PRINCIPLES OF CANCER

CHEMOTHERAPY

EGBEKUN I.E. (MB;BS Ib)TRAUMA AND SURGICAL CENTRE, ONDO, ONDO

NIGERIA. 01-04-2014

IntroductionHistorical perspectiveChemotherapeutic agentsCellular kineticsTumor kineticsAdministration of ChemotherapyDefinition of termsSide effects/toxicityAdvancement in cancer chemotherapy

INTRODUCTION

Cancer is an abnormal growth of cells caused by multiple changes in gene expression, leading to dysregulated balance of cell proliferation and cell death and ultimately evolving into a population of cells that can invade tissues and metastasize to distant sites, causing significant morbidity and, if untreated, death of the host.

Chemotherapy: the use of any drug to treat any disease, but in the context of cancer, chemotherapy refers to the use of drugs for cancer treatment.

Other modalities of cancer treatment include surgery, radiation, immunotherapy etc

History of Chemotherapy

History of ChemotherapyMustard gas was used as a chemical warfare agent during World War I and was studied further during World War II.

So, in the 1940s, several patients with advanced lymphomas were given the drug intravenously, rather than by inhalation the irritating gas.

History of Chemotherapy

Their improvement, although temporary, was remarkable. That experience led researchers to look for other substances that might have similar effects against cancer.

As a result, over a hundred antineoplastic drugs have been developed.

Tumorigenesis

Tumour characteristics

• Self sufficiency in growth signals

• Insensitivity to ant-growth signals

• Evading apoptosis• Limitless replicative

potential• Sustained

angiogenesis• Tissue invasion

and metastasis

Tumour markersProducts of the metabolic activity of tumours and are either tumour derived or tumour-associated although not necessarily tumour-specific.

May be secreted (into blood, urine or other body tluids) or expressed (at the cell surface) in quantities larger than those in normal tissue.

E.g. PSA, CEA, alpha fetoprotein, CA 15-3, HER2

Chemotherapeutic agents

Alkylating agentsMechanism of action

Base alkylation resulting in DNA cross-linking

Single strand breaks

Double strand breaks and strand misreading

Alkylating agentsClasses

Nitrogen mustards: chlorambucil,

cyclophosphamide

The platinum drugs (cisplatin, carboplatin

Nitrosoureas: streptozocin, carmustine

Alkyl sulfonates: busulfan

Triazines: dacarbazine , temozolomide

Ethylenimines: thiotepa, altretamine

Anti-tumor Antibiotics

AnthracyclinesOther Anti-tumor atibiotics

Anti-tumor AntibioticsAnthracyclines

Mechanism of actionAnthracyclines derived from the fungus Streptomyces percetus var caesius.

interfere with enzymes involved in DNA replication. Intercalate between strands of DNA double helix formation of drug free radicals inhibition of topoisomerase II

Examples: daunorubicin ,doxorubicin, epirubicin, mitoxantrone

Other Anti-tumor Antibiotics

Bleomycin: preferentially intercalates DNA at guanine-cytosine and guanine-thymine sequences

inducing single-strand and double-strand DNA breaks

Actinomycin-D: inhibits DNA-dependent RNA synthesis by intercalating DNA at guanine-cytosine base pairs

Antimetabolites

Purine analoguesPyrimidine analoguesAntifolatesSubstituted ureasAdenosine deaminase inhibitors

AntimetabolitesMechanisms of action

compete with normal metabolites for the catalytic or regulatory site of a key enzyme

substitute for a metabolite that is normally incorporated into DNA and RNA

nonlinear dose-response curve, such that after a certain dose, no more cells are killed despite increasing doses (fluorouracil [5-FU] is an exception).

AntimetabolitesClassesPyrimidine analogues

Uracil: 5-fluorouracil (5-fluoro-2’-deoxyuridine) Cytosine: Cytosine arabinoside; 5-azacytidine

Purine analogues Adenine: 6-mercaptopurine Guanine: 6-thioguanine

Adenosine deaminase inhibitor: Cladribine, Fludarabine

Folate analogues: Methothrexate

Substituted ureas:Hydroxyurea

Mitotic inhibitors

Vinca Alkaloids

Taxanes

Epothilones: ixabepilone

Estramustine

Vinca Alkaloids

Derived from the periwinkle plant Vinca rosea.

inhibit polymerization of tubulin resulting in impaired mitotic spindle formation in the M phase.

Examples: Vincristine, Vinblastine, Vinorelbine

Taxanes

semisynthetic derivatives of extracted precursors from the needles of yew plants.

promote microtubular assembly and stability, resulting in mitotic arrest

Examples: Docetaxel, Paclitaxel

Topoisomerase inhibitorsCamptotecins: inhibit topoisomerase I interrupting the elongation phase of DNA replication.

Examples: Irinotecan, topotecan

Podophylotoxins: Inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex;

Examples: Etoposide, Teniposide

CorticosteroidsMechanism of action: unclear –induce apoptosis of lymphoblasts and effective in lymphoid malignancies.

Examples: prednisone, dexamethasone

Miscellaneous chemotherapeutic agents

L-asparaginase: converts asparagine to aspartate and NH3. Normal cells can reverse this process to form asparagine.

Lymphoblasts lack asparagine synthetase and die without preformed asparagine in plasma. Drug has activity in acute lymphocytic leukemia.

Bortezomib: proteosome inhibitor

Other types of anticancer drugs

Other drugs and biological treatments are also used to treat cancer.

target different properties that set cancer cells apart from normal cells.

less serious side effects because they are targeted to work mainly on cancer cells, not normal, healthy cells.

Hormone therapysex hormones, or hormone-like drugs, that change

the action or production of female or male hormones.

They are used to slow the growth of breast, prostate, and endometrial (uterine) cancers, which normally grow in response to natural hormones in the body.

Prevent the cancer cell from using the hormone it needs to grow, or prevent the body from making the hormones.

Hormonal therapyExamples

The anti-estrogens: fulvestrant, tamoxifen, and toremifene

Aromatase inhibitors: anastrozole, exemestane, and letrozole

Progestins: megestrol acetateEstrogens: EstradiolAnti-androgens: bicalutamide, flutamide, and nilutamide

Gonadotropin-releasing hormone (GnRH), agonists or analogs: leuprolide and goserelin

Other types of anticancer drugs

Targeted therapies: more selective than traditional chemotherapy drugs.

Most attack cells with mutant versions of certain genes, or cells that express too many copies of a particular gene.

Examples of targeted therapies include imatinib (Gleevec®), gefitinib (Iressa®), sunitinib

Other types of anticancer drugs

Biologic response modifiers: (Immunotherapy) is a type of treatment that mobilizes the body's immune system to fight cancer.

ExamplesMonoclonal antibodies: rituximab, alentuzumabNonspecific immunotherapies/adjuvants: BCG, IL-2, Interferon-α

Immune modulating drugs: thalidomide

Cancer Vaccines: Provenge- for advanced prostate ca

Other types of anticancer drugsDifferentiating agents:These drugs act on the cancer cells to make them mature into normal cells.

Examples include the retinoids, tretinoin and bexarotene , as well as arsenic trioxide.

Cellular kinetics

Cellular kinetics

G1 phase: This phase lasts about 18 to 30 hours.

S phase: lasts about 18 to 20 hours.

G2 phase: This phase lasts from 2 to 10 hours

M phase (mitosis): lasts only 30 to 60 minutes, the cell actually splits into 2 new cells.

Cellular kineticsSome drugs specifically attack cells in a particular phase of the cell cycle (the M or S phases, for example).

Understanding how these drugs work helps oncologists predict which drugs are likely to work well together.

Cell cycle phase specific Primarily affect cells that are actively replicating

Cell cycle phase-non-specificMore toxicMore effective for slow-growing tumors

S PHASE DEPENDENT M PHASE DEPENDENT

Cell cycle phase specific drugs

Antimetabolites6-mercaptopurine5-fluorouracilMethothrexateHydroxyureaFludarabine

G1 PHASE DEPENDENT

L-Asparaginase

Vinca Alkaloids: Vincristin

Podophylotoxins: Etoposide

Taxanes: Docetaxel

G2 PHASE DEPENDENT

BleomycinCamptotecins: Irinotecan

Cell cycle phase non-specific drugs

Nitrogen mustards: cyclophosphamide

Nitrosoureas:streptozocin

Alkyl sulfonates: busulfan

Triazines:dacarbazine

Ethylenimines: thiotepa

Platinum drugs :cisplatin

Daunorubicin

Doxorubicin

Mitoxantrone

ALKYLATING AGENTS ANTHRACYCLINES

(ANTITUMOR ANTIBIOTICS)

Agents that are cell-cycle-phase–nonspecific have a linear dose-response curve; i.e the greater the dose of drug, the greater is the fraction of cell kill.

However, cell-cycle-phase–specific drugs have a plateau with respect to cell killing ability, and cell kill will not increase with further increases in drug dosage.

Goals of chemotherapy

Curative intent.

Control of tumor growth when cure is not possible;

Palliation- to relieve symptoms (such as pain)

Tumor Kinetics

Tumor KineticsThe rate of growth of a tumor is a reflection of the proportion of actively dividing cells (the growth fraction), the length of the cell cycle (doubling time), and the rate of cell loss.

Tumors characteristically exhibit a sigmoid-shaped Gompertzian growth curve, in which tumor doubling time varies with tumor size.

Tumors grow most rapidly at small tumor volumes. As tumors become larger, growth slows based on a complex process dependent on cell loss and tumor blood and oxygen supply

Principle of exponential cell-kill(log-kill hypothesis)It states that a given dose of chemotherapy, kills the same fraction of tumor cells, regardless of the size of the tumor at the time of the treatment.(first-order kinetics)

Example: 2 log cell kill 106 —104

104 —102

4 log cell kill 106 — 102

104 — 100

Methods of Cancer Chemotherapy use

Methods of Cancer Chemotherapy useSingle agent

ContinuousIntermittent

CombinationContinuousIntermittentSequential

Chemoradiation

Continuous single agent chemotherapyLow response rates. Complete remissions were infrequent. Kill small fractions of tumour cellPotentiates the development of drug resistance

Intermittent single agent chemotherapy, eg, mitoxantrone, epirubicin, irinotecanOften 2nd line regimenMetastatic diseasePalliative treatment

Combination chemotherapyCombination chemotherapy accomplishes three important objectives not possible with single-agent therapy:

(1) It provides maximum cell kill within the range of toxicity tolerated by the host for each drug;

(2) it offers a broader range of coverage of resistant cell lines in a heterogeneous tumor population; and

(3) it prevents or slows the development of new drug-resistant cell lines.

Principles of combination chemotherapyDrugs known to be active as single agents. Preferentially, drugs that induce complete remissions should be included.

Drugs with different mechanisms of action; in order to allow for additive or synergistic effects on the tumor.

Drugs with differing dose-limiting toxicities; to allow each drug to be given at full or nearly full therapeutic doses.

Principles of combination chemotherapyDrugs should be used in their optimal dose and schedule.

Drugs should be given at consistent intervals.

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

Drug synergy, antagonism, and additive effectsDrug effects are additive when their use in combination

gives results equivalent to their sequential independent use.

Lesser effects suggest antagonism.Greater effects suggest synergism.

Drug A 60 % response rate Drug B 30 % response rate Drug A + B

60 % respond to A12 % respond to B [30 % of 40

non-responders to A]72 % = additive response rate

Administation of Cancer Chemotherapy

Routes of administrationSystemic chemotherapy:Oral (PO) Intravenous (IV)

Regional chemotherapyIntra-arterial

Intracavitary chemotherapyIntravesicalIntrapleuralIntraperitoneal Intrathecal

Intralesional/intratumoral

Topical

Choice of chemotherapy

Research

Stage of the cancer/Goal of therapy

The Health of the Patient

Previous cancer regimen used

Dosing considerationsNarrow therapeutic index, hence the need for precision in dosing

Calculated based on BSA and body weightDosing for children and adults differOther considerations

elderly poor nutritional status Obese patients Have already taken or are currently taking other medicines Have already had or are currently receiving radiation

therapy Have low blood cell counts Have liver or kidney diseases

Schedules(Cycles)Each course of chemotherapy is generally given at regular intervals called cycles.

A chemotherapy cycle may involve a dose of one or more drugs followed by several days or weeks without treatment.

This gives normal cells time to recover from the drug’s side effects.

Each drug is given on a schedule that is carefully set up to make the most of its anticancer actions and minimize side effects.

Pre-chemotherapy assessmentEssential Prerequisites:Definitive Diagnosis- histologyAccurate stagingWork upDetailed history: Age, Occupation, Duration of symptoms, Weight loss, PMHx, FSHx, drug rxn.

Physical Examination: Lymphadenopathy, tumour size, Organomegaly, States of the heart & lungs, Bone involvement, metastasis, Ht, Wt, BSA

Pre-chemotherapy assessmentInvestigationsHematologic – FBC, ESR, BM biopsyBiochemical – LFT, E/U/CrImaging – CXR, USS, Bone scan, CT, MRI, ECHO

Tumour markers

Pre-chemotherapy assessment

Counseling Nature of cancer and stage Treatment options Nature of prescribed chemotherapy Side effects and management Possible outcome of treatment Consent

Optimization Fluid & Electrolytes Blood if anaemic Antibiotics when indicated G-CSF

Monitoring

Tumor markersTumor sizeImaging: CT, USS, bone scanHematological indices

Hb >12g/dlWBC > 3.0 x 109/lNeutrophils > 1.5 x 109/lPlatelets > 100 x 109/l

Definition of terminologies

Definition of terminologiesInduction: High-dose, usually combination, chemotherapy given with the intent of inducing complete remission when initiating a curative regimen.

Consolidation: Repetition of the induction regimen in a patient who has achieved a complete remission after induction, with the intent of increasing cure rate or prolonging remission

Intensification: Chemotherapy after complete remission with higher doses of the same agents used for induction or with different agents at high doses with the intent of increasing cure rate or remission duration.

Maintenance: Long-term, low-dose, single or combination chemotherapy in a patient who has achieved a complete remission, with the intent of delaying the regrowth of residual tumor cells.

Adjuvant: A short course of high-dose, usually combination chemotherapy in a patient with no evidence of residual cancer after surgery or radiotherapy, given with the intent of destroying a low number of residual tumor cells.

Neoadjuvant: Adjuvant chemotherapy given in the preoperative or perioperative period.

Palliative: Chemotherapy given to control symptoms or prolong life in a patient in whom cure is unlikely.

Salvage: A potentially curative, high-dose, usually combination, regimen given in a patient who has failed or recurred following a different curative regimen

Remission: Decrease or disappearance of signs and symptoms of cancer, although cancer may still be present.

ResponseComplete response: disappearance of all evidence of disease and no appearance of new disease confirmed at ≥4wks

Partial response: a reduction by at least 50% in the sum of the products of the two longest diameters of all lesions, with no appearance of new disease, confirmed at ≥4wks

Progression: ≥25% growth of existing disease or appearance of new disease during chemotherapy.

Stable disease: Neither partial response nor progression criteria met (no change)

Resistance to chemotherapy

Resistance to chemotherapyPrimary resistance: Absence of response on first exposure to currently available standard agents

Acquired resistance: Absence of response which develops in an originally drug-sensitive tumor type

Resistance to chemotherapyMechanism Increased expression of an MDR1 gene coding

for a transmembrane P-glycoprotein by tumor

cells, resulting in increased efflux of the drug

Alterations in drug uptake or transport (e.g.

anthracyclines)

Increased repair of drug-induced nucleic acid

damage (e.g., platinum drugs)

Cancer cells may mutate and develops mechanisms for drug inactivation

Development of resistant clones of cancer cells

Sanctuary sites(brain/testes)

Side effects/Toxicities

Side effects of cancer chemotherapy and toxicitiesAlthough chemotherapy is given to kill cancer cells, it also damages normal cells. The normal cells most likely to be damaged are those that divide rapidly, for instance

Bone marrow/blood cellsCells of hair folliclesCells lining the digestive tractCells lining the reproductive tract

Side effects/ToxicitiesGeneral

Bone marrowLeukopenia & resulting infections Thrombocytopenia Immunosuppression Anemia

GIOral & intestinal ulcerationsDiarrhoea

OthersHair Follicles - AlopeciaWounds - impaired healingGonads - menstrual irregularities including premature menarche; impaired spermatogenesisFetus - Teratogenesis)

Side effects/toxicitiesRenal toxicity: Cisplatin, Methotrexate

Hepatic toxicity: 6-MP, Busulfan, Cyclophosphamide

Pulmonary toxicity: Bleomycin, Busulfan, Procarbazine

Cardiac toxicity: Doxorubicin, Daunorubicin

Neurotoxicity: Vincristine, Cisplatin, Paclitaxel

Immunosuppression: Cyclophosphamide, Cytarabine, Dactinomycin, Methotrexate

Hemorrhagic cystitis: cyclophosphomide

Pancreatitis: asparaginase

Leukemia: procarbazine

Prevention and management of side effects and toxicitiesNausea & Vomiting

5-HT3 receptor antagonist-Ondasetron, Ganisetron

dexamethasone

AnaemiaErythropoietinBlood transfusion

Immunosupression:Colony stimulating factorBroad-spectrum antibioticsBM transplant

Prevention and management of side effects and toxicitiesChemoprotective agents

Mesna: reduces bladder irritationLeucovorin: minimizes toxic effects on other

body cells when given with methothrexateAmifostine: reduces the level of renal injuryDesrazoxane: reduces the effect of

chemotherapy on the heart.

Secondary tumors: Careful follow-up

Extravasation injury refers to the damage caused by the leakage of solutions from the vein into the surrounding tissue spaces.

Depending on the substance that is extravasated into the tissue, the degree of injury can range from a very mild skin reaction to severe necrosis.

Extravasation of vesicants is a medical emergency

Chemotherapy Safety

Safe drug storageMinimal personnel exposureProtective clothingSafety precautions during drug reconstitution and administration

Patient care after chemotherapyProper cytotoxic waste disposal

AdvancementsLiposomal formulationsTargeted therapy, Angiogenesis inhibitorsMonoclonal antibodiesContinued Research into safer ways of treating cancer

THANK YOU FOR THE AUDIENCE

References Cancersbiology.blogspot.com/2012/07/definition-of-

cancer.html Harvard-MIT Division of Health Sciences and Technology

HST.151: Principles of Pharmocology Instructor: Dr. Donald Kufe

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Principles of chemotherapy; Ray Page, DO, PhD, and Chris Takimoto, MD, PhD

Cancer Chemotherapy; (ppt) Prof. Clement A. Adebamowo, BM ChB Hons. (Jos), FWACS, FACS, D.Sc. (Havard)