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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
Sites of Action of Cytotoxic Agents
Cell Cycle Level
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Cycle-Specific Agents
Sites of Action of Cytotoxic Agents
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DNA synthesis
Antimetabolites
DNA
DNA transcription DNA duplication
Mitosis
Alkylating agents
Spindle poisons &
Microtuble Stablizers
Intercalating agents
Sites of Action of Cytotoxic 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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