Hypersensitivity Reactions From Taxol
`
`By Raymond B. Weiss, Ross C. Donehower, Peter H. Wiernik, Takao Ohnuma, Richard J. Gralla,
`Donald L. Trump, James R. Baker, Jr, David A. Van Echo, Daniel D. Von Hoff, and Brian Leyland-Jones
`
`Taxol is an antitumor agent in clinical trial that has
`been shown to have activity against advanced ovar-
`ian carcinoma and melanoma. Hypersensitivity reac-
`tions (HSRs) have been one of the toxicities observed
`with administration of this drug. Of 301 patients
`treated, 32 patients have had definite (27 patients) or
`possible (five patients) hypersensitivity reactions to
`taxol. All but one patient had the reaction from the
`first or second exposure to this agent. Reactions
`occurred at a variety of doses and were characterized
`most frequently by dyspnea, hypotension, broncho-
`spasm, urticaria, and erythematous rashes. Thirteen
`
`(41%) patients had received premedication designed
`to prevent such toxicity; nevertheless, they sustained
`HSRs. Prolonging the drug infusion appears to have
`somewhat reduced, but not obviated, the risk of HSRs.
`The cause (taxol itself or its excipient Cremophor EL;
`Badische Anilin und Soda-Fabrik AG [BASF], Ludwig-
`shafen, Federal Republic of Germany) and the mecha-
`nism of these reactions to taxol are unknown. We
`
`provide guidelines to prevent or minimize such toxicity
`and treat reactions if they still occur.
`J Clin Oncol 8.- 1263- I268. (9 I 990 by American Soci-
`ety of Clinical Oncology.
`
`YPERSENSITIVITY reactions (HSRs)
`can be induced by many drugs, including
`most of the antitumor agents in clinical use.1'2
`These reactions to antitumor drugs usually have
`the features of type I hypersensitivity. However,
`many seem not to be mediated by immunoglobu-
`lin E (IgE), although for some drugs, proper
`studies have not been performed that define the
`reaction mechanism.2
`
`Taxol is an investigational antineoplastic agent
`derived from the bark of the western yew (Taxus
`brevifolia) with a unique antitumor mechanism
`of action. Its tumoricidal activity is attributed to
`its ability to induce irreversible aggregation of
`microtubules.3 It has been studied in phase I
`trials, and several phase II
`trials exhibiting
`clinical activity in metastatic melanomas and
`ovarian carcinomas.“ HSRs were among the
`major toxicities observed in some patients treated
`on these trials.“"“10 We have gathered detailed
`information on 32 patients who sustained such
`reactions from taxol to assess predisposing fac-
`tors, clinical manifestations, therapeutic manage-
`ment, and outcome. Some of these patients have
`had limited information published about their
`treaction,4’6'10 and others are unpublished. We
`attempt
`to define means of minimizing and
`treating taxol-induced HSRs and the mecha-
`nism(s) mediating these events.
`
`PATIENTS AND METHODS
`
`trials
`Clinicians using investigational drugs in phase I
`under sponsorship of the National Cancer Institute (NCI)
`are obligated to report to the NCI any adverse drug reactions.
`
`The records of such reports to the NCI on taxol were
`reviewed for possible HSRs. In addition, the published cases
`of such reactions were reviewed. Investigators reporting HSR
`events provided additional information upon request, and one
`of us (RBW) made site visits in several instances to gather
`details from the hospital records. Information on a total of 35
`patient reports was gathered. Two investigators (RBW and
`JRB, the latter an allergist-immunologist) analyzed these
`data and decided whether the reported reaction represented a
`true type I HSR based on the symptoms and clinical findings
`at the time of the reaction. Three patients had reactions that
`were considered to have none of the features of an HSR and
`were excluded from further analysis. These patients were
`excluded for the following reasons: reaction episode consisted
`of nausea and chest pain relieved by nitroglycerin, which was
`probably angina pectoris (one patient); dizziness, chest pain,
`and diaphoresis coincident with a new onset of atrial fibrilla-
`tion during the taxol infusion (one patient); anxiety and chest
`pain during taxol infusion relieved by a tranquilizer (one
`patient). These two investigators then categorized the remain-
`ing toxicity events into definite type I HSRs (27 patients) or
`
`From the Departments of Medicine, Walter Reed Army
`Medical Center and Uniformed Services University of the
`Health Sciences, Washington, DC: The Johns Hopkins Oncol-
`ogy Center, Baltimore, MD; Albert Einstein Cancer Center,
`New York, NY; Mt Sinai School of Medicine, New York,
`NY; Memorial Sloan-Kettering Cancer Center, New York,
`NY; University of Wisconsin Cancer Center, Madison, WI;
`University of Maryland Cancer Center, Baltimore, MD;
`University of Texas at San Antonio, San Antonio, TX;
`Division of Cancer Treatment, National Cancer Institute,
`Bethesda, MD.
`Submitted October 26, 1989; accepted March 7, 1990.
`Address reprint requests to Raymond B. Weiss, MD, Chief
`of Medical Oncolog, Walter Reed Army Medical Center,
`Washington, DC 20307.
`© 1990 by American Society of Clinical Oncology.
`0732—183X/90/0807—0018$3.00/0
`
`Journal of Clinical Oncology, Vol 8, No 7 (July), 1990. pp 1263-1268
`
`1263
`
`Genentech Exhibit 2028
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`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`Celltrion v. Genentech
`
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`
`

`

`1264
`
`WEISS ET AL
`
`possible, but not completely typical, reactions (five patients).
`These two patient groups are analyzed separately. Definite
`HSRs included at least two of the following symptoms and
`signs that appeared to be mediated by histamine release:
`hypotension, dyspnea and bronchospasm, and urticaria and
`skin reactions, along with any other manifestations of such
`reactions (eg, abdominal or extremity pain, which appeared
`to be secondary to hypoperfusion. angioedema, diaphoresis,
`etc). Possible hypersensitivity events included generalized
`erythema only, generalized pruritus only without skin lesions,
`dyspnea without documented bronchospasm, and hypoten-
`sion only without any other problem.
`
`RESULTS
`
`A total of 32 patients had clinical features of a
`definite or possible type I HSR. Table 1 provides
`characteristics of these patients. The cancer
`types were primarily melanoma and colon cancer
`with a variety of other carcinomas represented.
`Only one patient had a leukemia (acute myeloge-
`nous); no patients had lymphoma. This tumor
`spectrum reflects the fact that some patients with
`melanoma responded to taxol,4 and they were
`selectively entered on trials with this agent. The
`sex ratio was 50:50 men:women. The median age
`was 53 years; no children were treated in any of
`the studies involving this drug.
`The events of drug sensitivity occurred during
`the first taxol dose administered in 18 patients
`and the second dose in 13 patients. Only one
`patient had a reaction from a later drug dose,
`occurring during the sixth drug dose (the first
`day of a second 5-day course of taxol). Twenty-
`five (78%) of the patients had their symptoms
`
`Table 1. Clinical Features of 32 Patients With Definite or
`Possible Hypersensitivity Reactions
`
`No. of
`Patients
`
`aouuuwov
`
`16
`16
`
`Clinical Feature
`
`Tumor Types
`Melanoma
`Colon
`Other gastrointestinal
`Ovary
`Breast
`Lung
`Miscellaneous carcinomas
`Acute leukemia
`
`Sex
`Male
`Female
`
`Age
`Median, 53 years
`Range, 32-75 years
`
`develop within 10 minutes of starting the drug
`infusion; 17 of these were within 2 to 3 minutes of
`
`starting with as small a drug dose as only 1 to 3
`mg having been infused. The remainder had
`symptoms and signs develop later in the infusion
`time, from 30 to 90 minutes after starting. One
`patient with a definite type I reaction had onset
`of urticaria and skin erythema some 12 hours
`after completing his 6-hour drug infusion. One
`patient with a possible reaction developed gener-
`alized pruritus beginning approximately 3 hours
`after finishing the 6-hour taxol
`infusion. No
`patient had any reaction manifestations that
`began any later than described above.
`Reactions occurred at scheduled taxol doses of
`
`5 mg/m2 to 250 mg/mz. Planned drug infusion
`schedules were 1 to 6 hours in 18 patients and 24
`hours in 14 patients.
`The clinical features of the HSR among the 27
`patients with definite type I reactions are delin-
`eated in Table 2. Eighty-one percent had dysp-
`nea, with or without bronchospasm, and 41% had
`hypotension (defined as a decrease in blood
`pressure of at least 20 mm Hg, diastolic and /or
`systolic). Seven patients had nonmeasurable dias-
`tolic blood pressures as part of the reaction.
`Twelve patients had no significant change in
`blood pressure; four had an increase in pressure.
`One or more manifestations of angioedema (la-
`ryngeal stridor, epiglottic swelling, periorbital
`edema, etc) occurred in five (18.5%) patients.
`Urticaria, flushing, and/or erythematous rash
`
`Table 2. Clinical Manifestations of Definite Hypersensitivity
`Reactions in 27 Patients
`
`Symptoms/Signs
`
`Dyspnea with/without bronchospasm
`Yes
`No
`
`Urticaria/flushing/rashes
`Yes
`No
`
`Blood pressure changes
`Decrease
`No change
`Increase
`
`Angioedema and associated features
`Yes
`No
`
`No. of
`Patients (96)
`
`22 (81)
`5 (l 9)
`
`20 (74)
`7 (26)
`
`l l (41)
`12 (44)
`4 (i 5)
`
`5 (l 9)
`22 (8])
`
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`
`

`

`HYPERSENSITIVITY REACTIONS FROM TAXOL
`
`1265
`
`occurred in 20 (74%) patients. Miscellaneous
`features occurred in some patients: abdominal or
`extremity pain (four patients), vomiting as part
`of the reaction episode and not due to taxol
`gastrointestinal toxicity (three patients), fever
`and / or rigors (three patients).
`The treatment of these definite reactions var-
`
`ied greatly. The patients who had hypotension
`received intravenous fluids, antihistamines (usu-
`ally diphenhydramine), and in some cases a
`vasopressor. One patient received aminophylline,
`and some patients had treatment with intrave-
`nous corticosteroids.
`
`After the initial report of HSR events to the
`NCI,
`it was recommended that all patients
`receiving taxol be given prophylactic therapy
`with dexamethasone, cimetidine or rantidine,
`
`and diphenhydramine. Eleven of the 27 patients
`received this premedication and still developed
`HSRs. Only two were treated with a single agent;
`the remainder received all three recommended
`
`drugs. Five of these 11 patients received taxol in
`a 6-hour infusion, and the rest
`in a 24-hour
`infusion.
`The outcome of the HSR was known in all
`
`instances, One patient had a fatal reaction. He
`had asystole after a rapid-onset hypotensive epi-
`sode. He underwent maximal efforts at resuscita-
`
`tion, but they were unsuccessful. He had exten-
`sive pulmonary metastases from his cancer that
`may have played a role in the severity of HSR.
`All other patients recovered without any adverse
`consequences. Seven patients received more taxol
`and had no further problems. Five of these
`patients were given premedication before receiv-
`ing subsequent taxol treatment, whereas premed-
`ication had not been administered before the
`taxol dose that caused the HSR.
`
`lack
`The pretreatment allergic history or
`thereof was known in most patients. Only four
`had a known history of drug allergy: one to sulfa,
`two to penicillin, and one patient (the one who
`died) who experienced a reaction consisting of
`urticaria to the investigational antitumor agent,
`elliptinium. This agent is known to be immuno-
`genic and cause HSRs.2
`Two patients who experienced HSRs had sub-
`sequent intradermal and scratch skin tests with
`0.1 mL of diluted and undiluted taxol
`1 and 3
`
`months, respectively, after their severe reaction.
`
`Both patients had negative results. Four addi-
`tional patients about
`to receive taxol therapy
`were also skin tested, and no test reactions were
`observed. None of these four patients subse—
`quently had any sort of reaction to a 1-hour
`infusion of taxol. No other patients were studied
`to determine the mechanism of their HSR.
`
`Five patients had reactions that were possibly
`due to hypersensitivity. Table 3 outlines the
`symptoms and signs that
`these patients sus-
`tained. None of these patients had urticaria or
`angioedema and only one had flushing and skin
`erythema. Two became hypotensive, and two
`developed hypertension. Three of the five epi-
`sodes occurred within 10 minutes of beginning
`the taxol
`infusion. Two patients had received
`premedication with the three drugs used to sup—
`press reactions, and three had not.
`
`DISCUSSION
`
`Taxol is a unique new antineoplastic drug that
`is now known to induce type I HSRs. These
`reactions have the usual signs and symptoms of
`such events, varying from flushing, dyspnea and
`bronchospasm, and rashes to severe hypotension
`and asystole, resulting in death.
`The 32 patients involved in this survey repre-
`sent most of the definite or possible HSRs ob-
`served with this drug. It is difficult to determine a
`reliable overall incidence of such reactions be-
`cause of the wide variations in taxol doses and
`
`schedules used and the unknown degree of influ-
`ence that changing the infusion schedule and
`using premedication had on incidence. For exam-
`ple, three of five patients who received taxol in a
`3-hour infusion at greater than 190 mg /m2 with
`no premedication had reactions.9 In contrast,
`
`Table 3. Clinical Manifestations of Possible Hypersensitivity
`Reactions in Five Patients
`Reaction
`
`Patient No.
`
`1
`
`2
`
`3
`4
`
`5
`
`Erythema, flushing, hypertension
`(blood pressure increased to
`170/130)
`Dyspnoa (without bronchospasm),
`hypertension
`Generalized pruritus without rash
`Hypotension (blood pressure
`decreased to 80/60)
`Hypotension (blood pressure
`decreased to 60/20)
`
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`
`

`

`1266
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`WEISS ET AL
`
`Taxol
`Infusion
`Duration
`
`5 3 hours
`6 hours
`24 hours
`
`Total
`
`Table 4. Incidence of HSRs Based on Duration of Taxol Administration
`
`No. of
`No. of
`No. of
`Patients
`Patients
`Patients
`Treated"
`PremedicotedT
`With HSR1:
`
`62
`86
`153
`
`301
`
`o
`51 (59%)
`107 (70%)
`
`158 (52%)
`
`10 (16.l%)
`8 (9.3%)
`14 (9.1%)
`
`32 (10.6%)
`
`95% Confidence
`Limits
`
`8%-28%
`4%‘l7%
`5%-16%
`
`7%-15%
`
`*Figures derived from references 4-10, 21-23, and unpublished studies of the authors.
`TUsing antihistamine, corticosteroid, and H-2 receptor blocker.
`$Patients with definite or possible HSRs.
`
`only one of 30 patients treated with a 6-hour
`infusion at even higher doses and no premedica-
`tion had a reaction,10 thus suggesting that pro-
`longing the infusion by 3 hours is sufl‘icient to
`reduce the incidence. This suggestion is some-
`what supported by the data in Table 4 derived
`from analysis of compiled patients treated with
`taxol. However, seven patients in this present
`report received 250 mg/m2 of taxol administered
`in a 24—hour infusion, with five having triple-drug
`premedication, and they still sustained definite
`HSRs. Although prolonging the drug infusion to
`6 or 24 hours might have reduced the risk for an
`acute reaction,
`this also may not be the case
`because 78% of the reactions occurred within 10
`
`minutes of initiating the drug infusion, and the
`length of time planned for the total
`infusion
`would have no bearing. The drug concentration
`in the infusate also may not make a difference
`because 17 patients had reactions to as small an
`administered taxol dose as only several mg.
`The mechanism of these taxol HSRs is un-
`
`known, but it may be multifaceted. These reac-
`tions are unlikely to be due solely to IgE directed
`against
`taxol, because 56% of the reactions
`occurred from the first administration of taxol,
`thereby negating the prior sensitization neces-
`sary for the development of an IgE response. This
`fact suggests the involvement of direct release of
`mast cell mediators, possibly in a manner analo-
`gous to anaphylactoid reactions to agents such as
`radiographic contrast media. However,
`taxol-
`specific IgE has not been definitively ruled out for
`several reasons. Only two of the patients with
`reactions were prick skin-tested with taxol, and
`while neither of these patients’ skin tests were
`positive, reactivity to drug—protein conjugates or
`drug metabolites was not ascertained. The anti-
`genic cross-reactivity of taxol with other com-
`pounds is unknown, thus raising the possibility
`
`that prior sensitization may have occurred from
`exposure to substances other than taxol. Finally,
`the small amounts of drug involved in some of
`these reactions indicates that there is an amplifi-
`cation process underlying them. This can occur
`through complement activation with the release
`of anaphylotoxins,11 but it is also compatible with
`IgE-mediated release of mast cell mediators.
`Not only is the mechanism of taxol HSRs
`unknown, but it
`is also not clear whether the
`
`the
`itself is inducing the reactivity or
`taxol
`excipient (Cremophor EL; Badische Anilin und
`Soda-Fabrik AG [BASF], Ludwigshafen, Fed-
`eral Republic of Germany) used in the formula-
`tion. Due to taxol’s insolubility, a nonionic surfac-
`tant derived from castor oil, Cremophor EL (5%)
`is used as a solubilizer. Cremophor EL itself
`is suspected of
`inducing hypersensitivity
`reactions?"12 and studies in dogs have demon-
`strated that Cremophor and its fatty acid constit-
`uents can induce histamine release and hypoten-
`sion within 10 minutes of administration.” Some
`
`of these dogs died as a result of this hypotension.
`Other drugs formulated with Cremophor EL
`such as cyclosporine,14 teniposide,15 intravenous
`vitamin K,16 and didemnin B17 have also caused
`HSRs in humans, and Cremophor is the sus-
`pected etiology. On the other hand, Nolte et al18
`studied whether teniposide or Cremophor was
`the allergen using an in vitro histamine release
`test and found that
`teniposide alone caused
`basophil degranulation, whereas Cremophor did
`not. This work suggests that Cremophor is being
`falsely implicated as the allergen, at least in the
`case of teniposide. It would be useful to evaluate
`taxol and Cremophor EL in the same histamine
`release test.
`
`If Cremophor EL is a suspected initiator of
`reactions from taxol, could some substitute excip-
`ient be used that would be less apt to cause
`
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`
`

`

`HYPERSENSITIVITY REACTIONS FROM TAXOL
`
`1 267
`
`HSRs? Polyethylene glycol has been tried as a
`substitute, but this chemical appeared to de-
`crease the antitumor activity of taxol in murine
`tumor studies (unpublished observation, Febru-
`ary 1980, Arthur D. Little, Inc, Cambridge,
`MA). At present, there is no suitable substitute
`for Cremophor EL in taxol formulation.
`Investigators using taxol were requested to
`premedicate patients with an H-2 receptor antag-
`onist, antihistamines, and corticosteroids in hopes
`of preventing HSRs. The basis for this pretaxol
`regimen is the fact that prophylactic antihista-
`mines and hydrocortisone have reduced the inci-
`dence of anaphylactoid reactions to radiographic
`contrast dyes.19 However, there is no apparent
`value in using cimetidine or rantidine in such
`prophylaxis, and ephedrine appears to be a better
`third agent in the regimen.20 Forty-one percent of
`the patients having reactions in this present
`series had received prophylactic medication
`(diphenhydramine, dexamethasone, and cimeti-
`dine or rantidine), using three agents in all but
`two patient. Thus, it is apparent that premedica-
`tion is not fully protective. Whether it even
`reduces the risk of a reaction cannot be reliably
`determined. Nineteen (13.3%) patients among
`143 who received no premedication had reac-
`tions, whereas 13 (8.2%) had reactions among
`158 patients who did receive premedication (Ta-
`ble 4). Since these patients received different
`taxol" doses and infusion schedules,
`it
`is not
`possible to define what influence the premedica-
`tion itself had on the incidence of HSRs. How-
`
`ever, there is no known danger from use of the.
`prophylactic therapy. Therefore, if it fully.obvi-
`ates or just minimizes HSRs in even a few
`patients, it seems worthwhile to use it. In View of
`the better outcome using prophylactic ephedrine
`in radiographic contrast dye reactions,20 ephe-
`drine should also be considered for use with
`taxol.
`
`The present major obstacle to further clinical
`trial of taxol is the scarcity of drug supplies. It is
`a natural product that can be isolated only in
`small amounts from large quantities of the raw
`material, the yew tree. If adequate drug supplies
`can be obtained, through whatever means, trials
`in a variety of cancers will be speedily activated.
`If taxol undergoes further clinical testing, pa-
`tients will be at risk for HSRs and may have one
`or more of the clinical manifestations observed in
`
`the 32 patients in this series. The incidence of
`HSRs in a large number of patients treated with
`a uniform dose and schedule of taxol with uni-
`
`form premedication has not been determined.
`However, the figures in Table 4 suggest that up
`to a 10% risk is possible.
`Therefore, we recommend that investigators
`using taxol
`in future clinical trials follow the
`drug administration guidelines enumerated in
`Table 5. Use of a three-drug premedication
`regimen should reduce the risk of reactions.
`Bedside preparations to immediately handle any
`sudden HSRs will allow safe administration of
`
`taxol. If HSRs of anya‘degree occur, appropriate
`steps (Table 5) to treat them must be instituted.
`
`Table 5. Prophylaxis and Treatment of Taxol Hypersensitivity Reactions
`
`Premedication
`20 mg dexamethaxone orally 12 hours and 6 hours before taxol and 20 mg IV iust before treatment
`50 mg diphenhydramine orally and IV in same schedule as dexamethasone
`Consider 25 mg ephedrine sulfate orally 1 hour before taxol unless unstable angina or hypertension necessitates withholding it
`Slowly withdraw the patient (if possible) from any beta blocker medication that could potentiote a reaction" or make it harder to treat
`
`Treatment set-up
`IV access must be established
`Blood pressure monitoring must be available
`Treatment of reactions
`Discontinue taxol
`Administer epinephrine 0.35-O.5 cc IV every 15-20 minutes until the reaction subsides or a total of six doses are given
`If hypotension is present that does not respond to epinephrine, administer IV fluids
`If wheezing is present that is not responsive to epinephrine, administer 035 cc of nebulized albuterol solution
`Administer diphenhydramine 50 mg IV
`Although corticosteroids have no eflect on the. initial reaction, they have been shown to block “late” allergic reactions to a variety of
`substances.” Thus, methylprednisolone 125 mg IV (or its equivalent) may be administered to prevent recurrent or ongoing allergy
`manifestations
`
`Abbreviation: IV, intravenously.
`
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`
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`

`1268
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`WEISS ET AL
`
`When the patient recovers, it would be useful to
`perform proper tests2 to better define the mecha-
`nism(s) and the identity of the offending agent
`(taxol or Cremophor EL).
`
`REFERENCES
`
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