Cancer Chemotherapy Lecture [Dr. Edy]

7/30/2019 Cancer Chemotherapy Lecture [Dr. Edy]

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Pharmacotherapy

of Cancer


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Cancer

A cellular disorder, clonal origin

Progressive accumulation of a mass of

cells Progressive invasion of surrounding

tissues and organs

Ability to metastasize to distant organs


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Cancer

Essentially, a genetic disease

Mutation of genes: Oncogenes

Tumor suppressor genes Mismatch repair genes

Germline mutation: hereditary or familial

cancer Somatic mutation: sporadic cancer


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Cellular Kinetics

Human body contains 5x1013 cells

Cells can either be- non dividing and terminally differentiated

- continually proliferating

- rest but may be recruited into cell cycle

Tumour becomes clinically detectable when

there is a mass of 109 cells (1g)


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The Cell Cycle


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Tumor kinetic

Growth rate depends on:

growth fraction

-percent of proliferating cells within a given system

-human malignacy ranges from 20-70%

-bone marrow 30 %

cell cycle time

-time required for tumour to double in size

rate of cell loss


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Tumor Kinetics Original Hypothesis

Conventional views in the field of oncologysupport the notion that:

tumor growth is exponential

chemotherapy treatment is designed tokill in log intervals (kills constant fractionsof tumor)

Combination therapy and increased drug doselevels aim at improving ovarian cancerchemotherapy.


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Gompertzian Growth

Growth rates are exponential at early stages of

development and slower at later stages of

development.

- Biological growth follows this characteristic curve.- Biological growth follows this characteristic curve.


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Gompertzian growth model

Initial tumour growth is first order, with later growth beingmuch slower

Smaller tumour grows slowly but large % of cell dividing

Medium size tumour grows more quickly but with smaller

growth fraction

Large tumour has small growth rate and growth fraction


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number ofnumber ofcancer cellscancer cells

diagnosticdiagnostic

thresholdthreshold

(1cm)(1cm)

timetime

undetectableundetectable

cancercancer

detectabledetectable

cancercancer

limit of

clinicaldetection

host

death

10101212

101099

Tumor Growth


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Rationales in Human Cancers

Small tumors grow faster than larger

tumors

Human cancers grow by non-exponential

Gompertzian kinetics


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Principle of chemotherapy

First order cell kill theory

- a given dose of drug kills a constant percentage

of tumour cells rather than an absolute number

Maximum kill

Broad coverage of cell resistance


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The rate of tumor volume regression isproportional to the rate of growth.

Tumor cell regrowth can be prevented if tumor cells are

eradicated using a denser dose rate of cytotoxic therapy.

Tumors given less

time to grow in

between treatmentsare more likely to be

destroyed.

Hypothesis of Alternative Intervals


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Principle of chemotherapy

Rationale for combination chemotherapy

Different drugs exert their effect through different

mechanisms and at different stages of the cell cycle,

thus maximize cell kill

Decease the chance of drug resistance


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Paraneoplastic syndrome

Syndrome Clinical manifestationSystemic anorexia, cachexia, weight

loss, fever

Endocrine hypercalcemia,

hyponatremia,hypoglycemia, Cushingsyndrome

Skeletal / connective tissue digital clubbing,hypertrophic pulmonaryosteoarthropathy

Neurolgic / muscular myasthenia gravis, Eaton-Lambertsyndrome, polymyositis, peripheralneuropathy, subacute cerebellardegeneration


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Paraneoplastic syndrome

Syndrome Clinical manifestation

Hematologic anemia, polycythemia,

leukocytosis, thrombocytosis,deep vein thrombosis

Skin dermatomyositis, acanthosis

nigricans

Renal nephrotic syndrome,glomerulonephritis


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Psychosocial effects of cancer

Loss of control

Fear of pain and mutilation

Separation and loneliness


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The Changing Nature of Palliative Care

CURATIVE

CARE

PALLIATIVE

CARE

CURATIVE CARE

PALLIATIVE CARE

TIME


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AIM OF COMBINATION THERAPY

INCREASED EFFICACYINCREASED EFFICACY

Different mechanisms of action Compatible side effects

Different mechanisms of resistance

ACTIVITYACTIVITY SAFETYSAFETY


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It is easy to kill cancerIt is easy to kill cancer

cells, but the challenge iscells, but the challenge iskeeping the patient alive atkeeping the patient alive at

the same time..!the same time..!


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How to treat cancer

Clinical evaluation and treatment options

1. Diagnosis: pathological diagnosis

2. Evaluation of disease: staging

3. Treatment objectives: curative, palliative

4. Treatment options

5. Evaluation of response

6. Supportive therapy


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Modalities of treatment

Local treatment options

Surgery

Radiation

Systemic treatment options

Chemotherapy

Hormonal therapy

Biotherapy

Molecular-targeted therapy


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Principle of Treatment :

Most anticancer treatment is directed

towards killing actively dividing cells.

Complications: Marrow aplasia, alopecia,

sterility, GIT, lung, kidney damage).

Newer drugs target tumor cells by immune

mechanisms or hormones.


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General Disease-Related

Consequences of Cancer

Impaired immune and hematopoietic function

Altered gastrointestinal structure and function

Motor and sensory deficits

Decreased respiratory function


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Karnofsky Performance Scales


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Chemotherapy

Treating cancer with chemical agents

Major role in cancer therapy

Used to cure and increase survival time Some selectivity for killing cancer cells

over normal cells

Normal cells most affected: the skin, hair,intestinal tissues, spermatocytes, and

blood-forming cells


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Chemotherapy Drugs

Antimetabolites

Antitumor antibodies

Alkylating agents Antimitotic agents

Topoisomerase inhibitors

Miscellaneous chemotherapeutic agents Combination chemotherapy


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Treatment Issues

Drug dosage

Drug schedule

Drug administration Route : IV, IM, SC, IT

Extravasation

Vesicants


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Side Effects of Chemotherapy

Alopecia or hair loss Nausea and vomiting Mucositis in the entire gastrointestinal tract

Skin changes Anxiety, sleep disturbance Altered bowel elimination Decreased mobility

Hematopoietic system changes Bone marrow suppression Hypersensitivity (esp. taxanes, platinums)


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Immunotherapy: Biological

Response Modifiers

Drugs that modify the clients biologic

responses to tumor cells

Cytokines: enhance the immune system

Interleukins, interferons

Side effects: generalized and sometimes

severe inflammatory reactions, peripheralneuropathy, skin rashes, increased

depression


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Gene Therapy

Experimental as a cancer treatment

Renders tumor cells more susceptible to

damage or death by other treatments

Injection into tumor cells, enabling the

immune system to better recognize cancer

cells as foreign and kill them

Antisense drugs


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Definition

New technology and drugs that allow the cancer

treatment to target a certain cancer cell by interfering with

the natural functions of tumor growth

How they work

They target specific parts of a cancer cell or its actions;

hand in a glove analogy

What it means in cancer treatment Potentially fewer side effects

Targeted Therapies


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Targeted Therapies


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Targeted Therapies Monoclonal antibodies: proteins that trigger the bodys

pathways involved in cancer growth to fight cancer moreeffectively.

EGFR: family of receptors found on surface of normal and

cancer cells that bind with an epidermal growth factor (EGF)causing cells to divide.

Tyrosine Kinase Inhibitors: Part of the cell that signals it todivide and multiply; enhances cell growth. Stillinvestigational

Vaccines: stimulate the bodys immune system to fight thecancer


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Role of Chemotherapy in

Cancer Treatment

Adjuvant chemotherapy a short course of combination chemotherapy

in a patient with no evidence of residualcancer after surgery or radiotherapy, given

with the intent of destroying a small number

of residual tumor cells


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Neoadjuvant chemotherapy given in the preoperative or

perioperative period

Primary: same as neoadjuvant chemotherapy, also

applied to chemotherapy given in the absence of intended surgery or radiotherapy


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Salvage:- combination chemotherapy given in a

patient who has failed or recurred following

a different curative regimen

Palliative: chemotherapy given to control symptoms or

prolong life in a patient in whom cure isunlikely


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Induction: combination chemotherapy given

with the intent of inducing completeremission when initiating a curative regimen

Consolidation: repetition of the inductionregimen in a patient who has achieved a co

mplete remission after induction


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Intensification: chemotherapy after

complete remission with higher doses, with

the intent of increasing the cure rate or remi

ssion duration

Maintenance: long-term, low-dose

chemotherapy in a patient who has achieve

d a complete remission

Cli i l E d i t i E l ti


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Clinical Endpoints in Evaluating

Response to Chemotherapy

Objective Response Measurable disease (longest diameter)

Complete Response (CR)

Relapse-free survival after stopping treatment (>= 4 wks) Partial Response (PR)

At least a 50% reduction in measurable tumor mass

Progressive Disease (PD)

> 25% increase in one or more lesions

Stable Disease (SD)

Neither PR nor PD (no changes)


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Tumor which are Curable with

Chemotherapy : in advanced disease

Choriocarcinoma

Acute leukemia

Hodgkins disease High grade non-

Hodgkins lymphoma

Germ cell tumor

Wilms tumor

Embryonal

rhabdomyosarcoma Ewings sarcoma

Neuroblastoma

Small cell lung cancer

Ovarian cancer


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Neoadjuvant chemotherapy

Preservation of the tumor mass as a

biologic marker of responsiveness to the d

rugs

Sparing of vital normal organs


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Chemotherapy has Minor Activity

Brain tumor

(astrocytoma)

Cervical cancer

Colorectal cancer

Non small cell lung

cancer

Melanoma

Pancreatic cancer

Prostate cancer Soft tissue sarcoma

Hepatoma

Renal cell carcinoma


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CHEMOTHERAPEUTIC

AGENT :CLASSIFICATION

Alkylating agents: mechlorethamine, busulfan, nitrosoureas,

cyclophosphamide, chlorambucil, melphalan

Antimetabolites:

methotrexate, 5-fluorouracil, nucleoside

analogues

Anthracyclines:

doxorubicin, epirubicin


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Antimicrotubule agents: vinca alkaloids, taxanes

Platinum analogues: cisplatin, carboplatin

Topoisomerase II inhibitors: etoposide, tenoposide

Topoisomerase I inhibitors: camptothecins

Antibiotics: bleomycin, dactinomycin


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Types of chemotherapy

Cell cycle dependent

Cell cycle phase specific

Cell cycle independent Cell cycle phase non-specific

Sites of Action of Cytotoxic Agents


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Antibiotics Antimetabolites

S

(2-6h)G2

(2-32h)

M

(0.5-2h)

Alkylating agents

G1(2-h)

G0

Vinca alkaloids

Mitotic inhibitors

Taxoids


Cell Cycle Level


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Cycle-Specific Agents



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DNA synthesis

AntimetabolitesAntimetabolites

DNA

DNA transcription DNA duplication

Mitosis

Alkylating agentsAlkylating agents

Spindle poisonsSpindle poisons &&

Microtuble StablizersMicrotuble Stablizers

Intercalating agentsIntercalating agents


Cellular Level


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ALKYLATING AGENTS

Cyclophosphamide

alkylation of DNA through the formation of

reactive intermediates

oral bioavailability 100%

T1/2

3-10 hrs -- parent compound, 8.7 hrs --

phosphoramide mustard

metabolism:

microsomal hydroxylation

hydrolysis to phosphoramide mustard (active) and

acrolein

M t b li f


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CYCLOPHOSPHAMIDE

4-OH CYCLOPHOSPHAMIDE

ALDOPHOSPHAMIDE

PHOSPHORAMIDE

MUSTARD

4-KETOCYCLOPHOSPHAMIDE

CARBOXYPHOSPHAMIDE

ACROLEIN

HEPATICCYTOCHROMES

P 450ACTIVATION

CYTOTOXICITYTOXICITY

INACTIVATIONALDEHYDE

DEHYDROGENASE

Metabolism of

Cyclophosphamide


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Cyclophosphamide

toxicity: myelosuppression

alopecia

pulmonary fibrosis

cystitis: use MESNA with high-dose therapy SIADH

cardiac toxicity

leukemogenesis

infertility teratogenesis

Intake daytime pill

MESNA = 2-mercaptoethane sulfonate Na(Na = sodium), used

as chemotherapy adjuvant to detoxify metabolites of

cyclophosphamide & ifosfamide


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ANTIMETABOLITES

Methotrexate (MTX)

inhibition of dihydrofolate reductaseinhibition of dihydrofolate reductase--->partial

depletion of reduced folates

polyglutamates of MTX and dihydrofolate inhibitinhibit

purine and thymidylate biosynthesispurine and thymidylate biosynthesis

metabolism: converted to polyglutamates in normal

and malignant tissues

elimination: primarily as intact drug in urine, third-

space retention


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Methotrexate (MTX)

High dose toxicity: rescue by leucovorin

Pretreatment with MTX increases 5-FU and ara-C

nucleotide formation

NSAIDs decrease renal clearance and increase toxicity

Reduce dose in proportion to decrease in creatinine

clearance

NO high-dose MTX to patients with abnormal renal

function

Monitor plasma conc. of drug and hydrate patients

during high-dose therapy


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Methotrexate (MTX)


mucositis

renal tubular obstruction and injury

in high-dose therapy, requires urine alkalinizati

on and hydration

hepatotoxicity in chronic therapy

pneumonitis

hypersensitivity: rare

neurotoxicity


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5-fluorouracil (5-FU)

Interferes with RNA synthesis and functionInterferes with RNA synthesis and function

inhibition of thymidylate synthase (TS)inhibition of thymidylate synthase (TS)

Affect DNA stabilityAffect DNA stability

primary T1/2 8-14 min, clearance is faster withinfusional schedules, non-linear pharmacokinetics

90% is eliminated by metabolism,


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5-FU

Leucovorin increases activity and toxicity

Toxicity: GI epithelial ulceration

myelosuppression

skin toxicity

ocular toxicity

neurotoxicity

cardiac toxicitybiliary sclerosis (hepatic arterial infusion

of FUDR)


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Cytidine analogues

Cytosine arabinoside (araC)

2-2-difluoro-deoxycytidine (gemcitabine)

AraC inhibits DNA polymerase alpha

short plasma T1/2

elimination: deamination in liver, plasma and peripheral

tissue 100%

blocks DNA repair, enhances activity of alkylating

agents


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AraC


GI epithelial ulceration

intrahepatic cholestasis, pancreatitiscerebellar and cerebral dysfunction (high-

dose, elderly, impaired renal function)

conjuctivitis (high-dose)

hidradenitisnoncardiogenic pulmonary edema

ANTHRACYCLINES


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ANTHRACYCLINES

Pleiotropic effects:

Inhibition of dna topoisomerase ii activity

Activation of protein kinase c,

Generation of reactive oxygen and stimulation

of apoptosis Doxorubicin: protein binding 60-70%

Elimination: 50-60% by hepatic aldo-keto reductase

Drug clearance is decreased in the presence ofhyperbilirubinemia or patients with marked burden of metastatic tumor in liver


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Heparin binds to doxorubicin causing

aggregation

Toxicity:

Myelosuppression

Mucositis

Alopecia

Cardiac toxicity: acute and chronic, cumulative dose-

related (hypertensive heart disease, mediastinal)

Severe local tissue damage after drug extravasation Radiation sensitization of normal tissue


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Vinca alkaloids

toxicity: Neutropenia except vincristine thrombocytopenia

(vinblastine)

Peripheral neuropathy (capping of vincristine to

2.0 mg) jaw pain Constipation

SIADH (vincristine, vinblastine)


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Taxanes (paclitaxel, docetaxel)

High-affinity binding to microtubules,High-affinity binding to microtubules,

Stabilize microtubules against depolymerization,Stabilize microtubules against depolymerization,

Inhibit mitosisInhibit mitosis

Elimination: predominantly by hepatic hydroxylation

(p450 enzyme) and biliary excretion of metabolites,

less than 10% eliminated intact in urine

Dose should be modified in patients with abnormal liverfunction test


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Paclitaxel & Docetaxel

1971

1986

OH

European Yew: Taxus baccata

Pacific Yew: Taxus brevifolia


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Taxanes:

Toxicity: acute hypersensitivity reactions,

premedication with corticosteroid and antihistamines

(h1 and h2 blockers)

neutropenia, thrombocytopeniamucositis (esp. prolonged infusion, 96-hr)

alopecia

sensory neuropathy

cardiac conduction disturbances

fluid retention (docetaxel)


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PLATINUM ANALOGUES

Cisplatin, carboplatin, oxaliplatin

Cisplatin

Covalent binding to DNA Inactivated by sulfhydryl groups, covalently binds to

glutathione, metallothioneins, and sulfhydryls on

proteins

25% is excreted during the first 24 hrs, renal > 90%,bile < 10%


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Cisplatin

toxicity: renal insufficiency with Mg2+ wasting,

monitor electrolytes, Mg2+, Ca2+, use with caution in

the presence of other nephrotoxic drugs

nausea and vomiting

peripheral neuropathy

auditory impairment

myelosuppression

visual disturbance (rare)hypersensitivity (rare)

seizures (rare)


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Carboplatin

drug is primarily excreted, only a small fraction is

metabolized

90% excreted in urine in 24 hrs

toxicity: myelosuppression, esp.thrombocytopenia

nausea and vomiting

nephrotoxicity at high doses and in

patients with prior renal dysfuction reduce dose in proportion to reductions in

creatinine clearance


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Oxaliplatin

Greater distribution to tissue than cisplatin

(50 times)

Excrete by urine in metabolite form Never reconstitute in 0.9% NaCl (unstable)

Toxicities :

neurotoxic peripheral sensory neuropathy

N/V/D


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TOPOISOMERASE II INHIBITORS

Etoposide

Inhibition of DNA topoisomerase IIInhibition of DNA topoisomerase II

Terminal t1/2 6-8 hrs Hepatic metabolism, renal excretion 35-40%

Reduced dose proportionate to creatinine clearance

Toxicity: neutropenia, thrombocytopenia (mild), alopecia

hypersensitivity, mucositis (high doses)

CAMPTOTHECINS


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CAMPTOTHECINS

Irinotecan (CPT-11)Topotecan

Irinotecan inhibit topoisomerase Iinhibit topoisomerase I by stabilizing the cleavablecomplex in which the enzyme is covalently bound to DNA

at a single-stranded break site

is aprodrugprodrugwhich requires enzymatic cleavage by thecarboxylesterase converting enzyme to generate the biolo

gically active metabolite, SN-38

I i t


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Irinotecan

elimination: 22% is excreted unchanged in the urine,the rest by biliary excretion and conversion to SN-38

toxicity: diarrhea- early onset within hours or during the

infusion associated with cramping, vomiting, flushing and diap

horesis, controlled by atropine. late-onset diarrhea can occur later than 12 hoursfollowing drug administration, may be controlled by high-dose loperamide (an initial dose of 4 mg followed by 2 mg

every 2 hours or 4 mg every 4 hours during the night)

Irinotecan


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Irinotecan

toxicity: myelosuppression, neutropenia alopecia

nausea and vomiting

mucositis

fatigue

elevated liver function, caution in

patients with liver dysfunction

pulmanary toxicity (uncommon)

associated with a reticulonodular

infiltrate, fever, dyspnea, and

eosinophilia


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ANTIBIOTICS

Bleomycin, dactinomycin

Bleomycin

Oxidative cleavage of DNA initiated by hydrogenOxidative cleavage of DNA initiated by hydrogen

abstractionabstraction

Metabolism: activated by microsomal reduction and

degraded by hydrolase found in multiple tissues

Elemination: renal 45-70% in first 24 hrs


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Bleomycin

Reduce dose for creatinine clearance < 60 ml/min

Toxicity: pulmonary interstitial infiltrates and fibrosis,

increased risk in patients with underlying pulmonary disease

, age > 70, renal insufficiency, prior chest radiation, oxygenduring surgery, cisplatin

desquamation, esp of fingers and elbows

Reynaud phenomenon

hypersensitivity reaction (fever, anaphylaxis,eosinophilic pulmonary infiltrates)

Dactinomycin (actinomycin D)


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Dactinomycin (actinomycin D)

Inhibition of RNA and protein synthesis Elimination: renal 6-30%, bile 5-11%

Avoid extravasation: necrosis

Toxicity: myelosuppression

nausea and vomiting mucositis

diarrhea

radiation sensitization and recall reactions


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PROPHYLACTIC AGENTS

Antiemetic regimens: Acute emesis: serotonin antagonist +

dexamethasone or metoclopramide (1 mg/kg) + dexa

methasone

Delayed emesis: (cisplatin, carboplatin, doxorubicin,high dose cyclophosphamide):metoclopramide 0.5

mg/kg IV/PO QID x 2-4 d (8-16 doses) then every 4 hr

s PRN

Dexamethasone 4-8 mg IV/PO x 4 dDiphenhydramine 50 mg PO every 4 hrs, PRN only

for restlessness or acute dystonic reactions


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Hydration: cisplatin, ifosfamide, high dosemethotrexate

Premedications for paclitaxel: (preventhypersensitive reaction)

dexamethasone 20 mg PO 12 and 6 hrs prior topaclitaxel

20 mg IV 30-60 min prior to paclitaxel

diphenhydramine 50 mg IV/PO 30-60 min prior topaclitaxel

cimetidine 300 mg or ranitidine 50 mg IV 30-60 min priorto paclitaxel


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Growth factors: G-CSF for prophylaxis inprevious febrile neutropenia or high incidenc

e of grade IV neutropenia

MESNA

Prevention of Ifosfamide-induced hemorrhagic

cystitis

Prevention of high-dose cyclophosphamide-induced hemorrhagic cystitis

D l l ti i l


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Dosage calculation in oncology

Body surface area

derived in 1916 by Du Bois and Du Bois

reduce the interpatient variability of drug

exposure and, hence, drug effects

AUC (carboplatin) Dose (mg) = Target AUC (mg/mL/min) x [GFR (mL/min) + 25]

Fix dosing


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Body surface areacalculation:

Nomogram


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Managing Cancer TreatmentSide Effects and Toxicity

SIDE EFFECTS OF


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SIDE EFFECTS OF

CHEMOTHERAPY

Mucositis

Nausea/vomiting

Diarrhea

Cystitis

Sterility

Myalgia

Neuropathy

Alopecia

Pulmonary fibrosis

Cardiotoxicity

Local reaction

Renal failure

Myelosuppression

Phlebitis

I it t V i t


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Irritant vs. Vesicant

Local inflammatoryreaction

Intact blood return

Short-term injury Bleomycin

Platinum

Doxorubicin (bothforms)

Etoposide

Ifosfamide

Infiltrating surroundingtissue blistering

May be delayed 6-12hr

Severe necrosis

Absent of blood returnAnthracyclins

Vinca alkaloids Teniposide

Streptozocin

E t ti f C t t i d


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Extravasation of Cytotoxic drug

P t th


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Port-a-cathPort inserted in vein

for chemotherapy

A Port

B Catheter [tubing]

C Subclavian vein

D Superior Vena cava

E Pulmonary vein

F Aorta

G Heart

Sid Eff t f Ch th


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Side Effects of Chemotherapy

Alopecia or hair loss Nausea and vomiting Mucositis in the entire gastrointestinal tract Skin changes

Anxiety, sleep disturbance Altered bowel elimination Decreased mobility

Hematopoietic system changes Bone marrow suppression Hypersensitivity (esp. taxanes, platinums)

Al i (h i l )


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Alopecia (hair loss)

Anthracyclins Etoposide

Irinotecan (Campto)

Cyclophosphamide Taxanes

Ifosphamide

Vindesine

Vinorelbine

Topotecan



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2-3 days after within a few weeks

3-6 months regain after stopping treatment

baldness may be temporary, partial or

total

Tx

Cold cap

Wig


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Cancer-induced nausea and

vomitting

Etiology of Nausea and Vomiting in


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gy g

Patients with Cancer

Direct TreatmentRelated:

chemotherapy

- acute - delayed

- anticipatory

- breakthrough N/V

- refractory N/V

radiation therapy

prophylactic

antibiotics

Indirect Treatment Related:

mucositis

opiates

anti-infectives

gastroparesis

infection

hyperacidity

anorexia diarrhea

pain

anxiety

Etiologies of Nausea and


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g

Vomiting in Oncology Patients

Chemical (chemotherapy-induced: acute anddelayed; opioids)

Vestibular

CNS (increased intracranial pressure)

Visceral (direct disease-related sources,

abdominal irradiation)

Proposed Pathways for Chemotherapy-

Induced Nausea and Vomiting (CINV)


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Induced Nausea and Vomiting (CINV)

Increased afferent input to thechemoreceptor trigger zone and

vomiting center

Chemotherapy

Cell damage

Higher CNS centers

Release of neuroactive agentsActivation of vagus

and splanchnic nerves

Small

intestine

Chemoreceptor trigger zone

Medullaoblongata

Vomiting center

Adapted from Grunberg SM et al N Engl J Med1993;329:17901796.

CINV: Emetogenic risk


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g

CINV: Classification


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CINV: Classification

Anticipatory Acute Delayed

Chemo 16 - 24 hours

CINV: A Broad Definition


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CINV: A Broad Definition

Anticipatory Early acute

Chemo

Late acute Delayed

16 hours 24 hours

A t CINV D l d CINV


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Acute CINV Delayed CINV

No Acute

CINV

No Delayed76%

Delayed

24%

Yes Acute

CINV

No Delayed

20%

Delayed

80%

CINV: Current Problem


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CINV: Current Problem

CINV is still a clinical problem do not fully understand the pathophysiology of

CINV (e.g. acute, delayed)

traditional definition of acute and delayedCINV does not match the physiology

Appears that:

acute CINV impacts delayed CINV

prevention of acute CINV may help management of

delayed CINV

A t CINV


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Acute CINV

Starts within the first24 hours after

chemotherapy administration

Majority of chemotherapeutic agents induce emesis

approximately 13 hours following administration

Most researched type of CINV

Remains common despite dramatically improved

protection

Pisters KMW, Kris MG. In: Principles and Practice of Supportive Oncology. Lippincott-Raven; 1998. Antiemetic Subcommittee of the Multinational

Association of Supportive Care in Cancer.Ann Oncol1998;9:811819.

Delayed Chemotherapy-Induced Nausea


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and Vomiting (CINV)

Starts 24 hours or more afterchemotherapy administration

First defined with high doses of cisplatin but known to occur

with other chemotherapy agents

Carboplatin

Cyclophosphamide

Doxorubicin

Epirubicin

Anthracyclines

Mechanism not known; appears to differ from acute emesis

Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins, 2001:28692880. Antiemetic

Subcommittee of the Multinational Association of Supportive Care in Cancer.Ann Oncol1998;9:811819.

Ci l ti Bi h i P tt f CINV


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Cisplatin Biphasic Pattern of CINV

Maximal emetic intensity seen within 24 hours postdose

Distinct second phase seen, occurring on Days 25 postdose

Adapted from Tavorath R, Hesketh PJ Drugs 1996;52:639648. 1996. Used with permission from Adis International Limited.

Acute Delayed

Time (Days)

Postcisplatin: Differential Involvement


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of Neurotransmitters Over Time

Hesketh PJ et al Eur J Cancer2003;39:10741080.

0 8 2412 120

Hours after cisplatin

Substance Pdependentmechanisms

(central)

DELAYED (Days 25)ACUTE (Day 1)

Serotonin-dependent

mechanisms

(peripheral)

Serotonin and 5 HT Receptor Pathway


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Serotonin and 5-HT3 Receptor Pathway

First recognized with high-dosemetoclopramide

Development of 5-HT3 antagonists has had

dramatic impact

Highly effective in acute vomiting, less effectivefor delayed events

Optimal use is with dexamethasone

Primary mechanism of action appears to beperipheral

Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins; 2001:28692880. Gralla RJ et al J Clin

Oncol1999;17:29712994. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol1998;9:811819.

Endo T et al Toxicology2000;153:189201. Hesketh PJ et al Eur J Cancer2003;39:10741080.

5HT3 Receptor Antagonists


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Prototypes:

Ondansetron Granisetron

Dolasetron

Palonosetron

MOA: Inhibition of 5-HT3 receptors on vagalafferent neurons in GI and in CTZ

Efficacy improved when used with a steroid

Well tolerated, minimal side effects headache

constipation

bradycardia

Half-Life and Binding Affinities of


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*Log-scale.In vitro data; clinical significance has not been established.

5-HT3 Antagonist Half-Life (h) Binding Affinity (pKi)*

Palonosetron (Aloxi) 40.0 10.45

Ondansetron (Zofran) 4.0 8.39

Dolasetron (Anzemet) 7.3 7.60

Granisetron (Kytril) 9.0 8.91

5-HT3

Receptor Antagonists

Substance P


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prototypic neuropeptide of the 50 knownneuroactive molecules now recognized as a member of the tachykinin family

of neurotransmitters

neurokinins are tachykinins found in mammals(substance P, NKA, NKB)

3 categories of NK receptors NK1 - affinity for substance P

NK2 - affinity for NKA

NK3 - affinity for NKB

currently considered a modulator of nociception,stress, anxiety, nausea / vomiting

DeVane CL. Pharmacotherapy 2001:21:1061-9

CINV


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CINV

Emetic Center

CorticalGI

vestibular

Nausea / Vomiting

CTZ

Neurokinins:

Substance P

CINV: Aprepitant


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p p aprepitant (Emend, Merck & Co., Inc.) approved in

the US in 2003 Mechanism of action:

selective, high affinity antagonist of human substance P atneurokinin 1 (NK

1) receptors interferes with the substance

P pathway that produces N/V no affinity for serotonin (5HT

3), dopamine and corticosteroid

receptors

Indication:

combination with other antiemetics

indicated for the prevention of acute and delayed nausea

and vomiting associated with initial and repeat courses of

highly emetogenic cancer chemotherapy

A it t Ad i i t ti


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Aprepitant Administration

Given for three days as part of a regimenthat includes a 5-HT

3antagonist and a

corticosteroid

Recommended dose

125 mg po 1 hour prior to chemotherapy

80 mg daily in the morning on days 2 and 3

Supplied in 125- and 80-mg capsules

Aprepitant: Challenges for Care


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Aprepitant: Challenges for Care

Potential drug interactions with anticancermedication

Evaluation of drug interactions should look

at impact beyond 24 hours Potential drug interactions with other

medications (e.g. chronic)

CINV


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CINV

Emetic Center

CorticalGI

vestibular

Nausea / Vomiting

CTZ

Neurokinins:

Substance P DA

5HT

CINV: Triple Upfront Therapy


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Rationale: Clinical Guidelines

Guidelines include triple upfront

therapy for highly emetogenic

regimens:

MASCC

NCCN 2007

ASCO 2006

Kris MG, et al. JCO 2006:24:2932


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Nausea:


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Nausea:

Antiemetics

Diet (avoid fried, fatty foods)

Smaller meals

Diarrhea: Causes


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Diarrhea: Causes

Chemotherapy

Infection

Malabsorption

Radiation induced

Clostridium diffecile infection

Diarrhea


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Diarrhea

Chemotherapy induced Irinotecan

5-FU (50-80%)

Supportive management

Fluids & Electrolytes

Nutrition

Avoid problem foods and drugs

Medication management Opioids

Loperamide (more effective)

Diphenoxylate

Nephrotoxicity


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Nephrotoxicity

Chemotherapy induced nephrotoxicityAlkylating agents

Cisplatin

Ifosfamide

Carmustine Carboplatin

Antimetabolites

Methotrexate

Gemcitabine Other

Mitomycin C


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Bladder Toxicity:Hemorrhegic Cystitis


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g y

Agents Ifosfamide, cyclophosphamide high dose acroleinaccumulation in bladder

Clinical presentation

Onset : 2-3 days Hematuria, dysuria

Prevention MESNA + adequate prehydration

Treatment Stop chemo

Hydration

Adequate platelet

CNS Toxicity


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CNS Toxicity

Agents MTX (IT or IV)

Cytarabine

Ifosfamide

L-asparaginase

Cisplatin Lhermitts phenomena 5-FU

Taxanes IFN alpha

Vinca alkaloid (wrong route NEVER IT)

Neurotoxicity


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Neurotoxicity

High dose cytarabine ataxia L-asparaginase drowsiness, stupor

Cisplatin ototoxic, ataxia

Etoposide

Vinca alkaloid jaw pain,cranial nerve pulsies

Procarbazine

Metrotrexate acute arachnoiditis

Oxaliplatin sensory neurotoxic (cold triggersymptom parathesia

Prevention/Treatment chemotherapy

ind ced ne ropath


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induced neuropathy

Drug Prevention/ Treatment

Cisplatin Amifostine inj

Ifosfamide Methylene blue

Oxaliplatin Ca-gluconate & Mg sulfate

Paclitaxel Glutamine oral powder

Peripheral Neuropathy


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p p y

Sense of touch is distorted- ordinary touch can beunpleasant or painful.

Burning or prickling feeling without stimulus

Decreased touch sensation

Difficulty sensing the position, location, orientation,and movement of the body and its parts(Proprioception)

Important to report ANY of these symptoms to healthcare provider

Colon Cancer Treatment-Progressand Progress, Summer 2005, Vol.1

Cardiotoxicity


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y

Agents Anthracyclines

Cyclophosphamide

5-FU Trastuzumab (Herceptin)

Bevacizumab

Cisplatinin (Platinol)

Anthracyclin induce

cardioto icit


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cardiotoxicity

Congestive heart failure (mortality >20%) Risk factors

Cumulative dose (> 450 mg/m2 in Thai)

Dosing schedule

Age (>65 or


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prevention and treatement

Avoiding anthracyclines

Lowering cumulative dose

Lowering peak dose

2nd generation anthracyclines (Idarubicin,epirubicin, mitoxantrone)

Early detection of subclinical cardiotoxicity(Echocardiography)

Oxygen free radical scavengers vit.E, C,CoQ10

Liposomal formulations

Pulmonary Toxicity


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Risk factor Cumulative dose: bleomycin busulfan carmustine, aldesleukin

Age: bleomycin

Radiotherapy: bleomycin busulfan, mitomycin,cyclophosphamide, doxorubicin, actinomycin

Oxygen therapy: bleomycin, cyclophosphamide, mitomycin

Prevention Avoid risk factors

Amifostine

Free radical scavenger

Early detection

Treatment Corticosteroids

Diuretics (edema)

Hand-Foot Syndrome


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y

Description Local cutaneous reaction

after chemo.

Seen on palms, finger,soles

2-12 days after chemo

Tingling, burning of palms,hand, feet

Pain, peeling

Resolution in 7-14 daysafter stopping medication

Hand-Foot syndrome


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y

Common in high dosetherapy, prolonged

infusion, liposomal forms

Agents

Capecitabine Cytarabine

Docetaxel

Daunorubicin

Doxorubicin

5-FU (infusion)

MTX

Management Stop dosing

Topical wound care &

cold cream base

Pain management

Steroid creams

Pyridoxine

Avoid heat andpressure

Hematologic complications


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g p

Febrile neutropenia Anemia

Thrombocytopenia

Hematologic Toxicity: Prophylaxis

Recommendations (NCCN 2008 guidelines)


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Recommendations (NCCN 2008 guidelines)

Prevention & Treatment


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Febrile neutropenia Monitor fever (>38.5

C)

ANC < 1.0 x 109 /L

Anemia

Hb < 10 g/dL

Thrombocytopenia

Platelet < 20,000 /mm3

Antibiotics/antifungal/antiviral prophylaxis

(CSF prophylaxis)

Blood transfusion (Epoitin alpha)

Platelet transfusion

Stomatitis and Mucositis


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Occurs later in cycle with capecitabine Baking Soda and salt mouthwash Over the counter (OTC) enzyme containing mouthwash

for dry mouth

OTC dental anesthetic Stomatitis cocktail: 1:1:1 antacid solution containing

aluminum hydroxide, magnesium hydroxide/viscouslidocaine/diphenhydramine

National Peer Reviews in Colorectal Cancer, Scientific Updatesfrom the 30 th annual ONS Meeting, Orlando, Fl. 2005

Stomatitis


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Soft toothbrush Mild toothpaste

Mild gargles

Ice cubes Ibuprofen


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Monitoring Outcome: The 4 As


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Analgesia (pain relief)

Activities of Daily Living (psychosocialfunctioning)

Adverse effects (side effects)

Aberrant drug taking (addiction-related

outcomes)

(Passik and Weinreb, 1998)

Communicating About Pain


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Communicate Intensity

Location

What the pain feels like What makes it worse

What helps

Pain Intensity RatingNumerical Rating Scale


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Wong-Baker FACES Pain Rating Scales

g

Category Scale

WHO Analgesic
http://www.ganfyd.org/index.php?title=Image:WHO_Analgesic_Ladder.pnghttp://www.ganfyd.org/index.php?title=Image:WHO_Analgesic_Ladder.png


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WHO Analgesic

Ladders

Analgesic Classification
http://www.ganfyd.org/index.php?title=Image:WHO_Analgesic_Ladder.pnghttp://www.ganfyd.org/index.php?title=Image:WHO_Analgesic_Ladder.pnghttp://www.ganfyd.org/index.php?title=Image:WHO_Analgesic_Ladder.png


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1. Opioids

1. weak/full agonist, partial agonist and mixed agonist-antagonist (ceiling effect)

2. strong/full agonist (no ceiling effect no maximum

dose)

2. NSAIDs (ceiling effect) good for bone pain

3. Adjuvant analgesic or coanalgesics

1. TCA (amitryptyline) for neuropathic pain

2. Antiepileptics (gabapentin, oxcarbazepine) forneuropathic pain

3. Steroids for cord compression

4. Bisphosphonates

Concern about analgesics


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Opioids Some Should not for chronic use

Meperidine (neurotoxic)

Dextropropoxyphene (toxic)

Buprenorphine (partial agonist)

Nalbuphine (mix ago/antagonist)

Constipation sennosides, bisacodyl, MgOH

N/V

ondansetron Respiratory depression (Naloxone)

Sedation caffeine to resolve

What Not to Fear


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Addiction Tolerance (using meds too soon, i.e.,

before I really need them)

Side effects Good treatments exist for nausea, sedation

and a ground breaking treatment will soon be

available for constipation

Pain Treatment


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Acute Pain (Somatic and visceral pain)

Morphine bolus or IM morphine

When pain is relieved, off morphine oral weak opioidsor NSAIDS

Chronic painAround the clock medication opioids (long acting)

Neuropathic painAmitriptyline (10-75 mg/d) or

Pregabalin (150-600 mg/d)


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Maintaining Weight and MuscleMass

Cachexia and Nutritional Risk


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Nutritional risk (ie, unwanted weight loss), includingcachexia, is a common and distressing problem inadvanced cancer, affecting up to 80% of patients (Bruera,1993)

Negatively affects survival as well as quality of life(Delmore, 1993)

Etiologies: abnormal gastrointestinal functioning anorexia from nausea, anxiety, depression and cognitive

dysfunction metabolic abnormalities caused principally by cytokines(Keller, 1993)

Cachexia and Nutritional Risk


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4 main clinical manifestations of cachexia:Anorexia

Chronic nausea

Asthenia

Change in body image

Pharmacologic treatment of cachexia is targeted

principally at anorexia and chronic nausea (Bruera,1993)

Pharmacological Approaches


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The main pharmacologic approachesinclude:

Corticosteroids

Progestational agents (ie, megestrol acetate)

Cannabinoids (ie, dronabinol)

Antihistamines (ie, cyproheptadine)

Unique agents (ie, hydrazine sulfate)

Omega-3 fatty acids,EPA and

docosahexaneoic acid (DHA) (n-3s) (Barber, et al,2000; Hussey & Tisdale, 1999; Wigmore, et al, 2000)


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Fatigue and Chemobrain

Fatigue


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Highly prevalent effecting 2/3s ofpatients

Very disabling

Also makes the job of caregiving morestressful and exhausting for family

Fatigue what works?


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Exercise Modifications in diet

Stimulant medications

Acneform Rash


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Pharmacologic Mgmt.

Topical and/or

antibiotics

Topical and/or oral

antihistamines

Cool compresses

Petroleum jelly, silver

sulfadiazine ointment

for ulcerative lesions

Avoid sun, heat &

humidityUse mild soapsWater based makeup is

generally well tolerated


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Multiple white bands in the nails,

representing periods of growth

arrest, in this case due to cycles

of treatment with 5-fluorouracil.


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Oncologic Emergency

Oncologic Emergencies


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Sepsis and disseminated intravascularcoagulation

Collaborative management includes: Prevention (the best measure)

Intravenous antibiotic therapy

Anticoagulants, cryoprecipitated clottingfactors

Spinal Cord Compression


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Tumor directly enters the spinal cord orthe vertebrae collapse from tumor

degradation of the bone.(Continued)

Spinal Cord Compression(Continued)


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( )

Collaborative management includes: Early recognition and treatment

Palliative

High-dose corticosteroids High-dose radiation

Surgery

External back or neck braces to reducepressure in the spinal cord

Hypercalcemia


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Occurs most often in clients with bonemetastasis

Fatigue, loss of appetite, nausea and

vomiting, constipation, polyuria, severemuscle weakness, loss of deep tendon

reflexes, paralytic ileus, dehydration,

electrocardiographic changes

(Continued)

Hypercalcemia (Continued)


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Collaborative management includes: Oral hydration

Drug therapy

Dialysis

Superior Vena Cava Syndrome


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Superior vena cava is compressed orobstructed by tumor growth.

Condition can lead to a painful, life-

threatening emergency. Signs include edema of face, Stokes

sign, edema of arms and hands,

dyspnea, erythema, and epistaxis.

(Continued)

Figure 1 Photographs of the patient showing the reduction in swelling of the

f k d t iti


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face, neck and upper extremities

Chee CE et al. (2007) Superior vena cava syndrome: an increasingly frequent complication

of cardiac procedures

Nat Clin Pract Cardiovasc Med4: 226230 doi:10.1038/ncpcardio0850

Superior Vena Cava Syndrome(Continued)


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Late-stage signs include hemorrhage,cyanosis, change in mental status,

decreased cardiac output, and

hypotension.

Collaborative management includes high-

dose radiation therapy, but surgery onlyrarely.

Tumor Lysis Syndrome


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Large numbers of tumor cells aredestroyed rapidly, resulting in

intracellular contents being released

into the bloodstream faster than thebody can eliminate them.

Collaborative management includes:

Prevention Hydration

Drug therapy (Allopurinol)

Conclusions


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People with cancer are living longer The focus is on quality of life in addition to

quantity

People surviving cancer want to live normal lives

People with cancer have multiple symptoms

New treatments of various kinds are available

and there is no need to suffer


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Documents

Cancer Chemotherapy Lecture [Dr. Edy]