Re-visiting Hypersensitivity Reactions to Taxanes: A Comprehensive Review

Matthieu Picard & Mariana C. Castells
# Springer Science+Business Media New York 2014
Abstract Taxanes (a class of chemotherapeutic agents) are an important cause of hypersensitivity reactions (HSRs) in cancer patients. During the last decade, the development of rapid drug desensitization has been key to allow patients with HSRs to taxanes to be safely re- treated although the mechanisms of these HSRs are not fully understood. Earlier studies suggested that solvents, such as Cremophor EL used to solubilize paclitaxel, were responsible for HSRs through complement activa- tion, but recent findings have raised the possibility that some of these HSRs are IgE-mediated. Taxane skin testing, which identifies patients with an IgE-mediated sensitivity, appears as a promising diagnostic and risk stratification tool in the management of patients with HSRs to taxanes. The management of patients following a HSR involves risk stratification and re-exposure could be performed either through rapid drug desensitization or graded challenge based on the severity of the initial HSR and the skin test result. Rapid drug desensitization has been shown to be an effective and safe method to re-introduce taxanes in hundreds of patients, including those with life-threatening HSRs. Patients with non- severe delayed skin HSRs may benefit from rapid drug desensitization since they may be at increased risk for an immediate HSR upon re-exposure. This review fo- cuses on the clinical presentation, diagnosis, and novel mechanisms of immediate HSRs to taxanes. A new management strategy for HSRs to taxanes based on skin testing and rapid drug desensitization is proposed.
Keywords Taxane . Paclitaxel . Taxol . Docetaxel .
Taxotere . Nab-paclitaxel . Abraxane . Cabazitaxel .
Complement . Mechanism
Introduction
Hypersensitivity reactions (HSRs) to chemotherapy are in- creasingly common and represent an important impediment to the care of cancer patients as they may entail serious consequences and prevent patients from being treated with the most efficacious agent against their cancer [1]. During the last decade, different groups have developed rapid drug de- sensitization (RDD) protocols that allow the safe re- introduction of a chemotherapeutic agent to which a patient is allergic, and their use have recently been endorsed by the National Comprehensive Cancer Network (NCCN) [2].
Two classes of chemotherapeutic agents cause the vast majority of chemotherapy-related HSRs: platins and taxanes [3]. Although it has now been well described that HSRs to platins are IgE-mediated [4], the mechanism(s) of HSRs to taxanes remain to be established. This lack of a clear under- standing of what causes HSRs to taxanes has led in practice to a greater diversity of management strategies for taxanes com- pared with platins’ HSRs [5]. However, the possibility that an IgE-mediated mechanism might be implicated in some pa- tients with HSRs to taxanes has recently been raised, and skin testing has emerged as a new diagnostic and risk stratification tool [6, 7]. Therefore, the need arose to re-visit the knowledge acquired on HSRs to taxanes since the first use of the drug in the late 1980s.
This review provides a general overview of the different taxanes currently used in practice as well as a presentation of the different types of HSRs encountered with these agents
M. Picard :M. C. Castells (*) Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham andWomen’s Hospital, HarvardMedical School, 1 Jimmy Fund Way, Smith Building, Boston, MA 02115, USA e-mail: [email protected]
Clinic Rev Allerg Immunol DOI 10.1007/s12016-014-8416-0
(with a focus on immediate HSRs). This is followed by a discussion of the different mechanisms that could account for these HSRs. Finally, the different strategies used in the man- agement of HSRs to taxanes (with an emphasis on rapid drug desensitization) are reviewed.
Origins and Clinical Use of Taxanes
Paclitaxel
Paclitaxel (taxol) is a natural compound, originally isolated from the bark of the Pacific yew tree (Taxus brevifolia) in the 1960s, with potent anticancer properties [8]. It exerts its antineoplastic effects by interfering with the dynamics of microtubules (components of the cell cytoskeleton) thereby causing mitotic block and cell death [9, 10]. Taxol rarity in nature (the extraction of a single therapeutic dose necessitates the sacrifice of a 100-year-old Pacific yew tree) and its insol- ubility in water significantly hindered its development as a chemotherapeutic agent [11]. In the 1980s, a drug formulation suitable for intravenous injection was devised using Cremophor EL (polyoxyethylated castor oil), a solubilizer and emulsifying agent, and ethanol allowing clinical trials to proceed [12]. Following demonstration of its efficacy against notably ovarian and breast cancer, the need arose for a more sustainable and efficient mean of production. Total (synthetic) synthesis of paclitaxel was accomplished in 1994, but its complexity made it not commercially viable [11, 13]. A first solution came from the presence of paclitaxel precursors (10- deacetylbaccatin III and baccatin III), which can be trans- formed via a semisynthetic process into paclitaxel, in the needles of the European yew tree (Taxus baccata) (Fig. 1) [12]. European yew trees are more abundant than Pacific yew trees, and the needles can be harvested without killing the tree [12]. In recent years, plant cell cultures isolated from different Taxus species and grown in large bioreactors have become the method of choice for paclitaxel production [12]. Paclitaxel is used for the treatment of ovarian, breast, non-small cell lung cancers, and AIDS-related Kaposi’s sarcoma. It is either in- fused weekly, typically over 1 h, or every 3 weeks, typically over 3 h [14].
Docetaxel
Docetaxel (taxotere) was discovered in 1986 in the search for a more soluble and easier to produce alternative to paclitaxel [12]. It was obtained from a semisynthetic process using the paclitaxel precursor 10-deacetylbaccatin III extracted from the needles of T. baccata [12]. Its structure is therefore highly similar to paclitaxel. Despite a higher solubility than paclitax- el, the molecule remains insoluble in water [12]. Docetaxel is formulated in polysorbate 80 (Tween 80), a solubilizer and
emulsifying agent, and further diluted in an ethanol/water solution for intravenous administration [15]. It is used in the treatment of breast, ovarian, prostate, head and neck, and non- small cell lung cancers and gastric adenocarcinoma [15]. Docetaxel is usually administered as a 1-h infusion every 3 weeks [15].
Nab-Paclitaxel
Nanoparticule albumin-bound paclitaxel (nab-paclitaxel; Abraxane) is a novel paclitaxel formulation, which does not contain Cremophor EL [16, 17]. It uses human serum albumin to encapsulate hydrophobic paclitaxel molecules in particles of around 130 nm [18]. In addition, albumin is thought to increase paclitaxel tumor uptake by, among other mecha- nisms, binding to gp60 (albondin) receptor thereby enhancing the transendothelial transport of the drug [18, 19]. Abraxane was approved by the US FDA for the treatment of metastatic breast cancer in 2005 and is now also approved for the treatment of non-small cell lung cancer and adenocarcinoma of the pancreas [20, 21]. It is infused over 30 min and, in
Fig. 1 a Taxus baccata tree. b Taxus baccata needles and fruit. Pictures taken at Arnold Arboretum, Boston, MA
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contrast to the other taxanes, does not require the use of premedication to prevent HSR [21]. Many other nanoparticule delivery systems for paclitaxel are currently in development [20].
Cabazitaxel
Cabazitaxel (Jevtana) is a semisynthetic taxane derived from the precursor 10-deacetyl baccatin III contained in yew tree needles that was developed to overcome tumor drug resistance to paclitaxel and docetaxel [22]. Tumor cells can overexpress ATP-dependant membrane transporter proteins, such as P- glycoprotein, that decrease intracellular drug concentrations by pumping out of the cell drugs with affinity for the trans- porter [10]. Paclitaxel and docetaxel have a high affinity for P- glycoprotein whereas cabazitaxel has a poor affinity providing the rationale for its use in certain taxane-resistant neoplasia [22]. Similarly to docetaxel, it is formulated in polysorbate 80 and diluted in an ethanol/water solution before intravenous administration [23]. In 2010, it was approved by the US FDA in combination with prednisone for the treatment of hormone- resistant metastatic prostate cancer in patients previously treat- ed with docetaxel [22]. It is usually infused every 3 weeks over 1 h [23].
Hypersensitivity Reactions to Taxanes
Paclitaxel
Early phase I clinical trials of paclitaxel were complicated by a high incidence of HSRs occurring during the drug infusion (immediate HSR) [24, 25]. Premedication with corticosteroids (oral dexamethasone 20 mg 12 and 6 h pretaxol) and antihis- tamines (histamine (H)-1 (dyphendydramine 50 mg or equiv- alents) and H2 (cimetidine 300 mg or ranitidine 50 mg) re- ceptor blockers) administered intravenously 30 to 60 min pretaxol allowed for a dramatic reduction in their incidence [14, 24, 26]. Immediate HSRs to paclitaxel occur in around 10 % of premedicated patients and are severe in around 10 % of patients who react [27–38]. A simplified premedication regimen consisting of a single intravenous or oral dexameth- asone dose (10 mg) given 30–60 min before paclitaxel has been used with success by various groups without an obvious rise in immediate HSRs and has since gained wide acceptance as a reasonable alternative to the two-dose dexamethasone protocol [27–30, 33, 36]. However, at least one retrospective study reported a statistically significant lower rate of immedi- ate HSRs with the two-dose dexamethasone regimen com- pared to the simplified regimen (p=0.047); 7.5 % (0.9 %
severe) versus 17.3 % (7.3 % severe) [34]. Also, at least one death from a severe HSR has been reported in a patient premedicated with the simplified regimen [39]. In premedicated patients, the duration of the paclitaxel infusion (3 versus 24 h) and the dose administered (175 versus 135mg/ m2) do not influence the rate of HSRs [37, 40, 41]. Also, there is no indication that weekly paclitaxel regimens, which con- tain lower doses and are administered as 1-h infusions, in- crease the rate of HSRs, and some groups have even success- fully withdrawn corticosteroid premedication in patients that had not reacted during the initial cycles [42–46].
Docetaxel
Several unexpected adverse events were uncovered during phase II trials of docetaxel. A majority of patients (>50 %) experienced immediate HSRs that were not prevented by the addition of premedication with antihistamines or intravenous corticosteroid 30 min prior to the infusion [47–50]. Fluid retention, which was later found to be caused by capillary protein leak induced by docetaxel [51], was an important cause for treatment withdrawal in phase II studies and ap- peared to be related to the cumulative docetaxel dose [52]. Finally, many patients experienced a variety of toxic skin reactions presenting as desquamative rash, hand-foot syn- drome, and plaque-l ike erythrodysesthesia [52]. Premedication with oral dexamethasone 8 mg twice daily for 3 days starting the day before the infusion was thereafter adopted as the standard premedication regimen and found to greatly reduce the prevalence of fluid retention and immediate HSRs to between 3.5–16.5 % and to around 5 %, respectively [53–55]. The impact of premedication on toxic skin reactions is less clear as its prevalence has been found to vary greatly between different trials [56, 57]. In an effort to minimize the adverse effects of corticosteroids, different protocols have been used to reduce the duration of dexamethasone treatment in patients receiving weekly docetaxel regimens without a deleterious impact on the rate of HSRs, fluid retention, and skin toxicity [58, 59].
Nab-Paclitaxel
Since nab-paclitaxel is devoid of Cremophor EL, the suspected cause of taxol HSRs, it is administered without any premedication and as a 30-min infusion [21]. In a phase III trial, a direct comparison between nab-paclitaxel and taxol (administered with premedication) revealed that the rate of HSRs was higher in the taxol arm;12 versus 4 %, severe HSRs; 4 versus 0 % [60, 61]. However, postmarketing sur- veillance has revealed cases of severe and even fatal HSRs with nab-paclitaxel [21]. Its use in patients with a history of mild to severe HSR to taxol and/or docetaxel has been report- ed to be safe in a few case reports [62–65].
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Cabazitaxel
Cabazitaxel has mostly been studied in patients with metasta- tic castration-resistant prostate cancer (mCRPC) previ- ously treated with docetaxel and in combination with a daily oral prednisone regimen [66]. Premedication with an intravenous corticosteroid (dexamethasone 8 mg) and H1 (dyphendydramine 25 mg) and H2 (ranitidine 50 mg) blockers at least 30 min before the infusion is recommended given its potential to cause HSRs [23]. However, no HSR were reported in at least two trials cumu- lating 656 patients treated with cabazitaxel for mCRPC [67, 68]. Interestingly, a large phase III trial in which 662 men with mCRPC were treated with docetaxel in combination with daily prednisone also did not report any HSR [69]. In contrast, a phase II study of 71 patients with metastatic breast cancer resistant to taxanes (docetaxel and paclitaxael) found that 6 % of patients suffered a HSR to cabazitaxel [70]. Gender differ- ences and/or a higher and more prolonged intake of cortico- steroids in men with mCRPC could possibly account for this discrepancy.
Non-Immediate Hypersensitivity Reactions to Taxanes
Although less common than immediate HSRs, a range of delayed, possibly immune-mediated, reactions have been de- scribed with taxanes. Importantly, delayed onset skin erup- tions (most commonly a benign maculopapular rash) can be the prelude to an immediate HSR during the next infusion [7]. In one case, a 37-year-old woman that had presented with urticaria, lip swelling, and fever 10 days after her first pacli- taxel infusion suffered a fatal anaphylactic reaction shortly after the start of the second infusion despite premedication [71]. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have also been described in case reports and picked up in postmarketing surveillance with paclitaxel, do- cetaxel, and nab-paclitaxel [21, 72, 73]. Acute interstitial pneumonitis has been reported with paclitaxel, docetaxel, and more recently nab-paclitaxel and usually presents with fever, dry cough, dyspnea, bilateral interstitial lung infiltrates, and leukocytosis [74–77]. Around half of patients described in case reports required mechanical ventilation, and the mortality rate was high [75]. Patients are usually treated with high-dose corticosteroids for several weeks as the pneumonitis is thought to be T-cell mediated [78]. In a recent trial of nab-paclitaxel and gemcitabine in pancreatic cancer, 4 % of patients in the nab-paclitaxel/gemcitabine arm developed pneumonitis whereas only 1 % did in the gemcitabine arm [77]. Moreover, two patients in the nab-paclitaxel/gemcitabine arm died as a result [21]. Subacute cutaneous lupus erythe- matosus (SCLE), which presents as a photodistributed skin eruption often accompanied by the presence of antiRo/SSA antibodies, has been associated with paclitaxel, docetaxel, and
nab-paclitaxel [79–81]. Drug discontinuation usually leads to a complete resolution [80].
Clinical Features of Immediate Hypersensitivity Reactions to Taxanes
The majority of immediate HSRs to taxanes occurs during the first or second infusion of the drug and usually develops within minutes of starting the infusion [26, 33, 82]. The signs and symptoms of these reactions are thought to be the result of basophil/mast cell degranulation (Fig. 2) and are similar in premedicated and non-premedicated patients [3, 26, 33, 82]. Patients commonly complain of localized or generalized flushing, and a significant percentage report chest, back, and/or abdominal pain [3, 26, 82]. Respiratory and throat symptoms (dyspnea, chest tightness, wheezing, throat tight- ness) can be prominent and associated with a significant drop in oxygen saturation [3, 26, 82]. Cardiovascular involvement range from acute hypertension to hypotension, and patients may report a sense of impending doom [3, 26, 82]. Finally, gastrointestinal symptoms (nausea, vomiting, diarrhea) often accompany these HSRs [3, 26, 82]. Following the discontin- uation of the infusion, rapid resolution is the norm although patients with protracted courses (sometimes unresponsive to epinephrine) and biphasic reactions have been seen [26, 33, 83, 84]. As of 2009, mortality from severe anaphylactic reac- tions had been reported in 54 % of 290 docetaxel cases and in 29 % of 683 paclitaxel cases recorded by the US FDA [83].
Mechanisms of Immediate Hypersensitivity Reactions to Taxanes
Three different mechanisms may account for immediate HSRs to taxanes: (1) complement activation induced by Cremophor EL (compounded with paclitaxel) and poly- sorbate 80 (compounded with docetaxel) which generates
Fig. 2 Clinical features of immediate HSRs to taxanes. Created with data from J Allergy Clin Immunol. 2008;122:574–80 and Gynecol Oncol. 2005;99:393–9
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anaphylatoxins triggering basophil/mast cell activation [85, 86]; (2) histamine release through a direct but undefined effect of paclitaxel on basophils [87]; (3) an IgE/IgG-mediated mechanism directed against either the taxane moiety (pacli- taxel, docetaxel) or the solvent (Cremophor EL, polysorbate 80) (Fig. 3) [6, 88–92].
Paclitaxel (compounded with Cremophor EL) has been shown to cause a marked complement activation in vitro in 4/10 healthy subjects and 5/10 cancer patients at a concentra- tion of 100 μg/ml, which translates into a Cremophor EL concentration of 8.8 mg/ml [85]. In comparison, the maximal serum concentration of Cremophor EL reached with a 3-h paclitaxel infusion at a dose of 175 mg/m2 averages 3 mg/ml [93]. Furthermore, Cremophor EL alone was found to trigger complement activation to the same extent that paclitaxel/ Cremophor EL did at equivalent concentrations suggesting that Cremophor EL is solely responsible for this effect [85]. Similarly, docetaxel (compounded with polysorbate 80) and polysorbate 80 alone have been shown to cause complement activation in vitro [86]. These findings support the role of these emulsifying agents in triggering complement activation in a high proportion of healthy subjects and thereby to cause immediate HSRs through anaphylatoxin production. However, it remains to be demonstrated that complement activation occurs in vivo in humans who react to taxanes and that this mechanism accounts for patients who react despite premedication and a slower infusion rate.
Essayan et al. reported the case of an ovarian cancer patient that had suffered repeated immediate HSRs to paclitaxel starting with the first infusion [87]. Premedication and a significant reduction in the infusion rate did not prevent re- currences, and she received subsequent infusions through a desensitization protocol. Basophil activation tests on purified basophils were performed on the patient and three healthy controls with paclitaxel alone and Cremophor EL alone [87]. They found that paclitaxel without Cremophor EL induced histamine release from basophils in the patient and the three healthy controls at a concentration 10- to 100-fold higher than the expected paclitaxel serum concentration. In this study, Cremophor EL did not induce any histamine release, which might be explained by the fact that experiments were likely conducted in a decomplemented medium [85]. Also, paclitax- el did not induce any histamine release from purified human skin mast cells [87]. The authors therefore hypothesize that paclitaxel and not Cremophor EL might cause immediate HSRs by triggering basophil activation through a non-IgE- mediated mechanism. However, these findings also fail to identify a mechanism that differentiates highly reactive pa- tients from healthy controls, which are likely to tolerate taxanes if given premedication.
More recently, Prieto-Garcia and Pineda de la Losa de- scribed a patient that had suffered a severe anaphylactic reac- tion within seconds of her second lifetime paclitaxel infusion [6]. The patient had a positive intradermal skin test (IDT) to
Fig. 3 Mechanisms of immediate HSRs to taxanes. The taxane moiety may cause mast cell and/or basophil activation through three different mechanisms: (1) a direct but undefined action on basophils but not mast cells; (2) an IgE-mediated mechanism, or (3) an IgG-mediated mecha- nism that causes complement activation through immune complex for- mation leading to the production of anaphylatoxins (C3a and C5a) that can activate basophils and mast cells through their surface receptors. Solvents may cause mast cell and/or basophil activation through two
different mechanisms: (1) an IgE-mediated mechanism or (2) direct complement activation that leads to the production of anaphylatoxins. Following activation, mast cells and basophils release a variety of medi- ators that can be measured (serum tryptase or 24-h urinary methylhistamine), and the actions of which can be pharmaceutically blocked (histamine antihistamines; LTC4 montelukast; PGD2 aspirin). LTC4 leukotriene C4.…