Onco Exam 2

Primary induction chemotherapy

* for advanced cancers where no alt treatment exists

Neoadjunct chemotherapy

* localized cancers for which surgery is incomplete effective

Adjuvant chemotherapy

* used to complement early surgery to eradicate any remaining tumor cells/micrometastases

Drug resistance mechanisms

* gene mutations
* increased DNA repair capabilities
* P-glycoprotein (efflux pump; MDR1)
* increased production of scavengers (GSH), which interact with cancer drugs (trapping agents)

Alkylating Agents

* cell cycle nonspecific
* covalent attachment of alkyl groups to macromolecules, bis(chloroethyl)amine/ethyleneimine, alkylation of nucleophilic sites
* 2 types: monofunctional & bifunctional
* mispairing (both)
* ring opening (both)
* cross linking (bifunctional)
* Ex) Cyclophosphamide

Cyclophosphamide

* alkylating agent
* MOA: crosslinks DNA
* activated by CYP (so must be given orally)
* acrolein = toxic metabolite, can lead to intestinal cystitis
* SE: alopecia, hemorrhagic cystitis, myelosuppression, nephrotoxicity, infertility

Cisplatin

* MOA: intra/interstrand cross-linking of ___ to DNA inhibits S phase replication & activates p53 tumor suppressor → apoptosis
* IV administration
* SE: nephrotoxicity, ototoxicity, N/V, peripheral neuropathy

Oxaliplatin

* MOA: intra/interstrand cross-linking of ___ to DNA inhibits S phase replication & activates p53 tumor suppressor → apoptosis
* DNA alterations do not trigger resistance to this drug
* SE: nephrotoxicity, ototoxicity, N/V, peripheral neuropathy

Methotrexate

* MOA: inhibits purine & pyrimidine synthesis
* competitive inhibitor of DHF receptor
* can be given IV or oral - dosed multiple times per day due to short 1/2 life
* not metabolized, clearance depends on renal function
* SE: nausea, bone marrow suppression (hematotoxicity), mucosal ulcers, teratogen

Resistance methods to MTX

* altered DHF receptor
* decrease uptake
* decrease polyglutamation

5-Flurouracil

* MOA: suicide inhibitor to thymidylate synthase
* activation of this drug is dependent on DPD function : decreased DPD function can lead to increase risk of toxicity
* SE: mucositis, diarrhea, myelosuppression, hand foot syndrome, neurotoxicity

Capecitabine

* prodrug of 5-FUdump - gets converted into 5-DFUR
* excellent bioavailability
* metabolized in the liver
* MOA: metabolized to 5-FU by thymidine phosphorylase
* targets more tumor cells than 5-FU
* reduce incidence of SE

Cytarabine (Ara-C)

* MOA: competitive inhibitor of DNA polymerase to inhibit DNA synthesis, can be incorporated into DNA/RNA to affect elongation & ligation process
* Pyrimidine antagonist (think of A God is pure = purines) \[C & T = pyrimidine\]
* rapidly cleared
* Excreted: \~80-90% renally
* ADE (dose dependent):
* Myelosuppression
* Cytarabine rash
* Fever
* N/V

Resistance to Cytarabine (Ara-C)

* decrease deoxycytidine kinase
* ↑ cytidine deaminase
* ↑ dCTP

Gemcitabine

* MOA: competitive inhibitor of DNA polymerase to inhibit DNA synthesis, can be incorporated into DNA/RNA to affect elongation & ligation process, also inhibits ribonucleotides to deplete cellular dNTPs
* eliminated via metabolism
* effective in solid tumors

6-Thiopurines (6-MP)

* MOA: inhibit cancer cell replication
* worry about toxicity in those w/decrease TPMT activity
* decreased HPRT activity → resistance
* Allopurinol interferes with azathioprine metabolism (via XO), which can cause toxic levels of 6-MP

Vincristine/Vinblastine

* MOA: decrease microtubule formation
* resistance: p-glycoprotein, efflux, β-tubulin mutation

Paclitaxel/Docetaxel

* MOA: blocks MT depolymerization
* P450 metabolism
* resistance: p-glycoprotein, β-tubulin mutation

Abraxane

* reformulation of paclitaxel
* MOA: blocks MT depolymerization
* lack of hypersensitivity rxns

Ixabepilone

* effective against resistant tumors due to P-glycoprotein or mutated β-tubulin
* MOA: block MT depolymerization

Eribulin

* Microtubule subunit sequestorer
* effective against resistant tumors due to P-glycoprotein or mutated β-tubulin
* MOA: decrease microtubule formation

Irinotecan/Topotecan

* MOA: inhibit topo 1 by preventing resealing of nicked DNA, trapping Topo 1/DNA complex to inhibit replication
* active metabolite = SN-38
* SN-38 is glucronaidated through UGT1A1 so those w/decreased UGT1A1 activity have higher toxicities
* Resistance - ↓ carboxylesterase activity

Etoposide/Doxorubicin

* MOA: inhibit Topo 2 by stabilizing the Topo II/DNA complex by preventing re-sealing of the cleaved DNA which can interfere with both replication and Tx
* use lower dose in pts w/kidney (renal) disease

Daunorubicin/Doxorubicin

* MOA: inhibit DNA/RNA synthesis and inhibit Topo 2
* cardiomyopathy

Bleomycin

* MOA: generate oxygen radicals
* pulmonary hyperthermia

Leuprolide

* GnRH receptor agonist
* MOA: desensitizes pituitary receptors → reducing stimulation of androgen sensitive cancer cells → apoptosis

Goserelin

* synthetic analogue of LHRH
* MOA: reduces production of testosterone/estradiol → decreased stimulation of cancer cell growth

Degarelix

* competitive inhibitor at GnRH receptor
* MOA: lowers testosetone lvls → reducing stimulation of androgen sensitive cancer cells → apoptosis

Flutamide/Bicalutamide

* MOA: block androgen activity → inhibit transcription of androgen receptor genes
* liver toxicities = flutamide
* increase in estrogen levels (can lead to gynecomastia)

Enzalutamide

* MOA: reduces subsequent Tx of AR genes
* binds tighter than bicalutamide
* can not be given with CYP2C8 or 3A4 inhibitors
* pregnancy category X

Abiraterone

* progesterone derivative
* MOA: inhibits 17-a-hydroxylase (CYP17) irreversibly → reduce testosterone production
* CYP17 is needed for testosterone production

Anastrozole/Letrozole

* 2C19 (aromatase) inhibitors for HR+ breast cancers
* binds reversibly to heme

Exemestane

* suicide inhibitor
* used for HR+/ER+ breast cancers
* MOA: irreversibly inactives aromatase (2C19) via intermediate formation

Tamoxifen

* SERM
* MOA: antagonist @ estrogen receptor
* increases risk for uterine cancer (agonist)

Raloxifene

* SERM
* MOA: antagonists for high risk breast cancer & agonist for osteoporosis

Megestrol

* MOA: inhibits pituitary gonadotropin release → ↓ estrogen secretion
* progesterone derivative
* pregnancy category X

Fulvestrant

* SERD (selective estrogen receptor degrader)
* MOA: degrades estrogen receptor by stimulating ubiquitinylation

Rituximab

* MOA: Triggers direct Ab-dependent cellular toxicity, complement-dependent toxicity, antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent phagocytosis (ADP)
* chimeric monoclonal antibody
* Resistant: ↓ complement activation, ↓ Ab dependent cellular toxicity

Ibritumomab

* radiolabeled rituximab w/higher complete remission

Obinutuzumab

* fully humanized monoclonal antibody
* derivative of rituximab
* increases binding to effector cells, enhancing ADCC, & direct cell death

Ibrutinib

* irreversible, potent inhibitor of bruton’s tyrosine kinase (Btk)


* MOA: inhibitor of BtK inhibiting down-stream signaling via PLC → blocking cell growth, survival, & proliferation of malignant B cells

Bevacizumab

* MOA: binds to VEGF receptor to prevent VEGF from binding
* decreased angiogenesis

Sorafenib/Sunitinib

* MOA: blocks ATP binding to kinase
* inhibits VEGF receptor tyrosine kinase

Cetuximab (IgG1)

* chimeric monoclonal antibody
* MOA: inhibitor of EGF receptor signaling pathway (KRAS must not be mutated), blocks EGF (ligand) from binding to domain

Panitumumab (IgG2)

* fully humanized
* MOA: targets EGF receptor
* not effective if KRAS is mutated

Erlotinib

* 1st generation
* reversible EGF receptor kinase inhibitor
* MOA: blocks ATP binding
* take w/o food; metabolized by P450

Afatinib

* 2nd gen irreversible inhibitor of EGFR kinase & HER2
* P-glycoprotein substrate

Osimertinib

* 3rd gen irreversible EGFR inhibitor

Lapatinib

* reversible inhibitor of EGFR & HER2/neu tyrosine kinase
* MOA: block ATP binding site of kinase

Trastuzumab

* MOA: Ab-dependent cellular toxicity, decreased proliferation, anti-angiogenic effects

Pertuzumab

* MOA: prevents HER receptor dimerization

Enhertu

* antibody drug conjugate
* MOA: covalently linked to a Topo 1 inhibitor via a cleavable tetrapeptide killer

Gleevec (Imatinib)

* specific inhibitor of Bcr-Abl kinase


* MOA: binds to catalytic cleft in Bcr-Abl → stabilizes a catalytically inactive form of the enzyme
* do a drug interaction screening
* inhibits CYP3A4
* SE:
* fluid retention (facial/periorbital)
* heart failure
* nausea (take w/food)
* muscle cramps

Ponatinib (AP24534)

* overcomes T315I resistant mutation allowing for binding to Bcr-Abl kinase


* MOA: inhibits BCR-ABL (including T315I)
* SE:
* Arterial occlusion (MI/Stroke)
* Heart failure
* VTE
* arrthymia
* GI perforation
* impaired wound healing
* HTN
* ototoxicity
* peripheral neuropathy

Nilotinib

* overcomes gleevec resistance to most mutations
* MOA: inhibits BCR-ABL
* CYP3A4
* PPI reduce AUC
* avoid 3A4 inducers/inhibitors (can use inhibitors if needed)
* SE:
* BBW: QT prolongation & sudden death
* myelosuppression
* hepatotoxicity

Midosaturin

* inhibitor of FLT3
* MOA: prevents dimerization of FLT3 receptor → silence downstream signaling associated w/cancer cell proliferation & survival
* administer w/food
* 3A4 inhibitors/inducers as well as QT prolongating agents
* AE:
* QT prolongation
* myelosuppression
* headache
* pneumonitis
* N/V

Bortezomib

* proteasome inhibitor

Carfilzomib

* proteasome inhibitor


* MOA: irreversibly inhibits threonine protease activity of the proteasome
* treats refractory myeloma

Ivosidenib

* IDH1 inhibitor
* MOA: inhibits IDH1 → promoting differentiation of myeloid cells
* 3A4 inhibitors/inducers as well as QT prolonging agents
* 250 mg PO QD if using strong inhibitor
* AE:
* differentiation syndrome
* QT prolongation
* Guillian-Barre Syndrome
* hepatoxocitiy

Nivolumab

* Anti-PD1 monoclonal antibody
* MOA: blocks of PDL1 binding to PD1
* IV infusion

Pembrolizumab

* Anti-PD1 monoclonal antibody
* MOA: blocks of PDL1 binding to PD1

Durvalumab, avelumab, atezolizumab

* PDL1 inhibitors
* MOA: inhibit PDL1 interaction with the PD1 protein

CAR-T

* chimeric antigen receptor T-cells
* tailored to individual patient
* T cells are reprogrammed in the lab to express receptors for target antigen expressed on cancer cells
* Kill via perforin and granzyme granule secretion & activation of extrinsic apoptotic pathway

How common is cancer

* 4 in 10 Americans will be diagnosed

Leukemia

* derived from blood forming tissue in bone marrow

Lymphoma

* begin in the lymphatic system affecting B cells

Grades of adverse effect

* lower the grade = less severe side effect
* worse side effect as grade gets higher
* goes up to 5

TNM model

* t = tumor size
* n = nodal involvement
* m = metastatic disease

RECIST

* response evaluation criteria in solid tumors
* Hematologic malignancies do not follow this criteria
* measurement & definition for objective assessment of change in tumor size

Complete response

* ultimate goal
* disappearance of all target lesions

Partial response

* ≥ 30% decrease in the sum of diameters of target lesions from baseline

Objective response

* = complete response + partial response
* basically any patient who responds at all

AML

* cancer of WBC
* stem cells continue to proliferate but fail to differentiate (immature “myeloblast”)
* most common among adults
* disease of older age \~ 67 yrs

Risk factors for AML

* older age
* Prior chemotherapy
* ionizing radiation exposure
* benzene exposure
* cigarette smoking
* Hereditary chromosomal abnormalities (downs, blooms, kleinfelter’s)

Overcrowding

* this is what anemia, thrombocytopenia, & neutropenia is due to
* also known as “clogged pipe”
* If cancer cells take up all the space, there is no room for precursor cells to grow

Leukocytosis

* oncological emergency
* blood slugging
* Management:
* Hydroxyurea
* Leukapheresis - dialysis for WBC

AML diagnosis

* ≥ 20% myeloid blasts isolated on bone marrow biopsy
* cytogenetic indications:
* t(8;21)
* t(15;17)
* t(16:16)
* inv(16)

Favorable AML

* mutated NPM1 w/o FLT3-ITD or FLT3-ITDlow

Poor AML

* t(v;11q23.3)
* -5 or del(5q); -7; -17/abn(17p)
* Wild type NPM1 with FLT3-ITDhigh

Induction

* induce remission
* get as many myeloblast out as fast as possible

Consolidation

* prevent relapse
* Most pts:
* HiDAC = High dose Ara-C = High dose cytarabine
* cytarabine 1.5 - 3 g/m^2 q12h on days 1,3, & 5
* given every 28 days for 3-4 cycles
* if has targetable mutation:
* Gemtuzumab - CD33 positive
* Midostaurin - FLT3 mutation
* If pt is receiving liposomal daunorubicin & cytarabine this is used alone not HiDAC

7+3 for patients ≤ 60 years

* younger pts can tolerate the high doses
* Cytarabine 100-200 mg/m^2 for 7 days + daunorubicin 60-90 mg/m^2 for 3 days
* Idarubicin 12 mg/m^2 can be used instead of daunorubicin

7+3 for pts > 60 yrs

* Cytarabine 100-200 mg/m^2 for 7 days + daunorubicin 60 mg/m^2 for 3 days
* Idarubicin 12 mg/m^2 or mitoxantrone can be used instead of daunorubicin

Gemtuzumab

* used if pt is CD33-positive
* MOA: CD33 monoclonal antibody that gets internalized → releases calicheamicin derivative → causes DNA strand breaks → induces apoptosis
* premedicate w/acetaminophen & diphenhydramine 1 hr prior to infusion
* AE:
* hepatotoxicity → VOD (veno-occlusive disorder)
* myelosuppression
* TLS (tumor lysis syndrome)
* QT prolongation
* infusion reaction

Midostaurin

* use if pt has a FLT3 mutation

Intensive induction therapy for pts ≥ 60

* 7+3
* Gemtuzumab = if CD33 positive
* Midostaurin = if FLT3 mutation
* liposomal cytarabine & daunorubicin = therapy related or MDS related AML
* Elderly (≥ 75)
* Venetoclax & hypomethylating agent or low dose cytarabine

Candidates who can’t tolerate intensive therapy

* ≥ 75 yrs
* renal or hepatic dysfunction
* risk factors for significant CV events (such as EF

Induction for nonintensive therapy for AML w/o mutations

* hypomethylating agent alone


* Gemtuzumab alone = CD33 positive
* low dose cytarabine alone
* Glasdegib w/low dose cytarabine
* Older than ≥ 75:
* Venetoclax & hypomethylating agent or low dose cytarabine

Induction for nonintensive therapy for AML w/ mutations

* IDH1 mutation - Ivosidenib + Azacitidine (preferred) or ivosidenib monotherapy
* IDH2 mutation - Enasidenib
* FLT3 mutation:
* Hypomethylating agent + sorafenib
* Venetoclax & hypomethylating agent or low dose cytarabine (this is what is usually used)

HiDAC AE

* Neurotoxicity
* pt require frequent neuro checks
* Conjunctivitis
* must give steroid or artificial eye drops to prevent
* Mucositis

Anthracyclines

* Daunorubicin, doxorubicin, idarubicin
* generate free radicals - can affect myocardium
* primarily hepatic metabolism
* Doxorubicin = major substrate of 2D6 & 3A4
* Renal & hepatic impairment dosage adjustment

Anthracycline AE

* Extravasation
* Treatment: cold compress & DSMO 1-2 mL applied q6h for 7-14 days
* myelosuppression
* cardiomyopathy
* discoloration of secretion
* alopecia

Liposomal Daunorubicin & Cytarabine

* Vyxeos


* used for secondary AML
* fixed ratio of 1:5 daunorubicin to cytarabine
* SE:
* myelosuppression is longer
* copper toxicity in individuals w/Wilson’s disease

Decitabine

* hypomethylating agent
* MOA: incorporated into DNA & inhibits DNA methyltransferase → hypomethylation & cell death
* AE:
* hyperglycemia
* arthralgias/myalgias
* nephrotoxicity

Azacitidine

* hypomethylating agent
* MOA: incorporated into DNA & inhibits DNA methyltransferase → hypomethylation & cell death
* excreted through the urine (50-85%)
* AE:
* injection site reactions (polysorbate 80)
* N/V - moderate
* nephrotoxicity
* Caution in pts w/renal impairment

Veno-occlusive disorder

* VOD
* life threatening emergency
* occlusion in vein → liver
* median onset = 9 days (2 to 298 days)
* S/S:
* weight gain, ascites, jaundice, elevation in bilirubin/transaminase
* Treatment:
* discontinue therapy immediately - do not rechallenge
* consider defibrotide

Gilterinib

* used specifically in relapse setting
* MOA: inhibits FLT3
* given by itself
* give w/ or w/o food
* 3A4 inhibitors/inducers as well as QT prolonging agents
* AE:
* differentiation syndrome
* QT prolongation
* pancreatitis

IDH1 & IDH2

* increase production of 2-HG:
* impaired histone & DNA methylation
* impaired cellular differentiation

Enasidenib

* MOA: inhibits IDH2 → increase in 2-HG → impaired cellular differentiation
* AE:
* differentiation syndrome
* hepatotoxicity
* N/V

Differentiation syndrome

* oncologic emergency
* result of differentiation of leukemic blasts
* Symptoms:
* fever
* leukocytosis
* dyspnea
* weight gain
* acute resp distress w/interstitial pulmonary infiltrates/pleural effusions
* acute renal failure
* vascular capillary leak syndrome
* Treatment:
* High dose IV dexamethasone (mortality