gina.brown@rmh.nhs.uk

MRI: impact on rectal cancer

care and standardisation

Gina Brown

Department of Radiology

Royal Marsden Hospital

Imperial College, London

The Royal Marsden

STAGING

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Understanding rectal

tumor invasion Can you see high signal submucosa =

yes =T1

Cannot see submucosa but can see low signal muscularis = T1 sm3/T2

Cannot see full thickness of muscularis propria but tumor does not project beyond contour =T2 full thickness or T3<1mm

Tumour projects beyond muscularis propria =T3

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T2 tumor

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What is the T stage of this

tumor?1. T1 confined to submucosa

2. T2 0mm spread

3. T2/T3a <1mm spread

4. T3b 1-5mm spread

5. T3c >5mm

• insert slide of burg

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Measuring depth of extramural spread

(Radiology 2007)

295/311 (95 %) patients who underwent primary surgery.

The mean difference between MRI and histopathology assessment of

tumor EMD was -0.046 mm, SD = 3.85 mm, the 95 % CI was -0.487 to

0.395 mm.

MRI and histopathology assessment of tumor spread are considered

equivalent to within 0.5 mm (R). Radiology 2007

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Afferent lymphatic

Efferent lymphatics and

vessels

Medullary sinus

Follicle

Marginal sinus

Capsule

Nodal anatomy

Courtesy of DM Koh

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Afferent lymphatic

Efferent lymphatics and vessels

Medullary sinus

Follicle

Capsule

Nodal anatomy

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Lymph node border and intensity best–

measuring size of nodes worsens results

• node positive if either irregular border or mixed signal intensity was demonstrated, the sensitivity, specificity were high.

• Metastases were demonstrated in 51/56 nodes (91%, 95% CI 81% to 96%) with either an irregular border or a mixed intensity signal.

• only 9/225 nodes (4%, CI 2.1% to 7.4%) with smooth borders and a uniform signal contained metastases.

• Size of node bears no relationship to malignant risk

Brown et al Radiology 2003

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Malignant node

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Is this 6mm node benign or

malignant?

1. Benign

2. Malignant

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Is this a benign

or malignant node?Field of view (FOV) 22cm x 22cm

Slice thickness 3mmField of view (FOV) 16cm x 16cm

Slice thickness 3mm

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The Paradigm when MRI is

not necessary

T1/T2 no preoperative rad

therapy

Preoperative

CRT for all

T3/T4 tumours

EUS/CT/MRI

Is it T3?

Yes/No

80-90%

10%-20%

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Nodal status predicts recurrence

Patients undergoing non-TME / TME

surgery with incomplete specimens – nodal

status strongly predicts

local recurrence

18% incomplete

rates- Dutch TME

15% - CR07

North American

Trials – non TME

surgery

5% - MERCURY

Nodes left behind

cause pelvic recurrence

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Nodes do not predict

recurrence after TME

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Importance of mrCRM status

The Royal MarsdenPathological predictors of local

recurrence

Risk factors on

multivariate analysis

• CRM involvement

• AP excision

• Independent of age,

sex, type of

preoperative treatment

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MRI local

recurrence• MRI predictors of

local recurrence

• MRI CRM status

• Height <5cm from

anal verge

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T2 or T3 tumour without adverse

features

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pT3<5mm, N any

•T2 and T3 tumours

<5mm have 85-90%

5 year cancer

specific survivalMerkel et al(2001).Int J

Colorectal Dis 16(5): 298-304.

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MRI good prognosis rectal cancers

Taylor et al, MERCURY

Annals of Surgery 2011

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recurrence for node positive

vs negative if CRM is clear

• For a good quality TME CRM-ve –

no difference – CR07 5-6% LR

rates irrespective of node status

• OCUM trial follow up data...

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Canadian “Quicksilver Trial”

• Prospective trial testing avoidance of

CRT in MRI defined good risk tumours

T3b or less N stage any

EMVI negative

CRM and low rectal plane safe

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Sequelae of

Chemoradiotherapy• Higher anastomotic leak rate

• Higher permanent colostomy rate

• Second malignancy

• Faecal incontinence/ urgency / sexual and urinary dysfunction/ QoL penalties

• Balance risk of recurrence vs morbidity/mortality from preop CRT

• Chemotherapy related toxicity/deaths

WHICH PATIENTS ARE AT

RISK OF LOCAL

RECURRENCE?

MRI directed multidisciplinary team

preoperative treatment strategy:

the way to eliminate positive

circumferential margins?

• 26% rate of tumour involvement of margins when preoperative

discussion of MRI scans compared with 8% when preoperative

discussion takes place (p<0.001)

• Mandatory discussion of preoperative MRI scans introduced in

2003, positive CRM rate reduced to2-3%

Burton S, Brown G, Daniels IR, Norman AR, Mason B, Cunningham D.

Br J Cancer. 2006 Feb 13;94(3):351-7.

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Suboptimal low rectal cancer management

‘WAIST’ at PuborectalisCRM involvement

‘Standard’ APE

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low rectal cancer

Diseases Of The Colon & Rectum Volume 52: 4 (2009)G. V. Salerno et al: Magnetic resonance imaging prediction of an

involved surgical resection margin in low rectal cancer

Dis Colon Rectum; (52): 632-9. 2009

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MR CRM prediction for low rectal cancers:

TME plane safety

• 1. MRI Low Rectal Stage 1: tumour on MRI images appears confined to bowel wall (intact muscularispropria of the internal sphincter).

• 2. MRI Low Rectal Stage 2: tumour on MRI replaces the muscle coat but does not extend into the intersphincteric plane. Above sphincter it is confined to the mesorectum.

• 3. MRI Low Rectal Stage 3: invading into the intersphincteric plane or lying within 1mm of levatormuscle above the level of the sphincter complex.

• 4. MRI Low Rectal Stage 4: invading the external anal sphincter and infiltrating/ extending beyond the levators+/- invading adjacent organ.

“Shihab et al: MRI staging of low rectal cancer." Eur Radiol 19(3): 643-650.

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Results from 19 sites recruiting to MERCURY

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Primary Surgery for Low

Rectal Cancers• Almost half (44·4%, 124/279) of study participants had a ‘safe’

mrLRP and no adverse MRI features. The recommended management was to proceed straight to surgery with an intersphincteric resection, adhering to this guidance (50%) led to a clear 16 pCRM in 98% of cases.

• When MRI low-risk patients were offered CRT or an ELAPE -this resulted in a higher pCRM involvement. Additional treatment and more radical surgery did not result in a benefit to the patient and may represent overtreatment.

53%

MRI

Height <4cm 26 31

25

31

12%

5%

4%

9%

4%

12%

5%

15%

No Risk Factors

2% pCRM risk

MRI Tool for predicting risk of pCRM involvement

mr ‘Unsafe’ plane

mrEMVI

MRI invading edgeAnterior

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ASSESSING OTHER RISK

FACTORS FOR RECURRENCE

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How does tumour spread?

• Directly into neighbouring

structures

• Via the lymph nodes

• Via the blood vessels - EMVI

The Royal Marsden Characteristic features of blood

vessel invasion• Expansion of

vessels by tumour

• tubular extension

of tumour signal

MRI for detection of extramural vascular invasion

in rectal cancer.

AJR Am J Roentgenol 191(5): 1517-1522.

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0

20

40

60

80

100

0 1 2 3 4 5 6

Time since operation (Years)

% R

elap

se-f

ree

MRI-EMVI score= 0-2

MRI-EMVI score= 3-4

p = 0.0015

Smith et al BJS 2008, 95(2): 229-236

Prognostic significance of magnetic resonance imaging-detected extramural vascular invasion in rectal cancer

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MRI detected more persistent

EMVI post CRT than pathology

Chand M, Evans J, Swift RI, et al. Prognostic Significance of

Postchemoradiotherapy High-Resolution MRI and Histopathology

Detected Extramural Venous Invasion in Rectal Cancer. Ann Surg. 2014.

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Survival curves – 3-year DFS

mrVein invasion neg

mrVein converted pos

to neg

mrVein remains pos

after Rx

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Which came first the spread into the vessels

or spread into the lymph nodes?

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Irresectable liver metastases developed after 1 year

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Odds ratio 4.6

(95% CI 1.3-

16.2)

P=0.01

Odds Ratio 4.6

(95% CI 2.9-14.4)

P=0.001

94 low risk 136 high risk

Whole group:

33/230 (14.3%) distant

mets on PET/CT

230 patients with all

imaging available

6 patients (2.5%) imaging

unavailable for review236 patients enrolled

5/94 (5.3%)

distant mets on PET/CT

28/136 (20.6%)

distant mets on PET/CT

Same

mets

PET/CT

and CT

2/94

(2.1%)

Same

mets

PET/CT

and CT

10/136

(7.4%)

CT mets

& more

mets on

PET/CT

2/94

(2.1%)

CT Mets

& more

mets on

PET/CT

8/136

(5.9%)

Mets

only on

PET/CT

1/94

(1.1%)

Mets

only on

PET/CT

10/136

(7.4%)

Any mets on PET/CT

not CT

3/94 (3.2%)

Any mets on PET/CT

not CT

18/136 (13.2%)

T Vuong, A Garant, G Artho

R Lisbona

McGill University Health Centre

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Serenade trial

• Phase II study : in patients with high metastatic risk colorectal cancer (vein invasion visible on MRI,T3>5mm)

• primary objective : find early liver spread diagnosed by Liver diffusion weighted MRI when CT scan is negative for metastatic disease.

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Endpoint phase II

The primary endpoint will be to show a >5% increase in the detection of unsuspected spread to liver detected in patients at high risk by DW-MRI when standard CT is negative or not able to confirm the presence of metastatic disease.

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What do we hope to achieve

with the Serenade trial?• Improve survival by treating patients

with very early spread to liver earlier

and when spread is more susceptible

to chemotherapy/surgery

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MARVEL

• NCRN Study• Examining clinical behaviour in EMVI+ positive tumours following

CRT

• Radiological and molecular change

• Multi-centre

• Tissue banking of rectal cancers

• Microarray analysis of tumour profile

• Predict behaviour

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Hypothesis• mrEMVI positive rectal cancer has worse relapse rates than EMVI negative

rectal cancer following CRT CLINICAL endpoint

• Where mrEMVI positive rectal cancer changes to mrEMVI negative following

CRT, it is associated with an improvement in time to relapse. IMAGING PREDICTIVE

BIOMARKER

• mrEMVI positive rectal cancer is associated with worse response rates following

CRT. IMAGING PREDICTIVE BIOMARKER

• EMVI positive rectal cancer exhibits a distinct molecular/genetic profile

compared to EMVI negative rectal cancer. MECHANISM AND THERAPEUTIC PATHWAYS

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Mucinous carcinomaPoor prognosis

MRI more likely to diagnose

mucinous subtype

• diagnostic odds ratio MRI vs

biopsy = 4.67, p < 0.05.

• All 60 (100%) patients

undergoing surgery for

mrMucinous tumours were

confirmed as such on final

histopathology.

Yu SKT, Tait DM, Chand M, Brown G. Magnetic resonance imaging

defined mucinous rectal carcinoma is an independent imaging

biomarker for poor prognosis and poor response to preoperative

chemoradiotherapy. European Journal of Cancer 2014

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Technique

• Phased array Coil positioning critical

• High Res Axialsperpendicular to rectal wall

• Coronal imaging parallel to anal canal

• Don’t forget nodes

Brown et al BJR 2005

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MDT choices and making best use of

high resolution MRI

MRI based

Selection

of patients

For range

treatments

Local excision

MRI and PET surveillance

Deferral 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 CRT

MRI surveillance…

MRI Low rectal

Stage 3 or 4

Post CRT

yMRI 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

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Standardised Technique• 3mm, 16cm-18cm FOV, 4-6 NSA,

256x256 matrix, TR >3,000, TE 80-100, ETL 16

• In plane resolution 0.6mm x 0.6mm

• Brown G, Daniels IR, Richardson C et al Techniques and trouble-shooting in high spatial resolution thin slice MRI for rectal cancer.

Br J Radiol 2005; 78:245-251.

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Poor resolution

T2 weighted scan

beware of

3D techniques

especially for nodal

assessment

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What do you need?• Dedicated colorectal MDT

• Policy of preoperative MDT review of all rectal cancers using high resolution MRI with specialist colorectal radiologist – committed to MDT

• Patient education: importance of preoperative assessment – repeat scans when necessary

• Team member training and support: multidisciplinary workshops effective –most effective when surgeons and radiologists are together

• Learning curve but teachable e.g. participation and support in clinical trials

Reporting Minimum StandardsBaseline assessment of Rectal cancer MRI report

Primary tumour The primary tumour is demonstrated as an [ Annular | Semi-annular | Ulcerating | | Polypoidal |

Mucinous] mass with a [nodular / smooth] infiltrating border.

The distal edge of the luminal tumour arises at a height of [ ] mm from anal verge:

The distal edge of the tumour lies [ ]mm [Above,at, below] the top of the puborectalis sling

The tumour extends craniocaudally over a distance of [ ] mm

The proximal edge of tumour lies [above at below] the peritoneal reflection

Invading edge of tumour extends from [ to ] O’clock

Tumour is [confined to] [extends through] the muscularis propria:

Extramural spread is [ ] mm

mrT stage: [T1 ] [ T2 ] [ T3a] [ T3b ] [ T3c] [ T3d ] [T4visceral ] [T4

peritoneal]

Tumour is [present] [not present] the level of the puborectalis sling at this level:

[Tumour is confined to the submucosal layer/part thickness of muscularis propria indicating that the

intersphincteric plane/mesorectal plane is safe and intersphincteric APE or ultra low TME is

possible]

[Tumour extends through the full thickness of the muscularis propria : intersphincteric

plane/mesorectal plane is unsafe, Extralevator APE. is indicated for radial clearance]

[Tumour extends into the intersphincteric plane : intersphincteric plane/mesorectal plane is unsafe,

therefore an extralevator APE. is indicated for radial clearance]

[Tumour extends into the external sphincter : intersphincteric plane/mesorectal plane is unsafe.]

[ Tumour extends into adjacent [prostate/vagina/bladder/sacrum] : exenterative procedure will be

required

Additional comments:

.

Lymph node assessment

Only benign reactive and no suspicious nodes shown [N0]

[ ] mixed signal/irregular border nodes [N1/N2]

Extramural venous invasion: [ No evidence ] [ Evidence]

[ ] Small [ ]Medium [ ]Large vein invasion is present

CRM

The closest circumferential resection margin is at o’clock

The closest CRM is from [Direct spread of tumour] [Extramural venous invasion] [Tumour

deposit]

Minimum tumour distance to mesorectal fascia: mm [CRM clear ] [CRM involved]

Peritoneal deposits: [ No evidence] [ Evidence]

Pelvic side wall lymph nodes:

[ None] [ Benign] [ Malignant mixed signal/irreg border]

Location: [Obturator fossa • R •L ] . [External Iliac Nodes • R •L] .[ Internal iliac • R •L ]

Summary: MRI Overall stage: T N M [CRM clear] , [ CRM involved ] , [ EMVI

positive] [EMVI negative],[PSW positive ] [PSW negative]

No adverse features eligible for primary surgery

High risk safe margins for preoperative therapy : eligible for Serenade, Marvel

Poor prognosis unsafe margins eligible for preoperative chemoradiotherapy: eligible for 6 vs 12

trial

Low Rectal <6cm – eligible for the Low Rectal Study.

Post Treatment Assessment MRI Rectal Cancer

Comparison is made with the previous examination of:

• The treated tumour: shows no fibrosis,TRG5

• Less than <25% fibrosis, predominant tumour signal, TRG4

• 50% tumour/fibrosis, TRG 3

•>75% fibrosis, minimal tumour signal intensity,TRG2

•low signal fibrosis only no intermediate tumour signal TRG1

The distal edge of the luminal tumour arises at a height of [ ] mm from anal verge:

The distal edge of the tumour lies [ ]mm [Above, at, below] the top of the puborectalis sling

compared with []mm previously

The tumour extends craniocaudally over a distance of [ ] mm compared with [ ]mm previously

The proximal edge of tumour lies [above at below] the peritoneal reflection

The invading edge of treated tumour extends from [ to ] O’clock

Tumour signal is [Confined to / Extends through the muscularis propria.]

Fibrotic signal is [ Confined to / Extends through muscularis propria.]

Extramural spread: [ ]mm for tumour signal [ ]for fibrotic stroma

yMR T stage: • T1 • T2 • T3a • T3b • T3c • T3d •T4 visceral •T4 peritoneal

Treated tumour [is/ is not] present at or below the puborectalis sling

• tumour signal/fibrosis extends into the submucosal layer/part thickness of muscularis propria :

intersphincteric plane/mesorectal plane is safe intersphincteric APE or ultra low TME possible, CRM

is safe

• tumour signal/fibrosis extends through the full thickness of muscularis propria : intersphincteric

plane/mesorectal plane is unsafe, for extralevator APE.

• tumour signal/fibrosis extends into external sphincter : intersphincteric plane/mesorectal plane is

unsafe:for extralevator APE

•tumour signal/fibrosis extends into beyond external sphincter into [prostate/vagina ] : intersphincteric

plane / mesorectal plane is unsafe, for extralevator APE.

Lymph nodes:

• None /Only benign reactive [N0]

• Present number mixed signal/irregular border [N1/N2]

Extramural venous invasion: [• No evidence • Evidence]

[• Small • Medium • Large]

CRM Closest circumferential resection margin: [ ]O’clock

Closest CRM is from [ Direct spread of tumour • Extramural venous invasion • Tumour deposit]

Minimum tumour distance to mesorectal fascia: [ ]mm [ • CRM clear • CRM involved]

Peritoneal deposits: [• No evidence • Evidence ]

Pelvic side wall lymph nodes: • None • Benign • Malignant

[Location: Obturator fossa • R •L . External Iliac Nodes •R •L. Inf Hypogastric •R •L ]

Summary: y MRI Overall stage ymrT ymr N M , TRG

• Low/intermediate risk, CRM clear, TRG 1-2, EMVI negative

• High prognosis, CRM pos or TRG4/5 or EMVI positive

TRG1-2 low tumour – eligible for consideration for deferral of surgery

Reporting Template Post Treatment

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Key Bioimaging markers

for poor outcome at baseline and post CRT

• CRM involvement on MRI

• Depth of extramural spread >5mm

• Presence of MRI detected venous invasion

• MRI detected mucinous tumours

• Tumour spread into or beyond the intersphincteric plane

• MRI TRG status

Course Fee: £300 . For Sept 2015 and Jan 2016 course details please email :gina.brown@rmh.nhs.uk

Acknowledgements:• Pelican Cancer Foundation• European Mercury Study Group: Prof Bill Heald, Brendan Moran, Phil

Quirke, I Swift, P Tekkis, S Stelzner, G Branagan, M Gudgeon, J Strassburg, S Laurberg, T Holm

• Radiologists in MERCURY I and II: Nicola Bees, Helena Blake, Rob Bleehan, Lennart Blomqvist, Alan Chalmers, Mike Creagh, Hanne-Linne Emblemsvaag, Sarah Evans, Ashley Guthrie, Chris George, Knut Håkon Hole, Nick Hughes, Shaun McGee, Petra Knuth, Delia Peppercorn, Clemens Schubert, Andrew Thrower, Turid Vertrus

• Research fellows: Sarah Burton, Neil Smith, Gisella Salerno, Fiona Taylor, Shwetal Dighe, Oliver Shihab, Peter How, Uday Patel, Jessica Evans, Chris Hunter, Panagiotis Georgiou, Vera Tudyka, RafaySiddiqui, Jemma Bhoday, James Read, Manish Chand, Anita Wale, Alistair Slesser, Nick Battersby, Svetlana Balyasnikova