Lecture 14 - Colorectal Cancer Flashcards
Colorectal is ____ most common in incidence and death rates
3rd
Epidemiology
incidence is increased in industrialized nations with males having slightly increased incidence
Risk factors
age - increases starting after age 40 and is greater after 50 years of age; family history of colon cancer
dietary factors: high fat, low fiber, reduced folate, reduced calcium; polyps; smoking, alcohol, obesity; ulcerative colitis or crohn’s disease (chronic inflammation)
hereditary syndromes: familial adenomatous polyposis (FAP), autosomal dominant disorder, mutation of adenomatous polyposis coli gene on chromosome 5, hereditary nonpolyposis colorectal cancer
development of 100’s-1000’s of adenomatous polyps (nearly 100% lifetime risk of developing
Pathophysiology
malignant polyps tend to grow from inner basement membrane of bowel wall outward into mucosa, submucosa, muscularis, and serosa
metastatic spread via lymphatic and hematogenous routes to lymph nodes, lungs, liver, and bone
>95% are adenocarcinomas
Presentation
may be asymptomatic; rectal bleeding, anemia, N/V, change in bowel habits
some present with metastatic disease: jaundice, hepatomegaly, weight loss
Additional testing-work up
defective DNA mismatch repair (dMMR)
test for microsatellite instabilit (MSI) or test for loss of genes involved in DNA MMR
Early stage disease and MMR
dMMR or MSI-H tumor predicts decreased benefit from adjuvant 5-FU based therapy for stage II disease: chemo won’t work!!
stage III patients with dMMR or MSI-H disease can benefit from adjuvant 5-FU: chemo will be of benefit!
All pts with colon cancer diagnosis should be tested for
mismatch repair or microsatellite instability
Treatment options
surgery: early stage disease
radiation therapy: well established for rectal cancer, but more controversial in colon cancer; can be used to alleviate pain and decrease bleeding
chemo
Treatment goals for stage I,II, and III
considered potentially curable; achieve remission and avoid disease recurrence
Treatment goals for stage IV
incurable/palliation
decrease sx and avoid disease related complications
Localized therapy (stage I and II)
surgery alone is definitive therapy: partial or total colectomy + lymph nodes
no proven benefit with chemo in stage II; guidelines recommend against adjuvant chemo in stage II, can recommend if pt is high risk
if MSI-H or dMMR, then will NOT benefit from chemo in stage II
Stage II disease (chemo)
FOLFOX: reasonable for high risk or intermediate risk stage II pts - 5-FU, leucovorin, oxaliplatin
CapeOX also an option - capecitabine, oxaliplatin
Stage III disease
surgery including regional lymph node removal
chemo indicated for this stage
Stage III disease: chemotherapy
principles of adjuvant therapy: capecitabine appears to be = to bolus 5-FU/leucovorin in stage III pts
bevacizumab, cetuximab, panitumumab, and irinotecan DO NOT play a role in this setting
FOLFOX
FOLFOX = 5-FU, oxaliplatin, leucovorin
decrease in recurrence, increased 5-year disease free survival
toxicities with oxaliplatin (paresthesia, neutropenia, GI)
Adjuvant chemo options
mFOLFOX6: oxaliplatin, leucovorin, 5-F; pts take chemo pump home
CapeOX: oxaliplatin, capecitabine
Current recommendations by NCCN
low risk: CapeOX for 3 mo or FOLFOX for 3-6 mo
high risk: CapeOX for 3-6 mo or FOLFOX for 6 mo
IDEA trial conclusions
risk-based approach
with CapeOX: 3 mo as effective as 6 mo, especially in low-risk pts
with FOLFOX: 6 mo was more effective than 3 mo, especially in high risk pts
How to implement in practice: stage III colon cancer
low risk: CapeOX for 3 mo
high risk: FOLFOX for 6 mo
FOLFOX and CapeOX considerations
FOLFOX: requires port, 2-day pump, more infusions overall, increased myelosuppression and mouth sores; repeated every 2 weeks
CapeOX: port not required (oral agent), less infusions overall (not continuous), increased hand foot syndrome and diarrhea; capecitabine requires renal dose adjustments, adherence, copay, look into drug/drug interactions; repeat every 3 weeks
Metastatic disease colon cancer
chemo is mainstay of therapy
survival has increased from 12 mo with 5-FU monotherapy to ~2 years with the addition of irinotecan, oxaliplatin, and newer biologics
surgery could play a role in isolated disease
radiation therapy for palliation of sx
Which chemo regimen to use for mestatic disease
pt performance status
co-morbidities that determine therapy: neuropathy, UGT1A1 deficiency
Advanced disease and MMR
predict benefit to PD-L1 inhibitors: pembrolizumab and nivolumab shown benefit in metastatic setting, both approved for pts unresectable or metastatic, with dMMR or MSI-H tumors after FOLFOX and FOLFIRI
Predictive biomarkers: K-RAS
mutations predict lack of response to anti-EGFR monoclonal antibodies
cetuximab and panitumumab: DO NOT use if have KRAS mutation
Predictive biomarkers: BRAF
5-15% of pts will have this mutation
1st line metastatic disease chemo regimens: no targetable mutations
mFOLFOX6 +/- bevacizumab
CapeOX +/- bevacizumab
FOLFIRI +/- bevacizumab
FOLFIRINOX +/- bevacizumab
1st line metastatic disease chemo regimens: KRAS
FOLFOX or CapeOX + cetuximab or panitumumab OR FOLFIRI + cetuximab or panitumumab
1st line metastatic disease chemo regimens: dMMR/MSI-H
nivolumab + ipilimumab or pembrolizumab
1st line metastatic disease chemo regimens: HER2 +
trastuzumab + pertuzumab or lapatinib OR fam-trastuzumab deruxtecan-nxki
Metastatic chemo options
FOLFOX, CapeOX, FOLFIRI, bevacizumab, cetuximab, FOLFIRINOX
1st line metastatic disease if someone cannot tolerate intensive chemo: no targetable mutations
5-FU + leucovorin OR capeticabine +/- bevacizumab
1st line metastatic disease if someone cannot tolerate intensive chemo: KRAS
cetixumab OR panitumumab
1st line metastatic disease if someone cannot tolerate intensive chemo: dMMR/MSI-H
nivolumab +/- ipilumumab OR pembrolizumab
1st line metastatic disease if someone cannot tolerate intensive chemo: HER2 +
trastuzumab + pertuzumab or lapatinib or tucatinib
Second line therapy for metastatic disease
if prior oxaliplatin based regimens: use FOLFIRI
if prior irinotecan-based regimens: use FOLFOX
Colon cancer screening tests
- primarily detect cancer: fecal occult blood test (FOBT) and fecal immunohistochemical test (FIT), or FIT DNA
- detect cancer and advanced lesions: endoscopic and radiologic exams
Test to primarily detect colon cancer: Fecal occult blood testing
high false-negative rate, decreased mortality by 1/3rd
has increased sensitivity/specificity
to avoid false positives: avoid red meat and raw veggies with peroxidase activity
to avoid false negatives: avoid vit C
Test to primarily detect colon cancer: Fecal immunochemical test (FIT)
detects hemoglobin and is more specific than guaiac based tests
not subject to false negative rates like FOBT
FIT DNA: detects hemoglobin along with certain DNA biomarkers
Test to primarily detect cancer and advanced lesions: endoscopy
flexible sigmoidoscopy: examines lower 60% of bowel
colonoscopy: examines enture bowel and can remove premalignant lesions during procedure
Colon cancer screening guidelines applies to
men and women >/= 45 yrs old
ACS screening guidelines
avg risk: annual FOBT or annual FIT or multi-target stool DNA test every 3 yrs OR flexible sigmoidoscopy every 5 years or colonoscopy every 10 yrs or CT colonography every 5 yrs
ACS screening guidelines: family history
begin annual screening at 40
1st degree relative with colon cancer
ACS screening guidelines: HNPCC
begin annual screening at 20-25
ACS screening guidelines: FAP
being annual screening at 10-12
Colon cancer prevention - diet
diet: high fiber, low fat, (decrease fecal bile acids) diet high in antioxidant rich fruits and veggies
calcium rich diet decreases proliferative response to fatty/bile acids
Colon cancer prevention - cyclooxegenase inhibitors
celecoxib - decreases the number of adenomatous colorectal polyps in familial adenomatous polypsosis (FAP)
NSAIDS or aspirin
colectomy
5-fluorouracil
converted to FUTP and FdUMP; FUTP incorporates into RNA and impairs protein synthesis; FdUMP binds thymidylate synthase and reduces rate of DNA synthesis, replication, and repair
extensively metabolized by dihydropyrimidine dehydrogenase (DPD) in liver - pts with DPD deficiency have exaggerated 5-FU toxicities - diarrhea, mucositis, myelosuppression
Leucovorin
synergizer with 5-FU
stablizes the binding of FdUMP to TS resulting in enhancement of toxicity of FdUMP
Irinotecan
big SE: diarrhea and neutropenia
pro-drug of SN-38, inhibits topoisomerase I
early onset diarrhea (cholinergic syndrome) - give atropine
late onset diarrhea - give loperamide
UGT1A1 deficiency prevents SN-38 conversion and increased toxicity
Oxaliplatin
platinum compound, cross-links DNA, inhibiting DNA replication
inactive as single agent, given with 5-FU and leucovorin to make FOLFOX
toxicities: neuopathy, cold intolerances, sensation of not being able to breathe
Capecitabine
oral pro-drug of 5-FU
dose limiting toxicity is hand-foot syndrome and diarrhea
Cetuximab
do NOT use if KRAS mutation!; only used in KRAS wild type pts
monoclonal antibody, binds to extracellular domain of EGFR
AEs: acneform rash and hypomagnesemia; premedicate with H1 antagonist
Panitumumab
recombinant human IgG2 monoclonal antibody that binds to EGFR
AEs: acenform rash and hypomagnesemia
Bevacizumab
VEGF inhibitor: monoclonal antibody that binds VEGF potentially decreasing angiogenesis (new blood vessel formation)
given in combo with 5-FU, leucovorin, and irinotecan
significant toxicity: bleeding, HTN, proteinuria, thromboembolism, GI perforations, decreased wound healing
many black box warnings
