Colorectal Flashcards
What are the boundaries of the rectum
From dentate line (margin with anal canal) to rectosigmoid junction
What is the nodal drainage of the rectum
2/3 to para-rectal LNs -> inferior mesenteric nodes
1/3 to internal iliac nodes
What are the MMR proteins
MLH1
PMS2
MSH2
MSH6
What rate of MMR deficiency is sporadic
2/3
1/3 germline
Loss of which proteins indicates potential Lynch syndrome
MSH2 and/or MSH6 loss - paired - suspect Lynch syndrome
MLH1 & PMS2 loss - paired - need to determine B-Raf mutation or B-raf promotor hypermethylation
Approximately 1/3 have B-RAF mutation
B-RAF mutated: Unlikely to be Lynch (more likely MLH1 somatic acquired mutation)
B-RAF wild-type & no promoter hypermethylation - likely Lynch
What is Lynch syndrome
What is the inheritance
What is the lifetime risk of colorectal cancer
germline AD loss of MMR function, causing microsatellite instability
80% lifetime risk, typically right-sided tumours
What is Muir-Torre syndrome
What cancers are predisposed
What genes are affected
Subtype of Lynch syndrome
Develop colon, GU, and skin lesions - keratoacanthomas and sebaceous tumours
Genes affected = MLH1, MSH2, and MSH6
What tumours are associated with Lynch syndrome
What screening takes place
Renal
Upper GI - pancreatic and gastric
Ovarian and endometrial
2yrly colonoscopy from age 25
2yrly OGD from age 50-70
Consider TAH+BSO from age 40
What are the criteria within the Modified Amsterdam Criteria, to suggest Lynch syndrome
3+ relatives affected, with a related cancer (colorectal, small bowel, gastric, pancreatic, endometrial, ovarian, renal pelvis TCC (but not bladder))
2 generations affected
1 person diagnosed <50yrs
1 must be a first degree relative
Must exclude FAP
How is FAP inherited
What is the gene and chromosome
What surveillance takes place
AD inherited loss of APC on chromosome 5
Colonoscopy from age 15
What are the variants of FAP (3)
Gardner’s syndrome - colorectal polyps, skull and mandible osteomas, desmoid tumours & cysts, sebaceous cysts
Turcot’s syndrome - Colorectal polyps with CNS tumours (ependymomas, medulloblastomas)
Attenuated FAP - fewer polyps and lower risk of cancer
What is Gardner’s syndrome & what are its features
Variant of FAP
colorectal polyps, skull and mandible osteomas, desmoid tumours & cysts, sebaceous cysts
What is Turcot’s syndrome & what are its features
Variant of FAP
Colorectal polyps with CNS tumours (ependymomas, medulloblastomas)
What breast variant can metastasise to the bowel
Lobular breast cancer
What does B-raf predispose to
R sided tumours, worse prognosis
What are the commonest Ras mutations seen in colorectal cancer
What are the treatment implications
Ras G12 mutations
Can only given EGFR inhibitors (cetuximab / panitumumab) in Ras WT tumours
What screening exists for colorectal cancer
What is the outcome
Faecal immunohistochemical test (FIT)
Age 60-74 - 2-yearly
If ≥75 – can request to keep testing
Approx. 2% are positive -> undergo colonoscopy of which 1/300 will have cancer
High false positive rate (>90%)
Approx.15% reduction in mortality from screening (Nottingham trial 2006)
What investigations are needed for a newly diagnosed bowel cancer
Histology incl B-Raf & Ras status, and MMR
Imaging - CTCAP, MRI pelvis for rectal cancer
What are the Duke’s staging for colorectal cancer
A - T1-2 N0
B - T3-4 N0
C - T Any N1-2
D - metastatic disease
When should a colonoscopy be repeated following removal of an adenoma
1-2yrs
When should a colonoscopy be repeated following removal of an adenocarcinoma of pT1 only (submucosal invasion, not muscular)
1-2yrs
What risk factors would make a pT1 adenocarcinoma seen on colonoscopy, better managed by surgical workup and removal rather than removal at colonoscopy
Lymphatic or venous invasion
Grade 3 differentiation
Significant tumour budding
How is a stage 1 (T1-2 N0) colorectal cancer managed
Surgery only - no benefit to adjuvant chemotherapy
What are the options for neoadjuvant chemotherapy
and what duration
CapOx - capecitabine and oxaliplatin (3wkly regimen)
FolFox - Folinic acid, 5-FU, oxaliplatin (2wkly regimen)
6wks - 2 cycles capox or 3 cycles folfox
When is there minimal benefit from adjuvant chemotherapy
What drug should be avoided
dMMR / MSI-high
Potentiating effect of capecitabine
Use folfox or no adjuvant chemo
How is stage 2 colorectal cancer defined
T3-T4b N0
How is stage 3 colorectal cancer defined
Node positive disease
T1-4b N1-2
When should NACT be omitted for a stage ≥2 cancer
dMMR - no benefit to NACT as per Foxtrot trial
Proceed straight to surgery
How is stage 2 (T3-T4b N0) split regarding adjuvant tx
Low, intermediate and high risk
Low risk has no major or minor risk factors
Intermediate has minor, but not major risk factors
High risk has at least one major risk factor
What are the major risk factors when deciding adjuvant tx for stage 2 colorectal cancer (2)
pT4a stage including perforation
<12 LNs sampled
What are the minor risk factors when deciding adjuvant tx for stage 2 colorectal cancer (4)
Presentation with obstruction
LVSI / PNI
High grade / poor differentiation
High CEA pre-operatively (>5)
What adjuvant tx does a low risk stage 2 colorectal cancer receive
Assuming pMMR & No major or minor risk factors
No adjuvant tx indicated
What adjuvant tx does an intermediate risk colorectal cancer receive
Assuming pMMR, no major risk factors, but minor risk factor present
6mths single agent capecitabine or 5FU
What adjuvant treatment does a high risk stage 2 colorectal cancer receive
Assuming pMMR, and major risk factor present
3mths CapOx or 6mths Folfox
When might FolFox be a better adjuvant ChT regimen than CapOx?
Impaired renal function and ileostomy, as capox causes higher rates of diarrhoea
What is the benefit of adjuvant oxaliplatin, in addition to 5FU
4-5% benefit in OS - mosaic trial
What biomarkers should be sent for metastatic colon cancer
K-ras, N-Ras, EGF-R, B-raf, MMR, HER2
Imaging - CTCAP, MRI liver, PET CT
DPYD status
What is the follow up after surgery and adjuvant chemotherapy for colorectal cancer
Years 1-3:
3-6 month history, physical examination and CEA level
CT every 6-12mths
Colonoscopy every 3-5yrs, starting 1yr after surgery
Year 4-5:
6-12 month history, physical examination and CEA level
CT every 12mths
Colonoscopy every 3-5yrs
Where is the mesorectal fascia considered as the circumferential resection margin
Only for the non-peritonealised part of the rectum
What is the treatment for a stage I (T1-2 N0) rectal cancer
surgery - trans-anal, endoscopic submucosal or TME
Radical RT can be considered for those unwilling to have a stoma (necessary in APER), or unfit for surgery
What is the overall management of T3-4 or node positive rectal cancer
Pre-op RT/CRT followed by surgery
What are the indications for defunctioning ahead of treatment for rectal cancer?
Significant faecal urgency or incontinence which may compromise their ability to complete treatment
Symptoms or signs of obstruction on imaging or scope
Rectovaginal or rectovesical fistula from tumour
What are the indications for Neo-adjuvant treatment for rectal cancer
Involvement of the CRM
T3-4
Node positive disease
What are the benefits of neoadjuvant treatment in rectal cancer
Downstage disease, increasing rates of R0 resection
Reduce risk of local recurrence
When is long course Neo-adjuvant CRT indicated for treatment of rectal cancer
Threatened CRM (<1mm) or breached
Low tumours encroaching onto the intersphincteric plane or levator muscles
What is the long course neoadjuvant CRT regimen
45Gy/25# +/- 5.4Gy/3# boost to the tumour (50.4Gy/28# overall)
Or SIB to tumour (50Gy/25#) with 45Gy/25# to elective volume
With concurrent capecitabine 825mg/m2 bd on treatment days OR bolus 5FU on weeks 1 & 5
What is the follow up post long course NA CRT for rectal cancer
MRI pelvis and CTCAP 6-8wks following treatment, then proceed to surgery
What are the indications for short course neoadjuvant CRT for rectal cancer
And what is the regimen
CRM not threatened, but not felt pt would tolerate long course CRT
> T3b
Node positive
EMVI +
25Gy/5# over 5 days, and surgery within 10 days
What are the surgical options for a >T1 rectal cancer
TME
Anterior resection - middle / high rectal cancers
APER - very low rectal tumours
When is adjuvant chemoradiotherapy given in rectal cancer
What is the regimen
Only if pre-op LC-CRT or SC-CRT were not given (Primary surgery)
pT4 (not if pT4a above peritoneal reflection)
Tumour perforation (T4a)
Positive margins or residual disease
EMVI
Node positive disease
Regimen:
45Gy/25#/5wks +/- concomitant chemotherapy
If there is residual macroscopic disease, consider boost to tumour site up to 50Gy
What adjuvant regimen is given for a high risk stage 2 (T3-4 N0) rectal cancer
6mths of CapOx or Folfox (not 3mths CapOx like colon)
only if no NACT or SCPRT given (not long course)
How is oligometastatic disease defined
Up to 5 metastatic lesions, in up to 2 sites, with a controlled or resected primary, with all mets treatable
How is liver resectability defined?
≥30% of liver should remain
≥2 contiguous liver segments should remain disease free
No involvement of the hepatic vein
Limited extra-hepatic disease
For resectable metastatic liver disease, what is the recommended treatment?
If unfavourable prognostic criteria - what is the recommended treatment
No neoadjuvant treatment
Resect primary and liver mets
Adjuvant Folfox
Unfavourable prognostic criteria, but resectable:
3mths neoadjuvant folfox/folfoxiri, resection, followed by adjuvant CapOx/Folfox for 6mths
No additional benefit for cetuximab (pts did worse)
What is the treatment recommendation for a resectable primary tumour but unresectable mets
Attempt to convert unresectable mets into resectable, with Folfox/Folfiri/folfoxiri +/- cetux/panitumumab (L-sided tumour; EGFR WT) or +/- bevacizumab (R-sided tumour)
Once resectable, resect primary and mets.
If no converted to resectable, continue palliative ChT
What is the first line treatment for advanced metastatic colorectal cancer, that is L-sided
And dependent on what mutations
Folfox / CapOx / Folfiri / Folfirinox +/- Cetuximab (with folfiri) / Panitumumab (with folfox)
If Ras WT & B-Raf WT & left sided tumour -> add Cetuximab/panitumumab
3-4 month PFS & OS benefit
If Ras/Raf-mut, can consider doublet/triplet ChT with bevacizumab
FOLFOXIRI
Superior OS and response cf to FOLFIRI, but toxic and need to be fit!
What is the first line treatment for advanced metastatic colorectal cancer, that is R-sided
Folfox / CapOx / Folfiri / Folfirinox +/- Bevacizumab
If right sided tumour
FOLFOXIRI
Superior OS and response cf to FOLFIRI, but toxic and need to be fit!
What is the first line treatment for advanced metastatic colorectal cancer, if the pt is not fit enough for combination chemotherapy
5FU or capecitabine alone - if not fit enough for combination chemotherapy
What is the first line treatment for advanced metastatic colorectal cancer, that is dMMR/MSI-H
1st line - consider pembrolizumab (for 2yrs or until progression)
2nd line - chemo +/- targeted agent (ipi/nivo 2nd line if chemotherapy used 1st line)
What is licensed second line for the treatment of B-Raf V600E positive colorectal cancer
Encorafenib-cetuximab
Based on Beacon trial
What is the second line treatment of dMMR colorectal cancer after first line chemotherapy
Ipi-nivo (only if pembro not used first line)
What drug combination cannot be used with cetuximab/panitumumab
CapOx
What is the prognosis of metastatic colorectal cancer treated with folfox/folfiri
Combination chemo (FOLFOX/FOLFIRI): 22-24 months
How is the involvement of the MRF classified in rectal cancer
<1mm - involved
1-2mm - threatened
>1-2mm - clear
When should pre-op chemoRT not be offered for rectal cancer
Early rectal cancer - T1-2 N0
Offer to T1-2, N1-2 or any T3-4W
When is TNT indicated for rectal cancer
Stage II & III rectal cancer (T3-4 or node positive)
Fit pts
Large tumour, node positive
CRM involved
MMR proficient
What drug is contraindicated with capecitabine
warfarin
How is de novo metastatic rectal cancer managed
If resectable or potentially resectable, SCRT and 3/12 neoadjuvant chemotherapy, followed by imaging assessment and potentially surgery
If CRM not threatened in primary, can omit neoadjuvant chemotherapy
When is SCPRT followed by delayed imaging and surgery (10wks) used
In pts with poor performance status but still with an indication for pre-op RT
what adjuvant treatment is recommended for pts >70?
single agent cape/5FU (6mths) or surveillance
is levator involvement by a rectal cancer an indication for neoadjuvant chemotherapy
yes - indication for long course pre-op chemoRT
what must be tested for in colorectal cancer before deciding adjuvant treatment
how is this relevant in stage 2 disease
MSI status
dMMR in stage II disease:
Minimal benefit from adjuvant chemotherapy
Adjuvant capecitabine increases risk of potentiating mutation
Therefore give combination = FOLFOX or No adjuvant chemo
