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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) Gina.Brown@rmh.nhs.uk

Lisa Scerri (Clinical Trial Coordinator) lisa.scerri@rmh.nhs.uk 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.