES 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
- 46. EnRoute PROTOCOL RANDOMIZATION centrally-performed, computer-generated Datacenter Heelkunde LUMC 1:1 ratio block-randomization per center
- 47. EnRoute PROTOCOL CHEMOTHERAPY TREATMENT CAPOX 8 cycles of 2 weeks; 1 week interval
- 48. EnRoute PROTOCOL FOLLOW UP
- 49. 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
- 50. 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: PATHOLOGY PROTOCOL