Colorectal Cancer Flashcards
Epidemiology
- ___ leading cancer in incidence and death in men and women
- incidence is increased in industrialized nations with males having a slightly increased incidence
- 5-year survival is ~ 91% in early disease
- 3rd
Risk Factors
Age
- increases starting after age of __ and is greater after 50 years of age
Family history of colon cancer
Hereditary syndromes
- Familial Adenomatous Polyposis (FAP)
- Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
Dietary Factors:
* High fat, Low ___ , Reduced folate, Reduced calcium
Polyps: A small % of these will develop
into cancer
lifestyle
Ulcerative coitis/Crohn’s disease
- Chronic ___ may be predisposing factor
- 40
- fiber
- inflammation
Pathophysiology
Malignant polyps tend to grow from the
inner basement membrane of the ___outward into the mucosa,
submucosa, muscularis, and serosa
Metastatic spread
- Via lymphatic and hematogenous routes to the lymph nodes, lungs, liver, and bone
> 95% of colorectal cancers are
___
bowel wall $
adenocarcinomas
Presentation
- May be asymptomatic
- Often presents with rectal ___ ,
possibly associated with anemia - Change in bowel habits
- Nausea/vomiting
- 20 – 25% will present with ___
disease
– Jaundice, hepatomegaly, weight ___
bleeding
metastatic
loss
TNM Staging - Definition of T
basically how deep it goes
Additional Testing-Work Up
___ DNA ___ repair (dMMR)
- 19% of colorectal cancer
Test for microsatellite instability (MSI) or loss of genes involved in DNA MMR
* MSS = Microsatellite stable tumor
* MSI-L = Low level microsatellite instability
* MSI-H = High level microsatellite instability
* pMMR = Proficient mismatch repair
* dMMR = Defective mismatch repair
- Defective, mismatch
Early-Stage Disease and MMR
- dMMR or MSI-H tumor predicts a
decreased benefit from adjuvant 5-FU based therapy for stage __ disease - Stage ___ patients with dMMR or MSI-H disease **can benefit **from adjuvant 5-FU
- II
- III
T or F: All patients with a colon cancer diagnosis should be tested for mismatch repair or microsatellite instability
T
Treatment Goals
Stage I, II, III
– Considered potentially ___
– Intent of eradicating known and
micrometastatic tumor sites
– Achieve ___ and avoid disease recurrence
Stage IV
– Incurable/ ___
– Decrease symptoms, avoid disease-related complications
- curable
- remission
- palliation
Localized Therapy (Stage I and II)
___ alone is definitive therapy
- Partial or total colectomy + lymph nodes
No proven benefit with chemotherapy in stage ___ disease
- Patients receiving chemotherapy with no adverse prognostic features showed no difference in survival
- Can recommend adjuvant chemotherapy in Stage II disease if the patients are considered ___ risk
- Remember MSI and/or MMR status: If ___ or ___ , then will not benefit from chemotherapy
for stage II disease
Surgery
II
high risk
dMMR, MSI-H
Stage II Disease (Chemotherapy)
- ___ is reasonable for high risk or
intermediate risk stage II patients and is not indicated for good or average risk stage II patients - ___ can also be an option
- FOLFOX
- CapeOX
FOLFOX
5-Fluorouracil, leucovorin, and oxaliplatib
CapeOX
Capecitabine, oxaliplatin
FOLFIRI
- irinotecan
- leucovorin
- fluorouracil
Stage III Disease
- Surgery including regional lymph node
removal + Chemotherapy are indicated for this stage of disease - ___ appears to be = to bolus
5-FU/leucovorin in Stage III patients
Capecitabine
Stage II Chemo
- mFOLFOX6
- CapeOX
IDEA Conclusions
With CapeOx : 3 months as effective as 6 months
- Especially in low-risk patients
With FOLFOX : 6 months was ___ effective than 3
months
- Especially in high-risk patients
Results suggest risk-based approach to determiningduration of adjuvant therapy
- more
Regimen Considerations
FOLFOX
* Requires ___
* 2-day pump
* More infusions overall
* increased myelosuppression
and ___ sores
pump
mouth
Regimen Considerations
Port not required
* ___ infusions overall
* increased ___ syndrome and ___
Capecitabine
– ___ dose adjustments
– Adherence
– Copay
– Drug/drug interactions
- less
- hand-foot, diarrhea
- renal
Metastatic Disease
~ 50-60% of patients diagnosed with colon cancer will develop metastatic disease
- Chemotherapy is mainstay of therapy
- Survival has increased from 12 months with 5-FU monotherapy to ~ 2 years with the addition of
___ , ___ , and newer biologics
Surgery can play a role in isolated
disease
- Could achieve OS benefits of 20-50%
Radiation therapy
- Role for ___ of symptoms
- irinotecan, oxaliplatin
- palliation
Which Chemo Regimen To Use?
Other co-morbidities that may determine therapy:
- ___
– ___ deficiency
– 1 versus 2 versus 3 drugs
Neuropathy
UGT1A1
Advanced Disease and MMR
Predict benefit to PD-L1 inhibitors
- ___ and ___ shown benefit in metastatic setting
- Both drugs are approved for patients
unresectable or metastatic, with dMMR or MSI-H tumors ___ FOLFOX and FOLFIRI
- As stated previously, all patients should be tested for dMMR/MSI status regardless of stage
- Pembrolizumab, nivolumab
- after
Predictive Biomarkers
K-RAS
- Mutations predict lack of response to ___ monoclonal antibodies
- Do not use Cetuximab and panitumumab
- Recommend testing in all metastatic disease
BRAF
- 5-15% of patient will have this mutation
- Test all patients in metastatic setting
- anti-EGFR
metastatic chemo options (6)
- mFOLFOX6
- CapeOX
- FOLFIRI
- bevacizumab
- cetuximab
- FOLFIRINOX
1st Line Metastatic Disease
Accepted chemotherapy regimens if
someone can not tolerate intensive
chemotherapy include:
Second Line Therapy
Disease progression with prior oxaliplatin based regimens
Second Line Therapy
Disease progression with prior irinotecan-based regimens
Third Line Therapy
Colon Cancer Screening Tests
- Primarily detect cancer
Fecal occult blood test ( ___ )
- High false- ___ rate
Fecal immunohistochemical test (FIT), or FIT DNA
- Detects ___
OR
- Detect cancer and advanced lesions
- Endoscopic and radiologic exams
- colonoscopy
Screening guidelines applies to men and women > __ years old
- FOBT
- negative
- hemoglobin
- 45
Colon Cancer Prevention
Diet
- ___ fiber, ___ fat
- ___ -rich diet: ↓’s proliferative response to fatty acids and bile acid
NSAIDs, ASA
Colectomy
- high, low
- calcium
5-FU
- FUTP incorporates into RNA and impairs protein synthesis
– FdUMP binds thymidylate synthase (TS) and reduces rate of DNA synthesis, replication, and repair - Extensively metabolized by dihydropyrimidine dehydrogenase (DPD) in the liver
- Patients with DPD deficiency have exaggerated toxicities
- ___ stabilizes the binding of FdUMP to TS resulting in enhancement of the toxicity of FdUMP
- Leucovorin
Common Agents: Irinotecan
Irinotecan
- Inhibits topoisomerase __
- Dose-limiting toxicities are ___ and ___
- Early onset diarrhea – Can be while the patient is getting the drug - Cholinergic syndrome: treated with ___
- Late-onset diarrhea –Starts more than 24 hours after irinotecan administration
– May last 3-5 days and can be fatal (use high dose lopiramide)
- I
- neutropenia, diarrhea
- atropine
Oxaliplatin and Capecitabine
Oxaliplatin - 3rd generation platinum compound
- Cross-links DNA, inhibiting DNA replication
* Inactive as a single agent
* Given with 5-fluorouracil and leucovorin to make FOLFOX
* Unique toxicities: ___ , ___ intolerances, sensation of not being able to breathe
Capecitabine
- Three-step activation process
- Oral prodrug of ___
- Dose-limiting toxicity is ___ syndrome and diarrhea
- neuropathy
- cold
- 5-FU
- hand-foot
Cetuximab
Monoclonal antibody (human/mouse
chimeric)
- Binds to the extracellular domain of ___
- Used only in ___ wild type patients
Adverse events
* infusional reaction - Rapid onset of airway obstruction (bronchospasm, stridor, hoarseness) urticaria, or
hypotension; usually occurs with first infusion
* Acneform ___, asthenia/malaise, fever, nausea
* Hypo ___
– Premedicate with an ___ antagonist is recommended
Panitumumab has same AEs
- EGFR
- KRAS
- rash
- hypomagnesemia
- H1
Bevacizumab
Monoclonal antibody (recombinant humanized) which binds to ___ potentially decreasing angiogenesis
- Given in combination with 5-FU, leucovorin and irinotecan
- Significant toxicity: Bleeding, hypertension, proteinuria, thromoboembolism, gastrointestinal perforations, decreased wound healing
- many black box warnings
VEGF
Regorafenib
Multi-kinase inhibitor targeting angiogenesis ( ___ 1-3, KIT, PDGFR-alpha, PDGFR-beta, BRAF,
BRAFV600E, and others
- Can use in patients with ___ mutations
- Toxicities: Hypertension, mucositis, fatigue, hand
foot syndrome, hemorrhage, rash, metabolic disorders, diarrhea, myelosuppression, increased liver
function tests, proteinuria
- (Rare): Squamous cell carcinoma of the skin
- High fat meals increase drug concentrations
- Drug interactions to worry about: CYP3A4
VEGF
KRAS
TAS-102 (Trifluridine / Tipiracil)
Used after patients fail: 5-FU, oxaliplatin- and irinotecan-based chemo, an anti-VEGF therapy,
and if RAS wild-type, an anti-EGFR therapy
- pretty much after they faily everything
Adverse reactions:
–Fatigue, nausea/vomiting, decreased appetite, diarrhea, abdominal pain, anemia, neutropenia, thrombocytopenia, weakness
In general, better tolerated than ___
regorafenib
