Pharmacotherapy of Cancer

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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 genesMismatch 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 KineticsOriginal Hypothesis

Conventional views in the field of oncology supportthe notion that:

tumor growth is exponential

chemotherapy treatment is designed to kill in logintervals (kills constant fractions of tumor)

Combination therapy and increased drug dose levels

aim at improving ovarian cancer chemotherapy.


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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.


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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 of

cancer cells

diagnostic

threshold

(1cm)

time

undetectable

cancer

detectable

cancer

limit of

clinicaldetection

host

death

10 12

10 9

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 is proportionalto 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,Cushing syndrome

Skeletal / connective tissue digital clubbing,hypertrophic

pulmonary

osteoarthropathyNeurolgic / muscular myasthenia gravis, Eaton-Lambert

syndrome, 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

I NCREASED EFFICACY

Different mechanisms of action Compatible side effects

Different mechanisms of resistance

ACTIVITY SAFETY


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I t is easy to kil l cancer

cells, but the challenge iskeeping the patient alive at

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

BiotherapyMolecular-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 immunemechanisms 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 changesAnxiety, sleep disturbance

Altered bowel elimination

Decreased mobility

Hematopoietic system changesBone 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, peripheral neuropathy, 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

Monoclonal antibodies: proteins that trigger the bodys pathways

involved in cancer growth to fight cancer more effectively.

EGFR: family of receptors found on surface of normal and cancercells that bind with an epidermal growth factor (EGF) causing cells

to divide.

Tyrosine Kinase Inhibitors: Part of the cell that signals it to divideand multiply; enhances cell growth. Still investigational

Vaccines: stimulate the bodys immune system to fight the cancer


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Role of Chemotherapy in Cancer

Treatment

Adjuvant chemotherapya short course of combination chemotherapy in a patient

with no evidence of residual cancer 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 is unlikely


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Induction: combination chemotherapy given with the

intent of inducing complete remission when initiating acurative regimenConsolidation: repetition of the induction regimen in a

patient who has achieved a complete remission after

induction


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Intensification: chemotherapy after complete

remission with higher doses, with the intent of

increasing the cure rate or remission durationMaintenance: long-term, low-dose chemotherapy in a

patient who has achieved 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 ResponseMeasurable 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

ChoriocarcinomaAcute leukemiaHodgkins diseaseHigh grade non-Hodgkins

lymphomaGerm cell tumor

Wilms tumorEmbryonal

rhabdomyosarcoma

Ewings sarcomaNeuroblastomaSmall cell lung cancerOvarian cancer


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Neoadjuvant chemotherapy

Preservation of the tumor mass as a biologic marker

of responsiveness to the drugsSparing 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 cancerSoft 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 independentCell cycle phase non-specific

Sites of Action of Cytotoxic Agents


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AntibioticsAntimetabolites

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

Antimetabolites

DNA

DNA transcription DNA duplication

Mitosis

Alkylating agents

Spindle poisons &

Microtuble Stablizers

Intercalating 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


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CYCLOPHOSPHAMIDE

4-OH CYCLOPHOSPHAMIDE

ALDOPHOSPHAMIDE

PHOSPHORAMIDE

MUSTARD

4-KETOCYCLOPHOSPHAMIDE

CARBOXYPHOSPHAMIDE

ACROLEIN

HEPATICCYTOCHROMES

P 450

ACTIVATION

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 chemothe


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ANTIMETABOLITES

Methotrexate (MTX)

inhibition of dihydrofolate reductase--->partial depletion of

reduced folatespolyglutamates of MTX and dihydrofolate inhibit purine and

thymidylate biosynthesismetabolism: converted to polyglutamates in normal and

malignant tissueselimination: primarily as intact drug in urine, third-space

retention


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Methotrexate (MTX)

High dose toxicity: rescue by leucovorinPretreatment with MTX increases 5-FU and ara-C nucleotide

formationNSAIDs decrease renal clearance and increase toxicityReduce dose in proportion to decrease in creatinine clearanceNO high-dose MTX to patients with abnormal renal functionMonitor plasma conc. of drug and hydrate patients during high-

dose therapy


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Methotrexate (MTX)

toxicity: myelosuppression

mucositis

renal tubular obstruction and injury in

high-dose therapy, requires urine alkalinization and

hydration

hepatotoxicity in chronic therapy

pneumonitis

hypersensitivity: rare

neurotoxicity


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5-fluorouracil (5-FU)

Interferes with RNA synthesis and functioninhibition of thym idylate synthase (TS)Affect DNA stabilityprimary T1/2 8-14 min, clearance is faster with infusional schedules, non-linearpharmacokinetics

90% is eliminated by metabolism,


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5-FU

Leucovorin increases activity and toxicityToxicity: GI epithelial ulceration

myelosuppressionskin toxicityocular toxicityneurotoxicitycardiac toxicity

biliary 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 T1/2elimination: deamination in liver, plasma and peripheral tissue

100%blocks DNA repair, enhances activity of alkylating agents


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AraC

toxicity: myelosuppressionGI epithelial ulcerationintrahepatic 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 reductaseDrug clearance is decreased in the presence of hyperbilirubinemia or patientswith marked burden of metastatic tumor in liver


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Heparin binds to doxorubicin causing aggregation

Toxicity:

Myelosuppression MucositisAlopecia 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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ANTIMICROTUBULE AGENTS

Vinca alkaloids: vincristine, vinblastine, vinorelbine

Taxanes: paclitaxel, docetaxel

Vinca alkaloids

I nhibit polymer ization of tubuli nHepatic metabolism and biliary excretionPatients with abnormal liver function test should be treatedwith caution


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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,Stabilize microtubules against depolymerization,Inhibit mitosisElimination: predominantly by hepatic hydroxylation (p450 enzyme) and biliary

excretion of metabolites, less than 10% eliminated intact in urineDose should be modified in patients with abnormal liver function 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 withcorticosteroid and antihistamines (h1 and h2 blockers)

neutropenia, thrombocytopenia

mucositis (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 70, renal

insufficiency, prior chest radiation, oxygen during surgery, cisplatin

desquamation, esp of fingers and elbowsReynaud phenomenonhypersensitivity 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: myelosuppressionnausea and vomiting

mucositisdiarrhea

radiation sensitization and recall reactions


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PROPHYLACTIC AGENTS

Antiemetic regimens:

Acute emesis: serotonin antagonist + dexamethasone or

metoclopramide (1 mg/kg) + dexamethasone

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 hrs PRN

Dexamethasone 4-8 mg IV/PO x 4 d

Diphenhydramine 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: (prevent hypersensitivereaction)

dexamethasone 20 mg PO 12 and 6 hrs prior to paclitaxel

20 mg IV 30-60 min prior to paclitaxel

diphenhydramine 50 mg IV/PO 30-60 min prior to paclitaxel

cimetidine 300 mg or ranitidine 50 mg IV 30-60 min prior to

paclitaxel


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Growth factors: G-CSF for prophylaxis in previous

febrile neutropenia or high incidence of grade IV

neutropenia

MESNA

Prevention of Ifosfamide-induced hemorrhagic cystitis

Prevention of high-dose cyclophosphamide-induced

hemorrhagic cystitis


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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 effectsAUC (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 i V i


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Irritant vs. Vesicant

Local inflammatoryreaction

Intact blood return

Short-term injury

Bleomycin

Platinum

Doxorubicin (both forms)

Etoposide

Ifosfamide

Infiltrating surroundingtissue blistering

May be delayed 6-12 hr

Severe necrosis

Absent of blood return

Anthracyclins

Vinca alkaloids

TeniposideStreptozocin

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 lossNausea and vomiting

Mucositis in the entire gastrointestinal tract

Skin changes

Anxiety, sleep disturbance

Altered bowel elimination

Decreased mobility

Hematopoietic system changesBone marrow suppression

Hypersensitivity (esp. taxanes, platinums)

Al i (h i l )


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Alopecia (hair loss)

AnthracyclinsEtoposide

Irinotecan (Campto)

CyclophosphamideTaxanes

Ifosphamide

Vindesine

Vinorelbine

Topotecan

Al i (h i l )


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Alopecia (hair loss)

2-3 days afterwithin 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 Treatment Related:

chemotherapy

- acute

- delayed- anticipatory

- breakthrough N/V

- refractory N/V

radiation therapy

prophylactic antibiotics

Indirect Treatment Related:

mucositis

opiates

anti-infectives

gastroparesis

infection

hyperacidity

anorexiadiarrhea

pain

anxiety

Etiologies of Nausea and Vomiting in


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g g

Oncology Patients

Chemical (chemotherapy-induced: acute and delayed;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 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 delayed CINVdoes not match the physiology

Appears that:

acute CINV impacts delayed CINV

prevention of acute CINV may help management of delayed

CINV

A CINV


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Acute CINV

Starts within thefirst24 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. AntiemeticSubcommittee 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)

S t i d 5 HT R t P th


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Serotonin and 5-HT3 Receptor Pathway

First recognized with high-dose metoclopramideDevelopment of 5-HT3 antagonists has had dramaticimpact

Highly effective in acute vomiting, less effective for delayedevents

Optimal use is with dexamethasone

Primary mechanism of action appears to be peripheral

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:

OndansetronGranisetron

Dolasetron

Palonosetron

MOA: Inhibition of 5-HT3 receptors on vagal afferentneurons 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 known neuroactivemolecules

now recognized as a member of the tachykinin family ofneurotransmitters

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

in 2003Mechanism of action:

selective, high affinity antagonist of human substance P at neurokinin 1(NK1) receptors interferes with the substance P pathway that produces

N/Vno affinity for serotonin (5HT3), 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 regimen thatincludes a 5-HT3 antagonist 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 hoursPotential 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 inducedIrinotecan

5-FU (50-80%)

Supportive management

Fluids & Electrolytes

Nutrition

Avoid problem foods and drugs

Medication management

OpioidsLoperamide (more effective)

Diphenoxylate

Nephrotoxicity


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Nephrotoxicity

Chemotherapy induced nephrotoxicityAlkylating agents

Cisplatin

Ifosfamide

Carmustine

Carboplatin

Antimetabolites

Methotrexate

Gemcitabine

Other

Mitomycin C

Prevention of Nephrotoxicity


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eve o o Nep o o c y

CisplatinFractionate dose

Continuous IV

Adequate hydration

Use mannitol (increase urinevolume)

Prevent dehydration

Amifostine

Carboplatin substitute (not forall case esp in germ cell tumor

MetrotrexateAdequate hydration

Alkalinize of urine

Leucovorin rescue

Ifosfamide

Fractionated doses

Hydration

Monitor fluid retention (bodyweight)

Bladder Toxicity:Hemorrhegic Cystitis


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g y

AgentsIfosfamide, cyclophosphamide high dose acroleinaccumulation in bladder

Clinical presentation

Onset : 2-3 daysHematuria, dysuria

Prevention

MESNA + adequate prehydration

TreatmentStop chemo

Hydration

Adequate platelet

CNS Toxicity


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y

AgentsMTX (IT or IV)

Cytarabine

Ifosfamide

L-asparaginase

CisplatinLhermitts phenomena

5-FU

TaxanesIFN alpha

Vinca alkaloid (wrong route NEVER IT)

Neurotoxicity


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y

High dose cytarabine ataxiaL-asparaginase drowsiness, stupor

Cisplatin ototoxic, ataxia

Etoposide

Vinca alkaloidjaw pain,cranial nerve pulsies

Procarbazine

Metrotrexate acute arachnoiditis

Oxaliplatin sensory neurotoxic (cold trigger symptom parathesia

Prevention/Treatment chemotherapy

i d d th


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induced neuropathy

Peripheral Neuropathy


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p p y

Sense of touch is distorted- ordinary touch can be unpleasantor painful.

Burning or prickling feeling without stimulus

Decreased touch sensation

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

Important to report ANY of these symptoms to health careprovider

Colon Cancer Treatment-Progress

and Progress, Summer 2005, Vol.1

Cardiotoxicity


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y

AgentsAnthracyclines

Cyclophosphamide

5-FUTrastuzumab (Herceptin)

Bevacizumab

Cisplatinin (Platinol)

Anthracyclin induce cardiotoxicity


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y y

Congestive heart failure (mortality >20%)Risk factors

Cumulative dose (> 450 mg/m2 in Thai)

Dosing scheduleAge (>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 scavengersvit.E, C, CoQ10

Liposomal formulations

Pulmonary Toxicity


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Risk factorCumulative dose: bleomycin busulfan carmustine, aldesleukin

Age: bleomycin

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

Oxygen therapy: bleomycin, cyclophosphamide, mitomycin

PreventionAvoid risk factors

Amifostine

Free radical scavenger

Early detection

TreatmentCorticosteroids

Diuretics (edema)

Hand-Foot Syndrome


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y

DescriptionLocal cutaneous reaction afterchemo.

Seen on palms, finger, soles

2-12 days after chemoTingling, burning of palms, hand,feet

Pain, peeling

Resolution in 7-14 days afterstopping medication

Hand-Foot syndrome


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Common in high dose therapy,prolonged infusion, liposomal

forms

Agents

CapecitabineCytarabine

Docetaxel

Daunorubicin

Doxorubicin

5-FU (infusion)

MTX

ManagementStop dosing

Topical wound care & cold

cream base

Pain management

Steroid creams

Pyridoxine

Avoid heat and pressure

Hematologic complications


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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 neutropeniaMonitor 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 drymouth

OTC dental anestheticStomatitis cocktail: 1:1:1 antacid solution containing aluminumhydroxide, magnesium hydroxide/viscouslidocaine/diphenhydramine

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

Stomatitis


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Soft toothbrushMild toothpaste

Mild gargles

Ice cubesIbuprofen

Pain


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Cancer pain is common but not inevitable

Fatigue, GI upset, and psychosocial problems are oftenmore prevalent, but pain is the #1 feared aspect of

cancer for most patients

Rates of pain vary widely among disease sites:

35% in lymphoma56% in breast cancer

67% in head and neck cancer

Monitoring Outcome: The 4 As


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Analgesia (pain relief)

Activities of Daily Living (psychosocial functioning)

Adverse effects (side effects)

Aberrant drug taking (addiction-related outcomes)

(Passik and Weinreb, 1998)

Communicating About Pain


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CommunicateIntensity

Location

What the pain feels likeWhat 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


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WHO Analgesic

Ladders

Analgesic Classification


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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) for neuropathic

pain3.Steroids for cord compression

4.Bisphosphonates

Concern about analgesics


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OpioidsSome 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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AddictionTolerance (using meds too soon, i.e., before I really

need them)

Side effectsGood 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 orIM morphine

When pain is relieved, off morphine oral weak opioids orNSAIDS

Chronic pain

Around 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), including cachexia, isa common and distressing problem in advanced cancer, affectingup 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 approaches include: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 prevalenteffecting 2/3s of patientsVery disabling

Also makes the job of caregiving more stressful and

exhausting for family

Fatiguewhat works?


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ExerciseModifications 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 &

humidity

Use mild soaps

Water 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 intravascular coagulation

Collaborative management includes:

Prevention (the best measure)Intravenous antibiotic therapy

Anticoagulants, cryoprecipitated clotting factors

Spinal Cord Compression


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Tumor directly enters the spinal cord or thevertebrae 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 reduce pressure in the

spinal cord

Hypercalcemia


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Occurs most often in clients with bone metastasisFatigue, loss of appetite, nausea and vomiting,

constipation, polyuria, severe muscle 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 or obstructedby 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 only rarely.

Tumor Lysis Syndrome


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Large numbers of tumor cells are destroyedrapidly, resulting in intracellular contents being

released into the bloodstream faster than the body

can eliminate them.

Collaborative management includes:

Prevention

Hydration

Drug therapy (Allopurinol)

Conclusions


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People with cancer are living longerThe focus is on quality of life in addition to quantity

People surviving cancer want to live normal lives

People with cancer have multiple symptomsNew treatments of various kinds are available and there

is no need to suffer


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Pharmacotherapy of Cancer

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