Rectal Cancer Alliance of Canada

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Phase II study using MRI to identify “good prognosis” Stage II and Stage III

rectal cancer patients eligible for primary surgery

(QuickSilver)

Webinar Overview

QuickSilver Study Protocol• Discussion and Questions

Radiology Protocol

• Discussion and Questions

Pathology Protocol

• Discussion and Questions

• Wrap Up and Next Steps

QuickSilver Study and Site Leads

Study Leads

Radiology Laurent Milot (Toronto)

Mark Fruitman (Toronto)

Blair MacDonald (Ottawa)

Surgery Carl Brown (Vancouver)

Lara Williams (Halifax)

Pathology Richard Kirsch (Toronto)

David Driman (London)

Radiation Oncology Charles Cho (Toronto)

Raimond Wong (Hamilton)

Medical Oncology Monika Krzyzanowska (Toronto)

Ron Burkes (Toronto)

Principal Investigators Erin Kennedy, Nancy Baxter, Marko Simunovic, Robin McLeod

Introduction

PreCRT is recommended for Stage II and Stage III rectal cancer to decrease the risk of local recurrence

While preCRT reduces the risk of LR, it does not improve survival and leads to poorer bowel and sexual function than surgery alone

New approaches to improve selection and limit preCRT to Stage II and Stage III rectal cancer patients who are most likely to benefit from preCRT are important

Introduction

2 non-randomized, prospective studies have used MRI to identify “good prognosis” rectal tumours eligible for primary surgery

Patients with MRI predicted “good prognosis” tumours underwent primary surgery with favourable outcomes UK: Positive CRM 3.3% (4/122)

LR @ 2 years 3.3% (4/122)

German: Positive CRM 6.0% (11/181)Taylor, Annals of Surgery, 2011Strassburg. Annals of Surgical Oncology, 2011

MRI Criteria for “Good Prognosis” Tumours

UK (Mercury) German

Predicted CRM CRM > 1 mm CRM > 1 mm

T-category and

Extramural depth of invasion (EMD)

T1, T2 or T3 with < 5 mm EMD

T1, T2 or any T3

N-category N0, N1, N2 N0, N1, N2

Extramural vascular invasion (EMVI) Negative Not assessed

Tumour Height Any tumour 0-15 cm from anal verge**(Low rectal tumours < 5 cm from the anal verge with no invasion of the intersphincteric plane)

Any tumour > 6 cm and < 12 cm from the anal verge

N-category and Local Recurrence

May not be as important as previous RCTs suggest• Pre-operative staging by DRE; no routine imaging

• Quality of surgery

Study Local Staging

Dutch DRE – fixed tumours excluded

MRC CRO7 DRE- tumours fixed to pelvis excludedIf DRE inconclusive; EUA supplemented when appropriate by pelvic CT, MRI or TRUS

Study TME Complete

Dutch 57% (102/180)

MRC CR07 52% (604/1156)

QuickSilver Objectives

To conduct a pan Canadian Phase II study to assess the safety of using MRI criteria to identify “good prognosis” Stage II and Stage III rectal cancer patients eligible for primary surgery

QuickSilver Consensus Meeting

One-day investigator’s meeting on June 2013 attended by 35 physicians from across Canada

22 colorectal surgeons; 8 radiation oncologists; 4 radiologists; 1 pathologist

1 international expert (Dr. Gina Brown)

Review current evidence and select MRI criteria to identify “good prognosis” rectal tumours

Achieve consensus on the final study protocol

QuickSilver Study Overview

NEWLY DIAGNOSED PRIMARY RECTAL CANCER PATIENTS

CT chest, abdomen and pelvis Pelvic MRI Presentation at MCC

MRI PREDICTED “GOOD PROGNOSIS” RECTAL TUMOUR

INFORMED CONSENT

PRIMARY SURGERY

CRM STATUS

QuickSilver MRI Criteria

Good Prognosis Poor Prognosis

Predicted CRM* CRM > 1 mm CRM < 1 mm

T-category** and

Extramural depth of invasion (EMD)

Definite T2 , T2/early T3 or definite T3 with < 5 mm EMD

Definite T3 with > 5 mm EMD or T4

N-category N0, N1, N2 N0, N1, N2

Extramural vascular invasion (EMVI) Absent or equivocal Present

Tumour Height Any tumour 0-15 cm from anal verge with proximal extent at or below the sacral promontory and restorative resection is planned

*Primary tumour, discontinuous tumour nodule, suspicious lymph node or EMVI** Definite T1 and T1/early T2 tumours excluded from study protocol

QuickSilver Inclusion Criteria

Diagnosis of rectal cancer (0-15 cm from anal verge) on endoscopy and proximal extent of tumour at or below sacral promontory on CT and/or MRI

Meets all MRI criteria for “good prognosis” rectal tumour as defined by study protocol

No metastatic disease

18 years or older

Able to provide written consent

QuickSilver Exclusion Criteria

Planned APR

Planned local excision

T1/early T2 tumour on MRI (and/or TRUS)

Suspicious extramesorectal lymph nodes on MRI

Unable to undergo MRI

Metastatic disease

Pregnancy

Inflammatory bowel disease

Previous pelvic radiation

More than one primary tumour

Unfit for surgery

QuickSilver Clinical Assessment

If MCC not available, surgeon will organize meeting with Radiology and Radiation Oncology Leads at their centre to review the case

Surgeon responsible for initial pre-operative assessment Clinical and endoscopic examination

CT chest/abdo/pelvis

MRI pelvis

Presentation at Multidisciplinary Cancer Conference (MCC)

Attended at minimum by treating surgeon, radiologist and radiation oncologist

Final decision regarding eligibility at discretion of surgeon

QuickSilver Informed Consent

Surgeon responsible inviting eligible patients to participate in the study

Informed consent must be obtained from a research or clinic nurse outside the patient’s circle of care

The signed informed consent form must be kept in a locked area at each Site by the Surgery Site Lead

The study team will conduct an in-service for all research staff and clinic nurses involved in the informed consent process

Any questions or concerns about the consent process can be directed to the Project Coordinator

QuickSilver Surgical Assessment

Surgical procedure left to discretion of surgeon

Partial ME for upper rectal cancers (above peritoneal reflection)

TME for mid and low rectal cancers (at or below the peritoneal reflection)

Must have completed a colorectal or surgical oncology fellowship in Canada or US

Synoptic OR report provided (not mandatory) BC Cancer Agency Operative Synoptic Report

QuickSilverMRI and Pathology Assessment

Specific MRI and pathology protocols for study

Specific field requirements on MRI and pathology reports

Synoptic reports recommended but not mandatory Synoptic MRI report

CAP checklist

QuickSilver Primary Outcome

Primary outcome = positive CRM rate Any macroscopic or microscopic tumour, discontinuous tumour nodule

or positive lymph node located within 1 mm of the CRM on final pathologic assessment

Data Safety Monitoring Committee (DSMC) Consists of one statistician, one surgeon, one radiation oncologist and

one pathologist (not participating in the study)

Assess positive CRM rate after every 25 patients accrued

Study will be stopped if a positive CRM > 10% at any interim assessment

Secondary outcomes = LR, DR, OS, DFS @ 2 years

QuickSilver Sample Size

Minimum of 30 high volume surgeons at 15 centres ~ 300 new patients with primary rectal cancer

~30% (n= 90) “good prognosis”

~ 80% participation rate

• Sample size = 75 patients

• ~5-10 patients/centre

95% CI of +/- 6.7% around point estimate of 10% for positive CRM rate

If positive CRM rate is smaller (<10%), the precision around the point estimate will improve (95% CI < 6.7%)

QuickSilver Recommended Follow Up

pCRM-

MRI predicted “good prognosis” tumour

Primary Surgery

Post-operative CRT

pCRM+

pN- pN+

No further treatment

pN- or pN+

Chemo x 6 months(started within 8 weeks after surgery)

*Chemotherapy may be considered at the discretion of the treating oncologist for CRM- and LN- patients for

high-risk features such as EMVI

QuickSilver Data Collection

Participating surgeons will be responsible for:• de-identifying MRI, OR and pathology reports

• FAXing de-identified reports to central study office

All de-identified documents will be assigned a unique ID by the central study office

Research coordinator at the central study office will abstract data and enter into database for study

QuickSilver Relevance

Expected results on the use of MRI to identify “good prognosis” rectal cancers eligible for primary surgery

• Safe and feasible

• Not safe

• Not feasible

Potential to change current management of rectal cancer in Canada

Standardization of MRI, surgical and pathologic assessment across centres Canada

Facilitate a pan-Canadian community of practice for rectal cancer and participation in future clinical trials

QuickSilver Project Details

REB complete at all 15 participating centres

Website - available April 2015• Study Overview

• Participating Sites and Project Leads

• Radiology, Surgical and Pathologic Protocols and Reports

• MRI Training Sets

• REB and DSA Status

• Recruitment Updates

Information booklet – available January 2015

QUESTIONS

Safety and feasibility study to see if UK and German results can be replicated in the Canadian context

Inclusion criteria overlaps with N1048

• Experimental: FOLFOX (6 cycles); if > 20% regression; surgery; FOLFOX (6 cycles); observation

• T2N1, T3No, T3N1 based on MRI or TRUS

• Predicted CRM > 3 mm

• 5-12 cm from anal verge

• Consider as complementary rather than competing

QuickSilver Radiologic Assessment

MRI protocol for study as per MERCURY

Mandatory:

High resolution, axial T2 sequences

No endorectal coil

No rectal contrast

Optional:

T1 sequences and DWI

Gadolinium

Bowel preparation

Antiperistaltic agents

QuickSilver Radiologic Assessment

MRI report to include: Protocol details

T1, DWI, gad, bowel prep, antiperistaltics

• Distance to the MRF (i.e., predicted CRM) (in mm)

• T-category

• EMD for all tumours T3 or greater (in mm)

• N-category (suspicious nodes Y/N)

• EMVI (present/absent)

• Synoptic MRI template provided (not mandatory)

QuickSilver Radiologic Assessment

If any uncertainty regarding MRI criteria, the reporting radiologist will review with the Radiology Site Lead to achieve consensus

If consensus not achieved, central review by Lead Radiologists for study (Laurent Milot, Mark Fruitman)

MRI reports FAXed to central study office

Radiology Site Lead will be contacted if any missing data

QuickSilver Radiologic Assessment

Radiology Training sets have been developed and will be available to participating radiologists via the study website

QuickSilver Pathologic Assessment

Standard pathology protocol as per Quirke et al

72-96 hour fixation

inking of radial margin 3-5 mm slices through fixed, unopened tumour

minimum of 3 tumour blocks showing deepest invasion

Macroscopic assessment of quality of the TME *

*Specimen is scored according to worst area

Photographs of gross specimen

overall TME specimen – anterior and posterior

overview of slices + closer views of individual slices – as needed

Mesorectum Defects ConingCRM

(on tranverse section)

Complete intact, smooth no deeper than 5 mm none intact, smooth

Near Completemoderate bulk,

irregularno visible muscularis propria(except where levator inserts)

moderate mostly smooth with some

irregularities

Incomplete little bulk down to muscularis propriamoderate-

markedVery irregular

QuickSilver Pathologic Assessment

Pathology report checklist (required items)*Gross Assessment Items

Documentation of use of the Quirke method* (i.e. fixation of the unopened specimen followed by cross sectional slicing) Quality (i.e. completeness) of the TME (state various elements) 

Documentation of the number of tumour blocks with deepest tumour invasion (at least 3 required) to include CRM where applicable * 

Documentation that photographs of the specimen taken* 

Microscopic Assessment ItemsSite and relationship of tumour to the anterior peritoneal reflection* 

Microscopic tumour extension (T-category) 

 Extramural depth of invasion* (T3 tumours only) (i.e., deepest invasion of tumour into the mesorectal fat)

Lymph node status (N-category)

Closest distance of the distal margin in mm (in all cases, even when not the closest margin)* 

Closest distance of CRM in mm (in all cases, even when not the closest margin)* 

Structure closest to the CRM (tumour, tumour nodule, lymph node, venous invasion)* 

Extramural venous invasion (elastin stain: to be performed on 3 blocks with deepest invasion)* 

* Indicates item is not on CAP checklist but is required for this study

QuickSilver Pathologic Assessment

If any uncertainty about pathology criteria, the reporting pathologist will review with the Pathology Site Lead to achieve consensus

If consensus not achieved, central review by Lead Pathologists for study (Richard Kirsch, David Driman)

Pathology reports FAXed to central study office

Pathology Site Lead will be contacted in case of any missing data

NEXT STEPS

Thank you to everyone!

Welcome any further comments about the study up until Sept 29, 2014

Site Leads to review and finalize website and information booklet by Oct 1, 2014

Informed consent in-service with centres as REB is approved

Plan to start study on Oct 1, 2014 to March 2016