SGO Chemo/Targeted cards Flashcards
Anti-metabolites (5)
5-FU
capecitabine
MTX
Gemcitabine
Pemetrexed
Methotrexate:
1. Specific to which phase of the cell cycle
2. MOA
- S phase
- Inhibition of dihydrofolate reductase blocks DHFR from reducing dihydrofolate to tetrafolic acid > blocks thymidylate synthase and purine synthesis > arrests DNA/RNA/protein synthesis
Methotrexate:
1. Drug clearance
2. Dose reduction for___
3. Drug synergy
- Mostly renal, small amount in bile
- Renal insufficiency. Contraindicated for Crcl <40, Cr>2
- Hepatic insufficiency Bili 3.1-5. Avoid if Bili >5
- MTX and 5-FU are maximally synergistic when MTX is given 24 h before 5-FU, inhibiting the production of nl purine (remember purines are PUR As Gold = Adenine & Guanine) precursors
Methotrexate:
1. Dose-limiting toxicity for high dose regimens
2. Other SE/Tox
3. Tox related to intrathecal
- Nausea/vomiting - per B&H(!) (vs in general Stomatitis / mucositis & myelosuppression )
- Myelosuppression, mucositis (stomatitis*), elevated LFTs, pneumonitis, oliguric renal failure
- Acute aseptic meningitis (self-limited usually)
Medication to reverse the immediate cytotoxic effects of MTX
Leucovorin
5-Fluorouracil:
1. Specific to which phase of the cell cycle
2. MOA
- S phase
- Inhibits the formation of the DNA base thymidine by 3 mechanisms:
(1) Active metabolite 5-FdUMP inhibits thymidylate synthase (–> formation of an inactive ternary complex, enhanced by co-administration of folinic acid > depletes thymidine pools > inhibits DNA synthesis)
(2) Metabolite 5-FdUTP incorporation into DNA as a fraudulent thymidine precursor > induce single-strand breaks > cytotoxic effects
(3) Metabolite FUTP incorporation into RNA > impaired RNA function/ impaired protein synthesis
5 FU:
1. Activated in __
2. Drug Clearance
3. Contraindication
4. Drug synergy
- PRODRUG, activated in liver but also by target tissues
- Metabolized by liver
- Pregnancy
- MTX and 5-FU are maximally synergistic when MTX is given 24h before 5-FU, inhibiting the production of nl purine precursors
5 FU side effects/tox
1. Dose limiting tox
2. other common
3. Rare
- Myelosuppression
- Mucositis, diarrhea
- PPE, Dermatitis, cerebellar syndrome (PPD - headache, ataxia, nystagmus, confusion)
Adavosertib
Small molecule tyrosine kinase inhibitor of WEE1
MOA: inhibits WEE1 (nuclear protein, a tyrosine kinase involved in cell cycle regulation)
Not FDA approved, ovarian and UPSC clinical trials
SE: bone marrow toxicity, GI upset
Anastrozole
Aromatase inhibitor
MOA: non steroid competitive inhibitor of aromatase enzyme (blocks conversion of androgens to estrogens). Decrease estrogen
FDA: breast cancer
SE: loss bone density, bone/muscle pain, hot flashes, raises LDL
Atezolizumab
Anti-PDL1
MOA: binds to PD-L1 to stop interaction btw PD-1 on T cell and PDL1 on cancer cell.
FDA: none in gyn
SE: fatigue, immune related toxicities (MC irSAE is rash 20-30%)
Atezo, avelu, durva - all PD-L1
Avelumab
anti PD-L1
MOA: Anti PD-L1 with wild type Fc-1 region, binds to PD-L1
FDA: none in gyn cancers
SE: fatigue, immune related toxicities
Atezo, avelu, durva - all PD-L1
Balstilimab
Anti PD-1
MOA: routine anti PD-1
SE: fatigue, immune related toxicities
Bevacizumab
VEGF inhibitor
MOA: binds to and neutralizes the ligand VEGF (specifically VEGF-A) thus preventing association with FLT-1 (same thing as VEGFR1) and KDR (same thing as VEGFR2) — it is anti-angiogenic
FDA: ovarian and cervix
common side effects: HTN (give ACEI, ARB, CCB), Proteinuria, Joint pains (give NSAID), Rhinorrhea + bloody noses
less common side effects: VTE (ok to resume once anti coagulated), GI perforation, fistulas, hemorrhage, PRES
Cediranib
Tyrosine kinase inhibitor
MOA: small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor. It inhibits all 3 VEGF receptors which prevents activation of MAPK kinase signal transduction pathway and inhibits cellular replication
FDA: no approvals
Side effects: fatigue, HTN, diarrhea, nausea
Cemiplimab
Anti PD-1
MOA: routine anti PD-1
FDA: none
SE: in bold - IrAEs can occur up to 1 year after completion of therapy
Dostarlimab
anti PD-1
MOA: routine anti PD-1
FDA approval - MMR deficient endometrial cancers
SE: in bold - IrAEs can occur up to 1 year after completion of therapy (rash/hypothyroidism/diarrhea most reported in RUBY)
Durvalumab
-Class, MOA, FDA approval?, SE
Anti-PDL1
MOA: binds to PD-L1 to stop interaction btw PD-L1 and PD-1
FDA: NEW 6/2024 approved in dMMR advanced EMCa in combo with C/T
SE: fatigue, immune related toxicities
Atezo, avelu, durva - all PD-L1
Everolimus
-Class, MOA, FDA approval?, administration, SE
mTOR inhibitor
MOA: Binds intracellularly to FK binding protein 12–>creates a complex that binds to mTOR (a regulatory kinase part of the PI3K/Akt signal transduction pathway. Binding of mTOR results in inhibition of protein production.
FDA: metastatic breast, renal, NETs
Off label use: in combination w/ letrozole for recurrent/advanced endometrial cancer
PO daily dosing
SE: fatigue, stomatitis, metabolic: hyper triglyceridemia, hypercholesterolemia, and hyperglycemia, nausea. Rare but serious noninfectious pneumonitis
Erlotinib
-Class, MOA, FDA approval?, administration, SE, contraindications
Epidermal growth factor (EGFR) tyrosine kinase inhibitor
MOA: inhibits EGFR tyrosine kinase to prevent dimerization of EGFR and subsequent transduction of proliferative signals (MAPK, Atk, JNK pathways) –>uncontrolled cell division
FDA: non small cell lung cancer, pancreatic
Off label: advanced or recurrent/metastatic vulvar cancer
PO daily dosing
SE: Diarrhea can be severe, rash (49-85%!), fatigue, electrolyte abnl (due to diarrhea), dry eyes, elevated LFTs. Less common: renal failure, GI bleed/perf.
Contra: interstitial lung disease, severe renal impairment, hepatic impairment, GI bleed
Think Erlot like merlot. Some get rash (splotchy wine rash), others get diarrhea. Too much wine —> increased LFTs
Exemestane
-class, MOA, FDA approval/off label uses, dose adjustment reason, side effects
Aromatase inhibitor
MOA: blocking conversion of androgens into estrogen in peripheral tissue, lowers circulating estrogen (irreversible binding; steroidal)
FDA: Breast
Off label: recurrent ovary and endometrial
Dose adjustment: increase dose if also taking a CYP3A4 inducer (rifampin, phenytoin, dabrafenib, st john’s wort)
SE: hot flashes, fatigues, arthralgias, bone pain
Fulvestrant
-class, MOA, FDA approval/off label uses, route, dose adjustment reason, side effects, contraindications
Estrogen receptor antagonist
MOA: estrogen receptor antagonist, competitively binds to estrogen receptor on tumor tissue and other tissues. accelerates degradation of the estrogen receptor, resulting in pure antiestrogenic effects.
FDA: breast
Off label: recurrent ovary, recurrent endometrial
Route: IM injection
Dose adjustment: for mild liver impairment reduce the dose.
Common SE: hot flashes, fatigue, headache, injection site pain, *not associated with significant bone turnover
CI: pregnancy, renal failure
Ipilimumab
-Class, MOA, FDA/off label uses, side effects
Anti-CTLA-4 monoclonal Ab, immune checkpoint inhibitor
MOA: binds to CTLA-4 [cTla-4 on T cells], allows CTLs to destroy cancer cells. The antibody works by allowing the patients’ T cells to target a greater variety of antigens rather than by increasing the number of attacking a single antigen.
FDA: not GYN tumors, but in active investigation in multiple trials. Approved for melanoma, lung
SE:
-most common: dermatitis, enterocolitis, endocrinopathies
-less common but concerning: hepatitis, nephritis, stevens johnson, pancreatitis, myocarditis, diabetes
Ixabepilone
-Class, MOA, FDA/off label uses, side effects
Antimicrotubular epothilone B analog
MOA: Epothilone B analog that binds to beta-tubulin subunit of the microtubule to stabilize microtubular function resulting in the arrest of cell cycle in the G2/M phase leading to apoptosis. [similar to Taxol]
Of particular note is its activity in taxane- resistant cells.
FDA: breast cancer
Off label: plat resistant ovarian cancer in combo with bev or monotherapy; recurrent ovarian cancer as monotherapy
SE: Neuropathy - dose limiting and may require dose reduction; neutropenia, alopecia, n/v
Letrozole
-class, MOA, FDA/off label, side effects
Aromatase inhibitor
MOA: inhibits conversion of androgens to estrogens
FDA: breast cancer
Off label: ovarian, endometrial
SE: loss of bone density, elevation in cholesterol profile, arthralgias, weight gain, hot flushes, insomnia, nausea, edema, headache
Clinical pearl: Arthralgias are a class effect of the aromatase inhibitors (AI). While some patients may tolerate alternative other AI agent, there is usually similar crossover toxicity
Vinblastine
-Class
-MOA
-Cell cycle:
-Metabolism
-Excretion
-DLT
-Other SE
Plant alkaloid
MOA: binds to the tubulin dimer, inhibits assembly of microtubles during M phase. Also inhibits RNA synthesis, affecting DNA dependent RNA polymerase.
M phase
Metabolized in the liver
Excreted in the Bile
DLT: Neutropenia (VBB)
Other se: constipation, n/v, mucositis, interstitial pneumonitis
Vincristine
-MOA
-Cell cycle
-Metabolism
-Excretion
-DLT
Plant alkaloid
MOA: binds to the tubulin dimer, inhibits assembly of microtubles during M phase. Also inhibits RNA synthesis, affecting DNA dependent RNA polymerase.
M phase
Metabolized in the liver
Excreted in the Bile
DLT: peripheral neuropathy (think like Christ on a cross with pain in hands and feet. Binds tubulin DIE-mer)
Other se: alopecia (20-50%)
Vinorelbine MOA DLT Metabolism
Semi synthetic alkaloid derived from vinblastine
MOA: binds to the tubulin dimer, inhibits assembly of microtubles during M phase. Also inhibits RNA synthesis, affecting DNA dependent RNA polymerase.
M phase
Metabolized in the liver
Excreted in the Bile
DLT: Myelosuppresion (logical since, vinblastine DLT is neutropenia). (VBB very bad for bones)
Mirena - dosage of levonorgestrel released daily
Liletta - dosage of levonorgestrel released daily
20mcg/day for both!
Mirvetuximab
-Class
-MOA
-FDA
ADC: Folate receptor alpha-binding MAB (Payload is Maytansinoid DM4)
MOA: Antibody drug conjugate that targets the folate receptor alpha (FRα) and is then internalized by and degraded to DM4 and S-methyl-DM4. These catabolic molecules promote antimitotic activity, via inhibition of tubulin polymerization and microtubule assembly resulting in cell death and they are able to diffuse from antigen-positive tumor cells into neighboring cells and kill them in an antigen-independent manner, an effect known as ‘bystander’ killing
FDA: approved for plat resistant recurrent folic acid receptor positive ovarian/FT/PP cancer [FOLR1 75% 2+ IHC staining]
Mirvetuximab
-SE
-Contraindications
-dosage adjustments for renal/hepatic impairment
-SE: nausea (54%), diarrhea (44%), reversable ocular AEs (blurred vision, corneal ketatopathy), LFTs, peripheral neuropathy
-CI: avoid treatment in patients with preexisting occular conditions like glaucoma
-No dosage adjustment needed for renal disease
-avoid use in mod-severe hepatic impairment
Nivolumab
Class
MOA
FDA approval
off label uses
SE
Anti PD-1
MOA: routine anti PD-1
FDA: not in gyn
Off label: Recurrent cervical, vulvar or vaginal cancer, ovarian cancer, MSI-Hi/MMRd endometrial cancer
SE: fatigue, immune related toxicities
Oxaliplatin
Class
MOA
FDA
Off label
Dosing adjustments for…
SE
Platinum derivative
MOA: functions as an alkylating agent by binds to DNA forming cross-links which inhibit DNA replication and transcription, resulting in cell death
FDA-APPROVED: Advanced colorectal cancer OFF-LABEL: Mucinous ovarian cancer
Renal dose adjustments
SE: Grade 3/4 neutropenia (common when in combo with capecitabine); diarrhea; hand food syndrome
Box warning for use of capecitabine with which anti-coagulant?
Warfarin. The combo can increase anticoagulant effects of warfarin, bleeding events
Palbociclib
Cyclin-dependent kinase 4/6 inhibitor
MOA: Palbociclib is a reversible cyclin-dependent kinase inhibitor. It is specific to CDK4 and CDK6 which are responsible for cell cycle progression particularly at the G1/S phase of mitosis.
Normally, Phosphorylation of the retinoblastoma protein by CDK4 and 6 leads to passage through the G1-S phase
CDK4 and CDK6 inhibitors inhibit the phosphorylation of the retinoblastoma protein and prevent progression from G1 to S.
FDA approved: breast cancer
Off label: recurrent ovarian, ER+ recurrent endometrial (in combo with an AI)
SE: neutropenia, nausea, increased LFTs, ocular, fatigue
