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PRINCIPLES OF ONCOLOGIC PRINCIPLES OF ONCOLOGIC PHARMACOTHERAPYPHARMACOTHERAPY

Elshami M. Elamin, MDElshami M. Elamin, MDMedical OncologistMedical Oncologist

Central Care Cancer CenterCentral Care Cancer Center

www.cccancer.com

Wichita, KS - USAWichita, KS - USA

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Neoplastic Cell kinetics

Tumor cells can be subdivided into three general populations: 1- cells: not dividing and terminally differentiated 2- cells: continue to proliferate 3- cells: nondividing, currently quiescent but may be

recruited into the cell cycle.

The kinetic behavior of dividing cells is best described by the concept of the cell cycle.

Cell Cycle G1, or gap, phase,

in which the cell grows and prepares to synthesize DNA

S, or synthesis, phase, in which the cell synthesizes DNA

G2, or second gap, phase, in which the cell prepares to divide

M, or mitosis, phase, in which cell division occurs.

Check points1- As a cell approaches

the end of the G1 phase it is controlled at a vital checkpoint, called G1/S, where the cell determines whether or not to replicate its DNA

Cells with intact DNA continue to S phase; cells with damaged DNA that cannot be repaired are arrested and ‘‘commit suicide’’ through apoptosis

2- A second such checkpoint occurs at the G2 phase following the synthesis of DNA in S phase but before cell division in M phase

Cell cycle regulatory proteins

Cyclin Dependent Kinases, or CDKs, are specific enzymes that use signals to switch on cell cycle mechanisms.

CDKs are activated by forming complexes with cyclins (another group of regulatory proteins only present for short periods in the cell cycle)

Genetic mutations causing the malfunction or absence of one or more of the regulatory proteins at cell cycle checkpoints can result in the ‘‘molecular switch’’ being turned permanently on, permitting uncontrolled multiplication of the cell, leading to carcinogenesis, or tumor development.

Cell Cycle in Cancer

In normal cells, the cell cycle is controlled by a complex series of signaling pathways by which a cell grows, replicates its DNA and divides.

This process also includes mechanisms to ensure errors are corrected, and if not, the cells commit suicide (apoptosis).

In cancer, as a result of genetic mutations, this regulatory process malfunctions, resulting in uncontrolled cell proliferation.

How Cancer Drugs Work?

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Chemotherapeutic agents Chemotherapeutic agents classifiedclassified

by mechanism of actionby mechanism of action

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“Classic” Alkylating agents Nitrogen mustards cyclophosphamide (Cytoxan, Neosar), ifosfamide (Ifex) chlorambucil (Leukeran) Estramustine (Emcyt) Melphalan (Alkeran) Thiotepa Busulfan (Myleran) Nitrosoureas:

Carmustine (BiCNU) Lomustin (CeeNU) Streptozocin (Zanosar)

Bendamustine (Treanda)

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Alkylating agents

Impair cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups

The most important sites of alkylation are DNA, RNA, and proteins.

Depend on cell proliferation for activity but are not cell-cycle phase specific

have linear dose-response curves (ie, increasing the dose increases cytotoxicity)

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NitrosoureasCarmustine (BiCNU), Lomustin (CeeNU), Streptozocin (Zanosar)

The lipophilic nature of the nitrosoureas enables free passage across membranes; therefore, they rapidly penetrate the blood-brain barrier. used for a variety of brain tumors.

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Alkylating agents Toxicities

Nausea/Vomiting local vesicants skin rashes Bone marrow depression gonadal dysfunction leukemia hyperuricemia pulmonary fibrosis hemorrhagic cystitis (ifex, cytoxan) alopecia

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Alkylating agentsUses

CLL, HD, NHL, AML, ALL M. myeloma ovarian cancer Prostate ca Breast ca Germ-cell testicular lung cancer mycosis fungoides sarcoma Brain tumor: GlioBlastoma Multiforme Pancreatic islet-cell, carcinoid

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Nonclassic alkylators

Altretamine (Hexalen)

Dacarbazine (DTIC)

Procarbazine (Matulane)

Temozolomide (Temodar)

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Nonclassic alkylatorsToxicities

Nausea and vomiting CNS toxicity, Paresthesias Bone marrow depression alopecia

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Nonclassic alkylatorsUses

HD (dacarbazine) Brain (Procarbazine, Temozolomide) cervical cancers Malignant melanoma (DTIC,

Temozolomide) soft-tissue sarcomas (DTIC) Ovarian (Altretamine)

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Platinum complexes

Cisplaplatin

Carboplatin

Oxaliplatin

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Platinum

Inorganic heavy metal complex cell-cycle phase nonspecific inhibits the synthesis of DNA,

RNA, and proteins have linear dose-response curves

(ie, increasing the dose increases cytotoxicity)

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Platinum complexesToxicities

nausea and vomiting Bone marrow depression Renal toxicity peripheral neuropathy ototoxicity

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PlatinumUses

Ovarian cancer (Cis, carbo) Lung ca (Cis and carbo) Head/Neck acute leukemia NHL Breast bladder uterine cervical Colorectal (oxaliplatin) Gastric and Esophageal ca

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Antimetabolites Antimetabolites are structural analogs

of the naturally occurring metabolites involved in DNA and RNA synthesis.

Exert their cytotoxic activity either by: competing with normal metabolites for the

catalytic or regulatory site of a key enzyme or

substituting for a metabolite that is normally incorporated into DNA and RNA.

Most active when cells are in the S phase and have little effect on cells in the G0 phase.

Most effective against tumors that have a high growth fraction.

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Antimetabolites

folate analogs purine analogs pyrimidine analogs substituted ureas

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Folate analogs (Folate antagonist)

Methotrexate: Interferes with DNA synthesis, repair and

cell replication Inhibits dihydrofolate reductase

Pemetrexed (ALIMTA): Disrupts folate-dependent metabolic

process essential for cell replication Inhibits:

Thymidylate synthase dihydrofolate reductase Glycinamide ribosnucleotide formyltransferase All folate-dependent enzymes involved in

biosynthesis of purine and thymidine

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Folate analogsToxicites

Mucositis GI ulceration marrow depression pulmonary fibrosis Liver toxicity rash/skin desquamation

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Folate analogsUses

ALL, CNS leukemia (MTX) Breast (MTX) head and neck Mesothelioma (Alimta) NSCLC (Alimta) Gestational trophoblastic Tumors

(MTX) NHL, Burkitt’s lymphoma (MTX) Osteosarcoma (MTX)

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Purine analogs

Inhibit DNA synthesis: Fludarabine Pentostatin (Nipent) Cladribine Mercaptopurine Thioguanine

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Purine analogsToxicities

Bone marrow depression Malaise pulmonary infiltrates tumor lysis syndrome Skin rash

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Purine analogsUses

CLL (fludara, pentostatin) Hairy-cell leukemia (pentostatin,

cladribine) NHL (fludara) ALL AML

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Pyrimidine analogs

Inhibit DNA and RNA synthesis: Fluorouracil/Adrucil (5-FU) Capecitabine (xeloda) Floxuridine Cytarabine, DepoCyt

Inhibit DNA synthesis synthesis: Gemcitabine (gemzar)

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Pyrimidine analogsToxicities

Diarrhea Stomatitis/mucositis nausea and vomiting hand-foot syndrome Bone marrow depression hepatic dysfunction CNS

Fluorouracil/Adrucil (5-FU)Capecitabine (xeloda)

Severe toxicities in pts with: DihydroPyrimidine Dehydrogenase (DPD)

deficincy Thymidylate Synthase (TYMS/TS) mutation

associated with reduced TS production and subsequent 5-FU toxicity

Tests available for 5-FU toxicity

TheraGuide 5-FU: TYMS and DPYD genes mutation

25% of pts have them 60% risk of severe or life threatening toxicity

OnDose (target range AUC of 20-24mg.hr/L)

To optimize dosing of 5-FU To reduce 5-FU toxicity Do test at any time after 2 hr of C. I.

5FU

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Pyrimidine analogs Uses

Colorectal cancer Stomach Esophageal ca Head/Neck Breast cancer Skin cancer Leukemias

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Substituted urea

Hydroxyurea Inhibits DNA synthesis in S phase

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Substituted ureaToxicity

Bone marrow depression mild nausea and vomiting

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Substituted ureaUses

CML Essential thrombocytosis Polycythemia vera Acute leukemia Head/Neck cancer

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Natural productsNatural products(From plants, fungi, and (From plants, fungi, and

bacteria)bacteria)

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Antitumor antibiotics and Anthracyclines

Bleomycin Dactinomycin Mitomycin Doxorubicin Daunorubicin liposomal daunorubicin (Doxil) Mitoxantrone

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Antitumor antibiotics and Anthracyclines

Antitumor antibiotics: Bleomycin intercalates DNA at guanine-cytosine

and guanine-thymine sequences, resulting in spontaneous oxidation and formation of free oxygen radicals that cause strand breakage.

Anthracyclines: The anthracycline antibiotics are products of

the fungus Streptomyces percetus var caesius. The anthracyclines have several modes of

action. Most notable are intercalation between DNA base

pairs and inhibition of DNA– topoisomerases I and II. Oxygen free radical formation from reduced

doxorubicin intermediates is thought to be a mechanism associated with cardiotoxicity.

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Antitumor antibiotics and Anthracyclines

Toxicities vesication (local tissue necrosis) nausea and vomiting diarrhea, stomatitis cardiotoxicity (anthracyclines) Pneumonitis (bleomycin) pulmonary fibrosis (bleomycin) anaphylaxis (bleomycin) hyperpigmentation alopecia bone marrow depression red urine (doxo) blue urine and sclera (mitoxantrone) hand-foot syndrome (Doxil)

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Anthracycline: Cardiotoxicity

Heart less able to detoxify free radical low catalase in heart high iron in heart anthracycline inactivate glutathione

peroxidase

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Anthracycline: Cardiotoxicity

Cumulative doses: Doxorubicin

Toxic > 550mg/m 450-500mg/m = 1-10% CHF risk safe dose <360mg

Daunorubicin 700mg/m

idarubicin 180mg/m

mitoxantrone 120mg/m

Epirubicin 900mg/m (zinocard) safe dose <720mg

Doxil 500-550 mg/m = 11% CHF

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Antitumor antibiotics and Anthracyclines: Uses

Breast Ovarian cancer Testicular cancer Hodgkin’s AML, ALL, NHL Gestational trophoblastic Tumors Ewing’s sarcoma SCLC Kaposi’s sarcoma

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Epipodophyllotoxins

Etoposide (VP-16)

Teniposide

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Epipodophyllotoxins

Etoposide is a semisynthetic epipodophyllotoxin extracted from the root of Podophyllum peltatum (mandrake).

M-phase specific It inhibits topoisomerase II activity by

stabilizing the DNA–topoisomerase II complex This process ultimately results in the

inability to synthesize DNA, and the cell cycle is stopped in the G1 phase.

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EpipodophyllotoxinsToxicities

Bone marrow depression MDS, Leukemia Nausea and vomiting Diarrhea Alopecia Skin rash

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EpipodophyllotoxinsUses

Testicular SCLC NSCLC HD, NHL, AML GTT

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Microtubule agents

Taxanes:Docetaxel (taxotere)Paclitaxel (taxol) Nanoparticle Albumin-bound Cabazitaxel (Jevtana)

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Taxanes

Semisynthetic derivatives of extracted precursors from the needles of yew tree. Unlike the vinca alkaloids, which cause

microtubular disassembly, the taxanes promote microtubular assembly and stability

M-phase specific: therefore blocking the cell cycle in mitosis.

Docetaxel is more potent than paclitaxel in enhancing microtubular assembly and also induces apoptosis

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Microtubule agentsToxicities

Bone marrow depression Fluid retention Hypersensitivity Peripheral neuropathy,

Paresthesias Skin changes Nails changes Alopecia Myalgias

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Microtubule agentsUses

Breast (ixempra, Halaven) NSCL Prostate Ovarian head and neck Esophagus Stomach Cervical Kaposi’s sarcoma Uterine bladder

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Vinca alkaloids

Vinblastine Vincristine Vinorelbine

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Vinca alkaloids

Derived from the periwinkle plant Vinca rosea. bind rapidly to the tubulin. M-phase specific The binding occurs in the S phase

polymerization of microtubules is blocked, resulting in impaired mitotic spindle formation in the M phase.

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Vinca alkaloidsToxicities

Bone marrow depression nausea and vomiting ileus Peripheral neuropathy Alopecia Stomatitis myalgias hepatic insufficiency

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Vinca alkaloidsUses

ALL, NHL (Vincristine) HD (Vinblastine) NSCLC (Vinorebine) Gestational trophoblastic tumors Testicular Breast mycosis fungoides Kaposi’s sarcoma bladder and renal cancers

New Microtubule agents

Eribulin (Halaven)Eribulin (Halaven) Ixabepilone (Ixemra)Ixabepilone (Ixemra)

UsesUses Breast cancerBreast cancer

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Camptothecin analogs

Irinotecan (camptosar, CPT-11) Topotecan (Hycamtin) semisynthetic analogs of the

alkaloid camptothecin, derived from the Chinese ornamental tree Camptotheca acuminata inhibit topoisomerase I and

interrupt the elongation phase of DNA replication

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Camptothecin analogs

Diarrhea nausea and vomiting anorexia, weight loss Bone marrow depression Irintecan: Severe toxicities in pt

with UGT1A1 gene mutation

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Camptothecin analogsUses

Colorectal cancer (CPT-11) SCLC (CPT-11, Topo) Ovarian (Topo)

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Enzymes

Asparaginase

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EnzymesToxicities

Allergic reactions (fever, chills, anaphylaxis)

Skin rash Nausea vomiting, anorexia Liver dysfunction CNS depression Coagulopathy

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EnzymesUses

ALL AML

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Targeted Therapies

Targeted Therapies

1. Monoclonal antibodies (MAbs)

2. Small-molecules

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Monoclonal antibodies (MAbs)

Uses begin in late 1990s The number of new agents in this

class is growing exponentially

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Monoclonal antibodies (MAbs)

Rituximab (Rituxan), anti-CD20 (approved in 1997) Trastuzumab (Herceptin), anti-Her2-neu Alemtuzumab (Campath), anti-CD52 Bevacizumab (Avastin) (anti-VEGF) (approved in

2004) Cetuximab (Erbitux) (anti-EGFR) (approved in

2004) Down regulation of EGFR pathway Reverse tumor response to chemo (CPT-11)

Vectibix (humanized anti-EGFR) (approved in 2006)

Lapatinib (Tykerb) Her2 neu and EGFR inhibitor ONTAK (Denileukin, Diftitox) Diphtheria toxin

domains bound to human IL-2 MYLOTARG (gemtuzumab) anti-CD33 Ipilimumab (Yervoy), blocks CTLA-4

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Monoclonal antibodies (MAbs)Indictaions: CLL (Rituxan, Campath) B-NHL (Rituxan) T-cell NHL (Ontak) Breast cancer (Herceptin, Tykerb) Colorectal (Avastin, Erbitux, Vectibix) Head/Neck (Erbitux) NSCLC (Avastin) GBM (Avastin) Melanoma (Yervoy)

Bevacizumab (Avastin) (anti-VEGF) 68

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Monoclonal antibodies (MAbs)A.E. Infusion reactions Allergy/Anaphylaxis Acneform skin rash/pruritus tumor lysis syndrome opportunistic infections (campath) GI perforations (avastin) wound-healing complications (avastin) hypertension/hypertensive crisis (avastin) Proteinurea (Avastin) Cardiotoxicity (Herceptin, Tykerb) Severe immune-mediated reaction (Yervoy)

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Small-molecules Imatinib mesylate (Gleevec), TK inhibitor Dasatinib (SPRYCEL), TK inhibitor Dasatinib (SPRYCEL), TK inhibitor

(300-1000 potent than imatinib)(300-1000 potent than imatinib)

Nilotinib, Tasigna, TK inhibitor Nilotinib, Tasigna, TK inhibitor 20-50 potent than imatinib20-50 potent than imatinib not effective in T3151 mutantnot effective in T3151 mutant

Gefitinib (Iressa, EGFR inhibitor) Erlotinib (Tarceva, EGFR inhibitor) Bortezomib (Velcade, proteasome inhibitor) Sunitinib (sutent, multi-VEGFR, KIT) Sorafenib (Nexifar, multi-VEGFR, KIT) Temsirolimus (Torisel, mTOR inhibitor Everolimus (AFINITOR), mTOR inhibitorEverolimus (AFINITOR), mTOR inhibitor Pazopanib (Votrient), multikinase inhibitorPazopanib (Votrient), multikinase inhibitor Crizotinib (Xalkori), TK inhibitorCrizotinib (Xalkori), TK inhibitor Vemurafenib (Zelboraf ), TK inhibitorVemurafenib (Zelboraf ), TK inhibitor

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Tyrosine Kinase InhibitorsUses

NSCLC (Iressa, Tarceva, Xalkori) CML (Gleevec) Ph +ve ALL (Gleevec) GIST (Gleevec) Multiple myeloma (Velcade) Zelboraf (Met Melanoma, BRAF v600E Zelboraf (Met Melanoma, BRAF v600E

+)+)

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Targeted therapiesToxicities

Edema and fluid retention (Gleevec) Myalgias (Gleevec) diarrhea Nausea and vomiting (Gleevec) Myelosuppression (Sutent, Sorafenib) Liver toxicity (Gleevec) Acne-form skin rash (EGFR inhibitors) Hand foot syndrome (Sutent) peripheral neuropathy (Velcade) thrombocytopenia (Velcade)

Autologous Autologous Cellular Cellular

ImmunotherapImmunotherapyy

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PROVENGEPROVENGE Sipuleucel-T (Provenge) is the first Sipuleucel-T (Provenge) is the first

FDA-approved autologous cellular FDA-approved autologous cellular immunotherapy for the treatment of immunotherapy for the treatment of asymptomatic or minimally asymptomatic or minimally symptomatic met HRPCsymptomatic met HRPC

Provenge induces immune response against Provenge induces immune response against PAPPAP

Provenge is produced by taking cells from a Provenge is produced by taking cells from a patient's tumor, and incorporating them into a patient's tumor, and incorporating them into a vaccine consisting of the patient's own blood vaccine consisting of the patient's own blood cells (cells (autologous, with , with dendritic cells thought thought to be the most important) and the Dendreon to be the most important) and the Dendreon PAP--GM-CSF fusion protein

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Endocrine therapyEndocrine therapy FemaleFemale

AntiestrogensAntiestrogens TamoxifenTamoxifen Fulvestrant (Faslodex)Fulvestrant (Faslodex)

A.Is.A.Is. Anastrozole (Arimidex)Anastrozole (Arimidex) Lotrozole (Femara)Lotrozole (Femara) Exemestine (Armasin)Exemestine (Armasin)

MegestrolMegestrol

MaleMale LHRHLHRH

Leupromide Leupromide Goserelin (Zoladex)Goserelin (Zoladex) Abiraterone (Zytiga), Abiraterone (Zytiga), inhibit androgen synthesis. Inhibits CYP17inhibit androgen synthesis. Inhibits CYP17 Degarelix (gonadotropin-releasing hormone receptor inhibitor)Degarelix (gonadotropin-releasing hormone receptor inhibitor)

AntiandroginesAntiandrogines Bicalutamide (Casodex)Bicalutamide (Casodex) NilutamideNilutamide FlutamideFlutamide FlutamideFlutamide 75

Principles of Chemotherapy

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Chemotherapy Ideal Timing

Neoadjuvant/preoperative Adjuvant/postoperative

When to start ? about 3-6 wks from date surgery

For how long ?????!!!!! (3 – 6 m) Palliative

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Dose Calculation

Dosage calculated according to BSA (most of chemo drugs)

According to the weight (Avastin) AUC (Carboplatin)

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Principles of Combination Chemotherapy

Known active single agents should be selected

Drugs with different mechanisms of action and with additive or synergistic cytotoxic effects

Drugs with different dose-limiting toxicities Drugs should be used at their optimal dose

and schedule Drugs should be given at consistent

intervals Treatment-free period should be as short as

possible to allow for recovery for the most sensitive normal tissues

Drugs with different patterns of resistance should be used to minimize cross-resistance

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Principles of Combination Chemotherapy

Advantage: Maximize cell kill while minimizing host

toxicities May increase the range of drug activity

against tumor cells with endogenous resistance to specific types of therapy

May prevent or slow the development of newly resistant tumor cells.

Disadvantage: Toxicities and complications Cost

ROUTEROUTEHow chemotherapy How chemotherapy

given?given?

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Chemotherapy Toxicities

Vesicant ChemotherapyVesicant Chemotherapy Antitumor AntibioticsAntitumor Antibiotics

doxorubicin, daunorubicin, mitomycin, doxorubicin, daunorubicin, mitomycin, idarubicin, epirubicin and actinomycinidarubicin, epirubicin and actinomycin

MechlorethamineMechlorethamine nitrogen mustardnitrogen mustard

Vinca AlkaloidsVinca Alkaloids vinblastine, vinorelbine and vincristinevinblastine, vinorelbine and vincristine

TaxanesTaxanes paclitaxel, docetaxel, and Abraxanenepaclitaxel, docetaxel, and Abraxanene

OthersOthers amsacrine, VP16, streptozocin, oxaliplatin ifex, amsacrine, VP16, streptozocin, oxaliplatin ifex,

cisplatin, dacarbazine, mitoxantrone carmustinecisplatin, dacarbazine, mitoxantrone carmustine

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Extravasations vesicant chemotherapy as medication that

can cause damage to cells and tissues if it leaks into subcutaneous tissue.

Vesicant drugs may continue to cause tissue death months after the extravasation occurs.

Treatment: Elevation of the arm Cold compresses Warm compresses (Vinca Alkaloids) Steroid inj (Antitumor Antibiotics)Antitumor Antibiotics) hyaluronidase local inj (Taxane, Vinca alkaloid)hyaluronidase local inj (Taxane, Vinca alkaloid) isotonic sodium thiosulfate local inj (Mechlorethamine)isotonic sodium thiosulfate local inj (Mechlorethamine) Dexrazoxane/Totecd (anthracycline)Dexrazoxane/Totecd (anthracycline)

IV diff sites within 6hr of extravasationIV diff sites within 6hr of extravasation, , repeat in 24 repeat in 24 and 48hrand 48hr

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Neuotoxicity vinka alkaloid

Constipation = 50% reduct. Paresthesia=DC

Cisplatin Ototoxicity

Oxaliplatin Avoid cold Calcium + Mg supliment

Cytarabine Neuro check

Taxol Neuropathy = 20% reduct. Glutamine 10gm tidx4d, 24hr after taxol

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Chemotherapy Dose-Adjustment

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Renal Dysfunction Cisplatin

Cr Cl 30-60=50% <30=omit

VP-16 CrCl >50=ok 10-50=25% <10=50%

Cytoxan CrCl >50=ok 10-50=25% <10=50%

MTX (cr1.5-2=50%,cr >2=hold) CrCl>60=ok 30-60=50% <30=omit

Bleomycin CrCl>60=ok 10-60=25%red , <10=50%

Topotecan CrCl > 60=ok 10-60=50% <10=omit

Carboplatin Ifex Carmustine Fludarabine Hydroxurea Streptozocin Cladrabine Thiotepa 6-MP IL-2 Mitomycin-C Procarbazine L-asparaginase

CrCl<60=omit Ara-C Daunorubicin

Cr >3=50%

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Hepatic Dysfunction Adria/Doxil

bil 1.5-3=50% bil 3.1-5= 75% red bil>5=omit

Daunorubicin/Idarubicin bil 1.5-3=25% 3-5=50% >5 =omit

Mitoxantrone bil>3=25%red

Taxotere: Bil>ULN or AST/ALT>1.5ULN+

ALP>2.5ULN=omit

Taxol Bil 1.5-3,AST60-180: No formal

recommondation bil>5,AST>180=omit

Vincr/Vinbl bil<1.5,AST<60=No red bil1.5-3,AST60-180=50% bil>3,AST>180=omit

CPT-11 Cytoxan Dactinomycin VP-16

bil1.5-3,AST60-180=50% bil>3,AST>180=omit

Casodex/Flutamide bil>3=reduction

5-FU bil>5=omit

MTX bil3-5=25%,AST>180red bil>5=omit

Vinorelbine bil<2=No red bil2-3=50% bil3-5=75%red bil>5=omit

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Miscellaneous

Cardiac Adria >300mg/m2

Zinocard: Adria = 10:1 Mucositis

MTX, 5-FU, Adria = 50% reduction Bleomycin

450mg --> 3-5% pneumonitis/fibrosis

PFT/c-xray; prior to each cycle hold for >10% drop in DLco/VC