L3/4 - Antineoplastics I: Siver

Antimicrotubule agents and Topoisomerase II Inhibitors affect which phase in the cell cycle?

M phase specific

Antimetabolites and Topoisomerase II inhibitors target which phase in the cell cycle?

S phase specific

MOA of akylating agents

formation of positively charged ion that binds to electron rich nucleophilic sites on biological molecules

What are the alkylating agents class toxicities?

1. n/v

2. myelosuppression

3. 2ndary malignancies

4. infertility and teratogenicity (agent and dose specific)

5. alopecia

6. vesicants/irritants

CC unique toxicities of nitrogen mustards ifosfamide and cyclophosphamide

1. cyclophosphamide: mucositis, hemorrhagic cystitis, cardiotoxicity (at higher doses)

2. ifosfamide: encephalopathy/neurotoxicity (chloroacetaldehyde metabolite), hemorrhagic cystitis

CC metabolism of cyclophosphamide and ifosfamide

both prodrugs, metabolized by CYP450 enzymes

ifosfamide is an analog of cyclophosphamide

both nitrogen mustards need ___ and ___ for supportive care. What makes them different?

1. antiemetics and IV hydration

2. mesna for high dose cyclophosphamide and all ifosfamide doses (chemoprotective agent to prevent hemorrhagic cystitis)

What is high dose cyclophosphamide?

>1g/m² or >50mg/kg

what should be monitored for nitrogen mustards?

CBC, SCr, BUN, urinalysis (dipstick for RBCs), I/Os signs, S&S for hemorrhagic cystitis (and neurotox for ifosfamide)

Which of the following is true regarding the use of MESNA?

always required for ifosfamide

what causes hemorrhagic cystitis in cyclophosphamide?

acrolein → cancer and cell death

mechanism of action of platinum analogs cisplatin, carboplatin, and oxaliplatin

binds to DNA, causing intra and inter-strand crosslinks

where are the platinum analogs (platin) toxicities

otoxicity, nephrotoxicity, myelosuppression, peripheral neuropathy, n/v (cisplatin > carbo/oxaliplatin)

When is cisplatin commonly used?

bladder, ovarian, testicular, solid tumors

What are the unique toxicities of cisplatin?

severe n/v (acute and delayed), electrolyte wasting (dec Mg, K, Ca, Phos, Na) due to nephron dmg, vesicant

What is the supportive care for cisplatin?

antiemetics, ensure adequate urinary output with hydration pre and post (caution fluid overloading in HF pts), correct electrolytes prior to cisplatin

What should be monitored for cisplatin?

SCr, BUN, CrCl, I/Os, CBC, electrolytes (K, Mg, Ca, Na), audiologic exams

What is chemotherapy extravasation? What are the 3 categories?

infiltration (leakage) of chemotherapeutic agent drug from the IV infusion site into local surrounding tissue

• non-vesicant/neutral: no dmg

• irritant: inflamm, pain, burning to infilitrated

• vesicant: tissue necrosis, blistering

What is 2ml sq injection of sodium thiosulfate indicated for? What is the MOA?

treat extravasation of cisplatin, bendamustine, mechlorethamine by creating alkaline-rich site, to which alkylating agents have an affinity → neutralize vesicant

What is the colvert equation?

dose = AUC x (25+GFR); used to calculate carboplatin dose in mg

What are the unique toxicities of carboplatin?

hypersensitivity rxns: inc w cumulative dose (6-7 doses)

What is the supportive care needed for carboplatin? What should be monitored?

antiemetics, pre/post IV or oral hydration; monitor SCr, BUN, CrCl, I/O’s, CBC, electrolytes

Cockcroft Gault Equation

What is oxaliplatin indicated for? what are the unique toxicities?

colorectal cancer; hypersensitivity, cold-induced peripheral neuropathy

What are the supportive care and monitoring for oxaliplatin?

antiemetics, avoid touching cold objects or swallowing cold drinks; monitor SCr, BUN, I/O’s, CBC

What are topoisomerase inhibitors? CC I and II type

enzymes that control topology (winding/unwinding) of supercoiled DNA during DNA replication/repair; after cuts are made and repair is complete, strands are paired back together and coil reforms

• I: break only one strand of DNA

• II: break both strands of DNA

What is the moa of topoisomerase I inhibitors (irinotecan) what cell cycle phase does it target?

inhibit topoisomerase I resulting in DNA complex stabilization and prevent religation of cleaved strands causing single strand DNA breaks; S and G2 phase specific

Which of the following agents inhibits topoisomerase I, resulting in a single stranded DNA breaks?

irinotecan

What is irinotecan indicated for? what are its toxicities?

colorectal cancer, R/R pediatric gliomas; diarrhea, mod n/v

• supportive care: antidiarrheal and antiemetics

How is irinotecan metabolized? **

metabolized hepatically to its active (toxic) metabolite, SN-38

What are the clinical peals of irinotecan?

1. dose reduction for pts with homozygous UGT1A1*28 allele

2. avoid UGT1A1 inhibitors (atanazavir, gemfibrozil, idinavir)

How do you manage irinotecan induced diarrhea?

1. acute (<24h): atropine

2. delayed (>24h): high dose loperamide

what is the moa of topoisomerase II inhibitors podophyllotoxins (etopside)? What phase of the cell cycle does it target?

bind to DNA topoisomerase II complex inhibiting the religation of the double strand breaks; S or early G2 phase and prevent cells from entering mitosis

What are the toxicities of podophyllotoxins?

myelosuppression, n/v, alopecia, 2nday leukemia

When is etoposide indiciated?

SCLC, testicular cancer, AML, ewing sarcoma

What are the unique toxicities of etoposide?

transient HoT w rapid infusion (overcome by slowing infusion rate)

What are the clinical pearls of etoposide?

1. adjust dose for renal and hepatic impair

2. PO; IV = 2;1 (50% bioaval)

3. supportive care: antiemetics

4. Monitoring: CBC, BP

What is the moa of anthracyclines (antitumor ABX -rubicin)?

induce the formation of covalent topoisomerase II DNA complexes

• inhib top II prevent the re-ligation causing DNA ds break

• intercalations betw base apirs in the DNA are formed

• form free O2 radicals

What are the anthracycline class toxicities?

cardiomyopathy, extravasation (vesicants), myelosuppression, alopecia, mucositis, diarrhea

What is the lifetime max dose of doxorubicin? ***

450-550 mg/m²

What is used to treat anthracycline extravasation?

dexrazoxane

What is unique moa of anthracyclines doxorubicin, daunorubicin, and idarubicin?

top II inhibitor, inhib DNA and RNA synthesis by interacalation betwe DNA base, generates free radicals

What is unique about liposomal daunorubicin and cytarabine moa?

combination product with 1:5 molar ration of daunorubicin:cytarabine (antimetabolite)

What are the unique toxicities of doxorubicin and daunorubicin?

cardiotoxicity, extravasation, radiation recall, red discoloration of urine, mod to high N/V

• idarubicin DOES NOT have red discoloration

What is the supportive care and monitoring for anthracyclines?

dexrrazoxane (chemoprotective) and antiemetics; monitor CBC, ECHO/MUGA, Tbili

Dexrazoxane is a chelating agent that intracellularly interferes with iron-mediated oxygen free radical generation. How is it dosed for extravasation of anthracyclines?

10:1 ration of dexrazoxane: doxorubicin

• begin treatment ASAP (within 6 hrs of extravasation)

• withold cooling compresses at least 15 min b4 during infusion

• localize and neutralize → apply cold compress and admin neutralizing agents

Mitoxantrone is an antitumor antibiotic that is a synthetic agents related to doxorubicin. What is the moa?

1. top II inhib that intercalates DNA and results in crosslinks and strand breaks; inhib incorporation of uridine into RNA and thymidine into DNA

2. does not form free oxygen radicals (unlike anthracyclines) → lower risk of cardiotox

What are the common toxicities of mitoxantrone?

cardiotox, myelosuppression, alopecia, mucositis, blue/green urine discoloration

Bleomycine is an antitumor antibiotic. What is the moa?

type of glycopeptide antibiotic (like vanco) that targets tumor cells via generation of free oxygen radicals through chelation with metal ions

• intercalates into DNA and results in single and double strand breaks

What are the common toxicities of bleomycin?

pulmonary toxicity (fibrosis); lifetime max dose: 400 units

Antimicrotubules bind to tubulin and inhibit disassembly of microtubules; arrest cell at metaphase and inhib cell proliferation. (target M phase) What are the class toxicities?

peripheral neuropathy, hypersens rxns (less for paclitaxel), myelosuppression (dose limiting tox so omit/reduce subsequent doses), low incidence of n/v

When is docetaxel (taxane, antimicrotubule) is indicated? What are the unique toxicities?

1. breastm gastric, head and neck, lung, prostate cancers

2. fluid retention (diuretics), contains polysorbate 80 (hypersens rxn

What are the DDI of taxanes? (antimicrotubules)

CYP3A4 substrate

docetaxel: consider dose reduction by 50% when using strong CYP3A4 inhibitors (like voraconazole)

cabazitaxel: reduce by 25%

What supportive care is required for docetaxel? (antimicrotubules)

premed w corticosteroids

When is paclitaxel conventional (taxane, antimicrotubule) is indicated? What are the unique toxicities? supportive care required?

1. breast, kaposi sarcoma, lung, ovarian cancers

2. contains cremophor (high hypersens rxns)

3. premed w dexamethasone, diphenhydramine, H2RA (bc hypersens)

What should be monitored for taxanes (antimicrotubules)?

CBC, LFTs, S&S of neuropathy

When is paclitaxel protein-bound (taxane, antimicrotubule) is indicated? What are the unique toxicities? supportive care required?

1. breast, lung, pancreatic cancers

2. less hypersens rxns cuz no cremophor

   1. so pre med not necessary

When is carbazitaxel (taxane, antimicrotubule) is indicated? What are the unique toxicities? supportive care required?

1. metastatic castration-resistant prostate cancer

2. contains polysorbate 80, diarrhea

3. premed w antihistamine, steroid, H2RA

Vinca alkaloids (antimicrotubules) inhibit microtubule formation/assembly, arresting cell at metaphase. What are the class toxicities?

1. neurotoxicity(vincristine > vinblastine, vinorelbine)

2. constipation

3. extravasation

What is a fatal warning for vinca alkaloids

NOT FOR INTRATHECAL USE → FATAL

• dispense vinca alkaloids in a minibag (not in syringe)

SEQ the toxicities of vinca alkaloids from most to least

1. neurotox: vincristine > vinblastine > vinorelbine

2. myelosuppression: vinblastine > vinorelbine > vincristine

3. n/v: minimal

When is vinblastine indicated?

testicular cancer, lymphomas, kaposi sarcoma

When is vincristine indicated?

ALL, lymphomas, pediatric malignancies (wilms, neuroblastoma, rhabdomyosarcoma)

When is venorelbine indicated?

NSCLC, various solid tumors

What are the DDIs and supportive care of vinca alkaloids

1. DDI: CYP3A4 and Pgp substrate (vinorelbine only CYP3A4)

2. supportive care: prophylactic bowel regimen

All vinca alkaloids and taxanes are vesicants. What is the managment?

hy