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Journal of Clinical Oncology, Vol 24, No 13 (May 1), 2006: pp. 2084-2091
© 2006 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.04.2820
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Changes in Neurologic Function Tests May Predict Neurotoxicity Caused by Ixabepilone

James J. Lee, Jennifer A. Low, Earllaine Croarkin, Rebecca Parks, Arlene W. Berman, Nitin Mannan, Seth M. Steinberg, Sandra M. Swain

From the Cancer Therapeutics Branch, Medical Oncology Clinical Research Unit, and Biostatistics and Data Management Section, Center for Cancer Research, Cancer Therapy Evaluation Program; Division of Cancer Treatment and Diagnosis, National Cancer Institute; and Rehabilitation Medicine Department, National Institutes of Health, Bethesda, MD

Address reprint requests to Sandra M. Swain, MD, Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bldg 8, Rm 5101, 8901 Wisconsin Ave, Bethesda, MD 20889-5015; e-mail: swains{at}mail.nih.gov


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
PURPOSE: To investigate baseline factors and neurologic function tests (NFTs) that may predict the development of grade 2 or higher peripheral neuropathy (PN) after treatment with ixabepilone, an epothilone microtubule-stabilizing agent with antitumor activity.

PATIENTS AND METHODS: Advanced breast cancer patients were treated with ixabepilone (6 mg/m2) for 5 consecutive days every 3 weeks in a phase II clinical trial. Physical examinations, questionnaires, nerve conduction studies, and NFTs, including the Jebsen Test of Hand Function (JTH) and the Grooved Pegboard Test (GPT), were performed at baseline and during subsequent cycles.

RESULTS: Forty-seven patients assessable for PN received a median of five cycles of therapy (range, one to 22 cycles). Nine of these patients developed grade 2 PN, and two developed grade 3 PN, with a median time to onset of 144 days (range, 6 to 189 days). Among these 11 patients, PN resolved in eight patients, with a median of 15 days (range, 6 to 346 days) after onset, but PN did not resolve in three patients during follow-ups at 76, 361, and 746 days after onset. GPT and changes of JTH scores at onset of PN were significantly different between patients with and without PN at comparable follow-up times (P = .006 and P = .002, respectively). Changes in GPT and JTH scores over the first two cycles were often associated with the development of PN by exploratory actuarial analysis.

CONCLUSION: Serious ixabepilone-induced neuropathy was relatively rare on the treatment schedule used. NFTs, such as JTH and GPT, may have utility for predicting PN, but further testing is needed.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
A major adverse effect of treatment with microtubule-stabilizing agents, such as paclitaxel, is peripheral neuropathy (PN),1 which is probably caused by the interruption of axonal transport induced by microtubule-stabilizing agents.2-4 The development of neuropathy can be dose or treatment limiting for many cancer patients, and neuropathy can lead to permanent neuronal dysfunction in a minority of patients.

The National Cancer Institute (NCI) Common Toxicity Criteria are most commonly used to assess chemotherapy-induced PN,5 but other grading systems have been proposed.6,7 However, in all of these systems, there is substantial interobserver and intraobserver variation in grading neuropathy, at least partially because of the lack of objective tools to measure the extent of chemotherapy-induced neuropathy.8-10 Although there are several noninvasive methods for assessing neurologic function, such as quantitative sensory testing, no reliable test has been developed that can assess or predict the risk of chemotherapy-induced neuropathy.9,11

Several instruments have been evaluated to assess surrogates for overall neurologic dysfunction, especially in diabetic PN and stroke rehabilitation, as indicators of functional decline or improvement. The Semmes-Weinstein monofilaments (SWF) test has been extensively studied and found to correlate with a diagnosis of diabetic PN with a sensitivity of 60.0% and a specificity of 73.8%.12-14 The Jebsen Test of Hand Function (JTH) and the Grooved Pegboard Test (GPT) have been used to assess overall motor and sensory functions of the hand, especially as rehabilitative measures for patients with stroke or rheumatoid arthritis.15-19 Timed standing tests, including a unipedal stance and sharpened Romberg test, have also been used to test cerebellar and pedal function in patients with diabetic PN.20-22 These tests have been evaluated in the rehabilitative and occupational medicine settings but have rarely been evaluated in other medical fields.

Ixabepilone (BMS-247550) is a nontaxane microtubule-stabilizing epothilone analog23 evaluated in phase I and II clinical trials in many tumor types24-44 and in an ongoing phase III trial in breast cancer. Adverse effects of ixabepilone are similar to those of other microtubule-stabilizing agents, such as paclitaxel, and include PN.23,33 Grade 3 or 4 PN rates as high as 25%45 have been observed in clinical trials, depending on the ixabepilone treatment schedule.

As part of a clinical trial to assess the efficacy of ixabepilone in breast cancer patients, we evaluated a group of neurologic function tests (NFTs) for their ability to predict the development of PN. The usefulness of the NFTs was assessed by a matched-pair analysis, comparing similar patients who differed only in the development of PN, and by actuarial methods to identify factors potentially associated with the development of PN.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Study Design
The NCI Cancer Therapeutics Branch conducted a phase II clinical trial of ixabepilone in patients with metastatic and locally advanced breast cancer. This trial was approved by the NCI Institutional Review Board, and all patients provided written informed consent. The original design separated the patients into two cohorts (patients with prior taxane therapy and patients without prior taxane therapy) to analyze efficacy. Both cohorts are combined for the current analysis. Efficacy and toxicity results for the patients with prior taxane therapy have been published.33

Ixabepilone was administered intravenously for 1 hour at a starting dose of 6 mg/m2 daily for 5 consecutive days every 3 weeks. Toxicities were assessed with NCI Common Toxicity Criteria version 2.0,46 and patients with persistent grade 2 or grade 3 neuropathy lasting more than 7 days were removed from study. Patients were restaged every two cycles, or earlier if clinically indicated, and removed from study for progressive disease defined by Response Evaluation Criteria in Solid Tumors,47 for unresolved toxicity, or after receiving the maximum benefit for patients treated with neoadjuvant therapy.

Assessment of Neuropathy
All patients received a baseline physical examination and two baseline NFT assessments. Clinical neurologic examinations were conducted by the treating physician and included sensory and motor examinations of the extremities, with assessment of proprioception, vibration, sharp/dull discrimination, and deep tendon reflexes. NFTs were re-evaluated after even-numbered cycles or when patients were removed from study. NFTs included a questionnaire, a SWF test, unipedal and tandem (modified Romberg) stance tests, JTH, and GPT. These NFTs were administered by members of the Rehabilitation Medicine Department of the National Institutes of Health.

Light touch sensation was assessed with an SWF test by a forced-choice method,48 and 2.83-, 3.61-, 4.31-, 4.56-, and 5.07-gauge filaments (North Coast Medical, Inc, Morgan Hill, CA) were used. The test was initiated with 5.07- and 4.31-gauge filaments for foot and hand sites, respectively.48,49 Balance deficits were assessed with the eyes closed and the eyes open during the unipedal and tandem stance tests.20,21 The task was timed for a maximum of 30 seconds, and timing stopped when the subject moved out of position. The neuropathy questionnaire, which was created for this study, asked patients to identify the most symptomatic arm or leg and to report the intensity and frequency of symptoms in the most affected limb using a 0- to 10-point Likert scale.

The GPT tested manipulative dexterity (Lafayette Instrument Company, Lafayette, IN).19 The score recorded was the sum of the number of seconds required to complete peg insertion, the number of pegs placed, and the number of pegs dropped. The JTH comprises seven subtests that evaluate writing, simulated page turning, transferring small objects, simulated feeding, stacking, and lifting large objects (Sammons Preston, Bolingbrook, IL).15 Each subtest was timed and scored as the sum of the number of seconds required to complete all tasks.

After the first 22 patients were enrolled onto our study, the protocol was amended to add nerve conduction studies (NCSs) at baseline and after cycles 4 and 8. NCSs were performed with standard surface recording methods.50

Statistical Analysis
The values of baseline characteristics and of baseline NFTs were compared using a Fisher's exact test for binomial parameters and a Wilcoxon rank sum test for continuously measured parameters. For the matched-pair analysis, patients who developed ≥ grade 2 PN were matched with patients who did not develop ≥ grade 2 PN on the basis of age, previous taxane therapies, number of treatment cycles received, cumulative dose of taxanes, number of prior cytotoxic agents, and number of prior regimens. Comparability of the matching was confirmed with a Wilcoxon signed rank test. Values at baseline, values at the time of the development of neuropathy (or the corresponding cycle in the matched control), and the difference between the two values were then compared with a Wilcoxon signed rank test. Because of the large number of exploratory evaluations performed and because of the various degrees of independence, a statistically significant difference was defined as P < .01. All such P values are two tailed and reported without other adjustments.

To evaluate the ability of an NFT to predict the probability and time to PN development, exploratory actuarial methods were used. Patients included in this analysis had baseline and post–cycle 2 results and received at least three cycles of treatment. Two patients with ≥ grade 2 PN before starting cycle 3 were excluded. Time to PN was computed from day 1 of cycle 3 until ≥ grade 2 PN was noted. Censoring occurred when patients were removed from study for other reasons. The probability of developing PN as a function of time was determined by the Kaplan-Meier method,51 and the statistical significance of the difference among survival curves was determined by the Mantel-Haenszel method.52

The values of NFTs at cycle 0 and at cycle 2 and the differences between these values were individually evaluated in univariate analyses with exploratory intent. To determine estimated probabilities of developing PN, parameters were initially divided into three or four groups of approximately equal sizes on the basis of tertiles or quartiles of the observed parameter distribution. If a potential difference in prognosis was identified by this initial examination, the patients were subsequently divided into two groups with reasonably large differences in prognosis, followed by a corresponding Bonferroni-type adjustment to the P value. Parameters in the univariate analysis with a P ≤ .15 (unadjusted or adjusted, if required) were worthy of consideration for possible inclusion in a subsequent Cox model to determine whether any factors were jointly able to modify the development of PN. All P values from this actuarial analysis were also two sided.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Characteristics of Neuropathy
Between June 2002 and January 2005, 56 patients were enrolled onto a phase II trial of ixabepilone for patients with breast cancer. Eight patients were enrolled at another site not participating in NFTs, and one patient withdrew consent. The remaining 47 of these 56 patients had a baseline and at least one follow-up neurotoxicity assessment. Baseline characteristics of the patients are listed in Table 1. Seventeen patients had grade 1 PN at baseline, which presented as decreased deep tendon reflexes in 15 patients, decreased sensory function in four patients, and paresthesia in one patient.


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  		Table 1. Characteristics of Patients at Baseline

 
A Kaplan-Meier plot indicating time to development of neuropathy is shown in Figure 1. Patients were considered to have an event if they developed ≥ grade 2 PN (n = 11). Patients were also censored when removed from the study because their disease progressed (n = 33) or at removal from study for reasons not related to neuropathy (n = 3). The median onset of ≥ grade 2 PN was 144 days (range, 6 to 189 days).


Figure 1
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  		Fig 1. Kaplan-Meier plot showing the development of ≥ grade 2 peripheral neuropathy (PN) among all 47 study patients.

 
Among the 47 patients, 11 (23%) developed ≥ grade 2 PN during ixabepilone treatment (nine patients developed grade 2, and two patients developed grade 3; Fig 2). The grade 2 or 3 PN of eight patients resolved to grade 1 within a median duration of 15 days (range, 6 to 346 days) after onset, whereas the PN of three patients had not resolved during follow-ups at 76, 361, and 746 days after onset. Grade 2 PN presented as decreased hand function in two patients, decreased sensory function in seven patients, and paresthesia interfering with function in two patients. Grade 3 PN presented as motor weakness that interfered with activities of daily living in two patients.


Figure 2
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  		Fig 2. Incidence and outcomes for patients with peripheral sensory neuropathy. Numbers of patients in each category are shown in parentheses, with the median number of days to occurrence shown where applicable.

 
NCSs
Twenty-six patients had NCSs at baseline, and four of them (15%) had abnormal baseline NCS findings indicating axonal neuropathy. Only two of these four patients with abnormal NCS findings at baseline also had clinical grade 1 PN at baseline. Of the four patients who had abnormal NCS findings at baseline, one developed grade 2 PN, whereas seven of the 22 patients with a baseline NCS without evidence of neuropathy went on to develop ≥ grade 2 PN. Sixteen patients could be assessed by NCS after four cycles of ixabepilone; six (38%) of these 16 patients had axonal neuropathy. However, five of these six patients were normal at baseline.

Eight of the 11 patients who developed ≥ grade 2 PN had follow-up NCS findings during ixabepilone treatment; five of these eight patients had NCS abnormality indicating axonal neuropathy. The two patients who developed grade 3 PN had axonal neuropathy by NCS. Eight of the 36 patients without ≥ grade 2 PN had follow-up NCSs, and four of these eight patients had an NCS abnormality indicating new-onset axonal neuropathy, although there was no clinical evidence of PN.

Analysis of Baseline Values to Predict Neuropathy
To determine whether the baseline characteristics or the baseline NFT scores (Table 2) were predictive of developing neuropathy on study, the scores or values for each were compared between patients who did and did not develop ≥ grade 2 PN. None of these characteristics was statistically significantly associated with the development of ≥ grade 2 PN.


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  		Table 2. Analysis of Neurologic Tests at Baseline Among 47 Patients With Breast Cancer

 
Identification of NFTs Correlated With the Development of PN in the Matched-Pair Analysis
In the matched-pair analysis, each of the 11 patients who developed ≥ grade 2 PN (the case patients) was matched to a single patient among the remaining 36 patients who did not develop PN on study (the control patients). The similarity between these two groups was confirmed (P for all comparisons > .10). NFT scores of the patients who developed ≥ grade 2 PN were compared with the scores of their matched patients at baseline and at the same cycle in which the patient first developed ≥ grade 2 PN (Table 3). GPT scores with the dominant hand were significantly higher for patients at the onset of ≥ grade 2 PN than for the patients without ≥ grade 2 PN who were assessed at a corresponding treatment cycle (P = .006). The decreased JTH score with the nondominant hand between baseline and the onset of ≥ grade 2 PN was also significantly larger in patients with PN than in patients without ≥ grade 2 PN (P = .002). Although other tests also showed declines in the neurologic function at the onset of ≥ grade 2 PN, these other tests did not meet our threshold for statistical significance (P < .01).


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  		Table 3. Matched Pair Study

 
Evaluation of Factors Related to Time to Development of Neuropathy
To determine whether NFT scores could be used to predict ixabepilone-induced neuropathy, an actuarial analysis was performed with baseline factors and NFTs at baseline and at cycle 2 and for the change from baseline to cycle 2, for patients who continued treatment beyond cycle 2. Among the 31 patients identified, eight developed ≥ grade 2 PN after receiving at least three cycles of treatment (at a median time of 105 days after beginning cycle 3), and 23 did not (with a median time of 91 days of treatment beginning with cycle 3).

An exploratory univariate analysis was performed to identify factors that may have important associations with development of PN. The analysis found the most significant divisions in the data, based on tertiles or quartiles from the baseline factors and NFTs (at baseline, after cycle 2 of ixabepilone treatment, and the difference between the values at these two time points). Any parameters with P ≤ .15 after dividing into two groups or at a natural cut point were identified as potentially interesting in this exploration. Several illustrative evaluations of these large differences were plotted (Table 4 and Fig 3). JTH and GPT results were most frequently identified with development of ≥ grade 2 PN (Table 4). Among characteristics present at baseline, only the presence of baseline grade 1 neuropathy (P = .076) met the prespecified univariate threshold.


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  		Table 4. Univariate Log-Rank Analysis of Individual Parameters for Prognostic Significance in Development of ≥ Grade 2 Peripheral Neuropathy

 

Figure 3
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  		Fig 3. Kaplan-Meier plots from selected Jebsen Tests of Hand Function (JTH) and Grooved Pegboard Tests (GPT) with dominant or nondominant hand at baseline and at cycle 2 and changes from baseline to cycle 2 that illustrate the magnitude of some potential prognostic factors. Adjusted log-rank P values are shown based on the identified exploratory test score cut points (next to each curve), and the proportion of patients with ≥ grade 2 peripheral neuropathy (PN; failed) are indicated. (A) Baseline JTH, nondominant; (B) cycle 2 JTH, nondominant; (C) baseline to cycle 2 JTH, dominant; (D) baseline GPT, dominant; (E) cycle 2 GPT, dominant; (F) baseline to cycle 2 GPT, nondominant.

 
Although it would have been desirable to develop a Cox model to evaluate the impact of the factors simultaneously on prognosis, many of the parameters with P ≤ .15 on univariate analysis were not amenable for this (as indicated in Table 4, with sample Kaplan-Meier plots shown in Fig 3) because infinite hazard ratios were obtained. This is largely attributable to the limited number of patients and to the small number of patients who developed ≥ grade 2 PN. For example, most of the hazard ratios for JTH and GPT time points were infinite because events occurred in only one arm. Thus, because of limited events and a large number of factors with infinite hazard ratios, any Cox model analyses would have been of too little value to present.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
In this prospective analysis of ixabepilone-induced neuropathy in breast cancer patients, we assessed a battery of NFTs to determine whether these tests could be used to evaluate or predict ixabepilone-induced PN. We found that the JTH and GPT were most likely to provide results that might predict grade 2 PN. In contrast, results from NCSs and SWF tests were not useful for predicting the development of grade 2 PN.

Ixabepilone has been studied in several different treatment schedules, and severe (grade 3 or 4) neuropathy occurs in 7% to 19% of patients receiving a dose of 40 mg/m2 every 3 weeks.32,36,53 However, in the three published accounts of regimens in which ixabepilone was administered daily for 3 days or for 5 days, the incidence of grade 3 neurotoxicity was 0% to 3%24,30,33; it was 4% in the current study. Several randomized clinical trials of taxanes have found that the incidence of severe neuropathy depends on taxane dose and treatment schedule.54-57 When this study was originally designed, we were concerned about the potential for severe PN, and thus, we chose NFTs on the basis of their usefulness in other validated medical settings, the ease of use in a standard medical practice, and the breadth of assessment. The low incidence of grade 3 PN in this study limits the analysis of factors associated with the development of severe neuropathy.

Because of the small sample size and the relatively large proportion of patients whose disease progressed on study within the first two cycles, we recognized that predictors for neuropathy might not be identifiable. However, by using a matched-pair analysis and exploratory univariate survival analyses, we have been able, at least preliminarily, to identify factors that may be associated with the development of neuropathy.

The matched-pair study showed that dominant-hand GPT scores at the onset of ≥ grade 2 PN are significantly different between patients with and without ≥ grade 2 PN. Because we chose a stringent P value (P < .01) to define statistical significance and because of the small number of patients in our study, only dramatic findings were likely to actually be statistically significant. In univariate actuarial analyses, both GPT and JTH seemed potentially reasonable for prognostic grouping according to the probability of development of PN after cycle 3. However, because of the timing and distribution of the few neuropathy events by prognostic category, the factors that seemed to be the most strongly associated with the development of PN could not be evaluated in a Cox model.

Several confounding factors may have complicated interpretation of our results. Our study patients frequently had upper-extremity lymphedema, which could change with therapy and could affect their ability to perform some of the NFTs. Patients also frequently developed fingernail toxicity,33 which could create difficulty in differentiating between PN-induced and nail toxicity–induced declines on NFTs. Because many of the tests were skill based and, thus, scores could be improved with practice, many patients could improve their NFT scores over the course of treatment without a corresponding neurologic improvement.

Our data identify candidate tests that are associated with and may be predictive of PN development during ixabepilone treatment. These and other functional tests should be further evaluated in future clinical trials to validate their utility for the prediction and assessment of chemotherapy-induced neuropathy. Methods for early detection will be critical to develop better preventative and therapeutic strategies as more neurotoxic chemotherapeutics become available.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
Author Contributions
 REFERENCES
 
The authors indicated no potential conflicts of interest.


   Author Contributions
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
REFERENCES
 

Conception and design: James J. Lee, Jennifer A. Low, Earllaine Croarkin, Arlene W. Berman, Seth M. Steinberg, Sandra M. Swain

Administrative support: James J. Lee, Jennifer A. Low, Rebecca Parks

Provision of study materials or patients: James J. Lee, Jennifer A. Low, Sandra M. Swain

Collection and assembly of data: James J. Lee, Jennifer A. Low, Earllaine Croarkin, Rebecca Parks, Arlene W. Berman, Nitin Mannan, Sandra M. Swain

Data analysis and interpretation: James J. Lee, Jennifer A. Low, Rebecca Parks, Arlene W. Berman, Seth M. Steinberg, Sandra M. Swain

Manuscript writing: James J. Lee, Jennifer A. Low, Earllaine Croarkin, Rebecca Parks, Seth M. Steinberg, Sandra M. Swain

Final approval of manuscript: James J. Lee, Jennifer A. Low, Sandra M. Swain

 


   NOTES
 
Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD.

J.J.L. and J.A.L. contributed equally to this work.

Presented in part at the 26th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 3-6, 2003; and the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
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Submitted September 16, 2005; accepted February 21, 2006.




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