Defining Risks of Taxane Neuropathy: Insights from Randomized Clinical Trials
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Published OnlineFirst July 1, 2013; DOI: 10.1158/1078-0432.CCR-13-0572 Clinical Cancer Review Research Defining Risks of Taxane Neuropathy: Insights from Randomized Clinical Trials David Kudlowitz and Franco Muggia Abstract Sensory neuropathy is a common but difficult to quantify complication encountered during treatment of various cancers with taxane-containing regimens. Docetaxel, paclitaxel, and its nanoparticle albumin- bound formulation have been extensively studied in randomized clinical trials comparing various dose and schedules for the treatment of breast, lung, and ovarian cancers. This review highlights differences in extent of severe neuropathies encountered in such randomized trials and seeks to draw conclusions in terms of known pharmacologic factors that may lead to neuropathy. This basic knowledge provides an essential background for exploring pharmacogenomic differences among patients in relation to their susceptibility of developing severe manifestations. In addition, the differences highlighted may lead to greater insight into drug and basic host factors (such as age, sex, and ethnicity) contributing to axonal injury from taxanes. Clin Cancer Res; 19(17); 1–8. Ó2013 AACR. Introduction dules, whereas the shorter schedule proved safe but had Taxanes have become key drugs in the treatment of more sensory neuropathy. Soon after, docetaxel under- several malignancies as the antitumor activity of paclitaxel went clinical development as Taxotere (under sponsor- and docetaxel was established in the early 1990s. A major ship of Sanofi-Aventis) and became widely used for problem in the clinical use of these drugs, particularly breast and lung cancers (4). The nanoparticle albumin- paclitaxel, has been the development of sensory neurop- bound paclitaxel (nab-paclitaxel or Abraxane) achieved athy. To better define factors resulting in this neurotoxicity, approval for the treatment of breast cancer in 2005. we have reviewed the extent of taxane neuropathy observed Cabazitaxel (5) subsequently obtained U.S. Food and in randomized clinical trials with a particular focus on Drug Administration (FDA) approval for docetaxel- trials where paclitaxel, its nanoparticle albumin-bound refractory prostate cancer and paclitaxel polyglutamate paclitaxel formulation (nab-paclitaxel), and docetaxel are (6) is undergoing registration trials; both are less infor- compared. mative for the purpose of this review. Historically, the contributions of paclitaxel to the treat- The background describes taxane neuropathy and its risk ment of breast, ovarian, and lung cancers became apparent factors such as dose schedule, drug pharmacology, potential in the early 1990s. Bristol-Myers Squibb, once acquiring drug interactions, and preexisting conditions. Clinical trials licensing rights from the National Cancer Institute under in breast, lung, and ovarian cancers are then analyzed to the original generic name Taxol, proceeded to explore (in highlight dose and schedule risk factors for sensory ovarian cancer trials) dose schedule and hypersensitivity neuropathy. issues that had plagued its early development in the 1980s (1). Shorter than the established safe 24-hour Background infusions were explored including a randomized phase Description of taxane neurotoxicity II study with a 2 Â 2 design comparing every 3 weeks 135 Distal symmetrical paresthesias, at first transient and versus 175 mg/m2 doses, and 24- versus 3-hour infusions then constant (with gradual improvement over months to (2, 3). The higher dose was more active in both sche- years without further exposure), are the hallmark of pac- litaxel-induced neuropathy. Other manifestations (such as autonomic and motor changes) are occasionally seen Authors' Affiliation: New York University School of Medicine and Cancer upon coadministration of other neurotoxic drugs or by Institute, New York, New York the presence of preexisting conditions (such as long-stand- Note: Supplementary data for this article are available at Clinical Cancer ing diabetes mellitus). Plantar surfaces at the metatarsal– Research Online (http://clincancerres.aacrjournals.org/). phalangeal junction are often first affected. A frequent Corresponding Author: Franco Muggia, NYU Clinical Cancer Center, Rm finding is distal fingertip paresthesia. Unlike cisplatin- 429, 160 East 34th Street, New York, NY 10016. Phone: 212-263-6485; related neuropathies, taxanes rarely cause loss of distal Fax: 212-263-8210; E-mail: [email protected] deep tendon reflexes (7, 8). Asymmetrical findings usually doi: 10.1158/1078-0432.CCR-13-0572 point to other contributory causes like neurogenic damage Ó2013 American Association for Cancer Research. from discogenic root compression. www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst July 1, 2013; DOI: 10.1158/1078-0432.CCR-13-0572 Kudlowitz and Muggia Paclitaxel was initially paired with cisplatin in the first- in Table 1. Cross-resistance patterns (e.g., with doxorubicin line treatment of ovarian cancer before Gynecologic and vinca alkaloids) reflect, in part, the greater affinity of Oncology Group GOG158 trial showed the noninferiority paclitaxel for P-glycoprotein (P-gp; ref. 16). Moreover, as of the less neurotoxic carboplatin (9). This resulted in CrEL is also a substrate for P-gp, this solubilizing vehicle many women experiencing irreversible life-long neuro- modifies the influx and efflux of paclitaxel, affecting the pathy. When given by itself or with carboplatin, taxane development/reversibility of neuropathy and of myelosup- sensory neuropathy is usually fully reversible unless dosing pression (ref. 17; Fig. 1). However, factors other than P-gp is not modified before incurring in severe neurotoxicity explain the effect of CrEL on paclitaxel PK (18). Differences (10). Retreatment with taxanes is often associated with an in pharmacokinetics and intracellular dynamics may accelerated development of this toxicity. In summary, account for the variable occurrence of neuropathy and neurons conducting pain and touch sensations in the distal myelosuppression, as well as less common effects (e.g., extremities are most vulnerable to taxanes, to other anti- edema, skin rash, and nail changes). Further information tubulin agents, and to platinums (11). Pharmacogenomic on the drug properties of paclitaxel, docetaxel, and nab- studies are seeking to explain an individual susceptibility to paclitaxel is provided in the Supplementary Text (see Drug severe taxane neuropathy (12–15). The current analysis Properties). focuses on specific taxane clinical data on neuropathy from large randomized clinical trials. Methods Neuropathy, myelosuppression, and outcome reported by Drug formulations and pharmacology selected National Cancer Institute (NCI) U.S. cooperative Paclitaxel, docetaxel, and nab-paclitaxel target identical group trials in breast, ovarian, and lung cancers are reviewed. sequences in b-tubulin leading to stabilization of micro- All trials are full publications except for CALBG 40502 (19). tubular dynamics and "bundling." Major pharmacody- In addition, similar data from trials using response evalua- namic differences between these drugs are summarized tion and toxicity criteria adopted by NCI-supported trials are Table 1. Distinguishing pharmacologic features of nab-paclitaxel, paclitaxel, and docetaxel Feature Nab-paclitaxel Paclitaxel Docetaxel Linearity Linear Nonlinear Linear from 75 to 100 mg/m2 Vehicle Albumin CremophorEL and dehydrated Polysorbate 80 and 13% ethanol per ethanol USP (1:1, v/v) 1.5 mL Half-life 21.6 h (17.2 coeff variation 20.5 h (14.6 coeff of variation, for Alpha, beta, gamma 4.5, 38.3, and for 260 mg/m2) 175 mg/m2) 12.2 h Intracellular Albumin leading to tumor Major substrate for P-gp more than Longer intracellular retention time and pharmacodynamic accumulation via SPARC docetaxel (16) higher intracellular concentration in factors (67) target cells (compared with paclitaxel; ref. 68) Substrate for P-gp (69) Clinical delivery 10-min low-volume infusion Infusion rate limited by volume and Rate of delivery volume less also need for special tubing (PDR) constrained than for paclitaxel Issues in oral Not studied Low bioavailability CYP3A4 metabolization (72) bioavailability 1. P-gp transporters found in high Improved by ritonavir (CYP3A4 concentration in the inhibitor and minor P-gp inhibitor; gastrointestinal tract ref. 73) 2. Presystemic metabolism by CYP3A4 and CYP2C8 (70) 3. Improved by GF120918 (71) Intraperitoneal Not studied Ideal dosing in phase I study found to Pharmacologic advantage at 100 therapy be at 60–65 mg/m2 weekly in mg/m2 every 3 wks (76) ovarian cancer (74) Phase 2 trial showed that paclitaxel Lower concentrations than weekly intraperitoneal 60 mg/m2 intraperitoneal paclitaxel, but better with intraperitoneal carboplatin penetrance likely without mycelle every 3 wks had effective systemic formation due to CremophorEL (77) exposure (75) OF2 Clin Cancer Res; 19(17) September 1, 2013 Clinical Cancer Research Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst July 1, 2013; DOI: 10.1158/1078-0432.CCR-13-0572 Defining Risks of Taxane Neuropathy similar peripheral neuropathy when compared with con- CrEL CrEL current therapy (27). In 2005, the registration trial for nab-paclitaxel uPAC CrEL compared nab-paclitaxel 260 mg/m2 with paclitaxel N CrEL CrEL 175 mg/m2 (each every 3 weeks).