RATIONALE AND PROTOCOL
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RATIONALE AND PROTOCOL
INTRODUCTION• high disease recurrence in pN0 colon
cancer patients.• epidemiology pN0
– stage I: 16%– stage II: 38%
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
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
RATIONALE OF THE STUDY
INTRODUCTION• high disease recurrence in pN0 colon
cancer patients.• yearly estimates USA
148.000 new cases58.000 stage I/II30% recurrence and death
RATIONALE OF THE STUDY
INTRODUCTION• high disease recurrence in pN0 colon
cancer patients.
• need for 1.) improvement and 2.) study
EnRoute⊕ study
RATIONALE OF THE STUDY
RATIONALE OF THE STUDY
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
INTRODUCTION• high disease recurrence ?• high-risk pN0 group
– <10LNN, T4, perforation, obstruction, angioinvasion
– micrometastases (MM)
RATIONALE OF THE STUDY
MICROMETASTASES• a marker of tumor biology?
• relevant in pN0 colon cancer?
• treatment options?
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
RATIONALE OF THE STUDY
Van Schaik, EJSO 2008
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
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%
RATIONALE OF THE STUDY
Van Schaik, EJSO 2008
MICROMETASTASES• clinical relevance of MM: worse prognosis?• Van Schaik, EJSO 2008
RATIONALE OF THE STUDY
Van Schaik, EJSO 2008
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
MICROMETASTASES• clinical relevance of MM: worse prognosis?• Koyanagi, Clin Cancer Res 2008
RATIONALE OF THE STUDY
Koyanagi, Clin Cancer Res 2008
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 DFS5x > IHC and OS3x > RT-PCR and OS1x > IHC / RT-PCR and DFS / OS
RATIONALE OF THE STUDY
Iddings, Ann Surg Oncol 2006
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
RATIONALE OF THE STUDY
Iddings, Ann Surg Oncol 2006
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
RATIONALE OF THE STUDY
Iddings, Ann Surg Oncol 2006
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
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
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
MICROMETASTASES• clinical relevance of MM: worse prognosis?• current recruiting studies
RATIONALE OF THE STUDY
Clinicaltrials.gov
MICROMETASTASES• probable clinical relevance• treatment options?
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
RATIONALE OF THE STUDY
Oncoline.nl
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
MICROMETASTASESCochrane ReviewAdjuvant 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
EnRoute⊕ PROTOCOL
RATIONALE OF THE STUDY
RATIONALE OF THE STUDY
Cochrane.org
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)
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.
EnRoute⊕ PROTOCOL
HYPOTHESES
3. The presence of nodal ITC/MMs in pN0 colon cancer patients significantly influences prognosis negatively.
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.
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 without local or distant recurrence, or second primary colorectal cancer, during the defined period of time)
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
EnRoute⊕ PROTOCOL
EXCLUSION CRITERIA
Registration- age < 18 years
- previous colorectal surgery
- clinical tumor perforation or obstruction
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)
EnRoute⊕ PROTOCOL
EXCLUSION CRITERIA
Randomization- high risk pN0 according to: LNN < 10, T4,
perforation/obstruction, lymphangioinvasion
- chemotherapy-related exclusion criteria
EnRoute⊕ PROTOCOL
CONSORT STATEMENT
EnRoute⊕ PROTOCOL
RANDOMIZATION
• centrally-performed, computer-generated• Datacenter Heelkunde LUMC
• 1:1 ratio
• block-randomization per center
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
– micrometastases• enforcement quality colon cancer treatment
– standardized surgery– standardized pathological examination
ACKNOWLEDGEMENTSSteering 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
PARTICIPATE IN
www.enrouteplus.nl
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