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The Royal Marsden
Sigmoid and Colon cancer staging
Gina BrownAcademic Department of RadiologyRoyal Marsden Hospital, UK
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– Dukes Histological system for rectal cancers extrapolated for colon cancers
– 5 year survival:– 81% if confined to bowel wall– 64% if invasion through the wall– 27% if local lymph nodes involved
– AJCC TNM staging system– T stage, N stage, M stage– 7th Edition [Edge and Compton,
2010]
Staging of colon cancers
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– Extramural Vascular Invasion (EMVI)– Reduced 5 year survival
– Depth of extramural spread– Hermanek divided T3 tumours into 4 groups
– Involvement of Non Peritonealised Resection Margin – Very high risk local recurrence
– Histological grade– Well differentiated, 76% 5 year survival– Poorly differentiated, 31% 5 year survival
Other prognostic factors
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How often are prognostic factors reported preoperatively in colon cancer?- EMVI- depth of extramural spread in mm - non-peritonealised resection margin- transperitoneal breach?
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Currently: no role for imaging for local staging of colon cancers?
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Survival
Colon CancerAge-Standardised Five-Year Relative Survival RatesEngland and Wales 1971-1995, England 1996-2009
Rectal CancerAge-Standardised Five-Year Relative Survival RatesEngland and Wales 1971-1995, England 1996-2009
Cancer Research UK
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MRI based Selectionof patientsFor range treatments
Local excision
MRI and PET surveillanceDeferral of surgery
ChemoradiotherapyRestage:Timing of surgery
after CRT6 vs 12?
Biological agents and neoadjuvant chemotherapy for MRI EMVI
Further Therapy/Extended surgery
for mrCRM/low rectal
MRI T1/T2 NxEMS /TEMS
pre/post operative CRTMRI surveillance…
MRI Low rectal Stage 3 or 4
Post CRTyMRI TRG 1-2
MRI T3a/T3b N anyLow rectal stage 1/2
Primary TME Surgery: open v laparoscopic
MRI T3c/T3d N anyEMVI positive CRM safe
potential CRM unsafe
Treatment options for Rectal Cancer
Palliative ChemotherapyMetastatectomy
Primary colon resection: laparoscopic/open
CT StagingMetastatic disease?Yes/No 80-90%
10-20%
Treatment options for Colon Cancer
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Colon Cancer has a high recurrence rate.
O’Connell 2008 ACCENT Data Set
• n=17,381• recurrence= 5,722 (32%)
J Clin Oncol. 2008 May 10;26(14):2336-41.
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Metaanalysis
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Nodal Staging
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– Meta-analysis conducted on studies assessing accuracy of CT in staging colorectal cancer to detect tumour invasion beyond MP :– Sensitivity is as high as 86%.– Specificity of 78%
– The ability of CT to predict the nodal status is however poor.
– However none of the studies ever looked at the ability of CT to predict prognosis.
Dighe S, Purkayastha S, Swift I, Tekkis PP, Darzi A, A'Hern R, Brown G: Diagnostic precision of CT in local staging of colon cancers: A Meta analysis. Clin Radiol. 2010 Sep;65(9):708-19.
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Good prognosis T2/early T3
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T3 good tumour
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Understanding T4 disease
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Poor prognosis
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*
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Poor prognosis
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CT staging of colons
– To examine whether the radiological features of the primary colonic tumour seen on the pre-operative CT scan could be used to predict clinical outcome.
– To compare pre-operative CT-based prognostication with post-operative histology
Smith N, Bees, N. Predicting Prognosis in Colon Cancer: Validation of a New Preoperative CT Staging Classification and Implications for Clinical Trials. Colorectal Disease 2006; 8
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126 scans analysed
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Prognostic score
Histological variable
Good prognosis
Poor prognosis
T stage T1, T2 or T3<5mm
T3>5mm or T4
N stage N0, N1 N2
EMVI Absent Present
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Identification of poor prognosis tumours– 56% (70/126) had CT defined poor prognosis
tumours
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T staging / prognosis
– Stage-for-stage accuracy=60.3%– Poor prognosis (Stage T3/T4, N2,
EMVI)– Overall Accuracy=83.3%
(Sensitivity=92.4%; Specificity=42.1%)
– Positive Predictive Value=89.8%; Negative Predictive Value=50.0%
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CT prediction of prognosis
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– the depth of tumour invasion beyond the muscularis propria (MP) as seen on CT and demonstrated excellent correlation with histology. – T1/T2 + T3 <5mm tumour invasion
beyond MP (87% 3-year survival).– T4+T3≥5mm tumour invasion
beyond MP (53% 3 year survival).
Smith N, Bees, N. Predicting Prognosis in Colon Cancer: Validation of a New Preoperative CT Staging Classification and Implications for Clinical Trials. Colorectal Disease 2006; 8
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Can we refine the radiological definition of poor prognosis?
Involvement of peritoneal surfaces
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Can we refine the radiological definition of poor prognosis?
Sensitivity: 78%
Specificity: 67%
Accuracy: 74%
PPV: 81%
Dighe S, Blake H, Koh MD, Swift I, Arnaout A, Temple L, Barbachano Y, Brown G: Accuracy of multidetector computed tomography in identifying poor prognostic factors in colonic cancer. Br J Surg. 2010 Sep;97(9):1407-15.
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Can we refine the radiological definition of poor prognosis?
– Involvement of the peritoneal and mesenteric surfaces
– Lymph node involvement– Sensitivity 58%– Specificity 64%
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Can we refine the radiological definition of poor prognosis?
– Data collection– Involvement of
the peritoneal and mesenteric surfaces
– Lymph node involvement
– Extramural venous invasion
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Detection of EMVI using MDCT: high positive predictive value
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Value of >5mm Extramural Depth of Spread using CT
– 77 % of patients (42 of 54)with a histologically poor prognosis were identified based on T category
– also 74 % of node-positive patients (29 of 39) compared with 58% by using size
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FOxTROT trial design
3 Fu Ox± Pan
(6 weeks)9 Fu Ox
(18 weeks)
12 Fu Ox (24 weeks) ± Panitumumab (6 weeks)
CT stagingT3+ or N2+ colon cancer,
potentially curative
n=350
n=700
Primary outcome – freedom from disease at 2 years
Randomise
Surg
Surg
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End points of Foxtrot trial1050 patients over 3 years (150 pilot +
900)
– for recurrence free survival; 80% power at p<0.05 to detect 25% proportional reduction in treatment failure, e.g. Recurrence reduced from 32% to 24%.
– for tumour shrinkage; 90% power at p<0.01 to detect a small/moderate (0.3sd) difference in pathological tumour shrinkage with addition of panitumumab, i.e. Depth of invasion.
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Imaging– what’s new in this trial?
– New staging system– Knowledge and visualisation of
peritoneal anatomy– Identification of poor prognostic
features in vivo– Quality assurance: workshops,
detailed imaging data collection
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– This trial is thus reliant on the ability of the radiologists to identify a cohort of high risk patients suitable for randomisation to receive neoadjuvant therapy.
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Summary colon cancer staging– Tumour morphology: annular, semi-annular,
mucinous, ulcerating– Site : caecum, ascending, hep flexure,
transverse, splenic flexure, descending, sigmoid– Border of infiltration: mesenteric vs
peritonealised– Diameter and thickness– T substage (good or poor): T3<5mm or >5mm– Nodal and venous spread: ileocolic, middle
colic, left colic, sigmoidal veins– Adjacent organ
infiltration/perforation/obstruction– Synchronous metastatic disease
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Was CT successful in identifying high risk? Control arm pathology– 49/50 – pT3/4 (98%)– 2643/50 – AJCC pTNM stage II/III high
risk (86%)– /50 –pNode positive (52%)– 10/50 – 20% pCRM positive– 24/48 – (50%) pEMVI positive
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Sigmoid Cancer is a problem
Dis Colon Rectum. 2010 Jan;53(1):57-64.
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Recurrence sigmoid cancer
N= Follow-up
Local recurrence colon
Local recurrence sigmoid
Cass1976
Retrospective 1968-1974 280 Min 1 yr 22,5% 25%
Willett 1984 Retrospective 533 19% 21%
Sjövall 2007
Prospective 1996-2000
1,856 Min 3 yrs 11,5% 11,6%
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• MDT 2007-09• 296 sigmoid cancers • 104 for palliative care
• Curable sigmoid cancers: n=192• No FU data at all: n=42• With FU: n=150• FU 36 months (range 1-76, median 38)
• Recurrence: 62/192 (32%) • Local recurrence: 19 (11%)
Recurrence sigmoid cancer
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High risk features
• Tumour involving non peritonealised fascial margin
• Tumour penetration of adjacent organs
• 4 or more involved nodes• Extramural venous invasion• Depth of extramural spread >5mm
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Burton 2006 Int. J. Radiation Oncology Biol. Phys
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• Primary surgery n=57
• 16 at/above peritoneal reflection
• 19 rectosigmoid• 22 sigmoid
• Neoadj CRTx + surgery n=18
• 9 at/above peritoneal reflection
• 5 rectosigmoid • 4 sigmoid
Burton 2006 Int. J. Radiation Oncology Biol. Phys
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MRI predicted prognosis with final histological prognosis in 57 patients undergoing primary surgery
Final histological prognosis
Good Poor TotalMRI Good 31 6 37
PredictedPrognosis Poor 10 11 21
Totals 41 17 5884% (CI =72.6-92.7%) accuracy for MRI prediction of prognosisKappa = 0.63Sensitivity = 90%Specificity = 72%Positive predictive value = 88%Negative predictive value = 76%
Burton 2006 Int. J. Radiation Oncology Biol. Phys
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Neoadjuvant Treatment
Burton 2006 Int. J. Radiation Oncology Biol. Phys
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Pelvic sigmoid
Staging and treatment Sigmoid colon has traditionally been grouped with the
remainder of the colon Direct continuation of the rectum located in the pelvis treating
sigmoid cancer Subject to the same constraints as rectal cancer with similar
potential surgical challenges and risks of a threatened margin Improved image quality in rectal has enabled better tumour
depiction and superior risk stratification Precise imaging staging enables appropriate surgical and
oncological treatment planning This could translate into a reduction in pelvic recurrence
rates
Preoperative stagingCurrently CT is widely used to assess sigmoid
cancers, CT has limited ability to delineate pelvic structures
and detailed anatomyHigh resolution MRI better suited evaluating pelvic
structuresMay help to identify those at risk of incomplete
resection/ local recurrenceSuch patients may benefit from radical neoadjuvant
treatment and more accurate surgical ‘road-mapping’
IMPRESS Trial Hypothesis: Accurate preoperative imaging (MRI) will improve recurrence rate and survival through:
better surgical decision making
Greater proportion receiving radical treatment (neoadjuvant therapy or extended surgery)
Biopsy proven sigmoid cancer
OBSERVATIONAL PATHWAYMRI is local policy
MDT review CT & MRI
INTERVENTIONAL PATHWAY
Randomised to have MRI
Randomised not to have MRI
MDT review CT & MRI
MDT review CT only
Treatment Outcomes
Endpoints IMPRESS Trial
Primary: Observational: Measure difference in detection of high risk
patients between CT and MRI and the resultant difference in Rx strategy
Randomised: Compare the proportion of patients undergoing radical treatment in the two arms
Secondary: Recurrence rate at 1, 3 and 5 years OS and DFS at 1, 3 and 5 years Accuracy of CT and MRI to identify poor prognosis tumours
compared to the gold standard of histopathology Quality of surgery CRM positivity rates on pathology Permanent defunctioning stoma rates
Study designObservational and randomised arms (1:1)Expected improvement of 20% in sensitivity of
detection of high risk patients, 97 patients need to be randomised to each arm
Drop out rate 20%243 patients needed in randomisation armFolllow-up 5 years,
outcomes reported at 1, 3, and 5 years
Biopsy proven sigmoid cancer
OBSERVATIONAL PATHWAYMRI is local policy
MDT review CT & MRI
INTERVENTIONAL PATHWAY
Randomised to have MRI
Randomised not to have MRI
MDT review CT & MRI
MDT review CT only
Treatment Outcomes
SitesOpen: RMH Croydon Salisbury Harrogate St Mark’s
Opening: Portsmouth Taunton Yeovil Macclesfield Scunthorpe Manchester Royal Infirmary Hinchingbrooke East Kent Leigton North Tees Royal Free
IMPRESS TrialIMProving Radical treatment through MRI
Evaluation of pelvic Sigmoid cancerS
Contact Gina Brown (Principal Investigator) [email protected]
Lisa Scerri (Clinical Trial Coordinator) [email protected] 0208 915 6067
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Sigmoid cancer
• Sigmoid cancer has a high recurrence rate• Sigmoid cancer has a worse outcome than rectal
cancer• MRI is able to identify poor prognostic tumours
preoperatively• Preoperative staging enhances optimal treatment
strategy including neoadjuvant treatment• Sigmoid cancer with poor prognostic features should
be discussed for neoadjuvant treatment (IMPRESS Trial)
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Better staging Colon cancer: new treatment possibilities
MRI based Selectionof patientsFor range treatments
MRI and PET surveillanceScreen for metastatic disease
ChemoradiotherapyRestage:
Biological agents and neoadjuvant chemotherapy for MRI EMVI
Further Therapy/Extended surgery
MRI T1/T2/early T3 Primary Surgery: laparoscopic
MRI T3c/T3d N anyEMVI positive
CRM safe
MRI potential resection margin
unsafe in rectosigmoid
MRI potential resection margin
unsafe in colonExtended surgery
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Acknowledgements
• Shwetal Dighe, Sarah Burton and Neil Smith, Chris Hunter, Ian Swift and Muti Abulafi and the Royal Marsden Hospital Colorectal Multidisciplinary Network
• FoxTrot trial co-investigators: D Morton, P Quirke, M Seymour, R Gray, L Magill.