THERAPEUTIC MODALITIESTHERAPEUTIC MODALITIES

LOCAL TREATMENTSSURGERYRADIATION THERAPY

SYSTEMIC TREATMENTSCHEMOTHERAPYBIOLOGIC THERAPY

DRUG SELECTIONDRUG SELECTION

• SINGLE DRUG

• COMBINATION THERAPY

• ADJUVANT CHEMOTHERAPY

OUTLINEOUTLINE

I. The Cell Cycle

II. Categories of Drugs

III. Biologic Characteristics of Cancer Cells

IV. Mechanisms of Drug Resistance

V. Clinical Uses of Cytotoxic Agents

VI. Timing and Response to Chemotherapy

VII.Chemotherapeutic Agents

CELL CYCLECELL CYCLE

PHASESSTATE PHASE DESCRIPTION

Quiescent/ senescent

Gap 0 (G0) Resting phase; the cell left the cycle;Stopped dividing.

Interphase Gap 1 (G1) Cells increase in size G1 checkpoint control mechanism ensures everything ready for DNA synthesis.

Synthesis (S) DNA replication occurs.

Gap 2 (G2) The cell continues to grow. G2 checkpoint control mechanism ensures everything ready to enter the M phase and divide.

Cell Division Mitosis (M) Cell growth stops,cellular energy focused on the orderly division into two daughter cells. Metaphase Checkpoint ensures the cell ready to complete cell division.

Categories of Drugs

1. Phase nonspecific

a. Cycle-nonspecific drugs - nondividing cells (steroid hormones, antitumor antibiotics except bleomycin).

b. Cycle-specific, phase-nonspecific drugs – effective if cells proceed through the cycle

can inflict injury at any point in the cycle (alkylating agents).

Phase Nonspecific Drugs Pharmacokinetics

• Linear dose–response curve: the greater the amount of drug administered, the greater the fraction of cells killed.

Log-cell number(response)

dose

Categories of Drugs

2.Phase specific

Cycle-specific, phase-specific drugs are effective only if present during a particular phase of the cell cycle.

Cell Cycle & Phase Specific Drugs

G0 phase: glucocorticoids for mature lymphocytes

G1 phase: L-Asparaginase

S phase: procarbazine and antimetabolites

G2 phase: bleomycin and plant alkaloids

M phase: plant alkaloids

Phase Specific Drugs Pharmacokinetics

• Phase-specific drugs reach a limit in cell-killing ability, but its effect is a function of both time and concentration. (maintaining a drug conc’n over a period of time, more cells enter specific lethal phase of the cycle and killed.

Log-cell number

dosage

Biologic Characteristics of Cancer Cells and Possible use of Chemotherapy

Biologic characteristics of cancer cells can be exploited to make them susceptible to drugs.

Although malignant cellular proliferation occur in absence of normal growth controls, cancer cells depend on same mechanisms for cell division found in normal cells.

Damage to those mechanisms leads to cell death in both normal and malignant tissues.

 

Biologic Characteristics of Cancer Cells and Possible use of Chemotherapy• Exploitation of apoptosis in cancer (Radiation

and most cytotoxic agents kill cancer cells by damaging cell and inducing apoptosis.)

• Exploitation of proliferation control factors in cancer. (Biologic response modifiers stimulate selected immune cells, which then demonstrate anticancer activity [interferons, ILs, and GFs.]

• Exploitation of maturation abnormalities. Maturation factors (Transretinoic acid, Vit. D,

Cytosine arabinoside)/ Eradication of stem cells leaving behind a pop’n of maturing cells.

Biologic Characteristics of Cancer Cells and Possible use of Chemotherapy• Angiogenesis inhibition: exploitation of

dependence of cancer cells to induce the formation of their own blood supply to proliferate. Angiogenesis inhibition is being actively pursued as a tool for cancer treatment.

Mechanisms of drug resistance• Tumor cell heterogeneity

• Spontaneous genetic mutations/ drug-resistant

• Goldie-Coldman hypothesis indicates that probability of a tumor population containing resistant cells is a fxn of total # of cells present.

•  Single-drug resistance (Catabolic enzymes, transport proteins. 

• Multidrug resistance. (P-170 and the mdr-1 gene, loss of apoptosis)

Indications for use of Chemotherapy• To cure certain malignancies • To palliate symptoms in pxs with disseminated

cancer when potential benefits of treatment exceed side effects

• To treat asymptomatic pxs in ff circumstances:

a. When cancer is aggressive and treatable (e.g., acute leukemia, small cell lung cancer)

b. When treatment proven to decrease rate of relapse and increase disease-free interval or increase absolute survival (colon CA, stages I or II breast CA, Osteogenic sarcoma)

 

Contraindications for use of Chemotherapy1. Inadequate facilities to evaluate px’s response

to therapy & to monitor & manage toxic rxns

2. When px not likely to survive longer even if tumor shrinkage could be accomplished

3. When the px not likely to survive long enough to obtain benefits (severely debilitated patients)

4. When patient is asymptomatic with slow-growing, incurable tumors, in which case chemotherapy should be postponed until symptoms require palliation

Timing of ChemotherapyA) Induction chemotherapy (initial therapy to

achieve significant cytoreduction (complete remission) of disease.

B)Consolidation/Intensification chemotherapy (postremission, same drugs used in induction (consolidation) or non-cross resistant drugs (intensification) are repeated. (to prolong remission and overall survival eg. in ALL, AML).

C)Adjuvant chemotherapy After local treatment (surgical or radiation), adjuvant used to prevent local or distant relapse.

Timing of ChemotherapyD) Neoadjuvant chemotherapy. Before local

therapy, neoadjuvant chemotherapy is given in hopes of reducing extent of local treatment or increasing its effectiveness.

E) Maintenance chemotherapy. Prolonged, low-dose outpatient chemotherapy intended to prolong duration of remission and achieve cure in patients in remission.

F) Salvage chemotherapy After failure of other treatments (surgery, radiation, or prior chemo), used to control disease or provide palliation.

 

Response to Chemotherapy• Induction Therapy:• Complete response (CR) - disappearance of dx on

imaging for at least 1 mo. eg in AML, CR defined as <5% blasts in BM, no circulating blasts in blood & no extramedullary dx by day 14 after induction.

• Partial response (PR) - decrease of 50% or more in sum of products of biperpendicular diameters; no new sites of dx at least 1 month.

• Stable disease in pxs with <50% response without actual progression of disease.

• Progression 25% inc in sum of products of biperpendicular diameters of known lesions or any new sites of disease.

Response to Chemotherapy• Adjuvant chemotherapy:

• Relapse-free survival measures time from start of tx to regrowth of tumor to detectable levels.

• Salvage chemotherapy:

• Progression-free survival remains major end point in patients with advanced disease and equivalent of relapse-free survival in adjuvant setting.

CANCER CHEMOTHERAPY DRUGCLASSSIFICATION

Classification of Chemotherapy Drugs

• CELL-CYCLE SPECIFIC DRUGS

• Antimetabolites• Mitotic Inhibitors (Vinca

Alkaloids, Epipodophyllotoxins, Taxanes)

• Camptothecins

• CELL-CYCLE NONSPECIFIC DRUGS

• Alkylating agents• Antitumor antibiotics• Hormones• Hormone Antagonists• Miscellaneous Agents

Cell Cycle-Specific Agents

• Administered in divided doses or as a continuous infusion which facilitates lysis of cells in certain phases of the cycle.

• Reduce growth fraction (# of cells present in the cycle) of the tumor.

Antimetabolites• Structural analogues of normal molecules

essential for cell growth and replication.

• inhibit enzymes necessary for synthesis.

• major effect - interfering with building blocks of DNA synthesis

• activity greatest in S phase of cell cycle

• most effective when cell proliferation is rapid.

• Nonlinear dose-response curve (except FU).  • eg (Capecitabine, 5-FU, Cytosine arabinoside,

Gemcitabine, Deoxycoformycin, 6-Mercaptopurine, Floxuridine, Methotrexate, Fludarabine, Thioguanine

Methotrexate (amethopterin, MTX)I: A wide variety of conditions

MOA: Folic acid antimetabolite.

• blocks dihydrofolate reductase, preventing formation of

reduced tetrahydrofolic acid; block formation of thymidylate

from deoxyuridylate & prevents synthesis of DNA;

• also inhibits RNA and protein synthesis

• prevents cells from entering S phase.

Metab: min metabolized; excreted in urine unchanged (90%)

Toxicity (reversed with Leucovorin 1:1)

• Dose limiting. Myelosuppression, stomatitis, renal dysfxn

• High-dose regimens. N/V, RT necrosis, cortical blindness

Dose: 2.5-mg tablets and 20 to 1000-mg vials.

Modification. must not be given to px w/ CrCl <60mL/min

Mercaptopurine (6-MP, Purinethol) I: ALL (maintenance therapy)

MOA: Purine antimetabolite.

• Undergoes extensive metabolic changes; complex

• Inhibits de novo purine synthesis, purine interconversion

• Competes with ribotides for enzymes responsible for conversion of inosinic acid to adenine and xanthine ribotides.

Metab: slowly degraded in liver, largely by xanthine oxidase.

Toxicity

• Dose limiting. Myelosuppression

• Common. N/V, anorexia (25%); reversible cholestasis

Dose: Supplied as 50-mg tablets, 70 to 100mg/m2

Modification. Reduced by 50-75% for pxs w/ hepatic dysfxn.

Fluorouracil (5-FU, Adrucil) I: A wide variety of carcinomas

MOA: Pyrimidine Antimetabolite

• Interferes with DNA synthesis by blocking thymidylate

synthetase, (conversion of deoxyuridylic acid to thymidylic a)

• Incorporated into several RNA species, interfere with RNA fxn and protein synthesis.

• S-phase specific but acts in other cell cycle phases

• Unique in having a log linear cell-killing action.

Metab: hepatic; 90% excreted in urine, bile & breath (CO2).

Toxicity: Dose limiting Myelosuppression, mucositis/diarrhea

• Common: Nasal discharge; eye irritation and lacrimation

Dose: 500-mg vials

Modification: w/held if px has diarrhea, infection, leukopenia,

Leucovorin (citrovorum factor, folinic acid, 5-formyl tetra-hydrofolate)

I: Combined w/ 5-FU in tx of colorectal & other adenoCAs; rescue agent for antifol toxicity (MTX)

MOA: a tetrahydrofolic acid derivative that acts as a cofactor

for carbon transfer rxns in synthesis of purines & pyrimidines

• Inhibits effects of MTX & other DHFR antagonists.

Metabolism. Excreted in the urine as metabolites

Toxicity. Potentiates toxic effects of fluoropyrimidine therapy

Dose: 50-, 100-, and 350-mg vials for IV use and as a 60-mg bottle for oral use

Mitotic Inhibitors

• Mitotic inhibitors interfere with formation of mitotic spindle, causing metaphase arrest.

• M-phase active, but they may also have activity in G2 and S.

• Include the vinca alkaloids, the epipodophyllo-toxins, and the taxanes.

Vinca Alkaloids• A.k.a plant alkaloids - extracts of periwinkle

plant.

• bind to microtubular proteins, essential in forming mitotic spindle of the dividing cells. This binding arrests mitosis, which eventually causes cell death.

• act mainly in M phase; however, high doses can also disrupt RNA and protein synthesis.

• Vinblastine, Vincristine, Vindesine, Vinorelbine

Vinblastine (Velban) I: Lymphomas, testicular carcinoma

MOA: Binds to microtubular proteins. • Inhibits RNA synthesis by affecting DNA-dependent

RNA polymerases. • Cell cycle–phase specific; • arrests cells at the G2-phase and M-phase interface.

Metab: mainly hepatic, minimal renal

Toxicity: Dose-limiting Neutropenia • Common Cramps or severe jaw, back pain

Dose: 10-mg vials

Dose modification. Decrease dose by 50% for patients with serum bilirubin greater than 3.0 mg/dL.

Vincristine (Oncovin/Vincasar/leurocristine) I: A wide variety of malignancies

MOA: Same as vinblastine

Metabolism. Same as vinblastine

Toxicity Dose-limiting. Severe paresthesias, ataxia, Foot

drop (slapping gait), muscle wasting, cranial nerve palsies,

paralytic ileus, obstipation, abdominal pain, cortical

blindness, seizures

• Common. Tissue necrosis, alopecia (20% to 40%)

Dose: 1 mg/mL vials

Modification. Hepatic dysfunction; same as for vinblastine

Epipodophyllotoxins

• isolated from the mandrake plant (May crab apple).

• act in the premitotic phase, G2 and S, and interfere with topoisomerase II enzyme reaction.

• Inhibition of topoisomerase interferes with transcription and replication by causing DNA damage, inhibition of DNA replication, failure to repair strand breaks, and then, cell death.

•  Etoposide, Teniposide

Etoposide (VP-16, VePesid)I: Testicular CA, Lung CA, lymphoma, & other malignancies

MOA: An epipodophyllotoxin;

• a topoisomerase II inhibitor

• cell cycle–phase specific at G2, late S, and M phases.

Metab: Highly bound to plasma proteins; metabolized by the

liver. Excreted in urine (40%) intact & degraded drug;

excretion of remaining 60% is uncertain.

Toxicity Dose-limiting: Neutropenia

• Common. N/V (w/ oral dosing); mild alopecia ; hypotension if rapidly infused

Dose: 50 mg/m2 PO daily for 21 days/ 50 to 120 mg/m2 IV daily for 3 to 5 days

DI. CCBs, methotrexate may increase cytotoxicity 

Taxanes

• Taxanes cause mitotic arrest by forming abnormal spindle fibers and mitotic asters.

• Taxanes not only bind to microtubules but also promote microtubule assembly and resistance to depolymerization, resulting in production of nonfunctional microtubules.

• Docetaxel, Paclitaxel

Paclitaxel (Taxol) I: Breast, ovarian CA, AIDS-assoc Kaposi’s sarcoma, others

MOA: Taxane; bind to microtubules and promote

microtubule assembly & resistance to depolymerization,

resulting in production of nonfunctional microtubules. Metab: Nearly totally protein bound & distributed well to

body fluids (effusions) w/ a plasma half-life of about 5 hours

Toxicity Dose-limiting: Neutropenia, prev. treated w/ cisplatin

• Hypersensitivity, Peripheral neuropathy.

Common: Alopecia, thrombocytopenia; transient arthralgias

& myalgias w/in 3 days of tx (ameliorated by NSAIDs), brady

Dose: 30-, 100-, and 300-mg vials/ 135 to 175mg/m2

Dose modification. Hematologic

Camptothecins• Name derived from the Chinese tree

Camptotheca acuminata

• new subcategory of cell cycle–specific drugs.

• act in S phase and inhibit topoisomerase I, a nuclear enzyme necessary for maintaining DNA structure, resulting in single-stranded DNA breaks and subsequently cell death.

• Irinotecan, Topotecan

Irinotecan (Camptosar, CPT-11)

I: Colorectal CA refractory to 5-FU–based chemotherapy

MOA: water-soluble analogue of camptothecin, relatively inactive prodrug, converted to active agent

• Inhibits topoisomerase I

• cell cycle– phase specific.

Metab. Metabolized in liver. Renal clearance.

Toxicity Dose-limiting. Profuse diarrhea

• Common. Neutropenia; mild N/V, abdominal cramps; flushing during administration; alopecia

Dose: 100-mg vials/ 125mg/m2

Dose modification. Use with caution for hepatic insufficiency.

Cycle-Nonspecific Drugs• Effective through all phases of cell cycle

• Directly affect DNA molecule and display no specificity for cells that are dividing.

• More toxic than cycle–specific drugs (does not differentiate between normal & malignant cells.

• Given in bolus doses because they cause death independently of the proliferative state of cell.

• Reduce the number of cells that make up a tumor, which is known as the tumor burden.

Alkylating Agents• target DNA, cytotoxic, mutagenic & carcinogenic. All

produce alkylation through the formation of intermediates.

• Impair cell fxn by transferring alkyl groups to amino,

carboxyl, sulfhydryl, or phosphate groups of important mol.

• nucleic acids & proteins alkylated. (N-7) position of

guanine in DNA & RNA - most actively alkylated site; O-6

grp of guanine alkylated by nitrosoureas.

• Alkylation of guanine results in abnormal nucleotide

sequences, miscoding of messenger RNA, cross-linked

DNA strands that cannot replicate, breakage of strands, and

other damage to transcription & translation of genetic mat’l.

• Primary mode of action: cross-linking of DNA strands.

Alkylating AgentsMustard gas derivatives:  Mechlorethamine,

Cyclophosphamide, Chlorambucil, Melphalan,& Ifosfamide.

Ethylenimines:  Thiotepa & Hexamethylmelamine.

Alkylsulfonates:  Busulfan.

Hydrazines and Triazines: Altretamine, Procarbazine,

Dacarbazine and Temozolomide.

Nitrosureas:  Carmustine, Lomustine and Streptozocin

(unique, can cross BBB).

Metal salts:  Carboplatin, Cisplatin, and Oxaliplatin.

Cyclophosphamide (Cytoxan)I: Used in a wide variety of conditions

MOA: Alkylation, also inhibits DNA synthesis

Metab: requires activation by liver microsomal oxidase

system to form an aldehyde that decomposes in plasma and

peripheral tissues to yield acrolein & an alkylating metabolite

(phosphoramide mustard); excreted in urine.

Toxicity: Dose limiting: Myelosuppression, hemorrhagic

Cystitis

• Common. Alopecia, stomatitis, aspermia, amenorrhea; headache (fast onset, short duration), N/V.

Dose: 25 or 50mg tabs; vials contain 100 to 1000 mg

Dose modification. Hematologic; may be required for hepatic functional impairment

Busulfan (Myleran)I: CML, bone marrow transplantation (high doses)

MOA: Alkylation

Metabolism: Acts directly; catabolized to inactive products excreted in the urine.

Toxicity Dose limiting. Reversible and irreversible myelosuppression with slow recovery; blood cell counts fall for about 2 weeks after discontinuation of drug.

• Common. GI upset (mild), sterility

Dose: 2-mg tablets/ 2-8mg/day PO

Dose modification. Hematologic

Procarbazine (Matulane, Natulan, N-methylhydrazine)I: Hodgkin & Non-Hodgkin Lymphoma, Myeloma, Brain Ca

MOA: DNA alkylation and depolymerization; Methylation of

nucleic acids; Inhibition of DNA, RNA, and protein synthesis

Metab: Metabolic activation required. Readily enters CSF. Degraded in liver to inactive cmpds, excreted in urine

Toxicity: Dose limiting. Myelosuppression, which may not begin until several weeks after starting treatment

• Common. N/V, which decreases w/ continued use; myalgia, arthralgia; sensitizes tissues to radiation

Dose: 50-mg capsules

Modification Reduce dose in pxs w/ hepatic, renal, or bone marrow dysfunction.

Streptozocin (streptozotocin, Zanosar)I: Islet cell CA (w/ FU), carcinoid syndrome

MOA: Alkylation; Inhibits DNA synthesis & DNA repair

enzyme, guanine-O6-methyl transferase; affects pyrimidine

nucleotide metab, inhibits enzymes in gluconeogenesis

Metab: extensively metabolized, a short plasma half-life;

Crosses BBB; Excreted in urine.

Toxicity Dose limiting: Nephrotoxicity

• Common: N/V, myelosuppression, hypoglycemia, vein irritation

Dose: 1-g vials/ 1.0 g/m2 IV weekly, or 0.5 g/m2 IV daily

Modification. Proteinuria or elevated serum creatinine levels  

Cisplatin (cis-diaminedichloroplatinum [CDDP], Platinol)

I: A wide variety of malignancies

MOA: heavy metal alkylator of DNA; Covalently bonds to

proteins, RNA, & esp DNA, forming DNA cross-linking &

intrastrand N-7 adducts.

Metab: Widely distributed in body, except for CNS. Long

half-life in plasma (3 days); drug (30%) & metabolites

excreted in urine; biliary excretion <10%

Toxicity Dose limiting: Cumulative renal insufficiency/ Peripheral sensory neuropathy, Ototoxicity with tinnitus

• Common: Severe N/V, hypokalemia, hypomagnesemia & mild myelosuppressiona.

Dose: 10- and 50-mg vials/ 40 to 120mg

Mod: Renal fxn must return to normal before cisplatin given

Antitumor Antibiotics• Isolated from fermented broths ofStreptomyces • Focal point of cytotoxicity is the DNA. • Interfere w/ DNA-directed RNA synthesis by

intercalating between base pairs of DNA and

generating toxic oxygen-free radicals, causing

single- or double-stranded DNA breaks. • cycle–nonspecific, useful in slow-growing

tumors with low growth fractions. • Anthracyclines:  Doxorubicin, Daunorubicin, Epirubicin,

Mitoxantrone, and Idarubicin.

• Chromomycins:  Dactinomycin and Plicamycin.

• Miscellaneous:  Mitomycin and Bleomycin.

Actinomycin D (dactinomycin, Cosmegen)I: Trophoblastic neoplasms, sarcomas, testicular CA, Wilms’

MOA: Intercalates between DNA base pairs & prevents

synthesis of mRNA; inhibits topoisomerase II

Metab: Unknown; extensively bound to tissues, resulting in

long half-life in plasma & tissue, Excreted in bile and urine

Toxicity Dose limiting. Myelosuppression

• Common. N/V (worsening after successive daily doses);

alopecia, acne, erythema, desquamation,hyperpigmentation;

radiation-recall rxn; a vesicant that causes necrosis

Dose: 0.5-mg vials/ 0.25 to 0.60 mg/m2 IV daily for 5 days

Modification. Reduce by 50% in of renal or hepatic dysfxn.

Bleomycin (Blenoxane)I: Lymphoma, SCC, testicular Ca, malignant effusions others

MOA: Binds to DNA, inhibiting synthesis of DNA, RNA and

Proteins; Causes DNA strand cleavage by free radicals and

inhibits DNA repair by marked inhibition of DNA ligase.

G2-phase specific; also active in late G1, S, and M phases

Metab: tissue-bound, extensive degradation by hydrolysis in

nearly all tissues. Drug & metab products excreted in urine.

Toxicity Dose-limiting: Mild -severe shaking chills & febrile rxns, Bleomycin pneumonitis w/ dyspnea, dry cough

• Common Sensitizes tumor & tissues to radiation, anorexia hyperpigmentation of skin stretch areas, mucositisa.

Dose: 15-unit (mg) vials

Modification. COPD, erythroderma

Doxorubicin (Adriamycin/Rubex/hydroxydaunorubicin)

I: Effective in a large variety of tumors

MOA: Anthracycline; Intercalates b/w DNA base pairs, forms

free radicals, alters cell membranes, induces topoisomerase

II–dependent DNA damage, inhibits preribosomal DNA and

RNA. Cycle–phase nonspecific.

Metab: 70% bound to plasma proteins; metabolized by liver excreted in the bile

Toxicity Dose-limiting: Myelosuppression, Cardiomyopathy

• Common: Alopecia, N/V; stomatitis, ulceration & necrosis.

Dose: 10, 20, 50, 100 & 150mg vials/ 50-75 mg/m2 IV bolus

Modification. congestive heart failure,

Hormones & Hormone Antagonists• diverse group of drugs beneficial in cancer therapy.

• Some alter cellular environment & affect permeability of

cell membrane that will affect cell growth.

• inhibit tumor proliferation by blocking/ antagonizing

naturally occurring substance that stimulates tumor growth.Androgens: testosterone proprionate, methyltestosterone,

fluoxymesterone

Antiandrogens: flutamide

Antiestrogens: tamoxifen

Aromatase inhibitors: aminoglutethimide

Estrogens: diethylstilbestrol, estradiol

Glucocorticoids: prednisone, hydrocortisone, dexamethasone

Gonadotropin inhibitors: leuprolide, goserelin

Progestins: megestrol acetate

Hormones & Hormone AntagonistsAndrogens

I: Breast Ca, short-range anabolic, erythropoiesis stimulant

Toxicity & SE vary; Virilization, fluid retention & hepatotoxic, characterized by abnormal LFTs or cholestasis reversible,

Antiandrogens (bicalutamide, flutamide, nilutamide)

I: Prostate Ca in combination with medical therapy

MOA: Nonsteroidal antiandrogens bind to cytosol androgen

receptors & competitively inhibit uptake or binding

Toxicity Common Impotence, gynecomastia, hypogonadism

Antiestrogens (tamoxifen, toremifene)

I: Breast carcinoma

MOA: Nonsteroidal agents that bind to estrogen receptors,

exert antiestrogenic, estrogenic, or both activities • 3

MiscellaneousMiscellaneous

• BIOLOGICAL RESPONSE MODIFIERS– Interferon-alfa, Interleukin-2

• TYROSINE KINASE INHIBITORS– Imatinib (Glivec): CML

• MONOCLONAL ANTIBODIES– Versus GROWTH FACTOR RECEPTORS

• Rituximab (NHL,CLL), Trastuzumab (metastatic breast CA)

– Versus ANGIOGENIC FACTORS• Bevacizumab (coloretal CA, renal cell CA)

Interferon-a (IFN-a)Sources: Lymphocytes, macrophages, and other cells

Properties: Antitumor activity, Antiproliferative activity,

Inhibition of angiogenesis, Reg’n of differentiation,Interaction

w/ growth factors, oncogenes, other cytokine, enhancement

of tumor-associated antigens; NK cell activation, CTL

activation, induction of (MHC) class I, Antiviral activity

I: CML, hairy cell leukemia, myeloproliferative disorders, cutaneous T-cell lymphomas

D: recombinant forms (IFN-a2a (Roferon-A): 3, 6, 18, & 36million U/mL vials/ IFN-a2b (Intron-A): 3, 5, 18, & 50million U/mL vials

Rituximab (Rituxan)I: Relapsed or refractory low-grade or follicular CD20-(+), B-

cell non-Hodgkin lymphoma

MOA: antibody is a genetically engineered chimeric murine/ human monoclonal antibody directed against CD20 antigen found on the surface of normal and malignant B lymphocytes. In vitro, Fab domain of rituximab binds to CD20 antigen on B lymphocytes, and Fc domain recruits immune effector functions to mediate B-cell lysis.

Metab: detectable in serum 3 to 6 months; admin results in a rapid and sustained depletion of circulating and tissue-based B cells. B-cell levels return to normal by 12 months after completion of treatment.

Toxicity: Dose-limiting. Hypersensitivity rxns, arrhythmias

Common: infusion-related symptom complex responds to slowing infusion rate and consists of fever or chills (50%);

SAMPLE REGIMENS

HODGKIN LYMPHOMAHODGKIN LYMPHOMA

ABVD: Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine

BEACOPP: Bleomycin, etoposide, Adriamycin (doxorubicin), cyclophosphamide, Oncovin (vincristine), procarbazine, prednisone

MOPP: Mechlorethamine, Oncovin (vincristine), procarbazine, prednisone

ChlVPP/EVA Chlorambucil,vincristine (Oncovin), procarbazine, prednisone, etoposide, vinblastine, Adriamycin (doxorubicin)

BREAST CABREAST CA

• AC: Adriamycin (doxorubicin), cyclophosphamide• CA: Cyclophosphamide, Adriamycin (doxorubicin)

(same as AC)• CAF: Cyclophosphamide, Adriamycin (doxorubicin

), fluorouracil (5-FU)• CMF: Cyclophosphamide, methotrexate,

fluorouracil (5-FU)• EC: Epirubicin, cyclophosphamide• FEC: Fluorouracil (5-FU), epirubicin,

cyclophosphamide

COLORECTAL CACOLORECTAL CA

• FOLFOX: Fluorouracil (5-FU), leucovorin (folinic acid), oxaliplatin

• FOLFIRI: Fluorouracil (5-FU), leucovorin (folinic acid), irinotecan

• FL: Fluorouracil (5-FU), leucovorin (folinic acid)

LUNG CANCERLUNG CANCER

• CAV: Cyclophosphamide, Adriamycin (doxorubicin), vincristine

THANK YOU!