Colon Cancer 2

Question 1

Oxaliplatin

Answer 1

• Administered IV
• Dosing is based on BSA
• Alkylating Agent – “Platinums”
• Oxaliplatin forms reactive platinum complexes
which are believed to inhibit DNA synthesis by
forming inter-strand and intra-strand crosslinking of DNA molecules
• Toxicities – neuropathy and thrombocytopenia

Question 2

Oxaliplatin Induced Neuropathy

Answer 2

• Sensory Neuropathy
– Cumulative and dose related (more with more cycles)
• Cold dysesthesia
– Neuropathy type symptoms exacerbated by cold
• Tingling/numbness/stiffness in hands/feet
• Tightness in throat or jaw with difficulty swallowing +/- chest pressure
– This is scary for patients!!!
• Advise Patients to avoid exposure to cold
– Avoid cold drinks, frozen food (eg. Ice cream) and ice (including during the infusion)
– Avoid washing hands with cold water
– Avoid outdoor activities during cold weather
– Avoid close contact with air conditioners or freezers (wear gloves)

avoid cold for 5 daus

Question 3

5-Fluorouracil
(or Fluorouracil or 5FU)

Answer 3

• Antimetabolite - analog of uracil and thus acts as a
pyrimidine antagonist
– The metabolite FdUMP (fluorodeoxyuridine
monophosphate) competes with uracil to bind with
thymidylate synthetase and the folate cofactor leading to reduced thymidine production, and hence, a reduction in DNA synthesis and repair

rapidly dividing cells

Question 4

5-Fluorouracil
(or Fluorouracil or 5FU) side effects

Answer 4

– Stomatitis
– Myelosuppression
– Hand-foot syndrome rare with bolus 5FU but can
occur with continuous infusion 5FU

Question 5

Leucovorin

Answer 5

increased cytotoxic and toxic effects of fluorouracil
• leucovorin stabilizes the bond to thymidylate synthetase
• A fantastic example of exploiting a drug interaction to improve efficacy (and toxicity?)
Stop enzyme so it cant make dTMP
Increases N5, N10-mthylene THF and efficacy of 5-FU which increases toxicu=tiy

Question 6

Capecitabine – MOA and Dosing

Answer 6

• Capecitabine is an orally
bioavailable pro-drug
• Absorbable through the GI
tract and sequentially
converted to 5FU
• Available as 500 mg and 150
mg tablets.
Orally BID for 14 days, 7 days off
• Take with food
• Efficacy and safety based on studies when given 30 min after a meal
• Store at room temperature
• Must be dose adjusted for patients with renal
dysfunction (CrCl < 50 mls/min)

Question 7

Capecitabine – Toxicities

Answer 7

• Diarrhea - pretty bad
– If exceeds 4 bowel movements per day then
patient should contact cancer care team
• Mucositis (painful sores in the mouth)
• Hand –Foot Syndrome
• AKA Palmar-Plantar Erythrodysesthesia (PPE)
– Begins with reddening and/or drying of the skin
on palms of hands and soles of feet
– Can lead to blistering, splitting, and desquamation
– Can be accompanied by numbness, tingling, pain

Question 8

Metastatic colon cancer
• Management depends on location and extent
of metastases

Answer 8

– Usual site of metastasis is liver
– May also metastasize to lung
• met-CRC is usually no longer curable
– Goals of therapy are different than in Stage I, II, III
• NOTE - It may be possible to downstage patients with
limited metastases with neoadjuvant chemotherapy
or surgical resection of the metastases.

Question 9

Chemotherapy in Metastatic Colon Cancer

Answer 9

• Keep Goals in Mind!!
– Continue therapy until disease progression or unacceptable toxicities
– Patients may be given “Drug holidays”

• Chemotherapy
– FOLFOX6
– FOLFIRI (similar to FOLFOX but uses irinotecan instead of oxaliplatin)
– CAPOX
– CAPIRI (similar to CAPOX but uses irinotecan instead of oxaliplatin)

• +/- Biologic
– Bevacizumab, Panitumumab, or Cetuximab
• Palliative chemotherapy can improve median overall survival (24-28 months vs <6 months)

Question 10

– FOLFIRI q2weeks until unacceptable toxicities
or disease progression contains irinotecan

what is irinotecan?

Answer 10

• Topoisomerase I inhibitor
– TI1 is an enzyme that produces reversible singlestrand breaks in DNA during DNA replication
– These single-strand breaks relieve torsional strain
and allow DNA replication to proceed.
– Irinotecan binds to the topoisomerase I-DNA
complex to prevent religation of the DNA strand
• Side Effects – patient counselling
– Neutropenia – infection prevention
– Diarrhea – monitoring and management

Question 11

Irinotecan Induced Diarrhea
early onset vs late onset

Answer 11

• Early-onset
– Occurs during irinotecan infusion or within 24
hours of administration
– Usually transient (infrequently severe)
– Thought to be part of a cholinergic syndrome
mediated by increased anticholinesterase activity.
– May be accompanied by other cholinergic
symptoms (rhinitis, hypersalivation, miosis,
flushing)
– Treated with atropine 0.3-0.6 mg IV or SC prn up
to 1.2 mg

Late-onset
– > 24 hours after administration of irinotecan. More common
– Can be prolonged and severe and lead to
dehydration and electrolyte imbalance.
– Thought to be related to abnormal ion transport
in the injured intestinal mucosa

Question 12

Irinotecan Induced Diarrhea
• Late-onset (>24 hours after administration)
– Management

Answer 12

– Management should include prompt treatment
with high dose loperamide
• Loperamide 4 mg po asap followed by 2 mg q2h until
diarrhea free for 12 hours
• Stop laxatives in advance!
– Median onset of 5-11 days.
– Median duration is 3 days

Question 13

Irinotecan - Metabolism

Answer 13

• Irinotecan is activated to SN-38 (active drug) by carboxylesterase (CE) enzymes
• SN-38 is inactivated to SN-38 glucuronide (SN-38G) via hepatic UGT enzymes
(such as UGT1A1)
• Biliary-excreted SN-38G can be converted back to SN-38 by intestinal bacterial
ß-glucoronidase. Re-generated SN-38 can cause enteric injury leading to
diarrhea

Ifused IV, prodrug gets metabolized to SN-38
UGT1A1 glucuronidate and inactivate it
Sometimes excreted by bile into GI tract
The GI enzymes change it back to active SN-28
Cytotoxic sitting nstead intestines
Causes diarrhea

Question 14

Irinotecan Pharmacogenomics

Answer 14

• Reminder:
– Metabolism with UGT1A1 is important
to inactivate irinotecan
• Genetic polymorphisms can cause
deficiencies in UGT1A1
– UGT1A1*28 polymorphism (allele) is
associated with reduced UGT1A1
function (reduced glucuronidation of
SN-38
• People with a deficiency of UGT1A1
(“Gilberts Syndrome”) can
experience substantially worse
toxicities (especially neutropenia)

Reduction of action of ugt1a1 - less movement of inactive metabolite, thus more exposure to cytoxic drug
Leads to more neutropenia
Happening in blood, not gut

Question 15

Bevacizumab

Answer 15

• Indicated for advanced/metastatic CRC in
combination with:
– FOLFOX or CAPEOX (modest increases in PFS and OS)
– FOLFIRI (med PFS 11 mo, med OS 24 mo)
• administered on DAY 1 of chemo cycle (with chosen
chemo protocol)
• recombinant humanized monoclonal antibody
• vascular endothelial growth factor (VEGF) inhibitor
– Inhibits angiogenesis!!

Question 16

Bevacizumab – Side Effects

Answer 16

• Hypertension (up to 34%)
– patients may need anti-hypertensives or a dose increase if pre-existing HT

• Thromboembolism (blood clot)
– Arterial (up to 11%) or Venous (up to 13%)

• Impaired wound healing (up to 20%)
– surgical patients must hold bevacizumab for at least 6 weeks pre op and not reinitiate for 6-8 weeks post op (or until wound fully healed)

• Hemorrhage
– Self limiting epistaxis approximately 25%
– Serious examples: pulmonary hemorrhage (up to 31%) tumour associated hemorrhage (up to 5%)

• Proteinurea (up to 38%)
– Range from clinically asymptomatic to nephrotic syndrome

Question 17

EGFR targeting Monoclonal Antibodies

Answer 17

• EGFR = epithelial growth factor receptor
• EGFR targeting MAbs used in metastatic colon cancer:
– cetuximab and panitumumab
• MOA:
– Monoclonal antibody binds to EGFR blocking phosphorylation and activation of the EGFR associated kinases
– Leads to inhibition of cell growth and induction of apoptosis
– Cetuximab also induces internalization and degradation of EGFR, with resulting downregulation of cell surface receptors

4 diff receptors can be on cell surface o HER family
HER1 - EGFR
- When ligand binds, egfr will dimerize or couple with another receptor and start a cascade –> phosphorlyates and keeps growing
- RAS is one protein that signals go
- Own RAS mutation, doesn’t need signal, will just go on its own

Question 18

what is K-RAS

Answer 18

• KRAS is a gene that encodes the K-Ras protein involved in theEGFR signaling pathway.
• Evidence shows that patients with KRAS mutations do not benefit from EGFR inhibitors
–Must be KRAS “wild type” for these agents to be effective!
•Kras is Wild Type in up to 65% of cases
–Example of a predictive biomarker
•Genotyping of tumour tissue (either primary tumor or
metastasis) is recommended
–Quantitative PCR or direct DNA sequencing

Question 19

EGFR Targeting MAbs
Cetuximab & Panitumumab

Only in metastatic disease
If patholgy report says K-RAS wild type only

K-RAS is predictive biomarker of efficacy of cetuximab and panitumumab

Answer 19

• Cetuximab
–Indicated for metastatic colorectal cancer that is EGFR expressing KRas wild type as follows:
•in combination with FOLFOX6 or FOLFIRI
•as a single agent (monotherapy) if patient is intolerant to irinotecan or after failure of other treatments

• Panitumumab
– indicated for metastatic colorectal cancer that is EGFR expressing KRas wild type as follows:
•in combination with FOLFOX6 or FOLFIRI or as a single agent (monotherapy) after failure of other treatments
•AHS formulary

Question 20

which side primary tiumors use EGFR targeting MAbs

Answer 20

• Growing body of data shows
that location of the primary
tumor can be a predictive factor
for response to EGFR inhibitors
• Right sided primary tumors:
– Evidence suggests little to no benefit of EGFR targeting MAbs
– Poorer prognosis
• Left sided primary tumors:
– Response rate of approximately 40% with EGFR targeting MAbs

use only for left side

Question 21

Adverse effects of EGFR targeting MAbs

Answer 21

• Infusion reactions:
– Chills ,fever, dyspnea
• Rash
– Acneiform rash
– Erythema and pruritus
• Diarrhea
• Hair changes
– Curly and brittle hair with dry scalp
– Increased eyelash and eyebrow growth
• Nail changes:
– Nails become more brittle and start to crack

Question 22

Think about it……which biologic would you add to the chemo IF:
– Adjuvant treatment vs Treatment for stage IV disease?
– Patient is getting FOLFOX vs FOLFIRI?
– The K-RAS is mutated?
– The K-RAS is wild type?
– The Colon Cancer primary site is on the right side? Vs left side?

Answer 22

– Adjuvant treatment vs Treatment for stage IV disease?
No biologic for adjuvant, all for metastatic cancer

– Patient is getting FOLFOX vs FOLFIRI?
FOLFIRI - more inclined to use bevaciz

– The K-RAS is mutated?
Bevaciz - antiangiogenesis, not to do with K-RAS

– The K-RAS is wild type?
Could use either way if on left-side

– The Colon Cancer primary site is on the right side? Vs left side?
EGFR won’t work well with right side –> use Bev

Question 23

can you use EGFR targeted MAbs with
bevacizumab ?

Answer 23

REMEMBER, NOT BOTH TOGETHER!
– - Trials have shown that combining EGFR targeted MAbs with
bevacizumab results in worse outcomes.