Chemotherapy

Review

Present by Napannop Boonthanom, Pharmacist in Oncology Unit, Rajavithi Hospital

Slide by Suthan Chanthawong, Residency Pharmacist Faculty of Pharmaceutical Sciences, Khon Kaen University

Cell Cycle Phase

Synthesis of cellular Components required

for mitosis

Synthesis DNA precursors, proteins, etc.

Resting state (cell is not dividing)

Overview of Cell Cycle

teachline.ls.huji.ac.il/.../substance_x/q2a.html

Vinca,paclitaxel,docetaxel

Antimetabolite

Cell cycle (phase) Nonspecific agent

Alkylating agents

Anthracycline

Antitumor antibiotics

Asparaginase

Topo II Inh. :Bleomycin,Etoposide

Topo I Inh. : Irrinotecan, Topotevan

Biochemical classification

1. Alkylating agents 2. Antimetabolites 3. Antitumor antibiotics 4. Enzyme Inhibitors 5. Antimicrotubules 6. Miscellaneous

Cell cycle specific agents

M Vincristine, Vinorelbine, Vinblastin, Paclitaxel, Docetaxel

G0 Carmustine, Lomustine

G1 Asparagenase

S Cladribine, Cytarabine, Floxuridine (FUDR), Fludarabine, 5FU, Hydroxyurea, 6MP, MTX, Pentostatin, 6TG

G2 Bleomycin, Etoposide, Teniposide

Cell cycle non-specific agents

Busulfan Carboplatin Carmustine Chlorambucil Cisplatin Cyclophosphamide Decarbazine Dactinomycin

Daunorubicin Doxorubicin Idarubicin Ifosfamide Lomustine Mechlorethamine Melphalan Mitomycin C

Alkylating agents A. Nitrogen mustards

Chlorambucil Cyclophosphamide Ifosfamide Melphalan Mechlorethamine

B. Ethylenimines Thiotepa

C. Nitrosoureas Carmustine Lomustine Semustine Streptozocin

D. Alkyl sulfonates

Busulfan

E. Triazenes

Dacarbazine Temozolomide

F. Platinum analogues

Cisplatin Carboplatin Oxaliplatin

Alkylating agents

Mechanism of action (MOA):

Form covalent bonds Cross-linking between double DNA strands or

between bases in the same strand of DNA inhibit DNA replication

Cell-cycle non specific Damage DNA in any phase of the cell cycleGreatest effect seen in rapidly dividing cell

Alkylating agents

Nitrogen mustards

CTX and IFEX

MOA: Broadest spectrum of nitrogen mustards Prodrug: must be activated in the liver to active

metabolites Also form inactive metabolite Acrolein

IFEX metabolism occurs more slowly than CTX Require higher dose Higher risk of hemorrhagic cystitis

Prevention of Hemorrhagic Cystitis

by MESNA

Mercapto ethane sulfonate sodium Indication Hemorhagic cystitis 2nd to “Acrolein”

Hydration with frequently voiding May be sufficient with conventional dose of CTX Not with IFEX

MESNA

MOA: Sulhydryl group binds with acrolein Form a stable nontoxic product excreted in the urine Prevent bladder mucosa damage

Give before & at 4 and 8 hrs following IFEX dose Dose = 60% of IFEX dose Oral dose = 120% of IFEX dose due to bioavailability

CTX and IFEX

CTX Indication

NHL, HD, CLL, CML, ALL, AML, myeloma

Neuroblastoma, Breast, Ovarian, Retinoblastoma, NSCLC, SCLC, bladder, Sarcoma, Endometrial, BMT, SLE

IFEX Indication

NHL

Testicular, NSCLC, SCLC, Sarcoma

Cisplatin and Carboplatin

MOA: Alkylating-like agents which form a reactive

electrophile that covalently binds to DNA Indication:

Effective for the treatment of lung, testicular, bladder, breast, ovarian, colorectal, head and neck and gastric carcinomas

Cisplatin and Carboplatin

Dosage and Administration: Cisplatin:

Vigorous hydration with adequate urine flow rate Prehydration

1 L of NSS + 20 mEq KCl & 8mEq MgSO4 over 1-2 hrs to obtain a urine flow rate of > 100ml/hour

Posthydration consists of the same IV fluids

Carboplatin: Using the Calvert method: Dose(mg) = Target AUC x (CrCl + 25) Target AUC is 4-8

Oxaliplatin Cumulative peripheral neuropathy Acute (within the first two days), reversible (resolves

within 14 days), primarily peripheral symptoms that are often exacerbated by cold

Persistent (>14 days) that often interferes with daily activities such as writing, buttoning and swallowing symptoms may improve upon treatment

discontinuation

Minimal nephrotoxicity and ototoxicity Delayed hypersensitivity (800 mg/m2)

Cisplatin-induced N/V

Vomiting Center

Effector organs

Vestibular Cortex CTZ GI tract

AC

Histamine ??

5-HT3,D2, NK1 5-HT3,

NK1,

SP

Treatment/Prevention• Acute: Steroids + 5HT3 + Apprepitant

• Delayed: Steroids + Metoclopramide + Apprepitant • Anticipatory: Lorazepam

Risk Factors ?

Cisplatin-induced nephrotoxicities

Proximal tubules GFR decrease Risk factors High single doses cumulative doses Dehydration Preexisting renal impairment Concurrent renal toxic drugs

Prevention Aggressive hydration

Toxicities Common to most

Alkylating Agents

Nausea and vomiting Myelosuppression Alopecia Sterility/Infertility 2nd Malignancies

Toxicities unique to Specific

Alkylating Agents Hemorrhagic cystitis Cyclophosphamide,

Ifosfamide

Neurotoxicities Ifosfamide, Cisplatin

SIADH Cyclophosphamide, Ifosfamide

Nephrotoxicities, Ototoxicities

Cisplatin, Carboplatin

Antimetabolites

A. Folate antagonists

Methotrexate

Pemetrexed

B. Purine analogues

Cladribine Fludarabine Mercaptopurine Pentostatin

Thioguanine

C. Pyrimidine analogues Cytarabine Gemcitabine Fluorouracil Capecitabine

Antimetabolites

Structural analogues of natural compound MOA:

Replacing metabolites in key DNA/RNA replication molecules

Inhibit DNA/RNA function or synthesis Active on most rapidly proliferating cells

Folate antagonists

Methotrexate MOA: Inhibits the conversion of folic acid to tetrahydrofolate

by competitively inhibiting dihydrofolate reductase This results in inhibition of DNA synthesis via

blockage of thymidine and purine synthesis Effect on both cancer and normal cells Rescue by giving reduced folate (folinic acid) or

“leucovorin” Bypass the metabolic block induced by MTX

Methotrexate

Indication ALL,CNS Lymphoma, NHL, Bladder, Breast, Gastric,

Head and neck, Osteosarcoma, BMT

Drugs which are highly protein bound may displace MTX form albumin and increase toxicity sulfonamides, salicylates, phenytoin and tetracycline

NSAIDS compete for renal excretion of MTX and increase levels

Vitamin C will acidify the urine and may increase MTX levels

Pemetrexed

MOA: inhibit five major folate-dependent enzymes.

Thymidylate synthase Dihydrofolate reducatase Glycinamide ribonucleotide formyltransferase

Approved in February 2004 for malignant plural mesothelioma

Pemetrexed

Hanauske AR, et al. Oncologist 2001;6;363-373

Pemetrexed

Start vitamin supplements 1 weeks before initial dose of pemetrexed prevent BM supression Folic acid 350-1000 ug/day orally

(continuing for 21 days after last dose of pemetrexed) Vitamin B12 1000 ug IM q 9 weeks

Dexamethasone 4 mg twice daily start a day before andcontinue the day of and the day after to minimize cutaneous reactions

Purine analogue

Thioguanine (6-TG), Mercaptopurine (6-MP) MOA:

Converted to ribonucleotides inhibit purine biosynthesis

May be incorporated into DNA as false purines More so 6-TG

Administration: Oral form only

(variable bioavailability, reduced absorption by food)

6-TG and 6-MP

6-MP inactivated by xanthine oxidase Decrease dose 50% with allopurinol

Indication ALL, AML, CLL,Hairy cell leukemia

Toxicities Dose limiting leukopenia and thrombocytopenia Additional toxicities include:

Liver toxicity and jaundice (higher with 6-MP), stomatitis, mucositis, rash, N/V

Pyrimidine analogue: 5FU

MOA: Acts as a “false” pyrimidine inhibiting the formation

of the DNA base thymidine The main mechanism inhibit the enzyme

thymidylate synthase (TS), the rate limiting step in thymidine formation

Prodrug: must be metabolized to its active metabolite; fluorodeoxyuridine (F-dUMP)

Additionally, metabolites of 5-FU may incorporate into RNA inhibiting its synthesis

Fluorouracil (5-FU)

Administration Continuous infusion inhibit TS Intermitten bolus incorporate into RNA

Leucovorin co-administration Increase stability of FdUMP and TS complex Increase cytotoxicity to tumor cells

Indication: Colorectal, breast, gastric, pancreas, esophageal,

head and neck, cervical

Fluorouracil (5-FU)

Toxicities: Dose limiting leukopenia, thrombocytopenia and

anemia (with bolus administration) Dose limiting hand-foot and diarrhea (continuous

infusions) Additional toxicities include:

Skin discoloration Nail changes Photosensitivity Neurologic toxicity

Capecitabine

MOA:

Orally active prodrug of 5-FU

3-step conversion to 5-FU, the last step being

phosphorylation by thymidine phosphorylase (TP)

TP levels are reported to be higher in tumor cells then

normal tissues, therefore the systemic exposure of active

drug is minimized

Toxicities:

Dose-Limiting: Hand-foot syndrome, diarrhea

Additional toxicity: Nausea, vomiting, fatigue, rash

Cytarabine and Gemcitabine

MOA: Structural analogues of cytosine

Penetrated tumor cell : phosphorylated Ara-CTP

Inhibits DNA polymerase (strand elongation) : Acts as a chain terminate

Cytarabine and Gemcitabine

Indication: Cytarabine: ALL, AML, CML, CNS leukemia, NHL Gemcitabine: pancreatic, lung, breast, ovarian cancer

Toxicities: Dose limiting leukopenia and thrombocytopenia Additional toxicities: Nausea and vomiting, mucositis,

diarrhea, flu-like syndrome, rash High dose ara-C therapy (1-2 g/m2) excessive bone

marrow depression, CNS toxicity and conjunctivitis

Cytarabine and Gemcitabine

Additional issues: High doses of ara-C often given with

Allopurinol to prevent tumor lysis syndrome Dexamethasone eye drops 0.1% q 4-6 hrs for 7 days to prevent conjunctivitis

Gemcitabine should be administered within 30 mins

Prevent time dependent myelosuppression

Toxicities Common to most

Antimetabolites

Myelosuppression Mucositis Mild N/V Except high-dose cytarabine and high-dose

MTX may cause moderate to severe emetics complications

Toxicities Unique to

Specitic Antimetabolites Neurotoxicities High-dose cytarabine

(cerebella)

Nephrotoxicities High-dose MTX

Hepatotoxicities Chronic MTX administration

Rash and skin changes Cytarabine (Ara-C), Clardribine

Gastrointestinal Toxicities Fluorouracil (5-FU)

Oral mucositis

Occurs 5-7 days after CMT Supportive measures

Oral hygiene Stomatitis cocktail Pain control

Prevention Sucralfate suspension at

beginning of or prior to CMT Cryotherapy

Enzyme inhibitors TOPOISOMERSE II INHIBITORS

A. Anthracyclines Daunorubicin hydrochloride Doxorubicin hydrochloride Idarubicin Epirubicin Mitoxantrone

B. Epipodophyllotoxins Etoposide Teniposide

TOPOISOMERSE I INHIBITORS

C. Camptothecins Irinotecan Topotecan

Antitumor Antibiotic Anthracyclines

Daunorubicin hydrochloride Doxorubicin hydrochloride Idarubicin Epirubicin

Mitoxanthrone Antibiotics

Bleomycin Mitomycin Dactinomycin plicamycin

Doxorubicin hydrochloride

Anthracyclines

MOA: Inhibit Topoisomerase II Bind covalently to double strand DNA Insert between base pairs of DNA (intercalation) Free radical formation

Form hydroxy radical cleave DNA Require iron or copper

Anthracyclines

Doxorubicin ALL, AML, NHL, HD, Wilm’s tumor,

bladder, gastric, ovarian, thyroid, neuroblastoma, SCLC, osteosarcoma, sarcoma, KS, NSCLC, myeloma, endometrial

Daunorubicin AML, ALL, KS

Idarubicin AML

Epirubucin Breast

Anthracyclines

Dosage and Administration: Dose reductions required with hepatic impairment

dose by 50% if bilirubin levels 1.2-3.0 mg/dL dose by 75% for bilirubin levels > 3.0 mg/dL

All agents are potent vesicants and require immediate medical attention if extravasation occurs

Apply cold ice pack and evaluate for antidote use (99% DMSO 1-2% ml applied to site q 6 hours for 7-14 days)

Doxorubicin red discoloration of the urine and tear

Mitoxanthrone

Anthracycenedione (synthetic agent) MOA: similar to anthracyclines but

Lacks ability to produce free radicals

Indication: AML, prostate, NHL, HD, breast Toxicities: Dose limiting leukopenia. Additional toxicities include:

Nausea and vomiting alopecia cardiac toxicity

Patients’ urine may turn blue for 24-48 hrs after infusion

Mitomycin C

Fermentation product form streptomyces MOA: similar to alkylating agents may also produce

super oxide free radicals Indication:

Gastric, Pancreas, Bladder, Breast, Colorectal, Esophagus NSCLC

Toxicities common to most

Antitumor ATB

Myelosuppression (except bleomycin) Mucositis Nausea & Vomiting (except bleomycin) Alopecia Vesicant (except bleomycin & mitoxanthrone)

Extravasation of cytotoxic

Common Vinca alkaloids Anthracyclines

Management Withdraw CMT Antidote Supportive care

Cold/Warm compress Symptom management

Toxicities unique to specific

Antitumor antibiotic Pulmonary toxicity Bleomycin, Mitomycin

Skin changes Bleomycin

Radiation recall Doxorubicin, Daunorubicin

Fever Bleomycin

Cardiac toxicities Doxorubicin, Daunorubicin Idarubicin, Epirubicin

Hemolytic Uremic Syndrome Mitomycin

Anthracyclines

Rhythm disturbance

Cardiomyopathy Cumulative dose

doxorubicin < 450-550mg/m2

daunorubicin < 450-550mg/m2

Idarubicin < 150 mg/m2

Epirubicin < 900mg/m2

Shan K et al. Ann Intern Med. 1996;125(1):47-58.

Anthracyclines related

cardiac-toxicity

Risk factors Previous cardiac irradiation Elderly Very young Females Preexisting HTN or cardiac disease Peak concentration

Idarubicin less cardiotoxicity

Prevention of anthracyclines

cardiotoxicity

Dexrazoxane (Zinecard) Chelation of divalent ions e.g. ferric iron Prevent free radical formation FDA approved or breast cancer with cumulative

dose 300 mg/m2 with benefit from doxorubicin

Liposomal doxorubicin and daunorubicin Liposomes are not taken up as freely as free drug into the cardiac tissue

Relative cardiotoxicity of

anthracyclines

Drug Relative cardiotoxicity

Cumulative (mg/m2)

Doxorubicin

bolus weekly 24 hr infusion

1.000.700.64

400550550

Daunorubicin 0.75 800

Idarubicin 0.53 150

Epirubucin 0.66 900

Mitoxanthrone 0.50 160

Epipodophyllotoxins

Etoposide and Teniposide MOA:

Form complexes with topoisomerase II and DNA Inhibit strand breakage and rejoining for replication Cell cycle specific in S and early G2 phase

More effective in divided doses

Teniposide more potent at stimulating DNA cleavage

Etoposide and Teniposide

Indication Etoposide: testicular, SCLC, AML, HD, NHL,

NSCLC, gastric, BMT, KS Teniposide: ALL, neuroblastoma, NHL

Etoposide IV infusion should be infused over 30-60 minutes to

avoid hypotension IV solution should be diluted to a concentration

< 0.4 mg/ml Oral dose is 2x greater than the IV

Etoposide and Teniposide

ADRSMyelosuppression N/V (mild and more with oral form) Alopecia Mucositis Hypersensitivity Hypotension prevent with slow infusion 2nd leukemias

AML in 1-3 years

Topoisomerase I Inhibitor (camptothecin)

Irinotecan and Topotecan Semisynthetic derivatives of camtothecin Plant derivative MOA

Inhibit topoisomerase I Stabilize DNA single strand breaks and inhibit religation

Indication Irinothecan: colorectal, NSCLC, cervical Topotecan: ovarian, SCLC

Irinotecan and Topotecan

ADRMyelosuppression: neutrophil and platelets Diarrhea: irrinothecan, acute or delayed N/V – severe with irinotecan, mild with topotecan Alopecia Rash Low-grade fever Malaise mucositis

Antimicrotubules

A. Vinca alkaloids Vinblastine Vincristine Vinorelbine

B. Taxanes Paclitaxel Docetaxel

Vincristine, Vinblastine and Vinorelbine

Products derived form periwinkle (Vinca) plant

MOA: Act as mitotic inhibitor or “spindle poison” bind to tubulin Disrupt the normal balance between polymerization and

depolymerization of microtubules M phase arrest

Dosage and Administration Biliary excretion, require adjustments for hepatic impairment.

50% dose reduction for blilrubin > 1.5 mg/dL, 75% reduction for bilirubin > 3.0 mg/dL

Vincristine

ALL, HD, NHL, myeloma, SCLC, brain, breast, KS, sarcoma, osteosarcoma, neuroblastoma, wilm’s tumor

Do not give IT (IV max 2 mg) ADRs

Neurotoxicities Peripheral Autonomic Decrease deep tendon reflex (DTRs)

Extravasation warm compress + hyaluronidase Constipation SIADH (Syndrome of Inappropriate Anti-diuretic Hormone) Alopecia

Vinblastine

HD, NHL, testicular, KS, breast, NSCLC, bladder, prostate, renal cell

Do not give IT ADRs

Myelosuppression Extravasation warm compress + hyaluronidase Less neurotoxicities Constipation Alopecia

Vinorelbine

Semisynthetic NSCLC, breast, ovarian, HD, prostate Do not give IT ADRs

Myelosuppression Neurotoxicities

Intermediate Paresthesia Loss of deep tendon reflex (DTRs)

Extravasation warm compress + hyaluronidase Constipation N/V Alopecia

Taxanes: Paclitaxel and Docetaxel

Paclitaxel from bark of Pacific Yew tree Docetaxel in semisynthetic MOA:

Bind to tubulin but not interfere with tubulin assembly Promote microtubule assembly Interfere with microtubule disassemble by inducing tubulin polymerization

Paclitaxel and Docetaxel

MOA: Form stable but not functional microtubules Also act by promoting apoptosis

Docetaxel more active taken up (3X greater) Retained intracellularly for longer period of time

(5-6 hrs) Therefore, considered 2-4X more potent than paclitaxel

Paclitaxel and Docetaxel

ADRsMyelosuppression

Paclitaxel: related to duration of infusion, higher doses, combination CMT and q 3 weeks VS weekly regimen

Hypersensitivity More with paclitaxel due to 50% cremophor Premedication and infuse over 24 hrs

Bradycardia and hypotension

Paclitaxel and Docetaxel

Patients must receive premedication prior to receiving paclitaxel to decrease hypersensitivity reactions Dexamethasone 20 mg PO or IV prior to treatment

Before 12, 6 and 0 (15-30 min) hr

Diphenhydramine 50 mg and an H2 blocker (ranitidine 50 mg) IV 30 minutes prior tx

Patients receive both pre and postmedication with docetaxel to prevent fluid retention associated with use Dexamethasone 8 mg PO BID starting 1 day prior to

treatment and continuing for 2 additional days

Paclitaxel and Docetaxel

ADRs Peripheral neuropathy

> 175 mg/m2 (paclitaxel)

Longer infusion, History of Ethanol, DM Mucositis, N/V (mild) Alopecia Fluid retention

docetaxel (Wt gain, edema, pleural effusions) Rash: docetaxel (PPE, maculopapular) Nail changes: docetaxel

Antimicrotubules drug

http://www.cancerquest.emory.edu/images/mitosis-cycai.gif

Taxanes

Vinca alkaloids

Miscellaneous agent A. Asparaginase B. Hydroxyuria

L-asparagenase

Enzyme produced by bacteria Responsible for the degradation of asparagenase

L-asparagenase Nonessential amino acid Synthesized by most cells except certain human

malignant cells

Conjugation with polyethylene glycol (PEG) Prolong T1/2 Allow for lower doses Less frequent administration

L-asparagenase

Indication: ALL

ADRs: Anaphylaxis (PEG form is less immunogenic) Fever/chills Decrease clotting factors Decrease insulin Pancreastitis Somnolence or confusion Myelosuppression Nausea

L-asparagenase

Test dose 0.1 ml of dilute 20 unit/ml solutions (~2 units) prior to

initial administration and observe 1 hr for a wheal or erythema

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Hydroxyurea

Antimetabolite but not a nucleoside analogue MOA:

Inhibit ribonucleotide reductase, enzyme required to convert ribonucleotided to the deoxy form for the DNA synthesis and repair

Stop DNA synthesis without interfering with formation of RNA or protein

Cell accumulate in the S phase, only short DNA strand are produced

Hydroxyurea

Indication CML, melanoma, ovarian, head and neck

ADRs: Myelosuppression N/V Anorexia Mucositis Skin-hyperpigmentation and radiation recall Erythema of hands and face

Hormonal agents

A. Antiestrogens Tamoxifen citrate Megestrol acetate

B. Aromatase inhibitors Aminoglutethimide Anastrozole Letrozole Exemestane

C. LH-RH analogues Goserelin Leuprolide

D. Antiandrogens Bicalutamide Flutamide Nilutamide

E. Miscellaneous hormonal agents Estramustine

Targeted therapies A. Monoclonal antibodies

Gemtuzumab Alemtuzumab Rituximab Ibritumomab Tositumomab Trastuzumab Cetuximab

B. Tyrosine kinase inhibitors Erlotinib Gefitinib Imatinib mesylate Sunitinib malate

Thank you for your attention

and any questions???