.
Chemical structures of the taxanes paclitaxel and docetaxel.
 |
Although the taxanes affect microtubules, they are substantially different from the Vinca alkaloids in terms of their principal mechanisms of action, pharmacology, clinical indications, and toxicology. Interest in the taxanes began in 1963, when a crude extract of the bark of the Pacific yew tree, Taxus brevifolia, demonstrated broad activity in preclinical tumor models.136,138 In 1971, Wall and coworkers identified paclitaxel as the active constituent of the bark extract. Paclitaxel's early development was delayed considerably by the limited supply of its primary source that was exclusively derived from the Pacific yew tree; the difficulties inherent in large-scale isolation, extraction, and preparation of bulk compound for a natural product; and its poor aqueous solubility. Interest was maintained during this time by the characterization of its novel mechanism of cytotoxic action and the availability of an adequate drug supply for requisite preclinical and limited clinical evaluations. The early search for taxanes derived from more abundant and renewable resources led to the semisynthesis of docetaxel by the addition of a side chain to 10-deacetylbaccatin III, an inactive taxane precursor found in the needles and other components of more abundant yew species.138,139 The supply of paclitaxel is no longer preclusive because the agent is feasibly produced semisynthetically from 10-deacetylbaccatin III and other abundant precursors.
Chemical structures of the taxanes paclitaxel and docetaxel.
shows the structures of paclitaxel and docetaxel. Structurally, they are complex esters consisting of a 15-member taxane ring system linked to an unusual four-member oxetan ring.140 The taxane rings of both paclitaxel and docetaxel, but not 10-deacetylbaccatin III, are linked to an ester side chain attached to the C-13 position of the ring, which is essential for antimicrotubule and antitumor activity. The structures of paclitaxel and docetaxel differ in substitutions at the C-10 taxane ring position and on the ester side chain attached at C-13, which render docetaxel slightly more water soluble than paclitaxel and a more potent agent in acellular tubulin systems. However, the clinical ramifications of these differences are not clear at this time.
Paclitaxel initially received regulatory approval in the United States and many other countries for the treatment of patients with ovarian cancer after failure of first-line or subsequent chemotherapy.136–141 Its use in combination with a platinum compound as primary induction therapy in suboptimally debulked stage III or IV ovarian cancer has demonstrated a survival advantage in randomized Phase III studies.141 In the United States, paclitaxel is also indicated for treatment of patients with metastatic breast cancer after failure of combination chemotherapy or at relapse within 6 months of adjuvant chemotherapy, with prior therapy that includes an anthracycline unless clinically contraindicated.142 In the adjuvant setting, paclitaxel is indicated for the treatment of patients with lymph node-positive breast cancer when administered sequentially following standard doxorubicin-containing combination chemotherapy; however, the overall benefits and optimal uses of the taxanes in the adjuvant setting are not entirely clear and are undergoing intensive evaluation. Paclitaxel has also received regulatory approval in the United States for second-line treatment of Kaposi sarcoma associated with the acquired immunodeficiency syndrome, and in combination with cisplatin as primary treatment of patients with non-small-cell lung cancer who are not candidates for radiation therapy or potentially curative surgery.143,144
Docetaxel initially received regulatory approval in the United States for patients with metastatic or locally advanced breast cancer after failure of anthracycline-based chemotherapy, which was later broadened to a general second-line indication.138,139 Its role as a component of adjuvant and neoadjuvant chemotherapy following local treatment of early-stage breast cancer and first-line chemotherapy for locally advanced or metastatic breast cancer is currently under evaluation.145 Furthermore, docetaxel has received regulatory approval in many countries for treatment of locally advanced or metastatic non-small-cell lung carcinoma, and in the United States for treatment of non—small-cell lung cancer after failure of cisplatin-based therapy.146 Docetaxel has demonstrated prominent activity in patients with recurrent ovarian cancer following platinum-based therapy, and its potential advantages as a component of first-line treatment are being evaluated.
The clinical antitumor spectra for paclitaxel and docetaxel are similar, with activity noted in many other diverse tumor types which are generally refractory to conventional therapies, including lymphoma, and small-cell lung, head and neck, gastric, esophageal, endometrial, bladder, and prostate carcinomas. The extent to which apparent differences in response rates and other end points between the taxanes reflect differences in dose, schedule, or inherent drug activities cannot be determined at this juncture.
The binding site for paclitaxel on microtubules is different from the binding sites for exchangeable GTP, colchicine, podophyllotoxin, and vinblastine. Paclitaxel was initially demonstrated to bind to the N-terminal 31 amino acids of the β-tubulin subunit of the tubulin oligomers or polymers, although additional sites of interaction on both β- and α- tubulin may also be involved.3–6,147-151 Paclitaxel sits in a pocket that is lined by several hydrophobic residues and is situated on the luminal side of the microtubule wall, roughly in the middle of the β monomer along the protofilament direction. Docetaxel, which most likely shares the same binding site as paclitaxel, appears to have a 1.9-fold higher affinity for the site, and the tubulin assembly process induced by docetaxel proceeds with a critical protein concentration that is 2.1-fold lower than that of paclitaxel.151 However, it is not clear whether these differences translate into greater therapeutic indices for docetaxel in relevant clinical settings because greater potency may result in more severe toxicity at identical drug concentrations in vivo. Nevertheless, the results of both preclinical and clinical studies indicate that the taxanes may not be completely cross-resistant, but these results may reflect differences in delivered dose and schedule.152
The peeling apart of protofilaments in taxane-stabilized microtubules is greatly repressed, which suggests that the principal mechanism by which the taxanes stabilize microtubules is through strengthening of the lateral interactions between protofilaments. Although the molecular conformational mechanism for this effect is not entirely apparent, it is clear that the taxanes exert their principal effects on microtubules by stabilizing a molecular conformation, rather than by acting as a glue between protofilaments. In any case, the presence of the taxanes compensates for a conformational stress induced by GTP hydrolysis that tends to destabilize the microtubule. In essence, the taxanes alter the tubulin rate dissociation constants at both ends of the microtubules, thereby stabilizing microtubules against depolymerization.3–6,153–160 At substoichiometric concentrations, the taxanes suppress microtubule dynamics without appreciably increasing the rate of formation of polymerized tubulin.3,156 The taxanes also induce tubulin polymerization and increase microtubule mass, which occur at stoichiometric binding and submicromolar concentrations that are readily achieved in the clinic.3,157 The microtubules of taxane-treated cells are extraordinarily stable, resisting depolymerization by cold, calcium ions, dilution, GTP, and other antimicrotubule agents. These actions result in the suppression of treadmilling and dynamic instability which are essential for normal microtubule dynamics during both mitotic and nonmitotic phases of the cell cycle. Both stoichiometric and substoichiometric binding of the taxanes inhibit the proliferation of cells, principally by inducing a sustained mitotic block at the metaphase/anaphase boundary; however, morphologic findings, such as the formation of microtubule bundles during the mitotic phases of the cell cycle, suggest that the interphase microtubules in nonproliferating cells may also be affected.153,156,157
The precise mechanism by which mitotic arrest is linked to cell death has not been determined, but the taxanes do interact with numerous regulatory proteins and oncogenes that bind to the mitotic apparatus. The taxanes induce either apoptosis or programmed cell death through activation of caspases 3 and 8 (see Chapter 48, “Drug Resistance and its Clinical Circumvention”) or a process of “slow death” by means that neither trigger caspase activation nor use mechanisms associated with apoptosis.34–40,160–171 Following taxane treatment, even at substoichiometric concentrations that do not increase microtubule mass, cells exit from mitosis, but do not continue to proliferate. Instead, substantial DNA fragmentation, indicative of apoptosis, is noted and cell death occurs in 2 to 3 days.
Several critical genes that regulate apoptosis, such as p53 and p21, and regulatory proteins, such as Bcl-2 and Bcl-xL, also appear to be integrally involved in regulation of taxane-induced cytotoxicity and drug resistance.34,35,38–41, 160,164–166,169,170–177 The taxanes appear to induce apoptosis through several mechanisms, including a p53-independent pathway in cells blocked in prophase and a p53-dependent mechanism in cells that accumulate in G1 and require functional p53.175 Nevertheless, the direct role that p53 plays in determining cell sensitivity to paclitaxel and other antitumor agents is somewhat controversial. The consensus seems to be that in most cell lines, disruption of p53 has little effect on drug sensitivity. In support, inhibition of p53 function by transfection of the viral E6 gene, expression of dominant mutant p53, and attempts to correlate p53 status of glioma and lymphoma cell lines with drug sensitivity have all failed to demonstrate a role for p53.38 However, a role for p53 in taxane resistance in ovarian cancer and colorectal cancer cell lines has been demonstrated.178,179 MAPs are also likely to play a role in resistance to taxane-induced apoptosis, as illustrated by the fact that MAP4, which is negatively regulated by wild-type p53, enhances paclitaxel sensitivity.180,181 Finally, overexpression of p21, a downstream effector of p53, appears to block cells in G2 and prevent progression into the more drug-vulnerable mitotic phase of the cell cycle, thereby decreasing taxane sensitivity.180,181
The taxanes also modulate the function of genes involved in apoptotic regulation, and the disruption of microtubule dynamics by both paclitaxel and docetaxel results in the phosphorylation of regulatory proteins such as Bcl-xL and Bcl-2, thereby annulling the antiapoptotic functions of these regulators. Paclitaxel, docetaxel, and other drugs that affect the integrity of microtubules, including the Vinca alkaloids, result in the hyperphosphorylation of Bcl-2, increased expression of Bax, and increased apoptosis in cell lines, which involves the intrinsic pathway and caspase activation.34,131,170,177,178 Interestingly, paclitaxel-resistant cell lines, which have mutations in tubulin and fail to exhibit phosphorylation of Bcl-xL after paclitaxel treatment, have been described.34 These cells demonstrate Bcl-xL phosphorylation in the presence of other antimicrotubule agents, suggesting that apoptosis mediated by paclitaxel is related to the drug's ability to interact with microtubules.
The taxanes have been reported to induce transcription factors and enzymes that modulate proliferation, apoptosis, and inflammation. The taxanes induce many other effects in vivo that may not be related to their disruptive effects on microtubules. Paclitaxel inhibits chemotaxis, migration, hydrogen peroxide generation, and killing of phagocytosed microorganisms in human neutrophils, and paclitaxel, but not docetaxel, mimics the effects of endotoxic bacterial lipopolysaccharide on macrophages, which results in a rapid decrement in tumor necrosis factor (TNF)-α receptors and TNF-α release.182 The taxanes also inhibit angiogenic activity in preclinical studies and consequentially decrease intratumoral pressure, at concentrations below those that induce cytotoxicity.183–185 However, the contribution of this effect to the clinical activity of the taxanes is not known.
Both paclitaxel and docetaxel also enhance the effects of ionizing radiation in vitro at clinically achievable concentrations (< 50 nmol/L) and in vivo, which may be related to inhibition of cell-cycle progression in the G2 phase, which is the most radiosensitive phase of the cell cycle.186,187
Two general mechanisms of acquired taxane resistance have been described in cells made resistant by prolonged treatment at low drug concentrations. The best characterized mechanism is the MDR phenotype, which can be mediated by several multidrug transporters, particularly the 170-kDa Pgp efflux pump, encoded by the mdr1 gene (see “The Vinca Alkaloids: Mechanisms of Resistance”).5,60,61, 188–191 In experimental murine macrophage culture systems, the particular species of Pgp found in paclitaxel-resistant cells is similar, but not identical, to that found in vinblastine- and colchicine-resistant cells derived from the same parental line.5,64,188–191 These cells are cross-resistant with many other natural products, and resistance to both paclitaxel and docetaxel conferred by mdr1 can be reversed by many classes of drugs, including the calcium channel blockers, tamoxifen, cyclosporine A, antiarrhythmic agents, and even the principal component of the vehicles used to formulate paclitaxel and docetaxel—polyoxyethylated castor oil and polysorbate-80—respectively.61,190, 192–195 The feasibility of administering paclitaxel with known MDR modulators such as verapamil, cyclosporine A, the nonimmunomodulatory cyclosporine analog PSC 833, and other modulators that do not affect taxane pharmacokinetics and toxicity, thereby confounding interpretation of the inherent effects of these agents on MDR modulation, is being evaluated.61,192–195 In fact, plasma concentrations of polyoxyethylated castor oil achieved with paclitaxel on clinically relevant dose schedules are sufficient to reverse MDR, whereas sufficient modulatory concentrations of polysorbate-80 are not achieved with docetaxel in the clinic.192,193 Although the precise role of MDR in conferring resistance to the taxanes in relevant tumor types in the clinic has not been determined in a robust fashion in studies in which Pgp immunoreactivity and MDR expression in tumor biopsies are related to resistance to prior anthracyclines and paclitaxel, clinical observations to date suggest a lack of complete cross-resistance between the taxanes and anthracyclines in women with breast cancer.142 This may not have been anticipated if MDR was a clinically significant mechanism of taxane resistance. Clinical resistance to the taxanes does not appear to be conferred by MRP-1 nor MXR1/BCRP/ABCP ATP-dependent processes.61
Similar to the Vinca alkaloids, several human cell lines rendered taxane resistant by continuous treatment with high drug concentrations for protracted periods have been demonstrated to possess structurally altered α- and β-tubulins and an impaired ability to polymerize tubulin dimers into microtubules (see section entitled “The Vinca Alkaloids: Mechanisms of Resistance”).51,60,61,75,188,196–206 These cells lack normal microtubules in their interpolar mitotic spindles and have an inherently slow rate of microtubule assembly when grown in the absence of drug. The continuous presence of the taxanes is required for microtubule assembly to proceed. Furthermore, these mutants are also collaterally sensitive to the Vinca alkaloids. In some experimental systems, paclitaxel resistant cells had mutated β-tubulin alleles, with mutations involving the putative taxane binding sites; specifically, leucines at positions 215, 217, and 228 were mutated to histidine, arginine, or phenylalanine.201,202 Low-level expression resulted in drug resistance, whereas, high-level expression of any of these mutations caused impairment of microtubule assembly, cell-cycle arrest, and failure to proliferate, all of which were reversed by incubation with paclitaxel.202
Of the six different β-tubulin isotypes expressed in nonmalignant tissues, the class I isotype comprises 80% to 99% of cellular β-tubulin. High levels of the βIII isotype, a minor component of cellular β-tubulin that increases the dynamic instability of microtubules, impairs rates of microtubule assembly, and increases resistance to taxanes, have been documented in ovarian cancer specimens from patients with paclitaxel-resistance, as were cancer cell lines selected for resistance.198–200 In a series of patients with non-small-cell lung cancer, studies focusing on the importance of mutations of the β-tubulin gene in conferring clinical resistance to paclitaxel have yielded conflicting results, possibly because of differences in study methodology.204,206 Another change in tumor cells selected for drug resistance was upregulation of caveolin-1, a principal component of membrane-derived vesicles involved in transmembrane transport of small molecules and in intracellular signaling. Caveolae act as a scaffold for intracellular kinases.207 One cell line, 9-fold resistant to paclitaxel, had a 3.4-fold increase in caveolin-1, but no change in MDR-1 expression. Increased caveolin-1 was also found in cells selected for resistance to epothilone B, a related microtubule inhibitor (see section on novel compounds targeting microtubules and related organelles).
The relationship between the status of critical regulatory proteins and genes on taxane sensitivity and resistance is discussed in the section entitled “The Taxanes: Mechanisms of Action” in this chapter.
| Paclitaxel | Docetaxel | |
|---|---|---|
| Standard adult dose range | 135 (24-h infusion) | 75–100 (1-h infusion) |
 (mg/m2 q 3 wk) | 175–225 (3-h infusion) | |
| (mg/m2/wk) | 80 | 30–36 |
| Pharmacokinetic behavior (Clinically relevant doses) | Triphasic | Triphasic |
| (> 175 mg/m2) | Saturable taxane elimination distribution; pseudononlinearity due to vehicle | |
| Plasma half-lives (terminal) | 10–20 h | 10–20 h |
| Clearance | 20–25 L/ha | 36 L/h |
| Primary route | Hepatic metabolism and biliary elimination | Hepatic metabolism and biliary elimination |
| Principal toxicity | Neutropenia | Neutropenia |
| Other toxicities | Alopecia, neurotoxicity, myalgia, hypersensitivity reactions, asthenia | Alopecia, skin and nail toxicity, asthenia, myalgia, fluid retention, neurotoxicity, hypersensitivity reactions |
a175 mg/m2 over 3 h (dose schedule).
More recent pharmacologic evaluations of paclitaxel, which involved shorter administration schedules and more sensitive analytical assays than earlier studies, indicate that the pharmacokinetic behavior of paclitaxel is nonlinear or pseudononlinear. Nonlinear behavior is more apparent with shorter infusions since such schedules result in higher plasma paclitaxel concentrations that more effectively saturate both drug elimination and tissue distribution processes. Both saturable distribution and elimination processes may be, in part, responsible for paclitaxel's nonlinear behavior, with tissue distribution becoming effectively saturated at lower drug concentrations (achieved with paclitaxel doses of less than 175 mg/m2 over 3 h) as compared to elimination processes that are saturated at higher concentrations (achieved with paclitaxel doses greater than 175 mg/m2 over 3 h).209–211 A potential clinical ramification of true nonlinearity is that dose escalation may result in a disproportionate increase in drug exposure and toxicity, whereas dose reduction may result in a disproportionate decrease in drug exposure. However, the use of shorter infusion schedules also results in higher plasma concentrations of paclitaxel's polyoxyethylated castor oil vehicle, which may simulate nonlinearity (pseudononlinearity) by binding paclitaxel and inhibiting drug disposition.212,213
For the most part, the pharmacologic behavior of paclitaxel in plasma is triphasic.209–211,214–216 Paclitaxel's volume of distribution is much larger than the volume of total body water, indicating extensive drug binding to plasma proteins or other tissue elements, possibly tubulin. Plasma protein binding is high (> 95%) and readily reversible.209 Drug binding to platelets is extensive and saturable, and animal distribution studies with radiolabeled paclitaxel indicate extensive drug uptake and retention by virtually all tissues, except for normal sanctuary sites such as the normal brain and testes.216 In humans, peak plasma concentrations achieved with 3- to 96-h schedules (more than 0.05 to 10 μmol/L) and drug concentrations in third-space fluid collections such as ascites (over 0.1 μmol/L) are capable of inducing significant biologic effects in vitro.209,217–219
The principal mode of paclitaxel disposition is hepatic metabolism and biliary excretion. The liver metabolizes and excretes both paclitaxel and paclitaxel metabolites into the bile.209,217–219 In rats treated with radiolabeled paclitaxel, 98% of radioactivity is recovered from feces collected for 6 days, and approximately 71% of an administered dose of paclitaxel is excreted in the feces over 5 days as either parent compound or metabolites in humans, with 6α-hydroxypaclitaxel being the largest component, accounting for 26% of the dose; unmetabolized paclitaxel accounts for only 5% of the dose. Renal clearance of paclitaxel and metabolites may account for up to 14% of the administered dose.209,220 In humans, cytochrome P450 mixed-function oxidases are responsible for the bulk of drug disposition, specifically the isoenzymes CYP2C8 and CYP3A4, which metabolize paclitaxel to hydroxylated 6α-hydroxypaclitaxel (major) and another hydroxylated metabolite, both of which are inactive.209,217,218
Pharmacodynamic analyses demonstrate that several pharmacokinetic parameters indicative of drug exposure relate to the principal toxicities of paclitaxel, the most important and consistent of which is the relationship between the severity of neutropenia and the duration of drug exposure above biologically relevant plasma concentrations ranging from 0.05 to 0.1 μmol/L.215,217,221 A prospective analysis of pharmacokinetic determinants of outcome in several hundred patients with advanced non-small-cell lung cancer treated with the combination of cisplatin and paclitaxel at either 135 or 250 mg/m2 over 24 h demonstrated that the magnitude of the steady-state plasma paclitaxel concentration correlates poorly with antitumor activity, disease-free survival, and overall survival.222
The pharmacokinetics of docetaxel (1-h schedule) in plasma are triphasic and linear at doses of 115 mg/m2 or less.138,139,223–226 Terminal half-lives ranging from 11.1 to 18.5 h have been reported. In one population study, plasma concentration data revealed triphasic pharmacokinetics, and the following pharmacokinetic parameters were generated: t1/2γ of 12.4 h, clearance of 1 L/h/m2, and steady-state volume of distribution of 74 L/m2.223,224,226 The most important determinants of docetaxel clearance included the body surface area, hepatic function, and plasma α1-acid glycoprotein concentration, whereas age and plasma albumin level had significant, albeit minor, influences on clearance. Like paclitaxel, plasma protein binding is high (greater than 80% to 90%), and binding is primarily to α1-acid glycoprotein, albumin, and lipoproteins.223,226 Like paclitaxel, docetaxel is widely distributed, but does not enter the unperturbed central nervous system.227 In both dogs and mice treated with radiolabeled drug, fecal excretion accounts for 70% to 80% of total radioactivity, whereas urinary excretion accounts for 10% or less.222,227 The hepatic cytochrome P450 mixed-function oxidases, particularly isoforms CYP3A4 and CYP3A5, are primarily involved in biotransformation, which, in contrast to paclitaxel, principally affects the C-13 side chain and not the taxane ring.223,228–230
The principal pharmacokinetic determinants of toxicity, particularly neutropenia, are drug exposure and the time that plasma concentrations exceed biologically relevant concentrations.223,224,226 A population pharmacodynamic analysis of determinants of outcome in Phase II trials of docetaxel revealed that the most important determinants of the time to progression in patients with metastatic breast cancer are the pretreatment plasma concentration of α1-acid glycoprotein, number of prior chemotherapy regimens, and number of disease sites, whereas both drug exposure and the pretreatment plasma concentration of α1-acid glycoprotein were strong positive determinants of time to progression in patients with advanced lung cancer treated with docetaxel.224,226 Conversely, the pretreatment plasma level of α1-acid glycoprotein was negatively, albeit significantly, related to the probability of experiencing both severe neutropenia and febrile neutropenia. In one clinical study, the rate of docetaxel clearance was related to CYP3A4 activity, as assessed by the [14 C-N-methyl]erythromycin breath test.231
Both sequence- dependent pharmacokinetic and toxicologic interactions between taxanes and several other chemotherapy agents have been noted, largely as a consequence of the prominent cell-cycle-specific effects of this class of agents.232 The most prominent sequence-dependent effects relate to the platinum compound and the taxanes, particularly with protracted taxane administration schedules. Sequence dependence has been primarily reported with paclitaxel, which most likely relates to the fact that docetaxel has been evaluated on a shorter (1-h) schedule. For example, the sequence of cisplatin followed by paclitaxel (24-h schedule) induces more profound neutropenia than the reverse sequence, which is explained by a 33% reduction in the clearance of paclitaxel following cisplatin.233 The least toxic sequence, paclitaxel before cisplatin, was demonstrated to induce more cytotoxicity in vitro, and therefore it was selected for clinical development.232–234 Sequence dependence does not appear to be a clinically relevant phenomenon with the taxanes on shorter schedules.210 The modulation of cytochrome P450-dependent paclitaxel-metabolizing enzymes by cisplatin may, in part, explain these findings. Platinum compounds may reduce the activities of cytochrome P450 mixed-function oxidases. The ability to modulate cytochrome P450 mixed-function oxidases is not shared by all the platinum compounds. For example, carboplatin does not appear to be capable of modulating P450 systems, and does not affect the pharmacokinetics of paclitaxel.210 However, treatment with paclitaxel infused over 3 or 24 h followed by carboplatin seems to produce equivalent neutropenia and less thrombocytopenia as compared to carboplatin as a single agent, which is not explained by pharmacokinetic interactions.210,235–237
The potential for sequence-dependent interactions also has been studied during developmental studies of paclitaxel-doxorubicin and paclitaxel-cyclophosphamide combinations.232, 238–240 Both neutropenia and mucositis are more severe when paclitaxel on a 24-h schedule is administered before doxorubicin, as compared to the reverse sequence, which is most likely caused by an approximately 32% reduction in the clearance of doxorubicin and doxorubicinol when the agent is administered after paclitaxel.232,239–242 Neither sequence-dependent pharmacologic nor toxicologic interactions between doxorubicin and paclitaxel on a shorter (3-h) schedule have been noted; however, the doxorubicin clearance is reduced with both sequences, and the combination of paclitaxel (3-h schedule) and doxorubicin (bolus infusion) produces a much higher frequency of congestive cardiotoxicity than would have been expected from an equivalent cumulative doxorubicin dose given without paclitaxel (see “Toxicity” below, for a discussion of cardiotoxicity).241 Although similar decrements in the clearance of epirubicin and its metabolites have been reported in studies of paclitaxel combined with epirubicin, an increased incidence of cardiotoxicity has not been observed.242 The precise etiology for these interactions is unclear; however, competition for the hepatic and/or biliary Pgp transport of the anthracyclines with paclitaxel and/or its polyoxyethylated castor oil vehicle is a possible explanation.232,240 The vehicle is suspected because similar effects have not been noted with docetaxel, which is not formulated in polyoxyethylated castor oil. However, the lack of such interactions with docetaxel may also be a result of docetaxel's greater potency and therefore lower doses which have a lower likelihood of a pharmacologically relevant degree of competition for transport mechanisms involved in doxorubicin clearance. Hematologic toxicity has been more profound with the sequence of cyclophosphamide before paclitaxel (24-h schedule) than with the reverse sequence. Sequence-dependent cytotoxic effects have been reported when the taxanes are combined with 5- fluorouracil, etoposide, cytosine arabinoside, fludarabine, flavopiridol, and other antineoplastic agents in vitro.232 In human tumor xenografts, both paclitaxel and docetaxel induce thymidine phosphorylase activity, which may increase the metabolic activation of the oral fluoropyrimidine prodrug capecitabine.243
Drug interactions may also result from the effects of other classes of drugs on the cytochrome P450-dependent metabolism of the taxanes. Inducers of cytochrome P450 mixed-function oxidases such as the anticonvulsants phenytoin and phenobarbital profoundly accelerate the metabolism of both paclitaxel and docetaxel in human microsomal studies and in both children and adults who are concurrently receiving treatment with phenobarbital and phenytoin.244–247 On the other hand, many types of agents that inhibit cytochrome P450 mixed-function oxidases or are metabolized by the CYP3A isoenzyme, such as orphenadrine, erythromycin, cimetidine, testosterone, ketoconazole, fluconazole, midazolam, polyoxyethylated castor oil, and corticosteroids, interfere with human microsomal metabolism of paclitaxel and docetaxel in vitro, but the inhibitory concentrations of these agents exceed those achieved in clinical practice, and the overall relevance of these findings is not known.244–247 The results of a clinical trial in which patients were randomized to receive either cimetidine or famotidine premedication, which differentially inhibit P450 metabolism in vitro, before their first course of paclitaxel and then crossed over to the alternate premedication during their second course failed to show significant toxicologic and pharmacologic differences between the agents, and a review of early clinical trial results with docetaxel has not demonstrated significant alterations in docetaxel clearance by corticosteroids.248
The incidence of congestive heart failure has also been higher in breast cancer patients treated with the combination of trastuzumab and paclitaxel than with paclitaxel alone, but the explanation for this observation has not been determined.249
Myelosuppression is the principal toxicity of paclitaxel and docetaxel. However, despite similar structures, these agents possess modest differences in their toxicity spectra.
Neutropenia is the principal toxicity of paclitaxel. The onset is usually on days 8 to 10, and recovery is generally complete by days 15 to 21. The main clinical determinant for the severity of neutropenia is the extent of prior myelosuppressive therapy; however, paclitaxel-induced neutropenia is typically noncumulative and the duration of severe neutropenia, even in heavily pretreated patients, is generally brief. Pharmacokinetic parameters of paclitaxel in plasma that reflect drug exposure, particularly the duration that plasma concentrations are maintained above biologically relevant levels (0.05 to 0.10 μmol/L; see section above on “Clinical Pharmacology”) relate to the severity of neutropenia, which may explain why neutropenia is more severe with longer infusion schedules.136–138,250 But because paclitaxel distributes widely and avidly to peripheral tissues even following treatment on short schedules, this does not mean that more protracted schedules will portend superior antitumor activity. In contrast, the cumulative clinical experience to date indicates a lack of a clearly optimal schedule for any particular tumor type, although treatment with higher doses should be considered if shorter schedules are used.251 At paclitaxel doses exceeding 175 mg/m2 on a 24-h schedule and 225 mg/m2 on a 3-h schedule, neutrophil counts typically decrease to below 500/μL for fewer than 5 days in most courses, even in untreated patients. Even patients who have received extensive prior therapy can usually tolerate paclitaxel doses in the range of 175 to 200 mg/m2 administered over 3 or 24 h. More frequent administration schedules, particularly weekly treatment with 80 to 100 mg/m2, have resulted in less severe neutropenia than single-dosing schedules (see “Administration, Dose, and Schedule” below). Severe thrombocytopenia and anemia are unusual, except in heavily pretreated patients.
The incidence of major hypersensitivity reactions in early Phase I trials approached 30%, but the incidence is approximately 1% to 3% following the advent and broad adoption of effective prophylaxis.136–138,250,252,253 Most major reactions are characterized by dyspnea with bronchospasm, urticaria, and hypotension, which typically occur within the first 10 min after the first, and less frequently after the second, treatment. Major hypersensitivity reactions generally resolve completely after stopping treatment and occasionally after treatment with antihistamines, fluids, and vasopressors. Patients who have major reactions have been rechallenged successfully after receiving high doses of corticosteroids, but this approach is not always successful.253,254 Less-severe hypersensitivity phenomena, such as flushing and rashes, have been noted in as many as 40% of patients, and it is particularly important to note that minor hypersensitivity reactions do not portend the development of major reactions. The hypersensitivity reactions are most likely caused by a nonimmunologically mediated release of histamine or histamine-like substances because of the polyoxyethylated castor oil vehicle, but the taxane moiety may also be contributory. In some cases, complement activation has been demonstrated. Although the incidence of major hypersensitivity reactions is reduced with lower administration rates and longer infusion durations, the rates of major reactions are low on both 3- and 24-h schedules when patients are premedicated with corticosteroids and both H1-histamine and H2-histamine antagonists (see “Administration, Dose, and Schedule” below).255 In an assessment of the relative safety of two different paclitaxel schedules (24 vs 3 h), the rates of major reactions were low and similar (2.1% vs 1.0%) in patients receiving paclitaxel for 3 or 24 h, respectively, with premedication.255
A peripheral neuropathy dominated by sensory manifestations, such as numbness and paresthesia, in a glove-and-stocking distribution is the principal neurotoxic effect of paclitaxel.114, 136–138,250,255 There is often symmetric distal loss of sensation carried by both large (proprioception, vibration) and small (temperature, pinprick) fibers. Symptoms may begin as soon as 24 to 72 h after treatment with higher doses (≥ 250 mg/m2), but usually occur only after multiple courses at 135 to 250 mg/m2 every 3 weeks or 80 to 100 mg/m2 weekly, and are cumulative thereafter. Severe neurotoxicity precludes chronic treatment with paclitaxel at doses above 250 mg/m2 over 3 or 24 h, but severe neurotoxicity is uncommon at conventional doses (< 200 mg/m2) of paclitaxel alone even in patients who previously received other neurotoxic agents such as cisplatin. It appears that patients treated with paclitaxel over shorter (eg, 3-h) schedules are more prone to the neurotoxic effect of paclitaxel as compared to those treated with longer (eg, 24- or 96-h) schedules, which argues that peak concentrations may be a principal pharmacologic determinant of neurotoxicity. The incidence of neurotoxicity has been particularly high in patients receiving paclitaxel as a 3-h infusion combined with cisplatin.
The distal, symmetric, length-dependent neurologic deficits suggest that paclitaxel causes a sensory and motor axonal loss similar to the dying-back neuropathies that may have their origin in the cell body or in axonal transport, but a few patients have the simultaneous onset of symptoms in the arms and legs, involvement of the face (perioral numbness), the predominance of large fiber loss, and diffuse areflexia suggestive of a neuronopathy. Both types of neuropathy depend on the dose of paclitaxel or its combination with cisplatin.114,136–138,250,256–258 Motor and autonomic dysfunction may also occur, especially at high doses and in patients with preexisting neuropathies caused by diabetes mellitus and alcoholism. Although several measures, such as the administration of amifostine, glutamate, pyridoxine, and anticonvulsants, appear to reduce the neurotoxic effects of paclitaxel in some experimental models, anecdotal reports, or insufficiently powered randomized trials, there is no convincing evidence that any specific measure is effective at ameliorating existing manifestations or preventing the development or worsening of neurotoxicity.
Optic nerve disturbances, characterized by scintillating scotomata, may also occur.259 Acute encephalopathy, which can progress to coma and death, has been reported following treatment with high doses (> 600 mg/m2).260
Paclitaxel may produce transient myalgia without physical or biochemical evidence of myositis. Myalgia is typically experienced 2 to 5 days after therapy and after treatment with doses above 170 mg/m2.256 A constellation of muscular and neuropathic effects also often precludes continuous treatment with paclitaxel administered on a weekly schedule, requiring the institution of rest periods. In general, nonsteroidal antiinflammatory agents are minimally effective in palliating and preventing symptoms, and narcotics are usually administered prophylactically on days 2 to 5 posttreatment in patients who have been symptomatic. Antihistamines have also been anecdotally reported to prevent acute myalgia.261
In early studies in which routine cardiac monitoring was performed because of the high rate of major hypersensitivity phenomena, paclitaxel was noted to cause cardiac rhythm disturbances, the overwhelming majority of which were not associated with symptoms or sequelae; therefore, the clinical relevance of these effects is not known.136–138,250,262–264 The most common rhythm disturbance appears to be transient bradycardia. The cumulative experience to date suggests that isolated asymptomatic bradycardia without hemodynamic effects is not an indication for discontinuing paclitaxel. More important bradyarrhythmias, including Mobitz type I (Wenckebach syndrome), Mobitz type II, and third-degree heart block, have been noted, but the incidence in a large National Cancer Institute database was only 0.1%.263 Most documented episodes have been asymptomatic. Because such events were noted in patients enrolled in early trials that required continuous cardiac monitoring, second- and third-degree heart block are likely underreported because cardiac monitoring is not usually performed. Interestingly, reports of similar disturbances in both animals and humans who ingested various species of yew plants and related taxanes affecting cardiac automaticity and conduction suggest that the bradyarrhythmias are caused by paclitaxel. Myocardial infarction, cardiac ischemia, atrial arrhythmias, and ventricular tachycardia have been noted, but whether there is a causal relationship between paclitaxel and these events is uncertain. There is no evidence that chronic, long-term treatment with paclitaxel causes progressive cardiac dysfunction. Routine cardiac monitoring during paclitaxel therapy is not necessary, but is recommended for those patients who may not be able to tolerate bradyarrhythmias, such as those with atrioventricular conduction disturbances or ventricular dysfunction. Although patients with a wide range of cardiac abnormalities and cardiac histories were broadly and empirically restricted from participating in early clinical trials, paclitaxel treatment has been reported to be well tolerated in a small series of gynecologic cancer patients with major cardiac risk factors.263 On the other hand, repetitive treatment of patients with the combined regimen of paclitaxel on a 3-h schedule and doxorubicin as a brief infusion is associated with a higher frequency of congestive cardiotoxicity than would be expected to occur with the same cumulative doxorubicin dose given without paclitaxel (see “Drug Interactions” above).241, 242 In one study in previously untreated women with advanced breast cancer treated with escalating doses of paclitaxel as a 3-h infusion and doxorubicin 60 mg/m2 to a cumulative dose of 480 mg/m2, which would be predicted to result in a less than 5% incidence of congestive cardiotoxicity in patients treated with doxorubicin alone, the incidence of congestive cardiotoxicity was approximately 25%.240 However, the incidence of cardiotoxicity was less than 5% when similar patients received identical schedules of paclitaxel and doxorubicin, but the cumulative doxorubicin dose did not exceed 360 mg/m2. Both experimental and early clinical results suggest that dexrazoxane may reduce the cardiotoxicity of the doxorubicin-paclitaxel combination.265 The incidence of congestive heart failure was also significantly higher in breast cancer patients treated with the combination of trastuzumab and paclitaxel than in those treated with paclitaxel alone in a randomized Phase III trial; consequently, careful monitoring of patients receiving this combination is warranted.266
Gastrointestinal toxicities, including nausea, vomiting, and diarrhea, are uncommon. Higher paclitaxel doses may cause mucositis, especially in patients with leukemia who may be more prone to mucosal barrier breakdown or in patients receiving protracted infusions. Rare cases of neutropenic enterocolitis and gastrointestinal necrosis have been noted, particularly in patients given high doses of paclitaxel in combination with doxorubicin or cyclophosphamide.238,266–269 Severe hepatotoxicity and pancreatitis have also been noted, but these events are rare.269,270 Acute bilateral pneumonitis has been reported in less than 1% of patients treated on a 3-h schedule in one series, and both interstitial and parenchymal pulmonary toxicity have been reported, but clinically significant pulmonary effects are uncommon.271,272
Paclitaxel also induces reversible alopecia of the scalp, but all body hair is usually lost with cumulative therapy. Alopecia appears to be dose related and occurs only following repetitive treatment with weekly administration schedules. Although the agent is often not considered a vesicant, extravasation of large volumes can cause moderate soft-tissue injury. Inflammation at the injection site and along the course of an injected vein may occur. Nail disorders have been reported, particularly in patients treated on weekly schedules. Recall reactions in previously irradiated sites have also been noted.
Similar to paclitaxel, neutropenia is the principal toxicity of docetaxel.138,139,273 At doses ranging from 75 to 100 mg/m2 administered as a 1-h infusion, neutrophil counts usually decrease to below 500/μL. The onset of neutropenia is usually noted on day 8 and complete resolution typically occurs by days 15 to 21. Neutropenia is significantly less when low doses are administered frequently, such as on a weekly schedule (see “Administration, Dose, and Schedule” below). The most important determinant of neutropenia appears to be the extent of prior therapy, but α1-acid glycoprotein and the duration of drug exposure above biologically relevant concentrations appear to be important determinants (see section on clinical pharmacology). Because the activity of cytochrome P450 CYP3A4 has been related to docetaxel clearance, it might also be inversely related to toxicity.232 Significant effects on platelets and red blood cells are uncommon.
Even though docetaxel is not formulated in polyoxyethylated castor oil, hypersensitivity reactions have been reported in approximately 31% of patients receiving docetaxel without premedications.138,139,273 However, the majority of these reactions are not major. Nevertheless, major reactions, characterized by dyspnea, bronchospasm, and hypotension, particularly during the first two courses and within minutes after the start of treatment, have been reported. Manifestations generally resolve within 15 min after cessation of treatment, and docetaxel is usually able to be reinstituted without consequences, occasionally after treatment with an H1-histamine antagonist. Both the incidence and severity of hypersensitivity reactions appear to be reduced significantly by premedication with corticosteroids and both H1- and H2-histamine antagonists (see “Administration, Dose, and Schedule” below). Like paclitaxel, patients who experience major reactions have been retreated successfully after the resolution of symptoms and following treatment with corticosteroids and H1-histamine antagonists.
In early studies, a unique fluid retention syndrome, characterized by edema, weight gain, and third-space fluid collection, was noted in patients treated with multiple courses of docetaxel and was related to the absolute cumulate dose.138,139,273–275 Fluid retention did not appear to be related to hypoalbuminemia or cardiac, renal, or hepatic dysfunction, but to increased capillary permeability.274 Capillary filtration studies revealed a two-stage process with progressive congestion of the interstitial space by proteins and water, starting between the second and fourth course that progressed to insufficient lymphatic drainage.274 In early studies in which prophylactic medication was not used, fluid retention was not usually significant at cumulative docetaxel doses below 400 mg/m2; however, the incidence and severity of fluid retention increased sharply at cumulative doses of 400 mg/m2 or greater, and often resulted in the delay or termination of treatment. Prophylactic treatment with corticosteroids with or without H1- and H2-histamine antagonists reduces the overall incidence of fluid retention and increases the number of courses and cumulative docetaxel dose before the onset of this toxicity (see “Administration, Dose, and Schedule” below).275 In fact, drug-induced fluid retention has been uncommon following the broad adoption of corticosteroid premedication. Fluid retention resolves slowly after docetaxel is stopped, with complete resolution occurring several months after treatment in patients with severe toxicity. Aggressive and early treatment with progressively more potent diuretics, starting with potassium sparing diuretics, has been successfully used to manage fluid retention. The incidence of fluid retention appears to be lower in studies that used lower doses (60 to 75 mg/m2) of docetaxel during each course, but this may be a result of the administration of lower overall cumulative doses, and the effects of lower doses on antitumor activity are unknown.
Both neurosensory and neuromuscular effects appear to be less common and less severe with docetaxel as compared to paclitaxel.138,139,276,277 In a Phase III trial, patients with advanced ovarian carcinoma receiving first-line treatment with docetaxel and carboplatin experienced significantly less severe and less total neurotoxicity than did those receiving treatment with paclitaxel and carboplatin. Mild to moderate peripheral neurotoxicity is observed in approximately 40% of previously untreated patients. Previous treatment with cisplatin appears to increase the likelihood of developing neurotoxicity. The neurotoxicity is qualitatively similar to that of paclitaxel, with sensory effects predominating. Patients typically complain of paresthesia and numbness, but peripheral motor disturbances may also occur. Severe toxicity is unusual following repetitive treatment with docetaxel doses less than 100 mg/m2, except in patients with antecedent disorders such as alcohol abuse.
Although cardiovascular effects, including angina, arrhythmia, conduction disturbances, congestive heart failure, hypertension, and hypotension, have been noted rarely in the pretreatment period, there is no convincing evidence that directly links docetaxel to these events. Stomatitis appears to occur more frequently with docetaxel than paclitaxel, particularly with prolonged infusions which are used rarely. Nausea, vomiting, and diarrhea have also been observed infrequently, but severe manifestations are rare. Empiric use of antiemetic premedication does not appear to be warranted. Phlebitis along the course of the infused veins and local inflammation at the injection site are occasionally noted; however, severe tissue damage following drug extravasation is not generally observed. Transient arthralgia and myalgia without inflammatory manifestations are occasionally noted within days following treatment. Malaise, often referred to as asthenia, has been a prominent complaint in patients who have been treated with large cumulative doses, particularly when docetaxel is administered on a continuous weekly schedule.138,139,264,278
Skin toxicity may occur in as many as 50% to 75% of patients138,139,273,278,279; however, premedication may reduce the overall incidence of this toxicity. An erythematous pruritic maculopapular rash that affects the forearms, hands, and/or feet is typical. Other cutaneous effects include desquamation of the hands and feet, which is a component of a more general palmar-plantar syndrome that may respond to pyridoxine or cooling, and onychodystrophy characterized by brown discoloration, ridging, onycholysis, soreness, and brittleness and loss of the nail plate.279,280 Skin and nail changes appear to be most prominent in patients treated frequently with low doses (ie, weekly schedules).278
Discerning the optimal dose and schedule for the taxanes, principally paclitaxel, has been a major focus of many evaluations over the last decade.251 The collective results of these efforts indicate that paclitaxel has prominent antitumor activity on multiple schedules and that no particular schedule is superior from an efficacy standpoint; however, toxicity profiles may be vastly different. The earliest clinical studies of paclitaxel were limited to the 24-h schedule, largely as a consequence of an apparent increased rate of severe hypersensitivity reactions on shorter schedules, but the development of effective premedication regimens led to evaluation of a broad range of dosing schedules. Although paclitaxel 135 mg/m2 on a 24-h schedule was initially approved for patients with refractory and recurrent ovarian cancer, regulatory approval was later obtained for paclitaxel 175 mg/m2 on a 3-h schedule in these and other indications. In patients with advanced breast and ovarian cancers, the collective results of randomized studies in patients treated with paclitaxel on 3-, 24-, and 96-hour-every-3-weeks administration schedules indicate that they are largely equivalent, particularly with regard to event-free and overall survival, although response rates have occasionally been higher with more protracted schedules.251 The development of such schedules was based on the observation that the duration of exposure above a biologically relevant concentration threshold is one of the most important determinants of cytotoxicity in vitro (see section on clinical pharmacology), but there has been no clear evidence that more protracted infusion schedules are superior in terms of clinical efficacy and/or toxicity.251,280–282 The extensive distribution of the taxanes to peripheral tissues, as well as the avid and protracted tissue binding of these agents, may explain the lack of substantial differences in antitumor activity between short and more protracted administration schedules despite substantial differences in vitro. There has also been considerable interest in more intermittent dosing schedules, particularly those in which paclitaxel is administered as a 1-h infusion weekly, which has been consistently demonstrated to produce substantially less myelosuppression than conventional 3- and 24-hour-every-3-weeks schedules. Although intriguing preliminary results have been reported with paclitaxel on a 1-h weekly schedule in randomized trials in limited disease settings (ie, neoadjuvant setting in patients with locally advanced breast cancer), larger randomized trials in other disease settings are in progress.283 Nevertheless, the weekly schedule may be particularly advantageous for patients who are at high risk of developing severe myelosuppression.
Paclitaxel is indicated and generally administered at a dose of 175 mg/m2 over 3 h or 135 to 175 mg/m2 over 24 h every 3 weeks. Several randomized trials in patients with advanced lung, head and neck, and ovarian cancers have consistently failed to show that paclitaxel doses above 135 to 175 mg/m2 on a 24-h schedule are superior to conventional doses.142,251 Nearly identical results have been obtained in a Phase III study in patients with metastatic breast cancer, in which greater efficacy was not observed in patients treated with paclitaxel doses above 175 mg/m2 on a 3-h schedule.284 The following doses have been recommended on less-conventional schedules: 200 mg/m2 over 1 h as either a single dose or three divided doses every 3 weeks; 140 mg/m2 over 96 h every 3 weeks; and 80 to 100 mg/m2 weekly. The most common schedules evaluated in patients with Kaposi sarcoma caused by the acquired immunodeficiency syndrome are paclitaxel 135 mg/m2 over 3 or 24 h every 3 weeks and 100 mg/m2 every 2 weeks.191 Paclitaxel has also been administered into the pleural and peritoneal cavities.285,286 Biologically relevant plasma concentrations have been achieved with intraperitoneal administration, and concentrations in the peritoneal cavity are several orders of magnitude higher than plasma concentrations.
The following premedication is recommended to prevent major hypersensitivity reactions: dexamethasone 20 mg orally or intravenously, 12 and 6 h before treatment; an H1-histamine antagonist (such as diphenhydramine, 50 mg intravenously) 30 min before treatment; and an H2-histamine-antagonist (such as cimetidine, 300 mg; famotidine, 20 mg; or ranitidine, 150 mg intravenously) 30 min before treatment. A single dose of a corticosteroid (dexamethasone 20 mg intravenously) administered 30 min before treatment has also been reported to confer effective prophylaxis of major hypersensitivity reactions.243,278,287
Similar to the Vinca alkaloids and other agents in which hepatic metabolism and biliary excretion are the principal modes of drug disposition, paclitaxel dose modifications are required in patients with hepatic dysfunction. However, official recommendations have not been formulated, and study results are somewhat conflicting because of differences in the definitions of dose-limiting toxicity between various studies. Prospective evaluations indicate that patients with moderate to severe elevations in serum concentrations of hepatocellular enzymes and/or bilirubin are more likely to develop severe toxicity than patients without hepatic dysfunction.288,289 Therefore, it would be prudent to reduce paclitaxel doses by at least 50% in patients with moderate or severe hepatic excretory dysfunction (hyperbilirubinemia) and/or substantial elevations in hepatic transaminases. Renal clearance contributes minimally to overall clearance (5% to 10%), and patients with severe renal dysfunction do not appear to require dose modification.220 Based on the pharmacologic behavior, particularly the wide distributive properties of the taxanes, dose modifications are not required solely for peripheral edema and third-space fluid collections.
Contact of paclitaxel with plasticized polyvinyl chloride (PVC) equipment or devices must be avoided because of the risk of patient exposures to plasticizers that may be leached from PVC infusion bags or sets. Paclitaxel solutions should be diluted and stored in glass or polypropylene bottles or suitable plastic bags (polypropylene or polyolefin) and administered through polyethylene-lined administration sets that include an in-line filter with a microporous membrane not greater than 0.22 microns.
In the United States, docetaxel is indicated at a dose range of 60 to 100 mg/m2 and 75 mg/m2 over 1 h in patients with breast and non-small-cell lung cancers, respectively, but most early clinical trials in advanced breast, ovarian, and non-small-cell lung cancers evaluated doses at the higher end of this range (75 to 100 mg/m2), with scant data available for patients treated with docetaxel 60 mg/m2.138,139,290 Although some untreated or minimally pretreated patients generally tolerate docetaxel at a dose of 100 mg/m2 without severe toxicity, emerging data indicate poorer tolerance in more heavily pretreated patients, in whom 75 mg/m2 appears to be more reasonable from a toxicologic perspective.290 Docetaxel 75 mg/m2 is associated with a survival benefit in patients with non-small-cell lung cancer following first-line treatment. Like paclitaxel, docetaxel has also been administered as a 1-h infusion weekly. Although there is no clear benefit of chronic weekly drug administration in terms of antitumor activity at this time, and prospective randomized trials are in progress to address this issue, hematologic toxicity is much less with weekly dose schedules than with conventional dose schedules. Both cumulative asthenia and neurotoxicity are the principal toxicity of docetaxel administered weekly, precluding administration of docetaxel doses exceeding 36 mg/m2/wk.276,277 Despite the use of a polysorbate-80 formulation instead of polyoxyethylated castor oil which is used to formulate paclitaxel, a relatively high rate of hypersensitivity reactions and profound fluid retention in patients who did not receive premedication has led to the use of several effective premedication regimens, the most popular of which is dexamethasone 8 mg orally twice daily for 3 or 5 days starting 1 or 2 days, respectively, before docetaxel, with or without both H1- and H2-histamine antagonists given 30 min before docetaxel.275 Administration of docetaxel without corticosteroids is not recommended, even in patients who do not develop hypersensitivity manifestations because drug-related fluid retention requires drug discontinuation.
A retrospective review of docetaxel pharmacokinetics in patients without hyperbilirubinemia demonstrated that docetaxel clearance is reduced by approximately 25% in patients with elevations in serum concentrations of both hepatic transaminases (1.5-fold or greater) and alkaline phosphatase (2.5-fold or greater), regardless of whether the elevations are a result of hepatic metastases.222–230 Therefore, dose reductions by at least 25% are recommended for such individuals. More substantial reductions (50% or greater) may be required in patients who have moderate or severe hepatic excretory dysfunction (hyperbilirubinemia).284 Similar to paclitaxel (see “The Taxanes: Administration, Dose, and Schedule”), there is no rationale for dose modification solely for renal deficiency and/or third-space fluid accumulation. Also similar to the case with paclitaxel (see “The Taxanes: Administration, Dose, and Schedule”), glass bottles or polypropylene or polyolefin plastic products should be used for preparation and storage, and docetaxel should be administered through polyethylene-lined administration sets.
