Chemotherapy Agents
Jeremy S. Heiner CRNA
Objectives:
 Review current chemotherapeutic agents.
 Provide a systemic review of the toxic effects of chemotherapeutic agents.
 Identify anesthetic considerations for patients taking chemotherapeutic agents.
 Discuss the effects of surgery and anesthesia on cancer recurrence and the immune
system.
Cancer Incidence
 American Cancer Society’s annual estimate of new cancer cases in US for 2009 =
1.5 million
 Annual deaths attributed to cancer are more than 500,000
 Cancer is the 2nd most common death in the US
 Most common cancer in men is Prostate
 Most common cancer in women is Breast
 Lung and colorectal cancer are the 2nd and 3rd leading causes of cancer in both
men and women
Chemotherapeutic Agents (cytotoxic drugs)
 Act by interfering with the cell cycle at different phases of cell replication
 Damage healthy cells as well as cancer cells
 Rapidly replicating cells (such as cancer cells) are targets for cytotoxic agents
 Newer treatments are targeting cell-specific cancers
 Different classes of cytotoxic drugs affect different parts of cell cycle and DNA
synthesis
 Common side effects:
o Nausea/vomiting, hair loss, fatigue, diarrhea
Alkylating agents
 Transfer of alkyl group from one molecule to another
 Inhibit normal and cancer cell DNA processing
 Bind to DNA, then cause a cross linking and an abnormal base pairing which
results in intracellular imbalance and cell death
 Chemically modify a cells DNA (cyclophosphamide)
Antimetabolites
 Antimetabolites are chemicals similar to DNA building blocks (i.e. purine,
pyrimidine) that insert themselves and prevent normal DNA replication
 Specific metabolites are necessary for cell metabolism and for cell reproduction
 Can halt cell growth and cell division
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Antitumor antibiotics
1. Inhibit DNA and RNA synthesis by structural distortion (intercalation)
2. Blocks DNA transcription and replication
3. Damages DNA and cell membranes by creating iron-mediated free oxygen
radicals
Vinca alkaloids
 Anit-mitotic and anti-microtubule agents
 Interact and alter microtubule function (cellular structural proteins) that are
needed for cell division
 Immunosuppressive properties
 Derived from the sap of the Madagascar Periwinkle
 Cause hair loss
Miscellaneous agents (i.e. Taxanes)
 Mitotic cell division inhibitors
 Prevent normal chromosome function and interfere with cell division
 Stabilize and inhibit the normal breakdown of micurotubules causing them to
accumulate within the cell leading to programmed cell death (apoptosis)
 Stabilize microtubules preventing separation of chromosome during anaphase
Cancer Premedication
 Anti-nausea medications
o Serotonin 5-HT3 receptor antagonists (Ondansetron, Dolansetron,
Palinosetron, Granisetron)
o Diphenhydramine
o Substance P antagonists (Aprepitant)
o Steroids (Decadron, Methylprednisolone)
 Histamine 2 blockers
o Famotidine, ranitidine, cimitadine
Toxic effects of chemotherapeutic agents
 Related to the type of drug, cumulative dose, and dosing schedule
 Tissues that divide rapidly are the most susceptible to toxic effects (i.e.
hematopoietic cells, GI mucosal cells)
Myelosuppresion
 Bone marrow suppression
 Signs and symptoms
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o
o
o
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Anemia
Thrombocytopenia
Leukopenia
Coagulation disorders
Central Nervous System
 Signs and symptoms:
o Nausea and vomiting
o Seizures (Up to 24 hours after busulfan treatment)
o Peripheral neuropathies
o Loss of deep tendon reflex
o Extremity weakness
o Vocal cord paralysis
o Loss of extraocular muscle function
 Signs and symptoms usually disappear after cessation of chemotherapeutic agent
Cardiovascular System
 Cytostatic anthracycline antibiotics (daunorubicin, doxorubicin, epirubicin, and
idarbicin) are associated with cardiotoxicity
 Myocardium cells do not regenerate which can lead to permanent damage
 Cardiotoxic effects can occur years after termination of therapy
 Risk factors:
o Radiation of mediastinum or left chest can increases cardiotoxic effects
o Age (higher incidence in young children)
o Preexisting cardiac disease
o Left ventricular ejection fraction <50%
o Type of surgery
 Signs and symptoms:
o Abnormal ECG findings, ST-T wave changes, QT interval prolongation,
dysrhythmias
o Thrombosis, myocarditis, pericarditis, myocardial infarction,
cardiomyopathy
 Manifestations of progressive cardiotoxicity (generally occur within 1 year):
o Tachycardia
o Blood pressure changes
o Ventricular dilation
o Exercise intolerance
o Pulmonary and venous congestion
o Poor perfusion
o Evidence of congestive heart failure
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Pulmonary System
 Damage can occur directly or indirectly from inflammatory process
 Bleomycin can lead to pulmonary fibrosis and pulmonary edema
 Risk factors:
o Advanced age
o Existing pulmonary disease (COPD)
o Smoking history
o Genetic predisposition
o Thoracic radiation therapy
 Signs and symptoms:
o Early inflammatory interstitial pneumonitis
o Acute noncardiogenic pulmonary edema
o Bronchospasm
o Pleural effusion
o Dyspnea
o Cough
o Tachypnea
o Rales and/or wheezing
o Fever
Renal System
 May cause acute or chronic renal damage
 Nephrotoxicity may include damage to glomerular filtration, proximal tubular
function, and distal tubular function (cisplatin and methotrexate)
 Risk factors
o Previous renal dysfunction
o Decreased renal perfusion
 Signs and symptoms:
o Increased serum creatinine and urine creatinine clearance
o Uremia
o Electrolyte abnormalities
 Nonsteroidal anti-inflammatory drugs may precipitate acute renal failure
 Avoid or decrease the dose of medications that require renal clearance
Hepatic System
 Signs and symptoms
o Elevated liver enzymes
o Cirrhosis
o Coagulopathies
o Jaundice (flutamide hepatoxicity)
o Dark amber urine
 Methotrexate may induce hepatic cirrhosis and fibrosis
 Medications metabolized by the liver may have prolonged effect
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Gastrointestinal system
 GI mucosal injury can occur from chemotherapeutic agents
 Increased risk for aspiration
 Signs and symptoms:
o Oral mucositis
o Diarrhea
o Nausea and vomiting
o Usually occurs within 12-24 hours
o Can last up to 7 days
ANESTHETIC CONSIDERATIONS
Chemotherapeutic agents
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Comprehensive preoperative history and physical examination
Inquire as to type of cancer treatments (drugs, radiation, and surgery)
Consult with cancer physician
Consider corticosteroid supplementation
Aspiration prophylaxis
Patients may be taking antiemetic
Increased risk of sepsis
Decreased pseudocholinesterase activity (Thiopenta and cyclophosphamide)
Consider monitoring neuromuscular blockade in extremities
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Labs and tests (as indicated):
o Electrolytes, blood count, coagulation studies, cardiac enzymes, renal
function, urine creatinine clearance, and liver function tests
o Chest radiograph
o Obtain ECG, cardiac echocardiogram, and ejection fraction
o Obtain cardiac enzymes if evidence of cardiac toxicity
o Assess need for blood products (PRBC, Coagulation factors, platelets)
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Airway considerations:
o Assess for hoarseness (vocal cord paralysis)
o Oral inflammation and ulcerations
o Joint stiffness from radiation therapy
o Scarring from surgery
o Existing airway tumors
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Lines and monitoring:
o IV access may be difficult
o Arterial line
o Central line
o Transesophageal echocardiography
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CNS considerations:
o Assess for seizures and previous treatment
o Assess and document neuropathies (pad areas well)
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Cardiovascular considerations:
o Anthracycline antibiotics can cause altered cardiac function and
coagulation defects
o Consider non-adrenergic inatrope for blood pressure maintenance
o Avoid Ketamine
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Respiratory considerations:
o May require postoperative intubation
o Monitor peak airway pressures
o Pulmonary function tests as needed
o Avoid high inspired oxygen concentrations
o Avoid excessive fluid administration
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Renal and hepatic considerations:
o Avoid NSAID’s with nephrotoxic chemotherapeutic agents
o Avoid or decrease doses of medications that require renal clearance
o Avoid Sevoflurane
o Medications metabolized by the liver may have prolonged effect
o Nausea and vomiting, diarrhea, and decreased appetite may lead to fluid
loss and electrolyte imbalance
o Enzyme induction
Effects of Surgery and Anesthesia on Cancer Recurrence and the Immune System
 Tumor metastases depends on:
o Metastatic potential
o Anti-metastatic host defenses
 Major surgery suppresses cellular immunity for several days post-op
o Decrease in cytokines that promote cell-mediated immunity
o Increase in cytokines that interfere with cell-mediated immunity
o Decrease in the number of circulating natural killer (NK) cells, cytotoxic T
lymphocytes, dendritic cells, and T-helper cells
 Anesthesia can suppress host defenses (most studies have been done in vitro or in
animal models)
o Ketamine: reduced NK cell response
o Thiopental: reduced NK cell response
o Propofol: reduced NK cell number
o Volatile agents: inhibits immune activation and reduced NK cell number
o Nitrous oxide: associated with accelerated development of lung and liver
metastasis and depresses immune response and tumor surveillance
o Local anesthetics: lidocaine and ropivicaine inhibit tumor cell growth and
proliferation
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o Morphine: inhibits cell immunity and NK activity
o Fentanyl: inhibits NK activity
o Tramadol: stimulates NK activity
o COX-2 inhibitors: Display anti-angiogenesis and anti-tumor effects
Regional anesthesia (potential to improve long-term outcome after cancer
surgery)
o Attenuates the immunosuppressive effects of surgery
o Lower opioid requirement
o When used in combination, the general anesthetic requirement is reduced
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Chemotherapy Agents
Class
Drug
Alkylating agents
Cyclophosphamide
Oxaliplatin
Carmustine
Melphalan
Chlorambucil
Busulfan
Estramustine
Lomustine
Procarbazine
Dacarbazine
Cisplatin
Carboplatin
Thiopeta
Mechlorethamine
Ifosfamide
Sermustine
Antimetabolites
Methotrexate
Flurorouracil
Azathioprine
Thioguanine
Pemetrexed
Fludarabine
Cytarabine
Temozolomide
Clofarabine
Bleomycin
Doxorubicin
Mitomycin
Acinomycin D
Idarubicin
Dactinomycin
Liposomal doxorubicin
Liposomal daunorubicin
Plicamycin
Mitoxantrone
Gemcitabine
Capecitabine
Cladribine
Gemcitabine
Pentostatin
Mercaptopurine
Modifiers of Biological
Response and Hormones
Interferon-a
Docetaxel
Flutamide
Nab-paclitaxel
Irinotecan
Mitotane
Paclitaxel
Tamoxifen
Etoposide
Thalidomide
Topotecan
Azacytidine
Natural products Vinca
Alkaloids & Taxanes
Vinblastine
Vincristine
Vinorelbine
 Bind and inhibit normal cancer
cell DNA processing causing
intracellular imbalances and
cell death
 Cytotoxic effect by Alkylating
nucleic acid
 Substitute chemicals that are
structurally similar to DNA
building blocks, therefore
inhibiting normal DNA
synthesis and cell replication
 Inhibits specific enzyme
function hindering normal cells
Antitumor antibiotics
 Structurally distort DNA/RNA
molecule
 Block DNA/RNA transcription
and replication
 Damage DNA and cell
membranes by creating ironmediated free oxygen radicals
that
 Inhibit cell division by blocking
chromosomal separation
 Bind to microtubular protein
inhibiting mitosis
 Interact with microtubular
function to alter cell division
Adriamycin
Daunorubicin
Epirubicin
Cancers Treated
Breast
Lung and Bronchus
Colon and rectum
Uterus
Urinary bladder
Melanoma of the skin
Non-Hodgkin lymphoma/Leukemias
Thyroid
Ovary
Oral cavity
Leukemia
Pancreas
Breast
Colon and rectum
Uterus & Ovary
Urinary bladder
Non-Hodgkin lymphoma/Leukemias
Kidney and renal pelvis
Oral cavity
Leukemia
Pancreas
Prostate
Breast
Lung and Bronchus
Uterus
Urinary bladder
Non-Hodgkin lymphoma/Leukemias
Thyroid
Leukemia
Pancreas
Ovary
Breast
Lung and Bronchus
Melanoma of the skin
Non-Hodgkin lymphoma/Leukemia
Kidney and renal pelvis
Leukemia
Ovary
Anesthesia Considerations
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Can cause CNS, cardiovascular, pulmonary, renal, and gastrointestinal toxicity
High incidence of nausea and vomiting with cisplatin
Seizures can occur with busulfan treatment
Peripheral neuropathies with cisplatin and oxaliplatin
Assess renal function (cisplatin and ifosfamide are nephrotoxic)
Monitor electrolytes, CBC, urine creatinine clearance, and renal function tests
N/V, diarrhea, and/or altered renal function may lead to fluid deficits
Avoid NSAID’s and medications that undergo renal clearance
Avoid Sevoflurane
Thiopenta and cyclophosphamide decrease pseudocholinesterase activity
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Can cause cardiovascular, pulmonary, renal, liver, and gastrointestinal toxicity
Assess renal function (methotrexate is nephrotoxic)
Monitor electrolytes, CBC, coagulation studies, and liver function tests
N/V, diarrhea, and/or altered renal function may lead to fluid deficits
Avoid NSAID’s and medications that undergo renal clearance
Avoid Sevoflurane
Consider coagulation replacement as indicated
Medications cleared by the liver may have prolonged effect (NMBA)
Can cause cardiovascular, pulmonary, renal, liver, and gastrointestinal toxicity
Monitor electrolytes, CBC, coagulation studies, and renal/liver function tests
Anthracycline antibiotics are associated with cardiotoxicity, ECG changes, and
dysrhythmias
Obtain chest radiograph, ECG, echocardiogram, and cardiac enzymes
Myelosuppresion: Assess need for PRBC, platelets, and or coagulation factors
Enhanced cardiodepressive effects from anesthesia
Bleomycin most associated with pulmonary toxicity (assess PFT’s)
May require postoperative ventilation and monitor for high peak airway pressures
Avoid high FiO2
Consider corticosteroid
Avoid NSAID’s and medications that undergo renal clearance
Can cause CNS, cardiovascular, pulmonary, renal, liver, and GI toxicity
Monitor electrolytes, CBC, coagulation studies, and renal/liver function tests
Assess for neuropathies
Avoid NSAID’s and medications that undergo renal clearance
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 Can cause CNS and pulmonary toxicity
 Peripheral neuropathies, loss of deep tendon reflex, and extremity weakness can
occur with vincristine therapy
 Vocal cord paralysis (assess for hoarseness)
 Loss of extraocular muscle function (monitor neuromuscular blockade in arm)
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References
American Cancer Society. Cancer Facts and Figures 2012. Available at:
http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/docum
ent/acspc-031941.pdf
Arain MR, Buggy DI. Anaesthesia for cancer patients. Current Opinion in
Anaesthesiology. 2007; 20:247-253.
Exadaktylos AK, Buggy DI, et al. Can anesthetic technique for primary breast cancer
surgery affect recurrence or metastasis? Anesthesiology. 2006; 105(4):660-664.
Maracic L, Van Nostrand J. AANA journal course update for nurse anesthetists:
Anesthetic implications for cancer chemotherapy. AANA Journal. 2007; 75(3):219-226.
Sessler DI, Ben-Eliyahu S, et al. Can regional analgesia reduce the risk of recurrence
after breast cancer? Methodology of a multicenter randomized trial. Contemporary
Clinical Trials. 2008; 29(9);517-526.
Snyder GL, Greenberg S. Effect of anaesthetic technique and other perioperative factors
on cancer recurrence. British Journal of Anaesthesia. 2010; 105(2):106-115.
Zaniboni A, Prabhu S, et al. Chemotherapy and anaesthetic drugs: Too little is known.
Lancet Oncology. 2005; 6:176-181.
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