RATIONALE AND
  PROTOCOL
RATIONALE OF THE STUDY
INTRODUCTION
• high disease recurrence in pN0 colon
  cancer patients.
• epidemiology pN0
  – stage...
RATIONALE OF THE STUDY
INTRODUCTION
• high disease recurrence in pN0 colon
  cancer patients.
• epidemiology pN0       ~ 1...
RATIONALE OF THE STUDY
INTRODUCTION
• high disease recurrence in pN0 colon
  cancer patients.
• 5-yr disease recurrence   ...
RATIONALE OF THE STUDY
INTRODUCTION
• high disease recurrence in pN0 colon
  cancer patients.
• yearly estimates USA
    •...
RATIONALE OF THE STUDY
INTRODUCTION
• high disease recurrence in pN0 colon
  cancer patients.

• need for 1.) improvement ...
Medisch Contact 2010


RATIONALE OF THE STUDY
Steenbergen, EJSO 2009


RATIONALE OF THE STUDY
Van der Zaag, EJSO 2009


RATIONALE OF THE STUDY
Van der Zaag, EJSO 2009


RATIONALE OF THE STUDY
RATIONALE OF THE STUDY
INTRODUCTION
• high disease recurrence ?
• high-risk pN0 group
  – <10LNN, T4, perforation, obstruc...
RATIONALE OF THE STUDY
MICROMETASTASES
• a marker of tumor biology?

• relevant in pN0 colon cancer?

• treatment options?
Van Schaik, EJSO 2008


 RATIONALE OF THE STUDY
MICROMETASTASES
• clinical relevance of MM: worse prognosis?
• Van Schaik,...
Van Schaik, EJSO 2008


 RATIONALE OF THE STUDY
MICROMETASTASES
• clinical relevance of MM: worse prognosis?
• Van Schaik,...
Van Schaik, EJSO 2008


 RATIONALE OF THE STUDY
MICROMETASTASES
• clinical relevance of MM: worse prognosis?
• Van Schaik,...
Van Schaik, EJSO 2008


 RATIONALE OF THE STUDY
MICROMETASTASES
• clinical relevance of MM: worse prognosis?
• Van Schaik,...
Koyanagi, Clin Cancer Res 2008


 RATIONALE OF THE STUDY
MICROMETASTASES
• clinical relevance of MM: worse prognosis?
• Ko...
Koyanagi, Clin Cancer Res 2008


 RATIONALE OF THE STUDY
MICROMETASTASES
• clinical relevance of MM: worse prognosis?
• Ko...
Iddings, Ann Surg Oncol 2006


 RATIONALE OF THE STUDY
MICROMETASTASES
• clinical relevance of MM: worse prognosis?
• Iddi...
Iddings, Ann Surg Oncol 2006


 RATIONALE OF THE STUDY
MICROMETASTASES
• clinical relevance of MM: worse prognosis?
• Iddi...
Iddings, Ann Surg Oncol 2006


 RATIONALE OF THE STUDY
MICROMETASTASES
• clinical relevance of MM: worse prognosis?
• Iddi...
Iddings, Ann Surg Oncol 2006


 RATIONALE OF THE STUDY
MICROMETASTASES
• clinical relevance of MM: worse prognosis?
• Iddi...
Cahill, BMC Surg 2008


 RATIONALE OF THE STUDY
MICROMETASTASES
• clinical relevance of MM: worse prognosis?
• Cahill, BMC...
Cahill, BMC Surg 2008


 RATIONALE OF THE STUDY
MICROMETASTASES
• clinical relevance of MM: worse prognosis?
• Cahill, BMC...
Clinicaltrials.gov


 RATIONALE OF THE STUDY
MICROMETASTASES
• clinical relevance of MM: worse prognosis?
• current recrui...
RATIONALE OF THE STUDY
MICROMETASTASES
• probable clinical relevance
• treatment options?
Oncoline.nl


 RATIONALE OF THE STUDY
MICROMETASTASES
• treatment options?
• guideline: adjuvant chemotherapy not benefici...
Oncoline.nl


 RATIONALE OF THE STUDY
MICROMETASTASES
• treatment options?
• guideline: adjuvant chemotherapy not benefici...
Cochrane.org


 RATIONALE OF THE STUDY
MICROMETASTASES
Cochrane Review
Adjuvant therapy for completely
resected stage II c...
EnRoute PROTOCOL
RATIONALE OF THE STUDY
Cochrane.org


RATIONALE OF THE STUDY
EnRoute PROTOCOL
HYPOTHESES

 1. The high recurrence rate in pN0 colon cancer patients
    (up to 30% in 5 year) is due t...
EnRoute PROTOCOL
HYPOTHESES

 2. Ex vivo SLNM procedure and focussed examination of
    sentinel nodes by using serial se...
EnRoute PROTOCOL
HYPOTHESES

 3. The presence of nodal ITC/MMs in pN0 colon cancer
    patients significantly influences ...
EnRoute PROTOCOL
HYPOTHESES

 4. Treatment with adjuvant chemotherapy of
    pN0micro+ colon cancer patients results in b...
EnRoute PROTOCOL
STUDY DESIGN

• multicenter, open label, randomized clinical trial.
   – run-in phase
EnRoute PROTOCOL
STUDY DESIGN
flow chart
EnRoute PROTOCOL
PRIMARY END-POINT

- 3-year disease free survival (DFS) in study groups
  (proportion of patients withou...
EnRoute PROTOCOL
INCLUSION CRITERIA
Registration
- histological proven colon cancer, clinically localized, judged
  poten...
EnRoute PROTOCOL
EXCLUSION CRITERIA
Registration
- age < 18 years
- previous colorectal surgery
- clinical tumor perforat...
EnRoute PROTOCOL
INCLUSION CRITERIA
Randomization
- pN0micro+ colon cancer patients (stage I/II, Dukes A/B)
- patients de...
EnRoute PROTOCOL
EXCLUSION CRITERIA
Randomization
- high risk pN0 according to: LNN < 10, T4,
  perforation/obstruction, ...
EnRoute PROTOCOL
CONSORT STATEMENT
EnRoute PROTOCOL
RANDOMIZATION

•   centrally-performed, computer-generated
•   Datacenter Heelkunde LUMC
•   1:1 ratio
•...
EnRoute PROTOCOL
CHEMOTHERAPY TREATMENT

• CAPOX

• 8 cycles of 2 weeks; 1 week interval
EnRoute PROTOCOL
FOLLOW UP
EnRoute PROTOCOL
CONCLUSION
• high disease recurrence in pN0 colon
• delineation high risk pN0 patientgroup
  – micrometa...
PATHOLOGY PROTOCOL
ACKNOWLEDGEMENTS
Steering investigators
    –   K. (Koop) Bosscha (JBZ)             Principal Investiga...
PARTICIPATE IN




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Presentation study protocol

  1. 1. RATIONALE AND PROTOCOL
  2. 2. RATIONALE OF THE STUDY INTRODUCTION • high disease recurrence in pN0 colon cancer patients. • epidemiology pN0 – stage I: 16% – stage II: 38%
  3. 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. 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. 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. 6. RATIONALE OF THE STUDY INTRODUCTION • high disease recurrence in pN0 colon cancer patients. • need for 1.) improvement and 2.) study EnRoute study
  7. 7. Medisch Contact 2010 RATIONALE OF THE STUDY
  8. 8. Steenbergen, EJSO 2009 RATIONALE OF THE STUDY
  9. 9. Van der Zaag, EJSO 2009 RATIONALE OF THE STUDY
  10. 10. Van der Zaag, EJSO 2009 RATIONALE OF THE STUDY
  11. 11. RATIONALE OF THE STUDY INTRODUCTION • high disease recurrence ? • high-risk pN0 group – <10LNN, T4, perforation, obstruction, angioinvasi on – micrometastases (MM)
  12. 12. RATIONALE OF THE STUDY MICROMETASTASES • a marker of tumor biology? • relevant in pN0 colon cancer? • treatment options?
  13. 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. 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. 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. 16. Van Schaik, EJSO 2008 RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • Van Schaik, EJSO 2008
  17. 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. 18. Koyanagi, Clin Cancer Res 2008 RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • Koyanagi, Clin Cancer Res 2008
  19. 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. 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. 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. 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. 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. 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. 25. Clinicaltrials.gov RATIONALE OF THE STUDY MICROMETASTASES • clinical relevance of MM: worse prognosis? • current recruiting studies
  26. 26. RATIONALE OF THE STUDY MICROMETASTASES • probable clinical relevance • treatment options?
  27. 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. 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. 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. 30. EnRoute PROTOCOL
  31. 31. RATIONALE OF THE STUDY
  32. 32. Cochrane.org RATIONALE OF THE STUDY
  33. 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. 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. 35. EnRoute PROTOCOL HYPOTHESES 3. The presence of nodal ITC/MMs in pN0 colon cancer patients significantly influences prognosis negatively.
  36. 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. 37. EnRoute PROTOCOL STUDY DESIGN • multicenter, open label, randomized clinical trial. – run-in phase
  38. 38. EnRoute PROTOCOL STUDY DESIGN flow chart
  39. 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. 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. 41. EnRoute PROTOCOL EXCLUSION CRITERIA Registration - age < 18 years - previous colorectal surgery - clinical tumor perforation or obstruction
  42. 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. 43. EnRoute PROTOCOL EXCLUSION CRITERIA Randomization - high risk pN0 according to: LNN < 10, T4, perforation/obstruction, lymphangioinvasion - chemotherapy-related exclusion criteria
  44. 44. EnRoute PROTOCOL CONSORT STATEMENT
  45. 45. EnRoute PROTOCOL RANDOMIZATION • centrally-performed, computer-generated • Datacenter Heelkunde LUMC • 1:1 ratio • block-randomization per center
  46. 46. EnRoute PROTOCOL CHEMOTHERAPY TREATMENT • CAPOX • 8 cycles of 2 weeks; 1 week interval
  47. 47. EnRoute PROTOCOL FOLLOW UP
  48. 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. 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. 50. PARTICIPATE IN www.enrouteplus.nl
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