Colorectal Ca Flashcards
What is the most common cancer overall in Au?
pancreas then bowel then breast
mortality number 1 is lung
What is the risk per year of colon cancer in IBD?
1% per year after 8 years
What impact does calcium and vitamin D have on colon cancer risk?
Modest but definite benefit
What are the characteristics of a HNPCC cancer?
Often right sided, mucinous, poorly differentiated, inflammatory infiltrate, multiple primaries common
Early tumours have better prognosis than MSS
How has the testing for microsatellite instability been stabilised?
Check for five different repeats (three dinucleotide and two mononucleotide) MSI if over 40 percent, meaning 2 or more of the 5 marker panel. This is according to the Bethesda criteria.
How do you actually check for deficient mismatch repair in someone with cancer?
Microsatellite instability testing on tumour via PCR
Immunohistochemistry- look for LOSS of staining of MSH2 nd MLH1 or MSH 6
There is a 95% concordance between IHC and MSI- first is cheaper and easier. Need to go on to sequence after IHC if want to define the specific mutation and permit family screening.
What impact does FOBT testing have on patient outcomes?
Reduce mortality by 20%
In Au FOBT offerred at 50,55,60,65,70,74
Detect more at earlier stage (ie A)
In NEJM article, if you do multitarget stool DNA testing for colorectal cancer screening, how does it differ?
More advanced R sided lesions detected
Increased sensitivity, decreased specificity
What is lead time bias?
Screening data looks like patients have prolonged survival but they are just more likely to be diagnosed at earlier, asymptomatic stage and then live just as long
What is length time bias?
Slower growing, less aggressive tumours have longer asymptomatic phase where screening can detect compared with fast growing dangerous tumours- this makes it look like the screen detected patients have better outcomes.
What imaging should be done in rectal cancers now?
MRI to assess local extent (previously endorectal ultrasound)
MERCURY study showed correlation between rectal MRI and the histopathology
What chemo is given for stage 3 colorectal ca
Oxaliplatin + 5FU + leucovorin
Note that in high risk stage II cancers, would also consider administering
What is the chemo in advanced bowel ca?
Folfox = lukovorin +5FU + oxaliplatin
or
Folfiri = leukovorin +5FU + irinotecan
Sometimes combined with a biologic (bevacizumab or cetuximab)
Cancers associated with HNPCC
Colorectal Endometrial Ovarian Renal pelvis Ureter Small bowel
80% lifetime risk colorectal ca
Call the sporadic cancers and lynch cancers “MSI-hihg” if found to be deficient in MMR
Cancers associated with FAP
Colorectal Desmoid Small bowel Pancreas Papillary thyroid Brian Stomach Hepatobiliary Adrenal
95-100% lifetime risk colorectal Ca
What are the two pathways to microsatellite instability?
Germline pathway with mutations in MMR genes–>MSI-H
Sporadic CRC via CIMP positive pathway) where there is hypermethylation of MLH1–>MSI-H
IN each case defective MMR causes an accumulation/variation of repeated DNA sequences called microsatelites–>frame shift mutations–>defective proteins
What are the criteria called for identifying if someone may have Lynch syndrome?
Amsterdam criteria Bethesda criteria (newer, more lenient)
Use to decide if patient warrants genetic testing (or immunohistochemistry then genetic testing) based on family history of cancers and age of onset.
What mutations do you look for in HNPCC
MLH1 and MSH2 are the most important
Also MSH6 and PMS2 or EPCAM
How should MSI-H colon cancer be treated differently (two points)?
- No benefit to adjuvant 5FU
2. Evidence for aspirin as secondary prevention in the CAPP2 trial
TNM colon ca 5 year survivials
I- 90-95%
II- 70-85%
III - 25-70%
IV- 0-10%
What are the histopathological risk factors for recurrence?
T4 Tumour perforation Number involved LN Extramural vascular invasion Inadequate LN sampling Mucinous
What effect does preoperative radiation therapy have where there is curative intent?
Does not improve survival but does improve local recurrence rates
What is the best timing for radiotherapy? Before? After surgery?
Pre-op radiotherapy has a reduction in risk of local recurrence but disease free and overall survival remain the same.
Mechanism of bevacizumab
Blocks VEGF pathway by binding to the ligand before it can bind to the VEGF receptor
Ramucirumab
Blocks VEGF pathway by binding to the VEGF2 receptor
Cetuximab and Panitumumab…MOA?
Binds EGFR receptor
Why check for kras mutation in colorectal ca?
If wild type, may benefit from cetuximab
If mutated KRAS, constitutively active pathway, so blocking of receptor at cell surface via Cetuximab will have no effect
Side effects of Bevacizumab
GI perforation Bleeding Thrombosis Proteinuria Delayed wound healing Reversible posterior leukoencephalopathy syndrome
Side effects of Cetuximab
Acneiform rash - worse rash correlates with better disease response
Hypomagnesaemia
Diarrhoea
If just a mild rash, evidence that can escalate dose and no worries!
What is Regorafenib and how does it work?
Regorafenib is a protein kinase inhibitor with a similar structure to sorafenib. It is thought to work by inhibiting multiple signalling pathways involved in angiogenesis and tumour growth.
Final line after been through all chemos in metastatic colorectal Ca
When do you actually use Bevacizumab in colon cancer?
In metastatic colon cancer in combination with standard first line chemotherapy
You don’t use it in resectable disease
When do you actually use Cetuximab in colon cancer?
Metastatic colon cancer, not resectable disease
Also used in head and neck squamous cell ca
Has PET been validated pre-op in colorectal ca?
No
Should pre-op chemoradiotherapy be given in recal ca? What about post op?
Stage II or III should have pre-op 5-FU and radiotherapy (ie if any lymph nodes or it is a full thickness tumour). If thought to be stage I and then post op found to have LN involvement, get post op chemoradiation.
FOLFOX given post chemoradio to complete 6 months total
What is the mechanism of giving leukovorin with 5-FU?
Causes 5-FU to bind tumour more effectively, but no intrinsic antitumour activity
What about using anti-VEGF and anti-EGFR agents together?
Unexpected deleterious effect on outcomes
What is the MAIN reason for doing surveillance colonoscopy post resection?
To look for new polyps which could become second primaries
To a much lesser extent to identify recurrent disease.
Local recurrence is FAR more common in rectal cancer than colon cancer patients.
Also more likely to have metachronous cancer if proximal to the splenic flexure
Which type of FOBT should be used?
Two main types of FOBT are available: guaiac and faecal immunochemical tests.
Immunochemical tests are preferred as they have greater sensitivity and higher uptake.
Colon cancer screening in Au? Who?
5 yearly FOBT from age 50 to 74
Medium risk get 5 yearly colonoscopy with intervening FOBT from age 50 or 10 years younger than youngest person in family to get cancer
Who gets pap smears in au?
2 yearly age 18-70 if have been sexually active
First line for colon cancer in a well person
add oxaliplatin to 5Fu- recurrence rates halved if can add the oxaliplatin
pos FOBT- what chance cancer
5/10 normal colon
1/10 colon cancer
4/10 adenoma
Characteristics of a MSI tumour
more right sided poorly differentiated no point giving f-FU more mucinous component lymphocyte infiltration
Aspirin and NSAIDS in familial CRC?
NSAIDS reduce polyps but not cancer in FAP
aspirin reduces cancer by 15% in HNPCC
What are microsatelites
MMR proteins correct errors of DNA replication. If no correction then defective sequences called microsatellites develop–>frame shift mutation–>defective proteins
either from germline or sporadic as with hypermethylation of MLH-1 promoter region
CEA pre op useful how
predicts recurrence
What does radiation therapy achieve in stage 2 or 3?
reduce local recurrence
no effect on survival
Why leukovorin with folfox
potentiates the 5-FU inhibition of thymidylate synthase
MLH1 + PMS 2 lost
MSH 2 and 6 lost
MSH6 or PMS2 lost by themselves?
in either sporadic or hered
ONLY in HNPCC
only in HNPCC- rare
