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Chemotherapy

Taxane Agents

Cabazitaxel (Jevtana)
Docetaxel (Taxotere)
Paclitaxel (Taxol)
Albumin-bound paclitaxel (Abraxane)
Ixabepilone (Ixempra)

Vinca Alkaloids

Vinblastine
Vinorelbine
Vincristine

Anti-mitotic Agent

Eribulin (Halaven)

Microtubules fjunction

Principle components of the mitotic spindle apparatus
Separate the duplicate set of chromosomes during mitosis
Function to maintain the scaffolding and shape of the cell
Assembled by linear stacking of alternating units of alpha and beta tubulin

Tubulin polymerization function

Nucleation - elongation mechanism that allows a microtubule to shorten and elongate according the the cell cycle
Microtubules are in a constant state of motion (assembling and
disassembling)

Microtubule Dynamics

Treadmilling: net growth at one end of the microtubule (plus
end) and net shortening at the opposite end (minus end)
Dynamic instability: microtubule ends switch spontaneously
between states of slow sustained growth and rapid shortening

Microtubule have 2 ends

Plus end: More rapid and polymerization
Minus end: Faster release Of subunits (depolymerization)

Taxane Agents Mechanism of Action

M phase specific,
Binds β-tubulin subunit of the microtubule and prevents disassembly (depolymerization) of the tubulin
Results in formation of stable, nonfunctional microtubules
Cell is unable to complete cell division and undergoes
apoptosis

Paclitaxel (Taxol) Uses

Majority of solid tumors
Breast, Lung, Ovarian,
Testicular, Head and Neck,
among others

Paclitaxel (Taxol) Toxicities

Neutropenia (DLT)
Nausea / Vomiting
Peripheral neuropathy
Alopecia
Arthralgia / Myalgia
Anaphylactic
hypersensitivity (due to
Cremaphor)
Flushing / Rash
Cardiac arrhythmias

Paclitaxel (Taxol) Dose Adjustment

Hepatic dysfunction
Hepatic metabolism
through CYP 2C8

Paclitaxel (Taxol) Special Compounding

Drug is diluted in 50/50
Cremaphor (castor oil) and
alcohol
DO NOT MIX in PVC
Plasticizer DHEP leaches
into solution = Toxic

Paclitaxel (Taxol) Premedications
(30 minutes prior)

Histamine-2 receptor
antagonist
Famotidine 20mg IV
Diphenhydramine 25 mg
IV
3 doses of dexamethasone:
12 - 20 mg PO at 12, 6 and
1 hour prior to paclitaxel
Antiemetics

Albumin-Bound Paclitaxel (Abraxane)

Indicated only in metastatic breast cancer following
progression of an anthracycline-based therapy
Similar toxicities to paclitaxel
LOWER risk of hypersensitivity reaction
HIGHER rate of peripheral neuropathy and neutropenia
Dosing adjustments for hepatic dysfunction

Docetaxel (Taxotere) Uses

Solid tumors primarily
Prostate, Breast, Lung,
Ovarian, Bladder, Head
and Neck

Docetaxel (Taxotere) Toxicities

Neutropenia (DLT)
Peripheral neuropathy
Alopecia
Fluid retention
Anaphylactic
hypersensitivity (due
toTween 80)
Arthralgia / Myalgia
Nausea / Vomiting
Flushing / Rash

Docetaxel (Taxotere) Dose Adjustment

Hepatic dysfunction
Hepatic metabolism through
CYP 3A4/5*

Docetaxel (Taxotere) Special Compounding

Drug is diluted in Polysorbate
80 and alcohol
DO NOT MIX in PVC
Plasticizer DHEP leaches into
solution = Toxic

Docetaxel (Taxotere) Premedications (30 minutes prior)

Diphenhydramine 25 mg
Dexamethasone 8mg PO BID
beginning day before
docetaxel and continuing for
3 days (reduces edema)
Antiemetics

Ixabepilone (Ixempra) approved for

Only approved for use in breast cancer after failure of
anthracyclines, taxanes and capecitabine

Ixabepilone (Ixempra) Toxicities

Peripheral neuropathy (DLT)
Neutropenia
Myocardial ischemia
Myalgia
Fatigue
Nausea
Anaphylactic hypersensitivity
(contains Cremaphor*)
Premedicate like paclitaxel

Ixabepilone (Ixempra) dosing limitations

Dose reduce in hepatic dysfunction

Ixabepilone (Ixempra) Epithilone Drug Class MOA:

Binds to beta-tubulin (occupies different binding site than taxanes)
5 - 25x more potent than
paclitaxel

Eribulin (Halaven) MOA

non-taxane microtubule inhibitor, halichondrin B analog which inhibits growth phase of microtubules by inhibiting formation of
mitotic spindle

Eribulin (Halaven) Uses

Metastatic breast cancer

Eribulin (Halaven) Toxicities

Myelosuppression
Neutropenia
Anemia
QTc prolongation
Peripheral neuropathy
Alopecia

Cabazitaxel (Jevtana) Uses

Hormone refractory metastatic prostate cancer

Cabazitaxel (Jevtana) Toxicities

Neutropenia
Neuropathy
Hypersensitivity reaction
(contains polysorbate 80)
Premediate like paclitaxel
Nausea / vomiting /
diarrhea
Arthralgia
Alopecia

Vinca Alkaloids MOA

Inhibit tubulin polymerization Block ability to form a
mitotic spindle
Cell is unable to complete cell division and undergoes
apoptosis

Taxanes Vinca alkaloids MOA diagram

Vincristine (Oncovin) Uses

Leukemia, Lymphoma

Vincristine (Oncovin) Toxicities

Peripheral neuropathy
(DLT)
Paralytic ileus
Prophylactic stool
softeners
2 tabs QHS - titrate to regulate bowel movements
SIADH
Minimal nausea
MAX dose = 2 mg Vesicant

Vincristine (Oncovin) dose adjustments

Hepatic
Requires dosing
adjustment for hepatic
insufficiency

Vinblastine (Velban) Uses

Lymphoma, melanoma

Vinblastine (Velban) Toxicities

Neutropenia (DLT)
Thrombocytopenia
Alopecia
Mild peripheral neuropathy
SIADH
Minimal nausea
Vesicant

Vinblastine (Velban) dose adjustments

Requires dosing adjustment for hepatic insufficiency

Compounding Vinca Alklaloids

FATAL if given by intraTHECAL route
Slow, painful death from myeloencephalopathy
Ascending motor and sensory neuropathy
World Health Organization recommends compounding these
drugs in a piggyback
NO Syringes = NO confusion for intrathecal administration

"S" Phase Agents Antimetabolites

Methotrexate
Pemetrexed
Fluouracil / Capecitabine
Mercaptopurine
Thioguanine
Fludarabine
Pentostatin
Gemcitabine
Cytarabine
Azacytidine
Decitabine

Antifolate Drugs

Methotrexate and Pemetrexed

S Phase Specific Activity antifolate Deficiency

impairs thymidylate and purine synthesis (DNA synthesis)
Megaloblastic anemia

Methotrexate (Trexall) Uses

Leukemia, Lymphoma
Various solid tumors
(sarcoma, breast, head and
neck, choriocarcinoma)
Non-oncology
Psoriasis, rheumatoid arthritis,
Crohn's disease, graft versus
host therapy, abortifacient

Methotrexate (Trexall) MOA

Inhibits the enzyme dihydrofolate reductase
DHFR replenishing cell's tetrahydrofolate supply
Increasing levels of dihydrofolate inhibits activity of thymidylate synthase
Blockade of DHFR = inhibition of thymidylate and purine
synthesis

Methotrexate (Trexall) Special Notes

Wide variability in dosing!
2.5 mg once a week - 20 grams once a month
PO, IV, can give intrathecally
Eliminated in urine -adjust dose for renal dysfunction
High protein binding
3rd space fluid collection (pleural effusions, ascites)

Methotrexate (Trexall) Toxicities

Mucositis
Myelosuppression (neutropenia, thrombocytopenia)
Renal toxicity
Pneumonitis
Alopecia
Infertility

High-Dose Methotrexate can

High - dose methotrexate, Requires urine alkalinization (pH >
7.5), Requires high volume hydration (250 ml/m2/hr) for renal
protection, Requires leucovorin rescue which will rescue both healthy and malignant cells

High-Dose Methotrexate Leucovorin rescue

Initiated > 24 hours after the dose of methotrexate
20 mg IV/PO Q6H
Increase dose based on algorithm
Treat with leucovorin until methotrexate level < 1 x 10 -7 molar

Mucositis Tx

Supportive Care
IV/PO pain medication
Saliva substitute
Soft tooth brush and baking soda water rinse
Cryotherapy
"Magic Mouth Wash"
Hydrocortisone 110 mg IV, Diphenhydramine elixer 120 mL, Nystatin
suspension 120 mL (may substitute Maalox, tetracycline, sucralfate)
5 - 10 mL PO Q4H prn pain
+/- viscous lidocaine 2% (beware of cardiac adverse effects)

Pemetrexed (Alimta) Uses

Non-small cell lung cancer, drug of choice for mesothelioma

Pemetrexed (Alimta) MOA

Multi-targeted
Inhibits thymidylate synthase
Weakly inhibits DHFR
Inhbitis GARFT (glycinamide ribonucleotide formyltransferase) - enzyme necessary for purine synthesis

Pemetrexed (Alimta) Toxicities and Supportive Care

Myelosuppression
At least 7 days prior to 1st dose:
Cyanocobalamin 1000 mcg IM then every 9 weeks
Folic acid 1 mg PO daily
Pruritic rash (40%)
Dexamethasone 4 mg BID day -1, day 0 and day +1 t
Prevention of rash

Antifolate mechanism of action

Fluouracil (5-FU, Adrucil) is

Fluorinated analog of naturally occurring pyrimidine of uracil that is S-phase specific

Fluouracil (5-FU, Adrucil) MOA

Monophosphate form of 5-FU (F-dUMP) inhibits thymidylate
synthase
Competes with natural substrate, dUMP for
thymidylate synthase binding
dUMP required to make thymidine (building block of DNA)
Triphosphate form of 5-FU (FUTP) incorporates into RNA as
a false base pair

5-FU drug Interactions

Leucovorin
Addition of folates during 5-FU infusion increases the stability of the 5-FU monophosphate - thymidine sythase bond
Results in increased
cytotoxic activity
Warfarin
Increased PT/INR
Phenytoin
Increased phenytoin levels
Radiation
Radio-sensitizer

Fluoruracil Uses

Breast, Colorectal, Gastric, Esophageal, Head and Neck, Pancreatic, Cervical Cancer

Fluoruracil Toxicity

Myelosuppression
Mucositis
Diarrhea
Palmar-Plantar erythema (Hand-Foot Syndrome)
Photosensitivity
Mild Nausea
Neurotoxicity

Capecitabine (Xeloda) FDA indicated

Colorectal Cancer (CRC)
Single agent for adjuvant therapy after complete tumor
resection*
Single agent, first line therapy in metastatic CRC

Metastatic Breast Cancer
Single agent
In combination with docetaxel or lapatinib

Antipyrimidine Antimetabolites Cytidine Analogues

Cytarabine
Gemcitabine
Azacytidine
Decitabine

Cytarabine (Ara-C) Uses

Leukemia and Lymphoma
No activity in solid tumors

Cytarabine (Ara-C) Elimination

Enzyme cytidine deaminase
deactivates Ara-C
Enzyme present in low levels in
the CNS
Effective for intrathecal
administration
Dose adjust for renal dysfunction
(increased neurotoxicity)

Cytarabine (Ara-C) MOA

Analog of deoxycytidine
Incorporates into DNA
Terminates chain elongation
Inhibits DNA polymerase
Cytarabine is phosphorylated to an active triphosphate form (aca-CTP) within tumor cells

Cytarabine (Ara-C) Adverse Effects

Myelosuppression
Conjunctivitis
Nausea / Vomiting
Skin rash (palmar-plantar)
Cerebellar toxicity
LFT elevation (transient)
Diarrhea

Gemcitabine (Gemzar) Uses

Bladder, Pancreatic, Lung, Breast,
Ovarian Cancer
Radiation sensitizer

Gemcitabine (Gemzar) Toxicities

Edema
Acute respiratory distress syndrome
Rash
Nausea / Vomiting
Thrombocytopenia - DLT
Flu-like symptoms
Transient elevation in LFTs

Gemcitabine (Gemzar) MOA

Analog of deoxycytidine
Incorporates into DNA
Terminates chain elongation
Competes with the natural substrate, dCTP (deoxycytidine triphosphate), for DNA incorporation
Inhibits DNA polymerase
Inhibits DNA synthesis
Inhibiting an enzyme responsible for the production of deoxynucleotides, ribonucleotide reductase

Azacytidine (Vidaza) & Decitabine (Dacogen) Uses and MOA

Myelodysplastic syndrome
Acute myeloid leukemia
Limited activity

Hypomethylating agents
Incorporated into DNA and RNA

Azacytidine (Vidaza) & Decitabine (Dacogen) Elimination

Enzyme cytidine deaminase
deactivates Ara-C

Purine Antimetabolites Guanine Analogs

6-mercaptopurine (6-MP,Purinthol)
6-Thioguanine (6-TG)
Azothioprine (Imuran)

Purine Antimetabolites Adenosine Analogs

Pentostatin
Cladribine (2-cda, Leustatin)
Fludarabine (Fludara)

Guanine Analogs (6-MP, 6-TG) MOA and Uses

Converted to ribonucleotides that are incorporated into DNA
Inhibit purine synthesis

Uses: Leukemia

Guanine Analogs (6-MP, 6-TG)

Allopurinol increases 6-MP toxicity
6-MP is metabolized by xanthine oxidase
Allopurinol is a xanthine oxidase inhibitor

Adenosine Analogs Fludarabine Cladribine & Pentostatin Uses

lymphoma

Adenosine Analogs Fludarabine MOA

Inhibits DNA polymerase and ribonucleotide reductase,
incorporated into DNA

Cladribine & Pentostatin Adenosine Analogs MOA

Inhibits ribonucleotide reductase
Unlike fludarabine, these drugs are not deactivated by adenosine deaminase (cladribine inhibits AD)

Adenosine Analogs Fludarabine Cladribine & Pentostatin cause

DLT - myelosuppression (T cell depression)
Risk of opportunistic infections of PCP, HSV
*Recommend anti-infective prophylaxis*

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