CLINICAL JOURNAL OF ONCOLOGY NURSING • VOLUME 4, NUMBER 4 • HYPERSENSITIVITY REACTION TO PACLITAXEL 161

FEATURE ARTICLE

Hypersensitivity Reaction to Paclitaxel:Nursing Interventions

Jamie S. Myers, RN, MN, AOCN®

Submitted November 1999. Accepted forpublication January 3, 2000. (Mention of spe-cific products and opinions related to thoseproducts do not indicate or imply endorse-ment by the Clinical Journal of OncologyNursing or the Oncology Nursing Society.

P aclitaxel has been ap-proved as second-linetherapy for recurrent

ovarian carcinoma (Olson,Sood, Sorosky, Anderson, &Buller, 1998; Physicians’ DeskReference [PDR] Nurse’sHandbook, 1999) and is be-coming the standard of care forfirst-line therapy in ovariancancer when administered incombination with cisplatin orcarboplatin (Olson et al.).Paclitaxel also is used in com-bination with other agents totreat relapsed or resistant breastcancer and resistant AIDS-re-lated Kaposi’s sarcoma. Clini-cal studies are being conductedto evaluate its use for advancedhead and neck cancer, adeno-carcinoma of the upper gastrointestinaltract, hormone-refractory prostate cancer,advanced small cell and non-small cell lungcancer, and leukemias (PDR Nurse’s Hand-book).

Incidence and Etiology ofHypersensitivity Reactions

A significant incidence of hypersensi-tivity reactions (HSRs) has been associ-ated with paclitaxel. HSRs first wereobserved during phase I clinical trials.Prior to the advent of premedications, theincidence was estimated as high as 10%–16% and currently is estimated to be 1%–3% (Olson et al; 1998; Rowinsky & Done-hower, 1995; Weiss, 1992).

Most chemotherapy-induced HSRs aretype I reactions. Type I reactions occur be-cause initial exposure to the antigen stimu-lates the formation of specific IgE antibod-ies that attach to receptors on basophilsand mast cells. Upon subsequent exposureto the antigen, the IgE antibodies trigger

the release of chemical mediators (such ashistamine) that produce the anaphylacticresponse. Paclitaxel-related HSRs are con-sidered to be anaphylactoid rather thananaphylactic, as they are not caused by aspecific IgE antibody response to an anti-gen. Anaphylactoid reactions are not de-pendent on prior exposure to an antigen.Rather, the antigen binds to cell surfacesand causes the direct release of inflamma-tory mediators. The resultant clinicalmanifestations are identical to an anaphy-lactic reaction (Craig & Capizzi, 1985;Labovich, 1999). Paclitaxel is prepared ina diluent made up of polyoxyethylatedcastor oil (Cremophor El®, BASF Aktien-gesellschaft, Ludwigschafen, Germany)that is responsible for the histamine re-lease and HSRs in the majority of cases(Olson et al., 1998).

Premedication has markedly decreasedthe incidence of paclitaxel-related HSRs. Acommonly used premedication regimen in-cludes dexamethasone, diphenhydramine,and an H2-histamine antagonist such ascimetidine, ranitidine, or famotidine. The

dexamethasone may be admin-istered as 20 mg orally 12hours and 6 hours prior totherapy. However, recent re-search has indicated that asingle dose of dexamethasone20 mg IV 30 minutes prior totherapy is as efficacious as theoral regimen for the preventionof HSRs (Bookman, Kloth,Kover, Smolinski, & Ozols,1997; Markman et al., 1999;Micha et al., 1998). IV dosingwith dexamethasone just priorto treatment has simplified thepremedication regimen for pa-tients. Patients may forget totake one or both doses of theoral dexamethasone in prepara-tion for their treatments. Manypatients receive paclitaxel in

combination with more emetogenic agents,for which they may receive antiemetictherapy with a 5-HT3 receptor antagonist(dolasetron, ondansetron, or granisetron).The addition of IV dexamethasone to a 5-HT3 receptor antagonist has been to shownto increase antiemetic efficacy up to 20%(Hesketh et al., 1994).

Paclitaxel-related HSRs occur rapidly,typically during the first 10 minutes to anhour of the infusion (Peereboom et al.,1993; Rowinsky & Donehower, 1995).Signs and symptoms may include any or allof the following: respiratory distress, hy-potension, angioedema, flushing withurticaria, bronchospasm, diaphoresis, hy-pertension, and chest or back pain (Olson etal., 1998; Peereboom et al.; Weiss, 1992).

Paclitaxel, a mitotic inhibitor, is used to treat a va-riety of cancers. A significant incidence of pacli-taxel-related hypersensitivity reactions (HSRs)occurs because of the diluent used. Premedicationwith dexamethasone, diphenhydramine, and H2-histamine antagonists has markedly decreased theincidence of HSRs. Paclitaxel-related HSRs shouldbe managed immediately and appropriately by (a)stopping the infusion, (b) administering oxygen,(c) infusing fluids, (d) continuously monitoringblood pressure, pulse, and oxygenation, and (e)initiating standing orders for IV corticosteroids anddiphenhydramine or other emergency medications.Oncology nurses are key to the rapid recognitionand treatment of paclitaxel-related HSRs.

162 JULY/AUGUST 2000 • VOLUME 4, NUMBER 4 • CLINICAL JOURNAL OF ONCOLOGY NURSING

Facial flushing alone is not an indication forstopping the infusion.

Because of the incidence of paclitaxel-related HSRs and the fact that they tend tooccur early during the infusion, most insti-tutions have very specific standards for themonitoring of vital signs (see Figure 1).Because most paclitaxel-related HSRs oc-cur during the first or second dose, someinstitutions alter vital sign monitoring forsubsequent doses if the patient toleratesthe first one to two infusions well. One in-stitution has treated more than 1,100patients with one-hour paclitaxel infusions(Sarah Cannon Cancer Center in Nash-ville, TN). Researchers there recommendtaking baseline vital signs and continu-ously monitoring the patient for the first10 minutes of the infusion. Vital signs arerepeated if the patient becomes symptom-atic (Greco, Thomas, & Hainsworth,1999). Using a continuous blood pressuremonitoring device that can be set at spe-cific time intervals may be helpful. Thesedevices also may be equipped with oxygensaturation monitoring capabilities. In theevent of an HSR, oxygen saturation is avaluable assessment tool, as dyspnea andbronchospasm may be severe.

Nursing InterventionsIn the event of a paclitaxel-related HSR,

the nurse should stop the infusion immedi-ately and continue to administer IV fluids tomaintain blood pressure. Oxygen should beadministered to counteract shortness ofbreath and decreased oxygen saturation.Not all facility protocols specify the drugsof choice to treat the symptoms of HSR.Most recommend having emergency drugsavailable in the event of a reaction. The lit-erature states that the most commonly useddrugs are epinephrine, antihistamines, andcorticosteroids. (Compton, 1997; Craig &Capizzi, 1985; Labovich, 1999; Mackan,1995). Because of the potential rapidity andseverity of paclitaxel-related reactions, hav-ing standing orders for the agents to beadministered is ideal (see Figure 2). This al-lows the interventions to proceed while the

physician is being notified and may de-crease the need for intubation.

Current Literature onRechallenge

The literature supports rechallenging apatient who has had a paclitaxel-relatedHSR. Studies of paclitaxel rechallenge arebeing conducted because a survival advan-tage exists with the use of paclitaxel forwomen with advanced ovarian cancer ascompared to other regimens (McGuire etal., 1996). The first publication of researchresults (Peereboom et al., 1993) describedthe successful retreatment of eight patientswho had major paclitaxel-related HSRs.The patients were rechallenged within hoursto days with fresh solutions of paclitaxel atfull doses. Premedication regimens includedup to four doses of corticosteroids (typicallydexamethasone 20 mg IV every six hours)as well as IV diphenhydramine and an H2-histamine antagonist 30 minutes prior totherapy. Initial infusion rates were 10%–25% of the 24-hour infusion rate. This ratewas maintained for 1–2 hours and thengradually increased over the next 3–6 hoursto equal a 24-hour infusion rate. Two pa-tients had minor facial flushing that did notrequire intervention. One patient experi-enced a mild rash. One patient who had ex-perienced severe chest pain during HSR hadmild, transient chest pain during the re-challenge.

A retrospective study was published re-cently for six patients who were rechal-lenged after experiencing paclitaxel-re-lated HSRs (Olson et al., 1998). The rec-ommendations from this study were tostabilize the patient and remedicate withdexamethasone 20 mg IV, diphenhy-dramine 50 mg, and cimetidine 300 mgIV. Thirty minutes following premedica-tion, paclitaxel (using the original solu-tion) was reinitiated at 1–2 mg per hour.The rate was increased gradually over thenext 4–6 hours until a 24-hour rate wasobtained. Six of seven women were re-treated successfully without complica-

tions. One woman refused retreatmentover 24 hours. A three-hour retreatmentwas attempted, but she experienced a sec-ond severe HSR, requiring admission tothe intensive-care unit.

Additional research is needed beforerechallenge becomes the standard of care.To date, the sample sizes have been small.If rechallenge is being considered, itshould not be attempted in a setting that isnot equipped to handle respiratory and cir-culatory emergencies.

Current Literature onRates of Infusion

Several recent studies discuss the safetyof one-hour paclitaxel infusions (Greco etal., 1999; Hainsworth, Raefsky, & Greco,1995; Seidman et al., 1998). Both one- andthree-hour paclitaxel infusions have beenshown to be safe with no increase in theincidence of HSRs. Patients with a historyof recent myocardial infarction, second-degree or higher heart block, congestiveheart failure, or other contraindication toexcess fluid overload may be treated moresafely with a three-hour infusion (Greco etal.). Myelosuppression is less severe withthe shorter infusions as compared to 24-hour infusions. Peripheral neuropathy oc-curs with more frequency (Greco et al.).

One study evaluated the safety of pacli-taxel infusions given in less than one hour(Tsavaris & Kosmas, 1998). Paclitaxel at adose of 175 mg/m2 in 150 ml of normal sa-line was administered to four patients whohad received at least two prior cycles ofpaclitaxel without HSRs. All four patientsexperienced angioedema, sinus tachycar-dia, dyspnea, and diaphoresis within 5–15minutes of beginning the paclitaxel infu-sion. Three patients also experienced gen-eralized edema. The paclitaxel infusionswere stopped, and the patients were medi-cated with dimethindene maleate, rani-tidine, and methylprednisolone. All symp-toms resolved within 15–30 minutes, andthe patients were successfully retreatedwith the one-hour rate. The study con-

FIGURE 2. SAMPLE STANDING ORDERS FOR PACLITAXEL-RELATED HYPERSENSITIVITY REACTIONS

Note. Based on information from Craig & Capizzi, 1985; Labovich, 1999; Weiss, 1990.

• Stop paclitaxel infusion.• Infuse normal saline at 200 cc/hour until blood pressure stabilizes.• Administer oxygen at two to four liters per nasal cannula to maintain oxygenation.• Administer methylprednisolone 125 mg IV push to counteract respiratory distress.• Administer diphenhydramine 50 mg IV push to counteract respiratory distress and inflammation.• Continuously monitor blood pressure, pulse, and oxygen saturation.• Notify physician immediately for further orders.• Initiate a code if airway patency is not maintained or cardiopulmonary arrest occurs.

• Every 5 minutes x 3 (or continuous obser-vation for the first 15 minutes)

• Every 15 minutes x 2• Then hourly (Decrease to every 4 hours for

24-hour infusions.)

FIGURE 1. SAMPLE VITAL SIGN MONITORING

GUIDELINE FOR PACLITAXEL INFUSION

Note. Based on information from Greco et al.,1999; Labovich, 1999.

CLINICAL JOURNAL OF ONCOLOGY NURSING • VOLUME 4, NUMBER 4 • HYPERSENSITIVITY REACTION TO PACLITAXEL 163

cluded that paclitaxel infusions of lessthan one hour cannot be recommended.

Nursing RoleThe role of the oncology nurse is key to

early identification and management ofpaclitaxel-related reactions. Appropriatemonitoring of vital signs and prompt ini-tiation of interventions are vital to a posi-tive patient outcome. In addition, the on-cology nursing role includes patient/family education about the medication andpotential for side effects and toxicities. Inthe event that a reaction does occur, calmreassurance to the patient and family whileinterventions are efficiently administeredcan make a difference in their anxietylevel and perception of the event. Carefuldocumentation is necessary for an accuratemedical record. The physician will con-sider the severity of the HSR whendetermining whether to rechallenge thepatient after his or her condition stabilizes.

In the event that the physician wants torechallenge the patient with paclitaxel, edu-cation and reassurance are acutely neces-sary to help put the patient and family atease with the treatment plan. Patients andfamilies must be assured of the constantsurveillance of the nursing staff during theinitial 15–60 minutes of the infusion. Theyshould be informed of the immediate avail-ability of medications to treat any signs andsymptoms that they may experience. Theyshould be encouraged to discuss any issuesof concern about the treatment plan with theoncology nurse and the physician prior togiving consent to proceed.

Although premedication with dexa-methasone, diphenhydramine, and H2-his-tamine antagonists has greatly decreasedthe incidence of HSRs to paclitaxel, theystill have the potential to occur. Oncologynurses play a major role in the prevention of

type I HSRs and are instrumental in detect-ing these reactions early and interveningquickly and appropriately.

ReferencesBookman, M.A., Kloth, D.D., Kover, P.E.,

Smolinski, S., & Ozols, R.F. (1997). Intrave-nous prophylaxis for paclitaxel-related hy-persensitivity reactions. Seminars in Oncol-ogy, 24(Suppl. 19), S19-13–S19-15.

Compton, J. (1997). Use of glucagon in intract-able allergic reactions and as an alternative toepinephrine: An interesting case review. Jour-nal of Emergency Medicine, 23(1), 45–47.

Craig, J.B., & Capizzi, R.L. (1985). The preven-tion and treatment of immediate hypersensi-tivity reactions from cancer chemotherapy.Seminars in Oncology Nursing, 1, 285–291.

Greco, F.A., Thomas, M., & Hainsworth, J.D.(1999). One-hour paclitaxel infusions: Re-view of safety and efficacy. Cancer JournalFrom Scientific American, 5(3), 179–189.

Hainsworth, J.D., Raefsky, E.L., & Greco, F.A.(1995). Paclitaxel administered by a 1-hourinfusion: A phase I-II trial comparing twoschedules. Cancer Journal From ScientificAmerican, 1(4), 281.

Hesketh, P.J., Harvey, W.H., Harker, W.G.,Beck, T.M., Ryan, T., Bricker, L.J., Kish,J.A., Murphy, W.K., Hainsworth, J.D., &Haley, B. (1994). A randomized, double-blind comparison of intravenous ondansetronalone and in combination with intravenousdexamethasone in the prevention of high-dose cisplatin-induced emesis. Journal ofClinical Oncology, 12, 596–600.

Labovich, T.M. (1999). Acute hypersensitivityreactions to chemotherapy. Seminars in On-cology Nursing, 15, 222–231.

Mackan, M.M. (1995). Managing the patientwith anaphylaxis, part 2: Therapeutic strate-gies. Emergency Medicine, 27(3), 20–35.

Markman, M., Kennedy, A., Webster, K.,Peterson, G., Kulp, B., & Belinson, J. (1999).An effective and more convenient drug regi-men for prophylaxis against paclitaxel-asso-ciated hypersensitivity reactions. Journal ofCancer Research Clinical Oncology, 125,427–429.

McGuire, W.P., Hoskins, W.J., Brady, M.F.,Kucera, P.R., Partridge, E.E., Look, K.Y.,Clarke-Pearson, D.L., & Davidson, M. (1996).Cyclophosphamide and cisplatin comparedwith paclitaxel and cisplatin in patients withstage III and stage IV ovarian cancer. NewEngland Journal of Medicine, 334, 1–6.

Micha, J., Rettenmaier, M., Dillman, R., Fraser,P., Birk, C., & Brown, J.V. (1998). Single-dose dexamethasone paclitaxel premedica-tion. Gynecologic Oncology, 69, 122–124.

Olson, J.K., Sood, A.K., Sorosky, J.I., Ander-son, B., & Buller, R.E. (1998). Taxol hyper-sensitivity: Rapid retreatment is safe and costeffective. Gynecologic Oncology, 68, 25–28.

Peereboom, D.M., Donehower, R.C., Eisen-hauer, E.A., McGuire, W.P., Onetto, N.,Hubbard, J.L., Piccart, M., Gianni, L., &Rowinsky, E.K. (1993). Successful re-treat-ment with paclitaxel after major hypersensi-tivity reactions. Journal of Clinical Oncol-ogy, 11, 885–890.

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Author Contact: Jamie S. Myers, RN,MN, AOCN®, can be reached at ResearchMedical Center, c/o 7 East Oncology, 2316East Meyer Boulevard, Kansas City, MO64132 or at jsmyers@healthmidwest.org.

Rapid Recap

Hypersensitivity Reaction to Paclitaxel: Nursing Interventions

• Without appropriate premedication, a significant incidence of paclitaxel-related hypersensitivity reactions (HSRs)occurs.

• Dexamethasone may be given as an oral or IV premedication regimen along with IV diphenhydramine, an H2-his-tamine antagonist, and an antiemetic.

• Close monitoring of blood pressure, pulse, and oxygenation is important during initial doses of paclitaxel, particularlyduring the first 15 minutes of infusion.

• The availability of standing orders for the administration of emergency medications, such as methylprednisolone,diphenhydramine, and epinephrine, should be a standard of care for patients receiving paclitaxel.

• The literature supports the rechallenging of paclitaxel in patients who have experienced an HSR.• Oncology nurses are key to the rapid recognition and treatment of paclitaxel-related HSRs.

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