Defining Risks of Taxane Neuropathy: Insights from Randomized Clinical Trials

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. 2013 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 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 paclitaxel-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 2013 American Association for Cancer Research. from discogenic root compression.

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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)

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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). Nab-paclitaxel docu- CrEL CrEL mented better efficacy and less myelosuppression than CrEL bPAC CrEL paclitaxel [Gradishar and colleagues (28); Supplementary CrEL A Table S2]. Despite improved survival, nab-paclitaxel had CrEL CrEL CrEL CrEL significantly more neurotoxicity, possibly reflecting the SC CrEL higher doses administered, more protracted treatment, CrEL CrEL and unknown (paradoxically protective?) effects of CrEL. Neurotoxicity equilibrated by 28 days, suggesting that uPAC nab-paclitaxel neuropathy is more transient than pacli- CrEL CrEL taxel’s. This study was confirmed by Guan in 2007 (29), but subsequent studies have raised additional questions. Dosing schedules of nab-paclitaxel in randomized phase CCR Reviews II studies were further addressed by Gradishar and col- Figure 1. The framework for axonal damage from taxanes with unbound leagues (refs. 30, 31; Supplementary Table S2) in a study paclitaxel as well as its solubilizing vehicle (Cremophor EL) interacting that also included docetaxel 100 mg/m2 every 3 weeks with neurons, their axons, and Schwann cells. Once intracellular, taxanes leading to the selection of nab-paclitaxel 150 mg/m2 every bind to axonal microtubules or undergo metabolism and/or export via 1 week for the subsequent phase III intergroup trial versus ABC transporters. Nanoparticle albumin–bound paclitaxel is considered to behave as "unbound" paclitaxel unless facilitated cell entry takes place weekly paclitaxel. The results of this comparison were in neurons via SPARC (secreted protein acidic rich in cysteine; see Table given at the American Society of Clinical Oncology 1). A, axon; N, neuron; S, Schwann cell. Figure adapted from Mielke and (ASCO) 2012 presentation by Rugo (ref. 19; Supplemen- colleagues (66), Copyright 2006, with permission from Elsevier. tary Table S3). This Intergroup study compared nab-paclitaxel 150 mg/m2 every 1 week, paclitaxel 90 mg/m2 every analyzed. Neuropathy was defined by NCI common toxicity 1 week, and the microtubule-stabilizing drug ixabepilone criteria (CTC; ref. 20), supplemented at times by the FACT- (32) 16 mg/m2 every 1 week, all with bevacizumab every 2 Taxane (21), neurotoxicity self-reported assessments (22– weeks. There was no difference in overall survival among 24), and instruments aimed at better "quantifying" neurop- the three arms, but patients on paclitaxel and bevacizu- athy (25). To further characterize neurotoxicity risks, we mab had less neurotoxicity and neutropenia than those highlight comparison of the following schedules: (i) of the on nab-paclitaxel and bevacizumab [the ixabepilone arm same taxane (every 3 weeks vs. weekly) in the 3 cancers, (ii) terminated early when deemed unlikely that a superior of 2 different taxanes in breast and non–small cell lung progression-free survival (PFS) could occur]. Neurotoxic- cancer (NSCLC) trials, and (iii) of 2 different taxanes in ity (grades 2–4) and neutropenia (grades 3 and 4) were combination with platinums in ovarian and NSCLC. Studies milder with paclitaxel than with nab-paclitaxel. These not appearing in Supplementary Tables are cited. results are strikingly different than what Gradishar found in 2005 and 2009/2012. How bevacizumab contributed Results to these results (this trial is awaiting full publication) is Relative neurotoxic potential from randomized trials uncertain, although bevacizumab has not been shown to with taxanes alter neurotoxicity when added to most taxane regimens Breast cancer trials. Taxanes have a major role in the (33–35). Notably, the higher incidence of neuropathy in treatment of early and advanced breast cancers. The Eastern the E2100 trial attributed to paclitaxel 90 mg/m2 weekly Cooperative Oncology Group (ECOG) led an intergroup combined with bevacizumab at 10 mg/kg every 2 weeks study of optimal taxane dose schedules. The study was done versus paclitaxel alone (23.5% vs. 17.7%, P ¼ 0.05) is in the adjuvant setting after 4 cycles of doxorubicin and likely related to added paclitaxel treatment until progres- cyclophosphamide [Sparano and colleagues (26); Supple- sion in the bevacizumab-containing arm. There was a mentary Table S1]. The study found that paclitaxel 80 longer PFS of 11.8 months (compared with 5.9 months) mg/m2 every 1 week gave patients the best 5-year survival and median duration of 7.1 months of paclitaxel treat- rate when compared with every 3-week paclitaxel 175 ment (compared with 5.1 months) with this combination mg/m2 (89.7% vs. 86.5%; P ¼ 0.01). Increased grades 2 to compared with paclitaxel alone (36). 4 sensory neuropathy were seen in the weekly regimen, but Ovarian cancer trials. In Gynecologic Oncology Group importantly, grades 3 and 4 sensory neuropathy were sim- (GOG) trials, an every 3-week paclitaxel 135 mg/m2 given in ilar to docetaxel. These results, which contrast with studies 24-hour infusions with cisplatin had become standard in advanced breast cancer, point to the relatively low neu- following GOG104 (37). Longer paclitaxel infusions (96 rotoxic potential of 4 cycles of paclitaxel (which is also hours) had less neuropathy (4%–6% grade 3) versus the 24- relevant in advanced lung cancer trials). Subsequently, this hour infusion, but no difference in efficacy (38) when sequential therapy was superior in efficacy while yielding combined with cisplatin. Subsequently (after GOG158

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showed noninferiority of carboplatin þ paclitaxel vs. cis- Nab-paclitaxel was compared with paclitaxel (ref. 56; platin þ paclitaxel), 175 mg/m2 3-hour paclitaxel infusions Supplementary Tables S6) at the dose schedule from every 3 weeks were universally adopted in carboplatin- Socinski and colleagues (57): carboplatin was given with based regimens with "acceptable" rates of severe neuropa- either nab-paclitaxel 100 mg/m2 every 1 week or paclitaxel thy. The Japan GOG "paclitaxel dose-dense" study (ref. 39; 200 mg/m2 every 3 week. Results showed similar OS and Supplementary Table S4) showed that patients on paclitaxel PFS. The nab-paclitaxel had more objective responses (33% 80 mg/m2 every 1 week with carboplatin every 3 weeks had vs. 25%, P ¼ 0.005) with less severe neuropathy and better overall survival (OS) and PFS than patients receiving hematologic toxicity. The OS in patients older than 70 years 3-hour paclitaxel 180 mg/m2 with carboplatin every 3 was better (12.7 and 9.8 months, P ¼ 0.008) in the North weeks. Neurotoxicity grades 3 and 4 did not differ between American patients receiving nab-paclitaxel and carboplatin. "dose-dense" and every 3-week arms. However, it is impor- The significantly lesser neurotoxicity for nab-paclitaxel tant to note that not only schedule and dose but also weekly in these lung cancer trials must be contrasted with number of cycles is a key factor in the development of the findings with weekly paclitaxel in Rugo and colleagues sensory neuropathy with taxanes (40). Nab-paclitaxel 100 (19) breast cancer trials (Supplementary Table S3). This mg/m2 every 1 week has only recently been studied (41). underscores key issues relating to the lower weekly dose of A phase III comparing the every 3-week carboplatin þ nab-paclitaxel and lesser number of treatments as well as paclitaxel versus carboplatin þ docetaxel (42) conducted higher doses of paclitaxel in NSCLC trials in contrast to by the SCOTROC group (Vasey, Supplementary Table S4) tolerance comparisons in breast cancer trials. found no difference in efficacy. However, patients who received paclitaxel every 3 weeks had significantly higher Summary of taxane dose schedule effects in rates of grades 2–4 neurotoxicity than those treated with randomized trials docetaxel. Docetaxel administration incurred higher rates These studies in several disease categories show consis- of neutropenia, including febrile neutropenia—data con- tency in documenting grade 2 or greater peripheral neu- sistent with the adjuvant breast trial of Sparano and ropathies across taxane schedules (weekly or every 3 weeks) colleagues (26). and type of taxane-containing regimens (paclitaxel, nab- Another randomized study assessing the strategy of inhi- paclitaxel, and docetaxel). Differences across disease areas biting P-gp was ineffective but provided some glimpse at P- reflect, in part, patient-related susceptibilities and/or inves- gp contribution to protecting against taxane central nervous tigator coding practices. However, they support conclusions system toxicity (43–47). further addressed in the discussion. NSCLC trials. Both paclitaxel and docetaxel have played a significant role in NSCLC regimens in the past Taxane neuropathy in drug combinations 2 decades. Paclitaxel is generally paired with carboplatin, Neuropathy in any particular regimen is dependent on whereas docetaxel has preferably been combined with whether taxanes are coupled with other neurotoxic drugs, cisplatin. Paclitaxel doses per cycle are higher than in breast particularly platinums (Supplementary Table S4). The con- and gynecologic cancers (Supplementary Table S5 on pac- tribution of cisplatin to neuropathy is significantly greater litaxel dose schedules with or without carboplatin). In than carboplatin’s—originally reported by Neijt and col- CALBG 9730 (48), paclitaxel 225 mg/m2 every 3 weeks leagues (10) and in intraperitoneal GOG trials (58). In lung was compared with carboplatin and paclitaxel (same dose cancer, most platinum-doublet neurotoxic events are relat- 2 and schedule): no differences were found between the ed to paclitaxel used at 200 mg/m (59). Docetaxel or single agent and the combination in OS or peripheral paclitaxel combinations with nonneurotoxic drugs in neuropathy. An improved response rate and failure-free patients with breast cancer, leading to grade 2 or greater survival with the combination chemotherapy led to its neuropathy, did not differ between the 2 taxanes (60). On wide adoption. In addition, Belani and colleagues (49) the other hand, neuropathy observed in combinations of and other sources [including a meta-analysis (50)] have taxanes with other mitotic inhibitors often precluded going embraced 225 mg/m2 every 3 weeks as the optimal dosing beyond phase I studies, despite encouraging preclinical and for paclitaxel in NSCLCs. clinical effects (61–65). The similar outcomes following platinum-containing doublets (51) led to exploring non–taxane-containing Discussion doublets (partly to avoid neuropathy; refs. 52–54). The We have highlighted randomized studies potentially most recent addition to NSCLC treatment regimens is most informative for contributory clinical risk factors in nab-paclitaxel in combination with carboplatin: FDA the sensory neuropathy of taxanes. The lack of uniform approval followed data showing this regimen’s superior quantitation of this toxicity, its time of occurrence, and outcome in elderly patients with NSCLCs (ref. 55; select- extent of reversibility have been challenging. The current ed trials in Supplementary Tables S5 and S6 include direction, also tied to clinical trials, is to compare genome- comparisons of neurotoxicity paclitaxel weekly vs. every wide analysis of patients incurring in severe neuropathy 3 weeks). Docetaxel neurotoxicity has not been an issue; versus others. To aid in planning such future investigations, time on treatment in all these studies is generally shorter we have highlighted the diverse clinical settings for taxane than for breast cancer. use and what can be learned from existing clinical trials.

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Some general factors associated with taxane neuropathy the larger trials have not examined the effect of age on the emerge: susceptibility of developing sensory neuropathy. A sub- analysis of a previously discussed study conducted by 1. Both nab-paclitaxel and paclitaxel give rise to more Socinski and colleagues (refs. 55, 56; Supplementary Table severe sensory neuropathy than docetaxel. The sensory S6) focused on outcome in elderly patients with NSCLC. neuropathy of docetaxel is evident mostly when Neuropathy was assessed on the basis of the Functional compared with chemotherapy regimens not Assessment of Cancer Therapy or FACT (21) for self-report- containing mitotic inhibitors or platinums. Data on ing of various symptoms at baseline and at completion of nab-paclitaxel schedules are inconsistent and hard to therapy. An analysis of neurotoxicity was provided with 884 interpret based on greater dose rates and lesser patients <70 and 154 patients 70. Excess grade 2/3 neu- myelosuppression. ropathies in the older subset was particularly prominent in 2. The impact of CremophorEL on paclitaxel’s the paclitaxel 200 mg/m2 every 3-week arm (21%/22% vs. neuropathy is unclear. Intermittent (every 3-week) 19%/9%, respectively, in the younger population). All doses of paclitaxel have enhanced myelosuppression patients also received carboplatin. Both percentage of neu- presumably from vehicle-related enhanced exposure ropathies and differences by age were less prominent in the time above a 0.05 mmol/L paclitaxel threshold that has weekly nab-paclitaxel arms. Mining data from large clinical correlated with pharmacodynamics effects on breast cancer trials of taxanes for age-related differences myeloid cells. Nab-paclitaxel versus paclitaxel would be of interest. comparative studies are clouded by different doses used. Gender 3. How ABC transporters and metabolism lead to This factor would need to be confined to NSCLC trials, differential pharmacodynamics in specific tissues is and only indirectly hinted by comparisons across trials (e.g., unknown. The potent marrow and gastrointestinal prostate cancer vs. breast cancer). In fact, prostate cancer toxicities of docetaxel have been attributed to better trials report a high rate of neuropathies. However, this could protection against paclitaxel by ABC transporters. Not be, in part, related to age, and also longer duration of explained is lesser neurotoxicity of docetaxel, nor its therapy. The above NSCLC trial by Socisnski and colleagues therapeutically inferior results from weekly (55, 56) would be particularly suitable for an analysis on the administration relative to paclitaxel. Both nab- impact of gender, given the self-assessment toxicity deter- paclitaxel and docetaxel, but especially nab-paclitaxel, minations that have been carried out. Also, women repre- reportedly exhibit faster reversal of sensory sented about one fourth of the 1,052 patients entered, and neuropathy than paclitaxel, perhaps pointing to an comparisons by gender could shed light on potential differ- effect of CremophorEL in prolonging the exposure of ences in taxane tolerance. paclitaxel on neurons (in lieu of a postulated direct neurotoxic effect of the solvent). Ethnicity 4. Clinical and pharmacodynamic factors that Examining the impact of ethnicity would be particularly contribute to neuropathy from various taxanes and challenging, given the requirement for large patient cohorts their formulations require further study. Accelerated representing distinct ethnicities within a single trial. Only toxicities, primarily seen with paclitaxel or nab- indirect comparisons across trials are possible: it is of paclitaxel, point to predisposing pharmacogenomic interest that the Japan GOG study reported neuropathy factors in some individuals. However, a neglected rates not unlike those obtained in ovarian cancer trials by major impact relates to dose rate, cumulative doses, the GOG (39, 42). and the effect of other drugs. Beyond patient or In conclusion, this review of the comparative neurotoxic regimen-related susceptibilities, could investigator potential of 2 taxane products in common use reveals coding practices, gender-related handling of clinically relevant major gaps in our knowledge of this taxanes, as well as other accompanying drugs play a class-related toxicity. In addition to pharmacogenomic stud- role? Whereas breast and ovary trials are confined to ies, better quantitation of sensory neuropathy and charac- women, lung trials apply to male-preponderant terization of tissue-specific (e.g., pharmacodynamics) factors populations. in the handling of individual drugs both in the clinic and in the laboratory are needed to continue enhancing the ther- Analyzing data from clinical trials may shed light on apeutic index of these widely used drugs. Large clinical trials the possible impact of key demographic factors on neu- are a resource for continuing to address the questions that rosensory changes that have yet to be explored: age, have been raised. gender, and ethnicity; we comment separately on each one of these. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. Age Given the potential for complications in elderly indivi- Authors' Contributions Conception and design: D. Kudlowitz, F. Muggia duals manifesting neuropathy, it is surprising that some of Development of methodology: D. Kudlowitz, F. Muggia

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Acquisition of data (provided animals, acquired and managed patients, Administrative, technical, or material support (i.e., reporting or orga- provided facilities, etc.): D. Kudlowitz, F. Muggia nizing data, constructing databases): D. Kudlowitz, F. Muggia Analysis and interpretation of data (e.g., statistical analysis, biosta- Study supervision: D. Kudlowitz, F. Muggia tistics, computational analysis): D. Kudlowitz, F. Muggia Writing, review, and/or revision of the manuscript: D. Kudlowitz, F. Received March 4, 2013; revised June 4, 2013; accepted June 5, 2013; Muggia published OnlineFirst July 1, 2013.

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OF8 Clin Cancer Res; 19(17) September 1, 2013 Clinical Cancer Research

Defining Risks of Taxane Neuropathy: Insights from Randomized Clinical Trials

David Kudlowitz and Franco Muggia

Clin Cancer Res Published OnlineFirst July 1, 2013.

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