Colorectal Cancer

Question 1

How do colorectal cancers develop?

Answer 1

Begin as polyps on colon mucosa, grow outward into blood vessels and lymph nodes
Not all polyps become cancer!
Mostly ADENOMAS become cancerous

Question 2

What are risk factors of colorectal cancer development?

Answer 2

PMH of polyps
IBD (UC = 5x higher, Crohn’s = 10x higher)
Family hx
Genetics (FAP, HNPCC/Lynch Syndrome)
Lower socioeconomic
Age >45
Race (Black, Native American)
Modifiable
Smoking
Heavy EtOH
Physical inactivity

Question 3

What is Familial adenomatous polyposis (FAP)? (CRC)

Answer 3

Thousands of adenoma polyps cover colon and rectum
80% have mutations in APC gene and KRAS
Must identify via genetic testing
If untreated, 100% will get colorectal cancer by 40s

Question 4

What is Hereditary non-polyposis colorectal cancer (HNPCC/Lynch syndrome)?

Answer 4

No excessive polyps (unlike FAP)
When families have 3+ members with colorectal/endometrial cancer
Mostly causes right-side colon cancer
Mutations in genes -> leads to microsatellite instability (affects immunotherapy)

Question 5

What is the clinical presentation of colorectal cancer?

Answer 5

Bright/dark red blood in stool
Change in bowel frequency
Constipation/not completely empty
Narrower stools
General abdominal discomfort
Weight loss
Constant fatigue
N/V

Question 6

What are colorectal cancer prevention strategies?

Answer 6

High fiber diet (dilutes carcinogens)
Reduced dietary fat
Cyclo-oxygenate inhibition (COX2 is enhanced in almost all CRC)

Question 7

What is the gold standard screening test for colorectal cancer?

Answer 7

Colonoscopy
(1st degree relative = start screening at 40 instead of 45)
(FAP or Lynch = q1-2 years)

Question 8

Colorectal cancer follows TNM staging. What treatment format should be used for each stage?

Answer 8

I = no chemo, only surgery
II = surgery +/- adjuvant chemo
III = surgery + adjuvant chemo
IV = Chemo, target therapy, immunotherapy

Question 9

What are some patient considerations before starting treatment for CRC?

Answer 9

Disease Stage
Patient performance status
Comorbidities
Pharmacogenomics
- KRAS-wild type (test only if metastatic)
- Microsatellite Instability (MSI) - tests for DNA mismatch

Question 10

What indicates poor prognosis in CRC?

Answer 10

Advanced stage (3-4)
Lesions, lymphovascular invasion
Positive margins!
Bowel obstruction/perforation
T4 disease (deep primary tumor)
Low performance status
Lymph node involvement (>4)

Question 11

What is the MOA of 5-FU? What drug can be added for enhanced effects? What are some AEs?

Answer 11

MOA - inhibits DNA synthesis
+ LEUCOVORIN (enhances 5-FU cytotoxic events
AEs:
Bolus - myelosuppression
Infusion - Hand-foot syndrome, diarrhea, mucositis
(Almost never given as bolus now)

Question 12

What is the MOA of capcitabine? What are some indications for dose-adjusting? What are some AEs? (CRC)

Answer 12

MOA - 5-FU prodrug
Renal impairment - 25% dose reduce when CrCL 30-50
CYP2C9 inhibitor (avoid w warfarin, phenytoin)
CI in DPD deficiency
AEs:
Hyperbilirubinemia
Diarrhea
Hand-foot syndrome
Mucositis

Question 13

What are some AEs of oxaliplatin?

Answer 13

Platinum analog (like cisplatin)

AEs:
Peripheral neuropathy (cumulative)
- has a max limit
Cold intolerance (become unbearably sensitive and painful to cold)
Myelosuppression
[treatments for AEs are clinically inconclusive, possibly duloxetine for neuropathy]

Question 14

What are AEs of irinotecan?

Answer 14

I RUN TO THE CAN
Diarrhea
- acute or delayed
- treat acute w atropine
Fatigue
Alopecia
Myelosuppression

Question 15

What are TWO anti-angiogenesis drugs used in CRC? What are some AEs?

Answer 15

Bevacizumab (preferred) - approved for metastatic CRC w 5-FU infusions
Zig-aflibercept - approved in metastatic CRC who have progressed on an oxaliplatin regimen
given to cut off blood flow to cancer, only used adjunctively

AEs:
HTN (must control)
Delayed would healing
Proteinuria
Hemorrhage, nose bleeds
VTE

Question 16

Name the VEGF receptor-2 inhibitor used in CRC. What combo regimen is it used in?

Answer 16

Ramucirumab
Used in FOLFIRI

Question 17

What two EGFR inhibitors are used in CRC? Which is more likely to have an infusion reaction? What are AEs of EGFRis?

Answer 17

Cetuximab*
Panitunumab
*cetuximab is chimeric, more likely to have infusion rxn
- premeditate w Benadryl

AEs:
Hypomagnesemia
Acne-like rash (prevention: limit sun exposure, use moisturizers, use alcohol-free products, avoid hot showers and OTC acne products)
- mild = use hydrocortisone or clindamycin topicals
- moderate = hydrocortisone/clindamycin, doxycycline or minocycline oral
- severe = d/c drug, systemic oral retinoids, IV steroids, IV abx and IV hydration

Question 18

What is a multikinase inhibitor that can be used in CRC? What is the BBW?

Answer 18

Regorafenib
SALVAGE THERAPY, last line!
**BBW = hepatotoxicity **
AEs:
VEGF side effects, rarely well tolerated

Question 19

What endocrine therapies may be considered in CRC treatment?

Answer 19

Anti-HER2 therapies
ONLY is HER2(+) and overexpressed
Can use: trastuzumab + pertuzumab, Fam-trastuzumab derxtecan

Question 20

What is a last-line, oral combination chemo agent for CRC? What AE makes it not preferred?

Answer 20

Triluridine + Tipiracil (Lonsurf)
SEVERE MYELOSUPPRESSION
- monitor CBC prior to and on the day of each administration
Taken M-F with weekends off

Question 21

What immunosuppressive agents may be used in CRC?

Answer 21

Pembrolizumab
Nivolumab

Question 22

If a CRC patient has the BRAF V600E mutation then what drug may be used?

Answer 22

Doublet therapy!
Cetuximab + Encorafenib
(Need EGFR inhibitors to allow drug permeation)

Question 23

What is FIRST LINE TREATMENT for early-moderate stage CRC?

Answer 23

SURGERY! - remove polyps, lymph nodes
May add adjuvant chemo to “mop up” remaining cancer cells (esp for stage II w high risk/stage III)
- Use 5-FU

Question 24

If a patient has stage II CRC with high risk features (poor histology, lymph node involvement, bowel obstruction, perforation, positive margins) would adjuvant chemo be recommended? If so, what kind?

Answer 24

YES
- capecitabine (lower risk)
- 5-FU + leucovorin (lower risk)
- FOLFOX (higher risk)
- CapeOx (higher risk)

Question 25

If a patient has stage III CRC, what adjuvant chemo should be given after surgery? For what duration (based on high or low risk)?? What should NOT be given?

Answer 25

Preferred:
- FOLFOX
- CapeOx
HIGH RISK - 6 months (FOLFOX), 3-6 months (CapeOx)
LOW RISK - 3-6 months (FOLFOX), 3 months (CapeOx)

Avoid:
- target therapy
- Irinotecan

Not preferred:
- 5-FU + leucovorin

Question 26

How do we treat Stage 4 metastatic CRC?

Answer 26

If resectable - surgery (must be low volume tumor! (Give neoadjuvant chemo w/ FOLFIRI or FOLFOX)

Chemo:
5-FU-based regimen PLUS whatever worked for them before
FOLFOX + Bevacizumab usually initial
If progression after that = switch to FOLFIRI
If KRAS-wild type = give EGFRi (cetuximab)
If MSI-high = give immunotherapy (Pembrolizumab, nivolumab)

Question 27

How do we treat Stage 4 metastatic CRC in patients with POOR performance status?

Answer 27

Performance = ECOG ~2

Check if MSI-high, if so give immunotherapy (Pembrolizumab, nivolumab)
Consider single agent (5-FU, capecitabine if CrCl >30)

Question 28

If getting a resection surgery and using Bevacizumab, how many weeks should we hold the drug before and after surgery?

Answer 28

4 weeks