PHARM 444: colon cancer

unmodifiable colorectal cancer risk factors (5)

- age

- personal hx

- family hx

- familial adenomatous

polyposis (FAP) or Lynch Syndrome.

- IBD

modifiable colorectal cancer risk factors (6)

- diabetes

- obesity & high waist circumference

- > 2 drinks/day

- smoking

- diet (high red meat, processed meats, low veg/fruit)

- physical inactivity

CRC screening for average risk (asymptomatic)

a) age

b) test

c) is test positive follow up w/ ...

a) 50-74

b) FIT every 1-2 years

c) colonoscopy -- if normal restart FIT testing at 10 years

TRUE or FALSE if someone is symptomatic with colorectal cancer screening should be done with a FIT test

FALSE

should a FIT test be used in someone > 75 y.o.? why or why not

depends -- may be higher risk of bleeding with a colonoscopy and benefit might not out weight risks

if an individual has a 1st degree relative diagnosed with CRC at 60 years or older, then initiate screening with FIT test WHEN?

Every 1-2 years starting at 40 years.

If an individual has a 1st degree relative with CRC (or high risk adenomas) diagnosed at UNDER 60 or two or more affected relatives then refer for consideration of colonoscopy WHEN?

at age 40, or 10 years prior to the index case, whichever is earliest.

If an individual has a personal hx of CRC, colonic adenomas or IBD, ongoing monitoring/follow up is done via FIT test or colonoscopy.

colonoscopy

how does a FIT help to screen for colorectal cancer?

uses antibodies for human blood to find trace amounts of blood

what percentage of Canadians age 50-74 were being screened for colorectal cancer according to guidelines?

55%

what are signs and sx of colorectal cancer? (8)

- changes in bowel habits

- tenesmus

- changes in stool shape

- melena

- weight loss

- fatigue

- pallor (b/c possible blood loss & anemia)

- illeus

what are the goals of therapy roughly for

a) stage I, II, III

b) stage IV

a)

- CURE disease

- min toxicities

- maintain quality of life

b)

- min toxicity

- maintain quality of life

- palliative --> extend survival

what is the mainstay of colon cancer treatment for non-metastatic disease

surgical resection

treatment therapy for colon cancer stage 0, I, II tumours

- surgical resection

- no adjuvant therapy

- observe & colonoscopy @ year 1 then 3 years then 5 years

treatment therapy for colon cancer stage III tumours

surgical resection w/ adjuvant chemo

- CAPOX

- FOLFOX6

- capecitabine

what are considered high risk tumour features that would warrant a stage II tumour being treated as a stage III? (4)

- poorly differentiated

- perforation or obstruction

- lymphovascular invasion

- close/ (+) surgical margins

what drugs are in the FOLFOX6 regimen (3)

- Oxaliplatin (IV)

- Leucovorin (IV)

- 5-fluorouracil (IV)

what drugs are in the CAPOX regimen (2)

- Oxaliplatin (IV)

- capecitabine (PO)

Oxaliplatin

a) drug class

b) MOA

c) route

d) dosing based on ..

e) AE (3)

f) counselling points

a) Alkylating Agent - "Platinums"

b) forms reactive platinum complexes to inhibit DNA syn. by cross-linking of DNA

c) IV

d) BSA

e)

- peripheral neuropathy

- Cold dysesthesia

- thrombocytopenia

f)

- avoid cold drinks/ food

- avoid washing hands with cold water

- avoid outdoor activities during cold weather

- wear gloves

5-Fluorouracil (5FU)

a) drug class

b) MOA

c) route

d) dosing based on ..

e) AE (3)

a) antimetabolite -- pyrimidine antagonist

b) metabolite FdUMP competes w/ uracil to bind thymidylate synthetase & folate cofactor = reduced thymidine production = reduction in DNA syn/repair

c) IV

d) BSA

e)

- stomatitis

- Myelosuppression

- Hand-foot syndrome

Hand-foot syndrome due to 5FU is more common with bolus or continuous infusion

continuous infusion

Leucovorin

a) drug class

b) MOA

c) given in conjunction with what drug

d) route

e) dosing based on ..

a) folic acid analog

b) stabilizes the bond to thymidylate synthetase = increased cytotoxic effects of 5FU

c) 5FU

d) IV

e) BSA

Capecitabine

a) drug class

b) MOA

c) route

d) dosing based on ..

e) AE (3)

f) counselling points

a) 5FU prodrug (antimetabolite -- pyrimidine antagonist)

b) same as 5FU only absorbed via GI

c) PO

d) BSA

e)

- diarrhea

- mucositis

- Hand-foot syndrome (Palmar-Plantar Erythrodysesthesia)

f)

- take with food

- store at room temp

- reduce dose with renal dysfunction

what does metastatic colon cancer management depend on

metastases location & extent

- commonly mets in liver and sometimes lung

what are the possible chemo regimens for metastatic colon cancer (4)

- CAPOX

- CAPIRI (similar to CAPOX but uses irinotecan instead of oxaliplatin)

- FOLFOX6

- FOLFIRI6 (similar to FOLFOX but uses irinotecan instead of oxaliplatin)

Irinotecan

a) drug class

b) MOA

c) metabolism

d) route

e) dosing based on ..

f) AE (2)

g) counselling points

a) topoisomerase inhibitor

b) binds to the topoisomerase I-DNA complex to prevent re-ligation of the DNA strand

c)

- ACTIVATED via carboxylesterase enzyme (SN-38)

- INACTIVATED via UGT hepatic enzymes (SN-38G)

- Biliary-excreted SN-38G can be converted back to SN-38 by intestinal bacterial ß-glucoronidase which then can cause enteric injury leading to diarrhea

d) IV

e) BSA

f)

- neutropenia

- diarrhea

g) use high dose loperamide (4 mg po asap followed by 2 mg q2h until diarrhea free for 12 hours) for diarrhea

early vs late onset Irinotecan Induced Diarrhea

hint:

- duration

- cause

- treatment

EARLY

- within 24 hours

- usually transient

- cholinergic syndrome mediated (i.e accompanied by hypersalivation, flushing, rhinitis etc)

- TREAT = atropine

LATE

- > 24 hours

- can cause dehydration & electrolyte imbalance

- related to abnormal ion transport in mucosa

- TREAT = loperamide

People with a deficiency of UGT1A1, the gene associated with UGT enzyme responsible for converting Irinotecan into its inactive form can end up experiencing what as a result?

substantially worse toxicities (especially neutropenia)

Predictive biomarker

indicative of therapeutic efficacy b/c there is an interaction b/w the biomarker and therapy on patient outcome

Prognostic biomarker

Indicative of patient survival independent of the treatment received b/c the biomarker is an indicator of the innate tumour aggressiveness

Bevacizumab

a) drug class

b) MOA

c) indication

d) route

e) AE

a) VEGF inhibitor

b) targets vascular endothelial growth factor to inhibit angiogenesis

c) advanced/metastatic Colon Cancer in combination with FOLFOX, CAPEOX or FOLFIRI

d) IV -- administered on day 1 of chemo cycle

e)

- HTN

- thromboembolism

- impaired wound healing

- hemorrhage

- proteinuria

cetuximab

a) drug class

b) MOA

c) indication

d) route

e) mutations in what genes can lead to resistance of this drug

f) AE

a) EGFR targeting Monoclonal Antibodies

b) binds to EGFR blocking phosphorylation &activation of EGFR associated kinases = inhibition of cell growth & induction of apoptosis

** also induces internalization/degradation of EGFR = downregulation of cell surface receptors **

c) metastatic colon cancer in combination with FOLFOX or FOLFIRI

d) IV

e) KRAS & NRAS

f)

- infusion rxn (i.e. chills, fever)

- rash (i.e. Acneiform rash, erythema & pruritus)

- diarrhea

- hair changes (i.e. curly/ brittle hair, increased eyelash/brow growth)

- brittle nails

panitumumab

a) drug class

b) MOA

c) indication

d) route

e) mutations in what genes can lead to resistance of this drug

f) AE

a) EGFR targeting Monoclonal Antibodies

b) binds to EGFR blocking phosphorylation &activation of EGFR associated kinases = inhibition of cell growth & induction of apoptosis

c) metastatic colon cancer in combination with FOLFOX, FOLFIRI or as monotherapy

d) IV

e) KRAS & NRAS

f)

- infusion rxn (i.e. chills, fever)

- rash (i.e. Acneiform rash, erythema & pruritus)

- diarrhea

- hair changes (i.e. curly/ brittle hair, increased eyelash/brow growth)

- brittle nails

The location of the primary tumor can be a predictive factor for

response to EGFR inhibitors & prognosis. what are the differences between the R and L side of colon cancer

RIGHT

- poorer prognosis

- Better survival with bevacizumab + chemo

LEFT

- better prognosis

- Better survival with EGFR targeting Mabs + chemo