Clinic Rev Allerg Immunol DOI 10.1007/s12016-014-8416-0 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) Keywords Taxane . Paclitaxel . Taxol . Docetaxel . are an important cause of hypersensitivity reactions Taxotere . Nab-paclitaxel . Abraxane . Cabazitaxel . (HSRs) in cancer patients. During the last decade, the Chemotherapy . Hypersensitivity . Allergy . Skin test . development of rapid drug desensitization has been key Desensitization . Challenge . Diagnosis . Review . IgE . to allow patients with HSRs to taxanes to be safely re- Complement . Mechanism treated although the mechanisms of these HSRs are not fully understood. Earlier studies suggested that solvents, such as Cremophor EL used to solubilize paclitaxel, Introduction were responsible for HSRs through complement activa- tion, but recent findings have raised the possibility that Hypersensitivity reactions (HSRs) to chemotherapy are in- some of these HSRs are IgE-mediated. Taxane skin creasingly common and represent an important impediment testing, which identifies patients with an IgE-mediated to the care of cancer patients as they may entail serious sensitivity, appears as a promising diagnostic and risk consequences and prevent patients from being treated with stratification tool in the management of patients with the most efficacious agent against their cancer [1]. During the HSRs to taxanes. The management of patients following last decade, different groups have developed rapid drug de- a HSR involves risk stratification and re-exposure could sensitization (RDD) protocols that allow the safe re- be performed either through rapid drug desensitization introduction of a chemotherapeutic agent to which a patient or graded challenge based on the severity of the initial is allergic, and their use have recently been endorsed by the HSR and the skin test result. Rapid drug desensitization National Comprehensive Cancer Network (NCCN) [2]. hasbeenshowntobeaneffectiveandsafemethodto Two classes of chemotherapeutic agents cause the vast re-introduce taxanes in hundreds of patients, including majority of chemotherapy-related HSRs: platins and taxanes those with life-threatening HSRs. Patients with non- [3]. Although it has now been well described that HSRs to severe delayed skin HSRs may benefit from rapid drug platins are IgE-mediated [4], the mechanism(s) of HSRs to desensitization since they may be at increased risk for taxanes remain to be established. This lack of a clear under- an immediate HSR upon re-exposure. This review fo- standing of what causes HSRs to taxanes has led in practice to cuses on the clinical presentation, diagnosis, and novel a greater diversity of management strategies for taxanes com- mechanisms of immediate HSRs to taxanes. A new pared with platins’ HSRs [5]. However, the possibility that an managementstrategyforHSRstotaxanesbasedonskin IgE-mediated mechanism might be implicated in some pa- testing and rapid drug desensitization is proposed. 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 M. Picard M. C. Castells (*) the late 1980s. Division of Rheumatology, Immunology and Allergy, Department of This review provides a general overview of the different Medicine, Brigham and Women’s Hospital, Harvard Medical School, 1 Jimmy Fund Way, Smith Building, Boston, MA 02115, USA taxanes currently used in practice as well as a presentation of e-mail: [email protected] the different types of HSRs encountered with these agents Clinic Rev Allerg Immunol (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)inthe 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].Taxolrarityin 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- Fig. 1 a Taxus baccata tree. b Taxus baccata needles and fruit. Pictures taken at Arnold Arboretum, Boston, MA deacetylbaccatin III and baccatin III), which can be trans- formed via a semisynthetic process into paclitaxel, in the emulsifying agent, and further diluted in an ethanol/water needles of the European yew tree (Taxus baccata)(Fig.1) solution for intravenous administration [15]. It is used in the [12]. European yew trees are more abundant than Pacific yew treatment of breast, ovarian, prostate, head and neck, and non- trees, and the needles can be harvested without killing the tree small cell lung cancers and gastric adenocarcinoma [15]. [12]. In recent years, plant cell cultures isolated from different Docetaxel is usually administered as a 1-h infusion every Taxus species and grown in large bioreactors have become the 3weeks[15]. 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’ssarcoma.Itiseitherin- Nab-Paclitaxel fused weekly, typically over 1 h, or every 3 weeks, typically over 3 h [14]. Nanoparticule albumin-bound paclitaxel (nab-paclitaxel; Abraxane) is a novel paclitaxel formulation, which does not Docetaxel contain Cremophor EL [16, 17]. It uses human serum albumin to encapsulate hydrophobic paclitaxel molecules in particles Docetaxel (taxotere) was discovered in 1986 in the search for of around 130 nm [18]. In addition, albumin is thought to a more soluble and easier to produce alternative to paclitaxel increase paclitaxel tumor uptake by, among other mecha- [12]. It was obtained from a semisynthetic process using the nisms, binding to gp60 (albondin) receptor thereby enhancing paclitaxel precursor 10-deacetylbaccatin III extracted from the the transendothelial transport of the drug [18, 19]. Abraxane needles of T. baccata [12]. Its structure is therefore highly was approved by the US FDA for the treatment of metastatic similar to paclitaxel. Despite a higher solubility than paclitax- breast cancer in 2005 and is now also approved for the el, the molecule remains insoluble in water [12]. Docetaxel is treatment of non-small cell lung cancer and adenocarcinoma formulated in polysorbate 80 (Tween 80), a solubilizer and of the pancreas [20, 21]. It is infused over 30 min and, in Clinic Rev Allerg Immunol contrast to the other taxanes, does not require the use of severe) versus 17.3 % (7.3 % severe) [34]. Also, at least one premedication to prevent HSR [21]. Many other nanoparticule death from a severe HSR has been reported in a patient delivery systems for paclitaxel are currently in development premedicated with the simplified regimen [39]. In [20]. premedicated patients, the duration of the paclitaxel infusion (3 versus 24 h) and the dose administered (175 versus 135 mg/ Cabazitaxel m2) do not influence the rate of HSRs [37, 40, 41]. Also, there is no indication that weekly paclitaxel regimens, which con- Cabazitaxel (Jevtana) is a semisynthetic taxane derived from tain lower doses and are administered as 1-h infusions, in- the precursor 10-deacetyl baccatin III contained in yew tree crease the rate of HSRs, and some groups have even success- needles that was developed to overcome tumor drug resistance fully withdrawn corticosteroid premedication in patients that to paclitaxel and docetaxel [22]. Tumor cells can overexpress had not reacted during the initial cycles [42–46]. ATP-dependant membrane transporter proteins, such as P- glycoprotein, that decrease intracellular drug concentrations Docetaxel by pumping out of the cell drugs with affinity for the trans- porter [10]. Paclitaxel and docetaxel have a high affinity for P- Several unexpected adverse events were uncovered during glycoprotein whereas cabazitaxel has a poor affinity providing phase II trials of docetaxel. A majority of patients (>50 %) the rationale for its use in certain taxane-resistant neoplasia experienced immediate HSRs that were not prevented by the [22]. Similarly to docetaxel, it is formulated in polysorbate 80 addition of premedication with antihistamines or intravenous and diluted in an ethanol/water solution before intravenous corticosteroid 30 min prior to the infusion [47–50]. Fluid