Christopher J. Hoimes and Lyndsay N. Harris
MICROTUBULES
Microtubules are vital and dynamic cytoskeletal polymers that play a critical role in cell division, signaling, vesicle transport, shape, and polarity, which make them attractive targets in anticancer regimens and drug design.1Microtubules are composed of 13 linear protofilaments of polymerized α/β-tubulin heterodimers arranged in parallel around a cylindrical axis and associated with regulatory proteins such as microtubule-associated proteins, tau, and motor proteins kinesin and dynein.2 The specific biologic functions of microtubules are due to their unique polymerization dynamics. Tubulin polymerization is mediated by a nucleation-elongation mechanism. One end of the microtubules, termed the plus end, is kinetically more dynamic than the other end, termed the minus end (Fig. 21.1). Microtubule dynamics are governed by two principal processes driven by guanosine 5′-triphosphate (GTP) hydrolysis: treadmilling or poleward flux is the net growth at one end of the microtubule and the net shortening at the opposite end, and dynamic instability, which is a process in which the microtubule ends switch spontaneously between states of slow sustained growth and rapid depolymerization.2 Antimicrotubule agents are tubulin-binding drugs that directly bind tubules, inhibitors of tubulin-associated scaffold kinases, or inhibitors of their associated mitotic motor proteins to, ultimately, disrupt microtubule dynamics. They are broadly classified as microtubule stabilizing or microtubule destabilizing agents according to their effects on tubulin polymerization.
TAXANES
Taxanes were the first-in-class microtubule stabilizing drugs. Ancient medicinal attempts at cardiac pharmacotherapy using material from the toxic coniferous yew tree, Taxus spp., were likely related to the plant’s alkaloid taxineeffect on sodium and calcium channels. Taxane compounds are the result of a drug screening of 35,000 plant extracts in 1963 that led to the identification of activity from the bark extract of the Pacific yew tree, Taxus brevifolia.Paclitaxel was identified as the active constituent with a report of its activity in carcinoma cell lines in 1971.3 Motivation to identify taxanes derived from the more abundant and available needles of Taxus baccata led to the development of docetaxel, which is synthesized by the addition of a side chain to 10-deacetylbaccatin III, an inactive taxane precursor.4 The taxane rings of paclitaxel and docetaxel are linked to an ester side chain attached to the C13 position of the ring, which is essential for antimicrotubule and antitumor activity. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a formulation that avoids the solvent related side effects of non–water-soluble paclitaxel and docetaxel. Overcoming docetaxel and paclitaxel’s susceptibility to the P-glycoprotein efflux pump led to the development of cabazitaxel.5 Cabazitaxel is synthesized by adding two methoxy groups to the 10-deacetylbaccatin III, which results in the inhibition of the 5′-triphosphate–dependent efflux pump of P-glycoprotein.
Paclitaxel initially received regulatory approval in the United States in 1992 for the treatment of patients with ovarian cancer after failure of first-line or subsequent chemotherapy (Table 21.1).1,4 Subsequently, it has been approved for several other indications, including advanced breast cancer after anthracycline-based regimens6; combination chemotherapy of lymph node–positive breast cancer in the adjuvant setting7; advanced ovarian cancer in combination with a platinum compound; second-line treatment of AIDS-related Kaposi sarcoma; and first-line treatment of non–small-cell lung cancer (NSCLC) in combination with cisplatin8 (see Table 21.1). In addition to the U.S. Food and Drug Administration (FDA) on-label indications, paclitaxel is widely used for several other tumor types, such as cancers of unknown origin, bladder, esophagus, gastric, head and neck, and cervical cancers. The U.S. patent for paclitaxel expired in 2002, and a generic form of paclitaxel is now available.
Docetaxel was first approved for use in the United States in 1996 for patients with metastatic breast cancer that progressed or relapsed after anthracycline-based chemotherapy, which was later broadened to a general second-line indication (see Table 21.1).4,6 Subsequently, it received regulatory approval in adjuvant chemotherapy of stage II breast cancer in combination with Adriamycin and cyclophosphamide (TAC)9, and first-line treatment for locally advanced or metastatic breast cancer.10 In addition, docetaxel has indications in nonresectable, locally advanced, or metastatic NSCLC after failure of or in combination with cisplatin therapy; metastatic castration-resistant prostate cancer in combination with prednisone11; first-line treatment of gastric adenocarcinoma, including gastroesophageal junction adenocarcinoma in combination with cisplatin and 5-fluorouracil (5-FU)12; and inoperable locally advanced squamous cell cancer of the head and neck in combination with cisplatin and 5-FU (see Table 21.1). Docetaxel came off patent in 2010 and a generic form is available.
Mechanism of Action
The unique mechanism of action for paclitaxel was initially defined by Schiff et al.13 in 1979, who showed that it bound to the interior surface of the microtubule lumen at binding sites completely distinct from those of exchangeable GTP, colchicine, podophyllotoxin, and the vinca alkaloids.14 The taxanes profoundly alter the tubulin dissociation rate constants at both ends of the microtubule, suppressing treadmilling and dynamic instability. Dose-dependent taxane β-tubular binding induces mitotic arrest at the G2/M transition and induces cell death. By stabilizing microtubules, they also can stall ligand-dependent intracellular trafficking, as shown in sequestration of the androgen receptor to the cytosol in metastatic prostate cancer patients treated with docetaxel, and is associated with decreased androgen-regulated gene expression, such as prostate-specific antigen (PSA).15,16 Peripheral neuropathy is a common dose-limiting toxicity across the antimicrotubule agents and likely is a result of their direct effect on microtubules. Studies have shown that they inhibit anterograde and/or retrograde fast axonal transport and can explain the demyelinating “dying back” pattern seen and the vulnerability of sensory neurons with the longest axonal projections.17
Recent evidence suggests that microtubule inhibitors have collateral effects during interphase that lead to cell death. For instance, paclitaxel-stabilized microtubules serve as a scaffold for the binding of the death-effector domain of pro-caspase-8, and thereby enabling a caspase-8 downstream proteolytic cascade.18,19 This caspase-8–dependent mechanism also serves as an important basis for the understanding of the loss of function and/or low expression of the breast cancer 1, early onset gene (BRCA1) association with resistance to taxane therapy.20
Another mechanism of the anticancer effect of taxanes is currently being elaborated and is tied to the B-cell lymphoma-2 (Bcl-2) antiapoptosis family of proteins. Paclitaxel has been shown to cause the phosphorylation of Bcl-2 and the sequestration of Bak and Bim; however, this seemingly cancer-protective phosphorylation needs to be reconciled and likely correlates with Bcl-2–expression levels.21–23Interestingly, neutralizing Bcl-2 homology 3 (BH3) domains with compounds such as ABT-737 is synergistic with docetaxel.24
Clinical Pharmacology
Paclitaxel
With prolonged infusion schedules (6 and 24 hours), drug disposition is a biphasic process with values for alpha and beta half-lives averaging approximately 20 minutes and 6 hours, respectively.4 When administered as a 3-hour infusion, the pharmacokinetics are nonlinear and may lead to unexpected toxicity with a small dose escalation, or a disproportionate decrease in drug exposure and loss of tumor response with a dose reduction. Approximately 71% of an administered dose of paclitaxel is excreted in the stool via the enterohepatic circulation over 5 days as either the parent compound or metabolites in humans. Renal clearance of paclitaxel and metabolites is minimal, accounting for 14% of the administered dose. In humans, the bulk of drug disposition is metabolized by cytochrome P-450 mixed-function oxidases—specifically, the isoenzymes CYP2C8 and CYP3A4, which metabolize paclitaxel to hydroxylated 3′p-hydroxypaclitaxel (minor) and 6α-hydroxypaclitaxel (major), as well as dihydroxylated metabolites.
Nanoparticle Albumin-Bound Paclitaxel
Nab-paclitaxel is a solvent-free colloidal suspension made by homogenizing paclitaxel with 3% to 4% albumin under high pressure to form nanoparticles of ~130 nm that disperse in plasma to ~10 nm (see Table 21.1).25 It received regulatory approval in the United States in 2005 based on results in patients with metastatic breast cancer, and is now also approved in combination with carboplatin for first-line treatment of locally advanced or metastatic NSCLC, and in combination with gemcitabine for first-line treatment of metastatic pancreatic adenocarcinoma.26–28 The improved responses seen with nab-paclitaxel, when compared to solvent-based paclitaxel, are not fully understood. Nab-paclitaxel likely capitalizes on several mechanisms, which include an improved pharmacokinetic profile with a larger volume of distribution and a higher maximal concentration of circulating, unbound, free drug; improved tumor accumulation by the enhanced permeability and retention (EPR) effect; and receptor-mediated transcytosis via an albumin-specific receptor (gp60) for endothelial transcytosis and binding of secreted protein acidic and rich in cysteine (SPARC) in the tumor interstitium.29,30 In contrast to cremophor/ethanol (CrEL) solvent-based paclitaxel, nab-paclitaxel exhibits an extensive extravascular volume of distribution exceeding that of water, indicating extensive tissue and extravascular protein distribution. Some studies show that nab-paclitaxel achieves 33% higher drug concentration over CrEL-paclitaxel.31 Additionally, the maximum concentration (Cmax), the mean plasma half-life of 15 to 18 hours, the area under curve (AUC), and the dose-independent plasma clearance correspond to linear pharmacokinetics over 80 to 300 mg/m2.29,32 The improved deposition of a nanoparticle, such as nab-paclitaxel in a tumor tissue, can occur passively through an EPR effect in areas of leaky vasculature, sufficient vascular pore size, and decreased lymphatic flow.25,33 Once in the tissue, the nab-paclitaxel nanovehicle can deliver the drug locally or benefit from further receptor-mediated targeting to SPARC, which has been shown to be overexpressed, and correlates with disease progression in many tumor types.34–38 Although preclinical models, as well as one clinical trial, have shown how nanoparticle therapy can benefit from this targeted approach,39,40 correlative data for nab-paclitaxel is limited. The high stromal SPARC level was associated with longer survival in patients treated with nab-paclitaxel in the phase I/II study of patients with pancreatic cancer; however, this correlative analysis was not included in the phase III trial report and requires validation.28,41
Docetaxel
The pharmacokinetics of docetaxel on a 1-hour schedule is triexponential and linear at doses of 115 mg/m2 or less.4 Terminal half-lives ranging from 11.1 to 18.5 hours has been reported. The most important determinants of docetaxel clearance were the body surface area (BSA), hepatic function, and plasma α1-acid glycoprotein concentration. Plasma protein binding is high (greater than 80%), and binding is primarily to α1-acid glycoprotein, albumin, and lipoproteins. The hepatic cytochrome P-450 mixed-function oxidases, particularly isoforms CYP3A4 and CYP3A5, are principally involved in biotransformation. The principal pharmacokinetic determinants of toxicity, particularly neutropenia, are drug exposure and the time that plasma concentrations exceed biologically relevant concentrations. The baseline level of α1-acid glycoprotein may be elevated as an acute phase reactant in advanced disease and is an independent predictor of response and a major objective prognostic factor of survival in patients with non–small-cell lung cancer treated with docetaxel chemotherapy.
Cabazitaxel
Cabazitaxel is a semisynthetic derivative of the natural taxoid 10-deacetylbaccatin III. It binds to and stabilizes the β-tubulin subunit, resulting in the inhibition of microtubule depolymerization and cell division, cell cycle arrest in the G2/M phase, and the inhibition of tumor cell proliferation.5 It is active against diverse cancer cell lines and tumor models that are sensitive and resistant to docetaxel, including prostate, mammary, melanoma, kidney, colon, pancreas, lung, gastric, and head and neck.5 Cabazitaxel is a poor substrate for the membrane-associated, multidrug resistance P-glycoprotein efflux pump; therefore, is useful for treating docetaxel-refractory prostate cancer for which it gained FDA approval in 2010.5 In addition, it penetrates the blood–brain barrier.42 Pharmacokinetics of cabazitaxel is similar to docetaxel; however, cabazitaxel has a larger volume of distribution and a longer terminal half-life (mean 77.3 hours versus 11.2 hours for docetaxel).43,44
Tesetaxel
Tesetaxel (DJ-927, XRP6258) is a semisynthetic, orally bioavailable taxane currently in clinical trials in breast, gastric, and prostate cancer. Administration in phase I and II trials has been once per week or every 3 weeks and not associated with hypersensitivity and possibly less neurotoxicity compared to other taxanes. Dose-limiting toxicity has been neutropenia. Overall responses in phase II studies have been 50% and 38% in patients treated for first- and second-line breast cancer, respectively. A phase I/II study in advanced NSCLC showed an overall response rate of 5.6%. Tesetaxel activity is independent of P-glycoprotein expression.45 Pharmacokinetics on a schedule of every 3 weeks have an AUC of ~1,750 ng/mL per hour, a half life of ~170 hours, and no drug interactions that have been noted.46
Drug Interactions
Sequence-dependent pharmacokinetic and toxicologic interactions between paclitaxel and several other chemotherapy agents have been noted. The sequence of cisplatin followed by paclitaxel (on a 24-hour schedule) induces more profound neutropenia than the reverse sequence, which is explained by a 33% reduction in the clearance of paclitaxel after cisplatin.47 Treatment with paclitaxel on either a 3- or 24-hour schedule followed by carboplatin has been demonstrated to produce equivalent neutropenia and less thrombocytopenia as compared to carboplatin as a single agent, which is not explained by pharmacokinetic interactions. Neutropenia and mucositis are more severe when paclitaxel is administered on a 24-hour schedule before doxorubicin, compared to the reverse sequence, which is most likely due to an approximately 32% reduction in the clearance rates of doxorubicin and doxorubicinol when doxorubicin is administered after paclitaxel. Several agents that inhibit cytochrome P-450 mixed-function oxidases interfere with the metabolism of paclitaxel and docetaxel in human microsomes in vitro; however, the clinical relevance of these findings is not known.47
Toxicity
Paclitaxel
The micelle-forming CrEL vehicle, which is required for suspension and intravenous delivery of paclitaxel, causes its nonlinear pharmacokinetics and thereby impacts its therapeutic index. CrEL causes hypersensitivity reactions, with major reactions usually occurring within the first 10 minutes after the first treatment and resolving completely after stopping the treatment. All patients should be premedicated with steroids, diphenhydramine, and an H2 antagonist, although up to 3% will still have reactions. Those who have major reactions have been rechallenged successfully after receiving high doses of corticosteroids.
Neuropathy is the principal toxicity of paclitaxel. Paclitaxel induces a peripheral neuropathy that presents in a symmetric stocking glove distribution, at first transient and then persistent.48 A neurologic examination reveals sensory loss, and neurophysiologic studies reveal axonal degeneration and demyelination.48 Compared with cisplatin, a loss of deep tendon reflexes occurs less commonly; however, autonomic and motor changes can occur. Severe neurotoxicity is uncommon when paclitaxel is given alone at doses below 200 mg/m2 on a 3- or 24-hour schedule every 3 weeks, or below 100 mg/m2 on a continuous weekly schedule. There is no convincing evidence that any specific measure is effective at ameliorating existing manifestations or preventing the development or worsening of neurotoxicity.48
Neutropenia is also frequent with paclitaxel. The onset is usually on days 8 to 11, and recovery is generally complete by days 15 to 21 with an every 3 weeks dosing regimen. Neutropenia is noncumulative, and the duration of severe neutropenia—even in heavily pretreated patients—is usually brief. Severity of neutropenia is related to the duration of exposure above the biologically relevant levels of 0.05 to 0.10 μM/L, and paclitaxel’s nonlinear pharmacokinetics should be considered whenever adjusting dose.49
The most common cardiac rhythm disturbance, a transient sinus bradycardia, can be observed in up to 30% of patients. Routine cardiac monitoring during paclitaxel therapy is not necessary but is advisable for patients who may not be able to tolerate bradyarrhythmias. Drug-related gastrointestinal effects, such as vomiting and diarrhea, are uncommon. Severe hepatotoxicity and pancreatitis have also been noted rarely. Pulmonary toxicities, including acute bilateral pneumonitis, have been reported. Extravasation of large volumes can cause moderate soft tissue injury. Paclitaxel also induces reversible alopecia of the scalp in a dose-related fashion. Nail disorders have also been reported with paclitaxel use and include ridging, nail bed pigmentation, onychorrhexis, and onycholysis. These side effects have been reported more commonly with dose-intensified paclitaxel regimens.
Recent studies have suggested a role for the adenosine triphosphatase (ATP)-binding cassette (ABC) transporter polymorphisms in the development of neuropathy and neutropenia. Sissung et al.50 reported that patients carrying two reference alleles for the ABCB1 (P-glycoprotein, MDR1) 3435C greater than T polymorphism had a reduced risk to develop neuropathy as compared to patients carrying at least one variant allele (P = .09). Data from a large controlled trial to evaluate these and other candidate polymorphisms failed to detect a significant association between genotype and outcome or toxicity for any of the genes analyzed, although the correlative studies were retrospective and the sample size was inadequate to rule out smaller differences.51 A large randomized trial of the CALGB 40101 using an integrated genomewide associate study found two polymorphisms associated with paclitaxel-induced polyneuropathy.52 Both are involved in nerve development and maintenance, including the hereditary peripheral neuropathy Charcot-Marie-Tooth disease gene, FGD4. Further studies are required to adequately assess the role of these variants in predicting toxicity from taxane therapy.
Nab-paclitaxel
Hypersensitivity reactions have not been observed during the infusion period and, therefore, steroid premedications are not necessary. The main dose-limiting toxicities are neutropenia and sensory neuropathy. In a trial comparing weekly paclitaxel 90 mg/m2 to nab-paclitaxel 150 mg/m2 to ixabepilone in patients with metastatic breast cancer, there was more hematologic toxicity and peripheral neuropathy in the nab-paclitaxel arm compared to the paclitaxel arm, although median progression-free survival was not significantly different at the 12-month follow-up.53 This led to dose reductions in 45% of patients in the nab-paclitaxel arm compared with 15% for the paclitaxel arm.53 Other toxicities include alopecia, diarrhea, nausea and vomiting, elevations in liver enzymes, arthralgia, myalgia, and asthenia.
Docetaxel
Neutropenia is the main toxicity of docetaxel.4 When docetaxel is administered on an every 3 weeks schedule, the onset of neutropenia is usually noted on day 8, with complete resolution by days 15 to 21. Neutropenia is significantly less when low doses are administered weekly. FDA black box warnings include increased toxicity in patients with abnormal liver function and, in select NSCLC patients that received prior platinum, severe hypersensitivity reactions and severe fluid retention despite dexamethasone at-home premedication.
Hypersensitivity reactions were noted in approximately 31% of patients who received the drug without premedications in early studies.4 Symptoms include flushing, rash, chest tightness, back pain, dyspnea, and fever or chills. Severe hypotension, bronchospasm, generalized rash, and erythema may also occur.54 Major reactions usually occur during the first two courses and within minutes after the start of treatment. Signs and symptoms generally resolve within 15 minutes after cessation of treatment, and docetaxel can usually be reinstituted without sequelae after treatment with diphenhydramine and an H2-receptor antagonist. Docetaxel induces a unique fluid retention syndrome characterized by edema, weight gain, and third-space fluid collection. Fluid retention is cumulative and is due to increased capillary permeability. Prophylactic treatment with corticosteroids has been demonstrated to reduce the incidence of fluid retention. Aggressive and early treatment with diuretics has been successfully used to manage fluid retention. Skin toxicity may occur in as many as 50% to 75% of patients; however, premedication may reduce the overall incidence of this effect.4 Other cutaneous effects include palmar–plantar erythrodysesthesia and onychodystrophy. Docetaxel produces neurotoxicity, which is qualitatively similar to that of paclitaxel; however, neurosensory and neuromuscular effects are generally less frequent and less severe than with paclitaxel. Mild-to-moderate peripheral neurotoxicity occurs in approximately 40% of untreated patients.55 Asthenia has been a prominent complaint in patients who have been treated with large cumulative doses. Stomatitis appears to occur more frequently with docetaxel than with paclitaxel. Other reported toxicities of note include necrotizing enterocolitis, interstitial pneumonitis, and organizing pneumonia.56,57
Cabazitaxel
A phase III multi-institutional study of men with metastatic castration-resistant prostate cancer who had failed docetaxel improved overall median survival on cabazitaxel compared to mitoxantrone.58Cabazitaxel was approved by the FDA in June 2010 to treat metastatic castration-resistant prostate cancer in those who had received prior chemotherapy. This was despite a higher rate of adverse deaths (4.9%), a third of which were due to neutropenic sepsis. Cabazitaxel was associated with more grade 3 or 4 neutropenia (82%) than mitoxantrone (58%). Side effects reported in more than 20% of patients treated with cabazitaxel included myelosuppression, diarrhea, nausea, vomiting, constipation, abdominal pain, or asthenia. FDA black box warnings are similar to those for docetaxel.
VINCA ALKALOIDS
The vinca alkaloids have been some of the most active agents in cancer chemotherapy since their introduction 40 years ago. The naturally occurring members of the family, vinblastine (VBL) and vincristine (VCR), were isolated from the leaves of the periwinkle plant Catharanthus roseus G. Don. In the late 1950s, their antimitotic and, therefore, cancer chemotherapeutic potential was discovered by groups both at Eli Lilly Research Laboratories and at the University of Western Ontario, and they came into widespread use for the single-agent treatment of childhood hematologic and solid malignancies and, shortly after, for adult hematologic malignancies (see Table 21.1).1 Their clinical efficacy in several combination therapies has led to the development of various novel semisynthetic analogs, including vinorelbine (VRL), vindesine (VDS), and vinflunine (VFL).
Mechanism of Action
In contrast to the taxanes, the vinca alkaloids depolymerize microtubules and destroy mitotic spindles.1 At low but clinically relevant concentrations, VBL does not depolymerize spindle microtubules, yet it powerfully blocks mitosis. This has been suggested to occur as a result of the suppression of microtubule dynamics rather than microtubule depolymerization. This group of compounds binds to the β subunit of tubulin dimers at a distinct region called the vinca-binding domain. Importantly, VBL binding induces a conformational change in tubulin in connection with tubulin self-association. In mitotic spindles, the slowing of the growth and shortening or treadmilling dynamics of the microtubules block mitotic progression. Disruption of the normal mitotic spindle assembly leads to delayed cell cycle progress with chromosomes stuck at the spindle poles and unable to pass from metaphase into anaphase, which eventually induces to apoptosis. The naturally occurring vinca alkaloids VCR and VBL, the semisynthetic analog VRL, and a novel bifluorinated analog VFL have similar mechanisms of action.
Tissue and tumor sensitivities to the vinca alkaloids, which, in part, relate to differences in drug transport and accumulation, also vary. Intracellular or extracellular concentration ratios range from five- to 500-fold depending on the individual cell type, lipophilicity, tissue-specific factors such as tubulin isotype composition, and tissue-specific microtubule-associated proteins (MAP).59–61 Although the vinca alkaloids are retained in cells for long periods of time and thus may have prolonged cellular effects, intracellular retention is markedly different among the various vinca alkaloids. For instance, VBL appears to be retained in lipophilic tissue much more than either VCR or VDS.59Newer theories of antimicrotubule agents’ mechanism of action have emerged, suggesting that the more important target of these drugs may be the tumor vasculature, as reviewed in the next section.
Clinical Pharmacology
The vinca alkaloids are usually administered intravenously as a brief infusion, and their pharmacokinetic behavior in plasma has generally been explained by a three-compartment model. The vinca alkaloids share many pharmacokinetic properties, including large volumes of distribution, high clearance rates, and long terminal half-lives that reflect the high magnitude and avidity of drug binding in peripheral tissues. VCR has the longest terminal half-life and the lowest clearance rate; VBL has the shortest terminal half-life and the highest clearance rate; and VDS has intermediate characteristics. Although prolonged infusion schedules may avoid excessively toxic peak concentrations and increase the duration of drug exposure in plasma above biologically relevant threshold concentrations, there is little evidence to support the notion that prolonged infusions are more effective than bolus schedules. The longest half-life and lowest clearance rate of VCR may account for its greater propensity to induce neurotoxicity, but there are many other nonpharmacokinetic determinants of tissue sensitivity, as discussed in the previous section.
Vincristine
After conventional doses of VCR (1.4 mg/m2) given as brief infusions, peak plasma levels approach 0.4 μmol. Plasma clearance is slow, and terminal half-lives that range from 23 to 85 hours have been reported. VCR is metabolized and excreted primarily by the hepatobiliary system. The nature of the VCR metabolites identified to date, as well as the results of metabolic studies in vitro, indicate that VCR metabolism is mediated principally by hepatic cytochrome P-450 CYP3A5.
Vinblastine
The clinical pharmacology of VBL is similar to that of VCR. VBL binding to plasma proteins and formed elements of blood is extensive.62,63 Peak plasma drug concentrations are approximately 0.4 μm after rapid intravenous injections of VBL at standard doses. Distribution is rapid, and terminal half-lives range from 20 to 24 hours. Like VCR, VBL disposition is principally through the hepatobiliary system with excretion in feces (approximately 95%); however, fecal excretion of the parent compound is low, indicating that hepatic metabolism is extensive.59
Vinorelbine
The pharmacologic behavior of VRL is similar to that of the other vinca alkaloids, and plasma concentrations after rapid intravenous administration have been reported to decline in either a biexponential or triexponential manner.64After intravenous administration, there is a rapid decay of VRL concentrations followed by a much slower elimination phase (terminal half-life, 18 to 49 hours). Plasma protein binding, principally to α1-acid glycoprotein, albumin, and lipoproteins, has been reported to range from 80% to 91%, and drug binding to platelets is extensive.64 VRL is widely distributed, and high concentrations are found in virtually all tissues, except the central nervous system.64 The wide distribution of VRL reflects its lipophilicity, which is among the highest of the vinca alkaloids. As with other vinca alkaloids, the liver is the principal excretory organ, and up to 80% of VRL is excreted in the feces, whereas urinary excretion represents only 16% to 30% of total drug disposition, the bulk of which is unmetabolized VRL. Studies in humans indicate that 4-O-deacetyl-VRL and 3,6-epoxy-VRL are the principal metabolites, and several minor hydroxy-VRL isomer metabolites have been identified. Although most metabolites are inactive, the deacetyl-VRL metabolite may be as active as VRL. The cytochrome P-450 CYP3A isoenzyme appears to be principally involved in biotransformation.
Vinflunine
VFL is a novel semisynthetic microtubule inhibitor with a fluorinated catharanthine moiety, which translates into lower affinity for the vinca binding site on tubulin and, therefore, different quantitative effects on microtubule dynamics.65 The low affinity for tubulin may be responsible for its reduced clinical neurotoxicity. Despite this lower affinity, it is more active in vivo than other vinca alkaloids, and resistance develops more slowly. VFL is a new vinca and still under clinical development. Its volume of distribution is large, and has a terminal half-life of nearly 40 hours.65 The only active metabolite is 4-O-deacetylvinflunine, which has a terminal half-life approximately 5 days longer than that of the parent compound.65
Drug Interactions
Methotrexate accumulation in tumor cells is enhanced in vitro by the presence of VCR or VBL, an effect mediated by a vinca alkaloid–induced blockade of drug efflux; however, the minimal concentrations of VCR required to achieve this effect occur only transiently in vivo.66 The vinca alkaloids also inhibit the cellular influx of the epipodophyllotoxins in vitro, resulting in less cytotoxicity. However, the clinical implications of this potential interaction are unknown. L-asparaginase may reduce the hepatic clearance of the vinca alkaloids, which may result in increased vinca-related toxicity. To minimize the possibility of this interaction, the vinca alkaloids should be given 12 to 24 hours before L-asparaginase. The combined use of mitomycin C and the vinca alkaloids has been associated with acute dyspnea and bronchospasm. The onset of these pulmonary toxicities has ranged from within minutes to hours after treatment with the vinca alkaloids, or up to 2 weeks after mitomycin C.
Treatment with the vinca alkaloids has precipitated seizures associated with subtherapeutic plasma phenytoin concentrations.66 Reduced plasma phenytoin levels have been noted from 24 hours to 10 days after treatment with VCR and VBL. Because of the importance of the cytochrome P-450 CYP3A isoenzyme in vinca alkaloid metabolism, administration of the vinca alkaloids with erythromycin and other inhibitors of CYP3A may lead to severe toxicity.67Concomitantly administered drugs, such as pentobarbital and H2-receptor antagonists, may also influence VCR clearance by modulating hepatic cytochrome P-450 metabolic processes.66
Toxicity
Despite close similarities in structure, the vinca alkaloids differ in their safety profiles. Neutropenia is the principal dose-limiting toxicity of VBL and VRL. Thrombocytopenia and anemia occur less commonly. The onset of neutropenia is usually day 7 to 11, with recovery by day 14 to 21, and can be potentiated by hepatic dysfunction. Gastrointestinal autonomic dysfunction, as manifested by bloating, constipation, ileus, and abdominal pain, occur most commonly with VCR or high doses of the other vinca alkaloids. Mucositis occurs more frequently with VBL than with VRL and is least common with VCR. Nausea, vomiting, diarrhea,31,43,45 and pancreatitis53,54 also occur to a lesser extent.
VCR principally induces neurotoxicity characterized by a peripheral, symmetric mixed sensory motor and autonomic polyneuropathy.68,69 Toxic manifestations include constipation, abdominal cramps, paralytic ileus, urinary retention, orthostatic hypotension, and hypertension. Its primary neuropathologic effects are due to interference with axonal microtubule function. Early symmetric sensory impairment and paresthesias can progress to neuritic pain and loss of deep tendon reflexes with continued treatment, which may be followed by foot drop, wrist drop, motor dysfunction, ataxia, and paralysis. Cranial nerves are rarely affected because the uptake of VCR into the central nervous system is low. Severe neurotoxicity occurs infrequently with VBL and VDS. VRL has been shown to have a lower affinity for axonal microtubules than either VCR or VBL, which seems to be confirmed by clinical observations.70 Mild-to-moderate peripheral neuropathy, principally characterized by sensory effects, occurs in 7% to 31% of patients, and constipation and other autonomic effects are noted in 30% of patients, whereas severe toxicity occurs in 2% to 3%.
In adults, neurotoxicity may occur after treatment with cumulative doses as little as 5 to 6 mg, and manifestations may be profound after cumulative doses of 15 to 20 mg. Patients with delayed biliary excretion or hepatic dysfunction, and those with antecedent neurologic disorders, such as Charcot-Marie-Tooth disease, hereditary and sensory neuropathy type 1, and Guillain-Barré syndrome, are predisposed to neurotoxicity.
The vinca alkaloids are potent vesicants. To decrease the risk of phlebitis, the vein should be adequately flushed after treatment. If extravasation is suspected, treatment should be discontinued, aspiration of any residual drug remaining in the tissues should be attempted, and prompt application of heat (not ice) for 1 hour four times daily for 3 to 5 days can limit tissue damage.71 Hyaluronidase, 150 to 1,500 U (15 U/mL in 6 mL 0.9% sodium chloride solution) subcutaneously, through six clockwise injections in a circumferential manner using a 25-gauge needle (changing the needle with each new injection) into the surrounding tissues may minimize discomfort and latent cellulitis. A surgical consultation to consider early debridement is also recommended. Mild and reversible alopecia occurs in approximately 10% and 20% of patients treated with VLR and VCR, respectively. Acute cardiac ischemia, chest pains without evidence of ischemia, fever, Raynaud syndrome, hand–foot syndrome, and pulmonary and liver toxicity (transaminitis and hyperbilirubinemia) have also been reported with use of the vinca alkaloids. All of the vinca alkaloids can cause a syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and patients who are receiving intensive hydration are particularly prone to severe hyponatremia secondary to SIADH.
MICROTUBULE ANTAGONISTS
Estramustine Phosphate
Estramustine is a conjugate of nor-nitrogen mustard linked to 17β-estradiol by a carbamate ester bridge. Estramustine phosphate received regulatory approval in the United States in 1981 for treating patients with castration-resistant prostate cancer (CRPC). Although the recommended daily dose of estramustine phosphate is 14 mg/kg per day, patients are usually treated in the daily dosing range of 10 to 16 mg/kg in three to four divided daily doses (see Table 21.1). Estramustine has significant activity in CRPC and had been used in combination with VBL or docetaxel. However, phase III trials in patients with CRPC showed that when combined with docetaxel, there is no added benefit to overall survival compared to docetaxel alone.72,73
Estramustine binds to β-tubulin at a site distinct from the colchicine and vinca alkaloid binding sites. This agent depolymerizes microtubules and microfilaments, binds to and disrupts MAPs, and inhibits cell growth at high concentrations, resulting in mitotic arrest and apoptosis in tumor cells. The selective accumulation and actions of estramustine phosphate and its metabolite, estromustine, in specific tissues appear to be dependent on the expression of the estramustine-binding protein (EMBP). The disposition of estramustine is principally by rapid oxidative metabolism of the parent compound to estromustine. Estromustine concentrations in plasma are maximal within 2 to 4 hours after oral administration, and the mean elimination half-life of estromustine is 14 hours. Estromustine and estramustine are principally excreted in the feces, with only small amounts of conjugated estrone and estradiol detected in the urine (less than 1%).
In general, this agent has a manageable safety profile. Nausea and vomiting are the principal toxicities encountered. In contrast to the taxanes and the vinca alkaloids, myelosuppression is rarely clinically relevant. Common estrogenic side effects include gynecomastia, nipple tenderness, and fluid retention. Thromboembolic complications may occur in up to 10% of patients.
Epothilones
The epothilones are macrolide compounds that were initially isolated from the mycobacterium Sorangium cellulosum. They exert their cytotoxic effects by promoting tubulin polymerization and inducing mitotic arrest.74 In general, the epothilones are more potent than the taxanes. In contrast to the taxanes and vinca alkaloids, overexpression of the efflux protein P-glycoprotein minimally affects the cytotoxicity of epothilones. Epothilones include the natural epothilone B (patupilone; EPO906) and several semisynthetic epothilone compounds such as aza-epothilone B (ixabepilone; BMS-247550), epothilone D (deoxyepothilone B, KOS-862), and a fully synthetic analog, sagopilone (ZK-EPO).75
Ixabepilone has been evaluated in several schedules using a cremophor-based formulation and is FDA approved for the treatment of patients with breast cancer.75 It is active in breast cancer previously treated with paclitaxel or docetaxel. The principal toxicities observed include neutropenia and peripheral neuropathy, in addition to fatigue, nausea, emesis, and diarrhea.55,74 It also has been evaluated in other solid tumors such as ovarian, prostate, and renal cell carcinomas.75 Epothilones are still undergoing evaluations in several clinical trials. Pharmacokinetic studies based on patupilone have shown large volume of distribution (41-fold the total body water) and low body clearance (13% of hepatic blood flow).76 There do not appear to be active metabolites once the parent drug is hydrolyzed, which is the main elimination pathway.76
Maytansinoids and Auristatins: DM1, MMAE
Antibody drug conjugates (ADC) were first attempted with delivery of doxorubicin. Although tissue localization seemed promising, it became clear that the delivery of more potent chemotherapeutics was necessary.77,78 One of the major advances for the promise of ADC came with the discovery and development of highly potent anticancer compounds such as calicheamicins, maytansinoids, and auristatins.78The next necessary advance was a linker that released the drug only when intended, and avoiding, or in some cases capitalizing on, in vivo proteases, oxidizing, or reducing environments. Gemtuzumab ozogamicin was the first ADC using calicheamicin, a potent DNA minor groove binder (and not a microtubule agent), approved in 2000 although withdrawn from the market in 2013 due to failed confirmatory studies. Maytansinoids and auristatins are unrelated, although are both tubulin-binding agents of the vinca binding site and inhibit tubulin polymerization.78 They are 100- to 1,000-fold more cytotoxic that most cancer chemotherapeutics.79
Drug maytansinoid-1 (DM1) is the chemotherapeutic delivered using a thioether linker in the ADC ado-trastuzumab emtansine (T-DM1) that was FDA approved for patients with HER2- positive metastatic breast cancer previously treated with trastuzumab and taxane chemotherapy.80,81 In the international phase III study, there was a 3.2-month improved progression-free survival among patients that received T-DM1 compared to those receiving standard treatment with capecitabine and lapatinib.81 Despite a potent chemotherapeutic, the tolerability was much better in the experimental arm, which was dosed at 3.6 mg/kg intravenously every 21 days. The most common side effects in the trial were thrombocytopenia (12.8%), transient transaminitis (4.3%), as well as nausea, fatigue, myalgias, and arthralgias.81
Monomethyl auristatin E (MMAE) is linked to a monoclonal antibody against CD30 as an ADC (brentuximab vedotin, SGN35) and approved for refractory Hodgkin lymphoma or anaplastic large cell lymphoma. The linker is a peptide-based substrate for cathepsin-B and thereby designed to detect the lysosome/endosome compartment for drug release.82,83 Dose-limiting toxicities include thrombocytopenia, hyperglycemia, diarrhea, and vomiting, and the most common side effects in this heavily pretreated population (including autologous stem cell transplant) includes peripheral neuropathy (42%), nausea (35%), and fatigue (34%).84 The FDA black box warning includes contraindicated use with bleomycin due to increased pulmonary toxicity and the risk of John Cunningham (JC) virus–induced progressive multifocal leukoencephalopathy. Reports of severe pancreatitis are also emerging.85
MITOTIC MOTOR PROTEIN INHIBITORS
Aurora Kinase and Pololike Kinase Inhibitors
Aurora kinases are serine/threonine kinases crucial for mitosis in their recruitment of mitotic motor proteins for spindle formation. They are particularly overexpressed in high growth rate tumors. Aurora A and B kinases are expressed globally throughout all tissues, and Aurora C kinase is expressed in testes and participates in meiosis. Aurora A kinase is expressed and frequently amplified in many epithelial tumors and implicated in the microtubule-targeted agent-resistant phenotype.86 Aurora A kinase interacts with p53, and there is evidence that p53 wild-type tumors are more sensitive to aurora A kinase inhibitors than p53 mutant tumors.87 MLN-8237 has an IC50 of 1 nm for aurora A kinase and >200 nm for aurora B kinase and is in clinical development for treatment-related neuroendocrine prostate cancer.86,88 The main dose-limiting toxicity of these agents is neutropenia. Pololike kinases (PLKs) are serine or threonine kinases crucial for cell cycle process. Overexpression of PLKs has been shown to be related to histologic grading and poor prognosis in several types of cancer. BI-2536 and ON01910 are PLK inhibitors in early clinical development.89
Kinesin Spindle Protein Inhibitor
Ispinesib
Kinesin spindle protein (KSP; also known as EG5) is a kinesin motor protein required to establish mitotic-spindle bipolarity.90 Several KSP inhibitors have been evaluated in early phase clinical trials. SB-715992 (ispinesib) is a small-molecule inhibitor of KSP ATPase and has been evaluated in two different schedules.89 The dose-limiting toxicity is neutropenia. Ispinesib was found to be inactive in phase 2 studies evaluating efficacy in patients with castration-resistant and largely docetaxel-resistant prostate cancer, advanced renal cancer, and head and neck cancer.90–92
MECHANISMS OF RESISTANCE TO MICROTUBULE INHIBITORS
Drug resistance is often complex and multifaceted and can involve diverse mechanisms such as (1) factors that reduce the ability of drugs to reach their cellular target (e.g., activation of detoxification pathways and decreased drug accumulation); (2) modifications in the drug target; and (3) events downstream of the target (e.g., decreased sensitivity to, or defective, apoptotic signals). Many tubulin binding agents are substrates for multidrug transporters such as P-glycoprotein and the multidrug resistance gene (MDR1).93,94
The MDR1-encoded gene product MDR1 (ABC subfamily B1; ABCB1) and MDR2 (ABC subfamily ABCB4) are the best-characterized ABC transporters thought to confer drug resistance to taxanes.94,95MDR-related taxane resistance can be reversed by many classes of drugs, including the calcium channel blockers, cyclosporin A, and antiarrhythmic agents.94,95 However, the clinical utility of this approach has never been proven, despite several clinical trials. The role of ABC transporters in resistance to microtubule inhibitors remains to be determined.96
An increasing number of studies suggest that the expression of individual tubulin isotypes are altered in cells resistant to antimicrotubule drugs and may confer drug resistance.93,97 Inherent differences in microtubule dynamics and drug interactions have been observed with some isotypes in vitro and in vivo.98 Several taxane-resistant mutant cell lines that have structurally altered α- and β-tubulin proteins and an impaired ability to polymerize into microtubules have also been identified.99 Mutations of tubulin isotype genes, gene amplifications, and isotype switching have also been reported in taxane-resistant cell lines.99 In patients, levels of class III β-tubulin have been shown to correlate with response—those with high RNA levels have poor response—and immunohistochemical stains can correlate and may be predictive.96,100,101 As opposed to taxanes, resistance to vinca alkaloids has been associated with decreased class II β-tubulin expression.97,98
MAPs are important structural and regulatory components of microtubules that act in concert to remodel the microtubule network by stabilizing or destabilizing microtubules during mitosis or cytokinesis. Alterations in the activity and/or balance of stabilizing or destabilizing MAPs can profoundly affect microtubule function.99,102 The overexpression of stathmin, a destabilizing protein, has been reported to decrease sensitivity to paclitaxel and vinblastine.1 An analysis of predictive or prognostic factors in a large phase 3 study (National Surgical Adjuvant Breast and Bowel Project NSABP-B 28) in patients with node-positive breast cancer showed that MAP-tau, a stabilizing protein, was a prognostic factor; however, it was not predictive for benefit from paclitaxel-based chemotherapy.1,93 In a separate randomized controlled trial in breast cancer (TAX 307), where the only variable was docetaxel, MAP-tau was also shown to be prognostic, but not predictive of taxane benefit.103
Additional studies have shown a correlation with BRCA1 loss measured by gene or protein expression, or gene signatures, with resistance to taxane and sensitivity to DNA-damaging agents (such as cisplatin and anthracyclines).104–107 BRCA1 is a tumor-suppressor gene with DNA damage response and repair, as well as cell cycle checkpoint activation, which explains why its loss leads to enhanced cisplatin sensitivity.20 BRCA1 also indirectly regulates microtubule dynamics and stability and can favorably control how microtubules respond to paclitaxel treatment via their association with pro-caspase-8. The loss of BRCA1 can lead to impaired taxane-induced activation of apoptosis due to microtubules that are more dynamic and less susceptible to taxane-induced stabilization and proximity-induced activation of caspase-8 signaling.20
In addition to resistance, certain tumor subtypes may be sensitive to the taxane dosing schedule. In two randomized trials of low-dose, weekly paclitaxel, the luminal breast cancer subtype was found to have a better outcome compared with the control arm. This suggests that not only the drug, but also the schedule may influence the response to therapy and that genomic approaches may reveal these insights.108
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