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The Art and Science of Infusion Nursing

Gail Wilkes, MS, APRN-BC, AOCN

Intravenous Administration of Antineoplastic Drugs

Review of Basics and Whats New in 2009

ABSTRACT Today, newer treatment regimens combine chemotherapy with targeted therapy, based on an improved understanding of cancer pathophysiology. New diagnostic testing with microarray technology is helping to identify mutational sequences in patient tumors, so individualized treatment of cancer will occur during our lifetime. The administration of IV antineoplastic drugs continues to be an important role of infusion nurses. In addition, this therapy has also found a niche in the treatment of nonmalignant conditions such as rheumatoid arthritis. This article reviews the fundamentals of administration of IV antineoplastic drugs and current issues and trends.

THE BASICS
Cancer is a disease with molecular flaws leading to abnormal cell proliferation, lack of controlled growth, and the ability of the cell to metastasize. Most patients die from complications arising from metastatic disease, not from the primary tumor.1 Critical to reducing the many deaths from cancer is the control of the aberrant pathways in the cell and metastases, so that cancer becomes a chronic disease.2 Although this goal was initially sought to be achieved by 2015, it is likely to require more time.2 Chemotherapy is a systemic treatment that interferes with cellular function, causing either a cytostatic (preventing cell proliferation) or cytocidal (causing cell death) effect. Biological or targeted therapy is also systemic, but it zeroes in on molecular flaws in the cancer
Author Affiliation: Medical Surgical/Oncology Clinical Instructor, Boston Medical Center, Boston, Massachusetts. The author has disclosed that she has no financial relationships related to this article. Corresponding Author: Gail Wilkes, MS, APRN-BC, AOCN (gwilkes@comcast.net).

cell to stop uncontrolled cell growth, proliferation, and metastasis. Because chemotherapy is a cellular poison, normal cells are damaged as well, particularly normal, frequently dividing cells in organ systems having high cell turnover, such as the gastrointestinal tract, hair follicles, reproductive organs, and bone marrow. Fortunately, normal cells can repair themselves faster than malignant cells.3 Biological therapy has less general toxicity because the therapy is targeted, but it may cause toxicity specific to the drug. The infusion nurse must be knowledgeable about many factors before safely administering antineoplastic therapy. These factors include understanding chemotherapy and biotherapy drug mechanisms of action and potential toxicities, specific administration techniques, dose determinations, treatment regimens, and principles of combination therapy. Infusion nurses must also be knowledgeable about patient education to ensure effective patient self-care, symptom management to prevent or minimize toxicity, and personal protective equipment (PPE). Finally, nurses must have the knowledge and skill to ensure patent intravenous (IV) access, whether peripheral or central. Educational programs provide fundamental principles and evidence-based interventions to support the nurse, in addition to certification.4 Chemotherapy Principles of chemotherapy include type of chemotherapy prescribed, based on its mechanism of action; type and timing of expected toxicities; and strategies to minimize toxicity and maximize patient self-care, because most chemotherapy is administered in ambulatory settings. Expected toxicities can occur during IV administration, occur acutely within 24 hours or 1 to 2 weeks after treatment, or they can be delayed and occur months to years after the drug is given. Table 1 illustrates immediate, acute, and delayed adverse effects. Chemotherapy is generally categorized as to whether it is cell-cycle specific or nonspecific. Figure 1 shows the cell cycle, a cycle that all cells undergo to proliferate. The cell cycle is normally very tightly controlled, and most cells

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TABLE 1

Time Sequence of Chemotherapy Drug Toxicitiesa

Immediate Onset, Occurring Hours to Days After Administration Early Onset, Days to Weeks Delayed Onset, Weeks to Months Late Onset, Months to Years

Nausea, vomiting, phlebitis, hypeLeukopenia, thrombocytopenia, ruricemia, renal failure, anaphyalopecia, stomatitis, diarrhea laxis, skin rash, teratogenicity Drug-specific toxicities: hemorrhagic cystitis (cyclophosphamide), radiation recall (doxorubicin), fever/chills (bleomycin)
a

Anemia, aspermia, hepatocellular Sterility, hypogonadism, damage, hyperpigmentation, premature menopause, pulmonary fibrosis secondary malignancy Drug-specific toxicities: peripheral neuropathy (paclitaxel, vincristine, oxaliplatin, cisplatin), cardiac necrosis (doxorubicin, cyclophosphamide, SIADH (vincristine), hemolyticuremic syndrome (mitomycin C) Drug-specific toxicities: hepatic fibrosis/cirrhosis (methotrexate), encephalopathy (methotrexate with CNS radiation), bladder cancer (cyclophosphamide)

Drug-specific toxicities: paralytic ileus (vincristine), hypercalcemia (estrogen antagonists), hypomagnesemia (cisplatin), pulmonary infiltrates (methotrexate, bleomycin), ototoxicity (cisplatin)

Data from Wilkes and Barton-Burke.5

remain in the resting phase until recruited to divide; control of this cycle is subverted by cancer cells so that the cell cycle is always turned on. Chemotherapy is a cellular poison, so it interferes with either specific phases of the cell cycle, such as mitosis or synthesis of DNA (cell-cycle specific), or it can work throughout the cell cycle (cell-cycle nonspecific). Chemotherapy regimens often combine drugs from both categories so that they can maximize cell kill. In addition, drugs are combined so that their toxicities are not overlapping, which gives normal cells a chance to repair themselves. An example of a combination regimen is AC followed by T for breast cancer: doxorubicin (Adriamycin, Pharmacia Inc, Kalamazoo, Michigan), a cell-cycle nonspecific agent that causes bone marrow

depression days 10 to 14, alopecia, and cardiotoxicity; cyclophosphamide (Cytoxan, Bristol-Myers Squibb, New York), a cell-cycle nonspecific agent that is synergistic with doxorubicin and causes bone marrow depression earlier (day 7), bladder toxicity, and some degree of alopecia; and paclitaxel (Taxol, Bristol-Myers Squibb), which interferes with mitosis and is therefore cell-cycle specific, has toxicity in different organ systems such as the peripheral nerves (causing peripheral neuropathy, arthralgias, and myalgias), and rare cardiac toxicity.5 Table 2 depicts selected IV chemotherapy agents and their common toxicities. Biotherapy Biotherapy of targeted agents is an emerging field. The earliest targeted therapy was the oral agent tamoxifen, which specifically targeted the nucleus of the breast cancer cell blocking the estrogen receptor from stimulating breast cell proliferation. Intravenous-targeted agents began with the monoclonal antibody rituximab (Rituxan, Genentech, South San Francisco, California), which is directed against the CD20 (cluster of differentiation) marker on B lymphocytes. Each lymphocyte has a CD number identifying it. Like a guided missile, rituximab homes in on B lymphocytes expressing CD20 on their surface, attaches to the CD20 receptor, and causes the cells to die. Monoclonal antibodies can be naked, such as rituximab, or conjugated, such as gemtuzumab ozogamicin (Mylotarg, Wyeth, Madison, New Jersey), which is attached via a linker to the potent poison calicheamicin. Naked antibodies can kill cancer cells by stimulating and drawing the patients own immune cells to the cancer cell to kill the cancer cell (antibody-dependent cell cytotoxicity), or by blocking the cells receptor from being stimulated by other

Figure 1 Cell cycle and principal sites of action of chemotherapy agents. Copyright Clinical Tools, Inc. Reprinted with permission from Clinical Tools, Inc. Available at http://www2.geneticsolutions.com/?id= 1530:1873.

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TABLE 2

Selected Chemotherapy Agents and Principal Adverse Effectsa

Chemotherapy Drug Cell-Cycle Specificity Potential Adverse Effects
Hypersensitivity (5%) in lymphoma patients requiring test dose; pulmonary fibrosis (need baseline peritoneal function test followed serially), alopecia, hyperpigmentation of veins, skin and nail changes, stomatitis, tumor pain, chills Neutropenia, thrombocytopenia, nausea, vomiting, alopecia, hypotension, hypersensitivity reaction (bronchospasm) Dose-dependent neutropenia, thrombocytopenia, diarrhea, stomatitis, nausea, vomiting, hyperpigmentation of veins; continuous infusion: rare cardiac ischemia, hand-foot syndrome; irritant (pH of drug is 8; use a central catheter for continuous administrations). Peripheral neuropathy (sensorimotor), hypersensitivity reaction, nausea, vomiting, arthralgias, myalgias, cardiac arrhythmias; drug is an irritant (vesicant if concentrated drug is given) Peripheral neuropathy, constipation, paralytic ileus, foot drop; vesicant precautions Pink urine for 2-3 d after administration, cardiac myopathy at cumulative doses 550 mg/m2 (450 mg/m2 when given with cyclophosphamide), neutropenia, thrombocytopenia, nausea, vomiting, alopecia, radiation recall, photosensitivity, stomatitis; vesicant precautions Hemorrhagic cystitis (high dose requires concomitant bladder protection), neutropenia, thrombocytopenia, nausea, vomiting, secondary malignancy; cardiac toxicity when high doses used Neurotoxicity (acute and persistent), nausea, vomiting, diarrhea, delayed hypersensitivity reactions, neutropenia, thrombocytopenia, rare febrile neutropenia, pulmonary fibrosis; drug is an irritant Thrombocytopenia, neutropenia, nausea, vomiting, delayed hypersensitivity, mild alopecia, skin rash; area under the curve dosing Bleomycin G2 phase

Etoposide

G2 phase

5-Fluorouracil

S phase

Paclitaxel

M phase

Vincristine

M phase

Doxorubicin

G2 phase

Cyclophosphamide

Nonspecific

Oxaliplatin

Nonspecific

Carboplatin
a

Nonspecific

Data from Wilkes and Barton-Burke.5

substances that make the cancer cell grow and divide. Conjugated monoclonal antibodies bring with them either a poison or a radionucleotide that kills the cell once the monoclonal antibody is internalized into the cancer cell. Other monoclonal antibodies can block important biological growth factors. These include bevacizumab (Avastin, Genentech), which neutralizes vascular endothelial growth factor; trastuzumab
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(Herceptin, Genetech), which blocks the human epidermal growth factor receptor 2 from stimulating breast cancer cells to divide; and cetuximab (Erbitux, ImClone Sysytems, Inc, New York), which blocks the epidermal growth factor receptor from being stimulated by its ligand epidermal growth factor or other growth factors from proliferating, making new blood vessels, invading, and metastasizing. Table 3 shows biological

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TABLE 3

Biotherapy Agents, Indications, and Adverse Effectsa

Biotherapy Drug Monoclonal Antibodies
Alemtuzumab (Campath, Millennium and ILEX Partners, LP, Cambridge, Massachusetts)

Indications
B-cell chronic lymphocytic leukemia

Potential Adverse Effects

Neutropenia, thrombocytopenia, anemia, hypersensitivity reactions, hypotension, fever, chills, fatigue, rash, nausea, vomiting, diarrhea, dyspnea; increased risk for opportunistic infections Hypertension, nosebleeds, delayed wound healing. Uncommon: gastrointestinal tract (GI) perforation, arterial and vascular embolic events, nephritic syndrome, fistula formation; it may increase neutropenia when given together with some chemotherapy drugs Rare severe bronchospasm or anaphylaxis (90% occur during first infusiondo not rechallenge), infusion reactions (fever, chills, dyspneareduce infusion rate to 50%), papulopustular rash on sunexposed body parts, skin changes, nausea, vomiting, diarrhea, hypomagnesemia, rare interstitial lung disease (ILD) Severe neutropenia, thrombocytopenia, anemia; hypersensitivity reactions, hypotension, fever, chills, rigors, rare pulmonary infiltrates, pleural effusions, severe veno-occlusive disease, nausea, diarrhea, anorexia, hyperbilirubinemia Papulopapular rash of sun-exposed body areas (sterile, inflammatory rash), skin changes, drying of conjunctiva, rare anaphylaxis, hypomagnesemia, infusion reactions, ILD Severe infusion reactions (urtcaria, hypotension, hypoxia, bronchospasm), fever, chills, rigors, headache, myalgias, infection, mucocutaneous events, reactivation of hepatitis B infection, rare JC virus infection (progressive posterior leukoencephalopathy) Infusion reaction (chills, fever, headache, arthralgias, headache, dizziness, dyspnea, rash); cardiotoxicity, hypersensitivity reactions, diarrhea, neutropenia, anemia, rare pulmonary toxicity Fever, rigors, diarrhea, malaise, hypotension, headache, myalgias, arthralgias, tachycardia, arrhythmias, dyspnea, nausea, vomiting, stomatitis, thrombocytopenia, leucopenia, anemia, elevated renal and liver transaminases, skin rash, neurological changes, high dose: capillary leak syndrome Peripheral neuropathy, decreased white cell and platelet count, hypotension, nausea, vomiting, diarrhea, fatigue, blurred vision Hypersensitivity, hypotension, edema, fever, chills, headache, rash, anorexia, nausea, vomiting, hypoalbuminemia, increased transaminases, decreased lymphocytes; risk for vascular leak syndrome Hypersensitivity reactions, rash, mucositis, nausea, vomiting, decreased wound healing, rare GI perforation, ILD; decreased white and lymphocyte cell and platelet counts, hyperglycemia, hyperlipidemia, hypertriglyceridemia, increased alkaline phosphatase and aspartate aminotransferase, increased serum creatinine, hypophosphatemia

Bevacizumab (Avastin, Genentech, South San Francisco, California)

Advanced/metastatic colorectal, breast, lung renal cell cancers, and glioblastoma

Cetuximab (Erbitux, Bristol-Myers Squibb,

New York)

Advanced/metastatic colorectal cancer, head and neck cancer with radiation therapy, lung cancer

Gemtuzumab ozogamicin (Mylotarg, Wyeth, Madison, New Jersey)

CD33-positive acute myelogenous leukemia (age 60 patients who are not candidates for standard therapy) Single agent treatment of colorectal cancer patients with disease progression after fluoropyrimidine-, oxaliplatin-, or irinotecan-containing regimens

Panitumumab (Vectibix, Amgen Inc, Thousand Oaks, California)

Rituximab (Rituxan, Genentech, South San Francisco, California)

CD20-positive B-cell nonHodgkins lymphomas

Trastuzumab (Herceptin, Genentech, South San Francisco, California) Other IV biologicals

Human epidermal growth factor receptor 2 positive breast cancer adjuvant and in metastatic setting

Aldesleukin (Proleukin, Novartis, East Hanover, Renal cell carcinoma, metastatic melanoma New Jersey), interleukin 2, cytokine

Bortezomib (Velcade, Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts) Denileukin diftitox (Ontak, Seragen, Inc, Hopkinton, Massachusetts)

Multiple myeloma, mantle cell lymphoma

Persistent or recurrent cutaneous T-cell lymphoma

Temsirolimus (Torisel, Wyeth, Madison, New Jersey)

Advanced renal cell cancer

Data from Wilkes and Barton-Burke4 and Polovich et al.5

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targeted agents that are commonly administered, their indications, and their common adverse effects.

TREATMENT REGIMENS
The goals of chemotherapy and biotherapy are cure, control, or palliation. Adjuvant therapy is intended to augment the primary treatment, such as adjuvant chemotherapy for breast cancer following surgical resection of the breast lesion, and because it is a systemic therapy, it is aimed at eradicating micrometastatic disease. Neoadjuvant therapy is given prior to the primary therapy, often surgery, to make it more effective or even possible. An example of this is neoadjuvant chemotherapy given to a patient with breast cancer who wishes to have a lumpectomy but has a large primary tumor; neoadjuvant chemotherapy can shrink the tumor so that the surgical resection is possible. Combination chemotherapy and/or biotherapy combines drugs with different mechanisms of action, avoids overlapping toxicities, and because tumors tend to be heterogeneous, with more than 1 type or clone of cells, is more likely to increase the proportion of cells killed with each treatment. In addition, it reduces the likelihood that resistance will develop.6 Standard IV chemotherapy treatment regimens were originally designed to be administered in the outpatient setting every 21 days or when the normal cells, such as the cells in the bone marrow, that nadir (time at which the lowest blood counts after drug administration occur) at 10 to 14 days, have recovered sufficiently to allow another cycle of chemotherapy to be given. The theoretical purpose was to kill a certain number (log kill) of cancer cells with each cycle until only a few cancer cells remained, which could then be killed by the immune system. For some patients, the immune system is turned off or changed so that it does not recognize cancer cells as being foreign. The cancer cells mutate or become resistant, so they are no longer sensitive to the chemotherapy regimen. Researchers are actively looking into strategies to avoid resistance.7 More intensive regimens were developed that required the patient to be hospitalized to provide support and aggressive symptom management, such as induction therapy for a patient with acute myelogenous leukemia, or to undergo bone marrow transplantation. Today, with the greater skill and sophistication of nurses and resources in outpatient clinics and evidence of safety, a number of centers administer high-dose chemotherapy, with autologous stem cell rescue, in the ambulatory setting. Once the patient receives the therapy, however, the challenge is to support the patient so she or he can tolerate treatment and survive to complete the therapy. To benefit from a standard chemotherapy regimen, patients must receive a certain percentage of the prescribed drugs, usually 80%, to result in adequate cell kill.8 This is called relative dose intensity. It is imperative that the nurse collaborate effectively with
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the oncologist to prevent nausea/vomiting; minimize other symptoms, such as severe diarrhea, if possible; and teach patients to manage self-care strategies and notify their provider as soon as any complications occur. Furthermore, it is important for the nurse to help the patient understand that the therapy should be given on schedule and that vacations should be delayed until after the course of therapy is completed, especially when the patient is receiving potentially curable therapy. It is also important that the patient receive full doses. If the likelihood of febrile neutropenia is 20% or more, it is appropriate for the patient to receive growth factor support with granulocyte colony-stimulating factor, such as pegfilgrastim (Neulasta, Amgen, Inc, Thousand Oaks, California) or filgrastim (Neupogen, Amgen, Inc), so that the drug dose need not be reduced.9 There have also been advances in manipulating drug doses, such as the use of dose-dense therapy. In the adjuvant setting of breast cancer, studies showed that the increased dose delivered in a shorter time reduced tumor regrowth and increased survival.10 Growth factor support is necessary to prevent febrile neutropenia and ensure that the patient receives as close to 100% relative dose intensity as possible.11 Of course, there continue to be many clinical trials attempting to improve therapies.

DOSE DETERMINATION
Most chemotherapy drugs are administered on the basis of body surface area (BSA) in milligrams per meters squared (mg/m2); less commonly, milligrams per kilogram (mg/kg) or a dose based on the drugs area under the curve (AUC) are used. Years ago, a nomogram was used to determine BSA; today, a formula is used to determine BSA, and a number of Web sites offer BSA calculators. The formula for calculating BSA is as follows:

The most precise way of determining dose is based on the estimated serum level the drug will reach in a given person based on the function of the organ excreting the drug, such as the kidneys, and the patients age. The AUC is calculated using the Calvert formula, which uses 1 of 2 formulas, the Cockcroft-Gault or Jelliffe formulas, to calculate the estimated creatinine clearance or glomerular filtration rate (GFR). The dose for carboplatin is prescribed as a target AUC dose, which can range from 1 to 8. Radiosensitizing doses of carboplatin are written as a target AUC dose of 2, whereas a more aggressive treatment regimen might be a target AUC dose of 4 or 6. The dose is calculated using either of the 2 GFR formulas. For determining AUC, use the Calvert formula as follows:

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To calculate the GFR, use either of these formulas but make sure the formula is used consistently. Begin by calculating creatinine clearance based on a current serum creatinine level. A. Cockcroft-Gault formula

B. Jelliffe formula

SAFE HANDLING DURING DRUG ADMINISTRATION

Chemotherapy and certain biotherapy drugs are known to be potentially hazardous. Hazardous drugs are defined as capable of causing (1) changes in genes (genotoxic), (2) cancer (carcinogenic), (3) damage to the unborn fetus (teratogenic or impairing fertility), and (4) organ toxicity at low doses.12 In the early days of cancer treatment, nurses and pharmacists who mixed and administered these drugs were found to have mutagens in their urine, liver problems, miscarriages, and stillbirths, as well as acute symptoms such as eye irritation, rashes, allergic reactions, and alopecia.13-15 The American Society of Health-System Pharmacists (ASHP) developed the first guidelines in 1985 to limit exposure to chemotherapy,16 and the Occupational and Safety Administration (OSHA) issued guidelines for safe handling soon after.17 The ONS18 and the National Institute for Occupational Safety and Health (NIOSH) issued subsequent position statements and guidelines,12,19 and ASHP issued guidelines again.19 There are many potential routes of exposure: reconstitution of powdered or lyophilized drugs, expelling air from syringes, priming of tubing, handling of patient excreta, leaking of IV connections, transporting chemotherapy, chemotherapy spills, and removal of PPE. To minimize possible exposure, nurses should adopt recommendations from the OSHA, ASHP, ONS, and NIOSH. All drugs should be prepared in a biological safety cabinet (BSC), and secondary lines should be primed in the BSC with plain solution that does not contain drugs. A closed-system transfer device should be placed on the end of tubing and syringes when transported to the nurse administering the drug, and the drug should be transported in a zippered bag identified as chemotherapy or hazardous drugs. All syringes and tubing should have luer-

lock connections. Air bubbles should never be expelled from the syringe except under a BSC. The nurse should wear a moisture-impervious gown with a closed front and double gloves (nitrile, latex if not allergic, or other chemotherapy-tested gloves) and change them every 30 minutes. The inner glove should be placed first, followed by the gown with the cuff covering the glove cuff, and then the outer layer of gloves should cover the gown cuff. The nurse should be very careful not to eat or drink in the treatment area because any aerosolized drug will be ingested. The nurse should always work below eye level or wear splash goggles if there is risk of a splash. The nurse should be comfortable when administering the drug(s). IV push medications should be given with the nurse sitting next to the patient, with an absorbent gauze, under which is a moisture-proof pad, under the piggyback site into which the drug will be injected. Once the drug is given, the syringe should be encased in the gauze and pad and then dropped directly into the leak-proof, puncture-proof, chemotherapy waste container. If administering an IV bolus or short infusion, use the primary administration set to flush any remaining drug from the tubing, disconnect the entire IV set without disconnecting the chemotherapy bag and tubing from the primary administration set, and place it into the chemotherapy waste container when the administration is complete. When handling patient excreta, gloves and a gown should be worn. There should also be a chemotherapy spill kit in the infusion area or on the unit where the patient is being treated. If a spill occurs, cordon off the area with a sign to warn others. Wear the closed-front gown, double gloves, and face shield and goggles that are found in the spill kit, along with an N95 respirator mask. After cordoning off the spill, absorb wet spills with the included powder or an absorbent sponge and then clean the area 3 times with detergent and water. If glass is broken, use the included scoop and place the glass in the leak-proof, puncture-proof, closed hazardous waste container.20,21

ANTINEOPLASTIC DRUG ADMINISTRATION

Follow ONS and Infusion Nurses Society guidelines for the administration of antineoplastic drugs,4,22 as well as hospital policy and procedure. Before administering the prescribed drug(s), the nurse must organize and perform the following: Review ordered drug(s), doses, and routes, and whether additional supportive medications (eg, antiemetics) or fluids (eg, hydration) are needed. Patient assessment: knowledge of treatment, potential adverse effects, and self-care measures; consent; laboratory values (eg, complete blood cell count plus differential, renal and liver function tests, and cardiac function tests if drug causes cardiotoxicity).

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Confirm patent vascular access (peripheral: if a vesicant is being given, a new site should be started; if nonvesicant, site should be 24 hours old; and if central, confirm that the catheter tip terminates in the superior vena cava, brisk blood return). Drug reference to double-check regimen dosages, routes, adverse effects. Personal protective equipment: gown, gloves, goggles if needed, spill kit, hazardous waste container, closed system with luer-lock connectors. If a vesicant is being administered, review institutional extravasation policy and procedure. If a drug causing hypersensitivity reactions is being given, review institutional hypersensitivity policy and procedure; know where code cart is located. Once the written antineoplastic drug order has been reviewed, double-check that the drug and dose are appropriate for the patients condition, diagnosis, past therapies, and drug allergies. Find another nurse who is certified to administer antineoplastic therapy, and double-check the patients BSA, dose calculation, drug route, and appropriateness of drug and dose (eg, against a standard reference). When the drug(s) has been mixed by pharmacy, double-check the label against the order with a second nurse. Use 2 identifiers to identify the patient, usually name and medical record number as shown on the patient wristband. Review the planned chemotherapy with the patient and clarify any issues that arise. Reinforce teaching about potential adverse effects and self-care measures. Perform physical examination of oral mucosa if the drug can cause stomatitis; assess peripheral neuropathy by any difficulties with hand function, such as picking up a coin or walking, if the drug can cause peripheral neuropathy; and conduct other examinations appropriate to the anticipated drug toxicity. Assess patency of vascular access and site. If unsure of a peripheral IV site, start a new one in a separate vein pathway or proximal to a prior, old puncture (30 minutes). Implanted ports are often the central catheter of choice for ambulatory patients receiving ongoing antineoplastic therapy. Inspect the ipsilateral chest for signs or symptoms of vascular thrombosis. If unable to obtain a brisk blood return, discuss declotting the catheter per institutional protocol. If unable to establish a blood return successfully, discuss a flow study to establish patency with the physician. Use only noncoring Huber needles to access an implanted subcutaneous port. Antineoplastic drugs can be administered via IV push, IV bolus, or IV administration over 1 or more hours, or as a continuous infusion. If administering a vesicant, administer through the port of the primary administration set closest to the patient. Ensure that the IV flows smoothly when allowed to flow freely. Aspirate and confirm the presence of a blood return just prior to drug administration, after every 2 to 5 mL of drug administered, and at the completion. Continuously view the IV insertion site for any signs or symptoms of erythema or infiltration.

Teach the patient to advise immediately if any stinging, burning, or discomfort is noted. If extravasation is suspected, stop the infusion immediately and assess the site and whether extravasation has occurred. If in doubt, treat as an extravasation. Continuous IV administration of vesicants can be achieved only through a central catheter. Make certain the Huber needle is securely stabilized under the dressing, because infiltrations have occurred in patients with implanted ports. Following the administration of the antineoplastic agent, the nurse should document the presence of a blood return baseline, throughout administration and at the completion of the administration. In addition, the nurse should document the patients tolerance of the procedure and the plan for reinforcing teaching and follow-up.

ISSUES AND TRENDS

Extravasation Extravasation refers to infiltration of a drug, which can cause necrosis if allowed to go outside the vein. Common vesicant chemotherapy drugs are shown in Table 4. The nurse must be extremely vigilant when administering vesicantscontinually assessing the peripheral IV site if giving an IV push drug peripherally, and asking the patient to notify if any stinging or burning is felt. If the catheter punctures the back of the vein, with the bevel half in and half out of the vein, the drug can leak out and the nurse can still aspirate a blood return. If in doubt, always treat it as an extravasation. If the catheter stops infusing, the blood return is lost, or if the patient complains of stinging or burning, stop the administration immediately and assess.4,22 Aspirate any remaining drug from the tubing. If the drug is a vinca alkaloid, such as vincristine or vinblastine, administer hyaluronidase subcutaneously into the area of infiltration.4 Apply a compress and then heat topically. If the drug is an anthracycline, such as doxorubicin (Adriamycin, Pharmacia, Inc, Kalamazoo, Michigan), aspirate any remaining drug from the tubing and then remove the IV catheter. An incident report should be completed for any extravasation event. Dexrazonxane HCl (Totect, TopoTarget, Rockaway, New Jersey) is recommended to be administered within 6 hours of an anthracycline extravasation, which is discussed in the following text.4 Apply compress and then topical cold. Document the process precisely, because extravasation is the primary cause of oncology nurse malpractice court appearances.23 In 2008, dexrazonxane HCl was Food and Drug Administration approved as a treatment for extravasation involving doxorubicin, daunorubicin, epirubicin, and idarubicin. It is a free radical scavenger, first used in higher doses in patients who had received their lifetime maximum dose of doxorubicin and who required additional doxorubicin (dexrazonxane, Zinecard, Pfizer, Inc, New York). The drug is a hazardous drug (initially studied as a

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TABLE 4

Vesicant Chemotherapy Agents and Antidote If Knowna

Drug
Nitrogen mustard (Mustargen, Merck, Whitehouse Station, New Jersey) Daunorubicin (Cerubidine, Bedford Laboratories, Bedford, Ohio), doxorubicin (Adriamycin, Pharmacia, Inc, Kalamazoo, Michigan), epirubicin (Ellence, Pharmacia and Upjohn, Bridgewater, New Jersey), idarubicin (Idamycin, Pfizer, New York) Mitomycin C (Mutamycin, Bristol-Myers Squibb, Princeton, New Jersey), dactinomycin (Cosmegen, Merck, Whitehouse Station, New Jersey)

Antidote (if Known)

Sodium thiosulfate (1/6 M solution)

Totect IV administration daily for 3 d begun within 6 h of extravasation; topical cooling (stop 15 min before and after Totect treatment)

None; topical cooling for 1520 min at least 4 times a day

Vincristine (Oncovin, Gensia Sicor Pharmaceuticals, Inc, Irvine, Hyaluronidase (Hydase), recombinant hyaluronidase human injection California), vinblastine (Velban, Gensia Sicor Pharmaceuticals, Inc, (Hylenex), hyaluronidase, bovine (Amphadase); topical heat 4 Irvine, California), vinorelbine (Navelbine , GlaxoSmithKline Research, times a day Triangle Park, North Carolina)
a

Data from Polovich et al.4

chemotherapy drug), and PPE must be used for safe handling. The drug must be administered within 6 hours of the extravasation. Remove topical cooling 15 minutes before the drug is administered and throughout the treatment. The drug is dosed on the basis of BSA: 1000 mg/m2 IV on days 1 and 2 and 500 mg/m2 on day 3. The drug is diluted in 1 L of 0.9% normal saline and infused over 1 to 2 hours at about the same time daily for 3 days via a large vein in a different arm from the extravasation. Total dose should not exceed 2000 mg. Potential adverse effects are fever, injection site pain, peripheral edema, nausea, vomiting, and diarrhea.24 Infusion Nurses Societys Infusion Nursing Standards of Practice on extravasation (Standard 55) identifies 5 key actions23: 55.1: Extravasation shall be defined as the inadvertent administration of a vesicant medication or solution into surrounding tissue. 55.2: Extravasation shall be identified and assessed by the nurse, and appropriate nursing interventions shall be implemented to minimize the effects of the extravasation. 55.3: Extravasation shall prompt immediate discontinuation of the infusion and shall require immediate intervention and physician notification. 55.4: All information related to the event shall be documented in the patients permanent medical record. 55.5: An extravasation prevention plan that defines the skills of nurses who administer irritating or vesicant medications and solutions shall be strongly considered.
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Hypersensitivity Reactions Hypersensitivity reactions may occur with any drug, but there are a few antineoplastic agents, such as L-asparaginase and bleomycin, that are more likely to cause reactions. Administering a test dose is usually ordered prior to these drugs.5 Other drugs, such as cetuximab (Erbitux, Bristol-Myers Squibb) and rituximab (Rituxan, Genentech), can cause reactions ranging from infusion reactions (cytokine release syndrome with fever, urticaria, and dyspnea) to frank hypersensitivity reactions of severe bronchospasm (grade 3) and anaphylaxis (grade 4). If the patient develops fever, urticaria, or dyspnea, the infusion is stopped, the patient is assessed, and when stable, the drug is usually resumed at 50% of the infusion rate. If a patient experiences a grade 3 or 4 reaction, the drug is stopped immediately, and interventions to stabilize the patient are instituted. The primary nursing functions are to ensure a patent airway, breathing, and circulation. Maintain oxygenation with O2 and blood pressure with IV saline and drugs such as intramuscularly administered epinephrine as needed. Usual drug therapy includes H1 and H2 blockers (such as diphenhydramine, ranitidine), anti-inflammatory corticosteroids (such as hydrocortisone), bronchodilators, and, if needed, vasoconstrictor therapy with epinephrine.25 Table 5 summarizes nursing assessment and intervention parameters.

PATIENT/FAMILY TEACHING
Most adverse effects of antineoplastic drugs occur after the patient has left the clinic or hospital. Therefore, it is imperative to review patient self-care instructions and
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TABLE 5

Drugs, Signs and Symptoms of Hypersensitivity Reactions (HSRs), and Nursing Interventionsa
Drugs Associated With Chemotherapy Drugs
L-Asparaginase

Biologicals
Denileukin diftitox Ibritumomab tiuxetan, tositumomab (radioconjugate monoclonal antibodies) Cetuximab Rituximab Gemtuzumab ozogamicin Rarely, panitumumab

IV

Paclitaxel, docetaxel HSRs Cisplatin, carboplatin, oxaliplatin Etoposide Rarely, doxorubicin, bleomycin

Cytokine release syndrome associated with monoclonal antibodies

Symptoms: fever or chills, nausea, headache, rash, difficulty breathing Symptoms: generalized itching, chest tightness, difficulty speaking, uneasiness, dizziness, nausea, abdominal pain, sense of impending doom, desire to urinate or defecate, chills Immediately stop infusion, change tubing to primary administration set and keep patent, notify physician and stay with the patient. If a physician office practice, call 911 or emergency medical assistance. Have resuscitation equipment nearby.

Signs: hypotension, tachycardia, asthenia, dyspnea Signs: hypotension, localized or generalized urticaria, respiratory distress with or without wheezing, cyanosis, periorbital or facial edema

Signs and symptoms

Nursing actions

Monitor vital signs including oxygen saturation every 2 min until patient is stable, then every 5 min 30 min, and then every 15 min

Maintain patent airway, support breathing

Administer oxygen; administer bronchodilators as ordered; epinephrine 1:1000 (0.3-0.5 mg) intramuscularly (IM) into thigh or EpiPen (Meridian Medical Technologies, Inc, Columbia, Maryland) as ordered IV hydration such as 0.9% sodium chloride as ordered, often wide open if hypotensive; epinephrine 1:1000 (0.3-0.5 mg) IM into thigh or EpiPen if needed and as ordered Diphenhydramine 25-50 mg IV push; famotidine 20 mg IV or ranitidine 50 mg IV as needed to reverse H1 and H2 histamine release Hydrocortisone 100-500 mg IV, methylprednisolone 30-50 mg IV, or dexamethasone 10-20 mg IV

Maintain circulation

Manage hives, itching, flushing, edema of tongue or lips

Prevent recurrence of signs and symptoms Provide emotional support to patient and family Admit patient for observation if anaphylaxis Document patient assessment, interventions, and patient response
a

Signs and symptoms may recur after resuscitation drugs wear off

Data from Wilkes and Barton-Burke,4 Polovich et al,5 and Sampson et al.25

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ensure that the patient has a good understanding and can perform the required self-care measures or that accompanying family members can, and most important, that the patient and family know which adverse effects should be reported right away and whom to call. The nurse should document clearly the baseline nursing assessment, including laboratory test data; the procedure of drug administration, including the condition of the peripheral IV site or vascular access device and blood return; and patients response. In addition, it is important to document the teaching plan, including the patients and familys ability to follow the discharge instructions, as well as the follow-up plan and when the patient will be seen in clinic for the evaluation of possible adverse effects. If it is the first antineoplastic treatment in the outpatient area, the nurse should call the patient the next day to assess tolerance, whether any adverse effects have been experienced, and whether the patient is following the instructions. If the patient is having any untoward event, the nurse should decide whether the patient needs to be seen in person for an evaluation.

SUMMARY AND CONCLUSION

Nurses who administer antineoplastic drugs must have a strong foundation of knowledge about the disease and drugs used in treatment, as well as the skill of an infusion nurse to ensure safe drug therapy. The nurse must be able to deliver highly competent physical care and provide compassionate and understanding support for the patient and the family. The nurse must always be prepared for an untoward reaction from the drug and know the institutions policies and procedures for the management of extravasation and hypersensitivity reactions. Finally, the nurse must be an effective patient/family educator because most adverse effects occur after the patient has returned home following the drug administration.
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For more than 23 additional continuing education articles related to drug therapy, go to NursingCenter.com/CE.

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