Onco 2: cancer in the poo tube Flashcards
risk factors for colorectla cancer
- Hx of polyps
- IBD
- UC
- Chron’s
- Chronic inflammation
- Family hx and genetics
- FAP : much much adenomatous polyps
- HNPCC/Lynch syndrome): mutations in DNA msmatch repair genes
- Smoking
- Heavy EtOH use
- Physical inactiivty
- Low socioeconomic status
- Diabetes
- Increasing age
- Race
presentation of colorectal cacner
usually no symptoms early on in disease progression
- Bright red or dark blood in stool, anemia
- Change in frequency of bowel movements
- Constipation or feeling that bowel doesn’t empty completely
- Stool narrow than usualy
- General abdominal discomfort (frequent gas pains, bloating, and/or cramps)
- Wt loss with no known reason
- Constant fatigue
- N/V
gold sstandard for screening
colonoscopy
- start at age 45 for most people
- earlie in high risk
- Decision to screen in older pts should be individualized
colorectal chemo consdierations
we want good performing pts for chemo otherwise we might be doing more harm than good
- stage of disease
- performance status
- co-morbidities
- genomics
- if metastatic: previous agents used
favorable pronostic factors for colorectal cancer
- early disease: stage I-II
- grade 1-2 lesions
- no angiolymphatic invasion
- nevative margins
unfavorable prognositc factors for colorectal cncer
- advanced disease : stage III-IV
- grade 3-4 lesioins
- signet-ring cell or mucnous
- lyphovascular invasion
- positive margins
- bowel obstruction/perforation
- T4 disease
- performance status
- lymph node involvement > 4
stage I colocrectal treament
surgery alone, no adjuvant chemo
stage II colocrectal treament
Surgery +/- adjuvent cehmo (high risk stage II may benefit but no real data atm)
- if giving chemo, capecitabine preferred (can also do FOLFOX or CapeOx)
high risk
- < 12 lymph nodes examined
- Poorly differentiated histology (grade 3-4)
- Lymphovascular invasion
- Bowel obstruction
- Localized perforation
- Positive margins
5-FU metabolism
metabolized by DPD (rate limiting)
- some pts can be deficient in DPD (2 nonfunctional copies) -> life threatening tox -> avoid
5-FU MOA
breaks down into fDUMP -> inhibit thymidylate synthase -> inhibit DNA synthess
give with leucovrin (folinic acid) -> stabilies fDUMP
5-FU ADR
slow infusion -> ADR more tolerable and reduced myelosuppression
- still some hand-foot syndrome, diarrhea, and mucositis though
FOLFOX
- folinic acid
- 5-FU
- oxaliplatin
FOLFIRI
- folinic acid
- 5-FU
- irinotecan
neoadjuvant only, not adjuvant
FOLFOXIRI
FOLFIRINOX
- folinic acid
- 5-FU
- oxaliplatin
- irinotecan
the differene (per NiH i guess?) is that FOLFIRINOX has a higher dose of irinotecan and a bolus 5-FU
CapeOx
- capecitabine
- oxaliplatin
capecitabine MOA
it’s a 5-FU prodrug
can also be used as a radio-sensitizer (makes people more sensitive to raidation)
capecitabine admn
- renally dose adjusted
- BID wihtin 30 min of end of meal
dose limiting tox of capecitabine
- hyper ibli
- diarrhea
- hand-foot sydrome
- mucositis
CI in DPD deficiency
DDI with warfarin and phenytoin (CYP2C9)
oxaliplatin MOA
- platinum analog, alkyalting agent (creates cross links in DNA)
- not cell-cycle specific
oxaliplatin ADR
- peripheral neuroapthy (dose dependent)
- dt accumulation of platinum in dorsal root gannglia
- duloxetine may help
- cold intolerancesensitivity (type of neuro tox)
- happens right away
- dt drug being metabolized to oxalate (chelates Ca) → Na voltage gates remain open - hyperexcitability
- myelosupppresion
Irinotecan MOA
- topoisomerase-1 inhibitor
- SN-38 is the active drug
irinnotecan ADR
- diarrhea
- acute: dt cholinergic symptoms (diarrhea, watery eyes, flusshing, sweating) → give atropine in infusion center
- chronic: general gut tox dt cytotixc action of drug → loperamide
- fatigue
- alopecia
- myelosuppresion, neutropena
Bevacizumab use in colorectal cancer
- Given with chemo for synergistic effect (cuts off blood flow to tumor)
- Used for metastatic colorectal cancer with infusional 5-FU based regimens as 1st or 2nd line
can alternatively use Ziv-aflibercept, but bevacizumab is preferred
ramucirumab use in colorectal cancer
FDA approved for use in combo with FOLFIRI in pts who have progressed while being treated with 1st line bevacizumab, oxaplatin, and 5-FU/capecitabine regimen
- Admin 60 min prior to FOLFIRI inf
- Continue until disease progression or unacceptable tox
EGFR inhibitors MOA
- Inhibit epidermal growth factor receptor → skin ADR
- pt must be KRAS wild type (no mutation)
If KRAS wt → qualify EGFR inhibitor
Cetuximab
Panitumumab
EGFR use in colorectal cancer
used in metastatic colorectal cancer
colorectal gents
- cetuximab
- panitumumab
regorafenib MOA
- multikinase inhibitor: nhibit VEGFR 2 and 3, RET, KIT, PDGFR, and Raf kinase
regorafenib use in colorectal cancer
FDA approved for later line treatment in metastatic colorectal cancer as monotherapy (salvage therapy)
regorafenib DDI
CYP3A4
regorafenib admi
- PO QD with low fat meal 3W on, 1W off
- Sotre in original container, 28D expiration date after opening
regorafib ADR
- hepatoox (BBW): check LFTs prior to starting
- hemorrhage, delayed wound healing
- cardiac issues
- GI perforation
- hand foot syndrome
- diarrhea
- mucositits
- ifection
- much much much more (try ot match adr to what the drug targets)
very hard for pts to tolerate, many adr
HER2 therapy in colorectal cancers
Only indicated in HER2 amplifed tumors that are also RAS and BRAF wild type
- HER2 amplication rare in colorectal cancer
- recommenedd as subequent therapy options in pts who meet the above criteria
Agents
- trastuzumab + (pertuzumab or lapatinib): initial or subsequent
- fam-trastuzumab deruxtecan: subsequent
Trifluridine + tipiracil (Lonsurf) use in colorectal cancer
metastatic colorectal cancer if pt has previously received 5-FU/capecitabie-, oxaplatin-, and irinotecan- based chemo, an anti-VEGF biotherapy
- Additionally, if pt KRAS wild type, they need to have tried anti-EGFR therapy
- this bitch very last line
Trifluridine + tipiracil MOA
- PO chemo
- interefere iwth DNA syntehsis and inhibit cell proliferation by incorporation in DNA
- trifluridine: thymidine based nucleoside analog (main cytotoxic agent)
- tipiracil: thymidine phophorylase inhibitor → increases trifluridine exposure and has modest cytotoxic activity
Trifluridine + tipiracil admin
- PO BID on days 1-5 and 8-12 of a 28 day cycle
- take within 1 hr of the end of breakfast and dinner
- no need to dose adjust for hepatic or renal impairment
- could potentially do a regimen of this + bevacizumab
Trifluridine + tipiracil ADR
-
severe myelosuppression: monitor blood coutns prior to and on day 1 and 15 of each cycle
- dose reduce and/or hold admin as clincally indicated
- anemia
- neutropenia
- thrombocytopenia
- fatigue
- N/V/D
- decreased appetite
- abdominal pain
immunotherapy use in colorectal cancer
only for MSI-H tumors (typically in stage 4)
agets:
- pembrolizumab
- nivolizumab
BRAF inhibitor use in colorectal cacner
- Only for BRAF genotyped tumor tissue (BRAF V600E mutation postiive) - aggressive tumor with poor prognosis
**- Doublet therapy (Cetuximab + Encorafenib) - not first line (typically second or third)**
- Resistance to BRAF inhibitors by feedback re-activaation of EGFR and downstream MEK and ERK pathways
stage III colorectal cancer tratment
- surgery + adjuvat chemo in most pts (5-Fu is our standard of care here - FOLFOX or CapeOx)
- start chemo 4-8 weeks after surgery (can go up to 12 but not great), and do it for 6 months
- If pt was low risk, could consider only 3 months (best evidence for 3 months is pts with low risk and on CapeOx)
stage IV colorectal cancer treatment: resectable liver only or lung only metases
can consider sugery
- Give neoadjuvant first
- FOLFIRI, CapeOx, or FOLFOX +/- bevacizumab (remeber to dc bevacizumab 4 weeks prior
- FOLFIRI or FOLFOX +/- panitumumab or cetuximab if KRAS wildype
- Surgery, and then 2-3 months of chemo followed by staged resection of metastataic disease
stage IV colorectal cancer treatment: unresectable liver only or lung only metases
or resecctable not doing surgery
- chemo, targeted therapy, immunotherapy and evaluate disease Q2mo to determine resectability of live and/or lung mestases
- Consider coloc resection if risk of obstruction or significant bleeding
EGFR MAb ADR
- infusion related reactions (pre-medicate before cetuximab admin)
- hypoMg
- paronchyia: infection of folds of tissue surrounding nails
- acneiform rash
