Q U A L I T Y - O F - L I F E

O U T C O M E S

The Modied Total Neuropathy Score: A Clinically Feasible and Valid Measure of Taxane-Induced Peripheral Neuropathy in Women With Breast Cancer
Meredith A. Wampler, PT, DPTSc, Christine Miaskowski, RN, PhD, Kate Hamel, PhD, Nancy Byl, PT, PhD, Hope Rugo, MD, and Kimberly S. Topp, PT, PhD

aclitaxel and docetaxel (Taxotere) are effective antimitotic chemotherapeutics commonly used to treat invasive breast cancer. Taxanes polymerize free cellular tubulin into stabilized microtubules, which prevents the separation of chromosomes during mitosis.1 However, other cellular functions that rely on tubulin (eg, axonal transport and cytoskeletal support of transmembrane proteins) also may be disrupted.24 Such disruptions may contribute to the axonal atrophy of large diameter peripheral nerve axons observed in paclitaxel-induced neuropathy.5,6 Peripheral neuropathy develops in 50%60% of patients who use taxanes.7,8 Patients present with symptoms such as neuropathic pain, dysesthesias, and paresthesias in a stocking-and-glove pattern, decreased deep tendon reexes, increased vibration thresholds, and decreased sensory nerve action potential amplitudes.913 As cumulative doses of paclitaxel or docetaxel increase, weakness of distal muscles may develop.11,13
From University of California, San Francisco and San Francisco State University, San Francisco, California. The authors acknowledge research support from the California Breast Cancer Research Program (grant #10GB-0001). Additional support for the corresponding authors program of research was provided through a graduate fellowship from the Howard Keane Endowment Fund. The authors have indicated no potential conicts of interest. Manuscript submitted December 14, 2005; accepted March 28, 2006. Correspondence to: Meredith Wampler, PT, DPTSc, Graduate Program in Physical Therapy, San Francisco State University, 1600 Holloway Avenue, Gym 103, San Francisco, CA 94132; telephone: (415) 338-6837; fax: (415) 338-0907; e-mail: oncologyrehab@hotmail.com
J Support Oncol 2006;4:W9W16 2006 Elsevier Inc. All rights reserved.

Abstract This prospective, correlational study sought to identify a clinically feasible, valid measure of taxane-induced peripheral neuropathy that correlated with impairments in balance, physical performance, pain, and quality of life (QOL). In all, the study included 20 breast cancer patients who completed taxane chemotherapy and 20 healthy women who were matched by age, height, and weight. All participants completed a testing session that included measures of peripheral neuropathy, balance, physical performance, pain, and QOL. Modied Total Neuropathy Scores (mTNS) discriminated between women in the breast cancer and control groups. Positive correlations were found between the mTNS and the Total Neuropathy Score (r = 0.99; P < 0.001) and physical performance (r = 0.654; P = 0.002). Negative correlations were found between the mTNS and measures of balance (r = 0.638; P = 0.002) and QOL (r = 0.615; P = 0.004). Pain was experienced by 70% of the women with breast cancer. Pain intensity scores did not correlate with any measure of peripheral neuropathy. The mTNS may be a valid clinical measure to monitor the severity of peripheral neuropathy in women receiving a taxane for breast cancer, because it correlated strongly with the TNS. In addition, because the mTNS was correlated with measures of balance, physical performance, and QOL, it may help clinicians to identify patients who may benet from rehabilitative services. Pain and peripheral neuropathy may need to be assessed separately.

Oncologists must monitor for taxane-induced peripheral neuropathy, because peripheral neuropathy has a negative impact on upper extremity function, balance, physical performance, and quality of life (QOL) in other populations.1421 Some 25%56% of individuals treated with taxanes experience painful neuropathy.10,11 Moreover, patients often report that their symptoms are more severe and long lasting than reported by healthcare providers22; thus the impact of peripheral neuropathy on function and QOL may be underrecognized and undertreated. Of course, this

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Table 1

Common Qualities of Peripheral Neuropathy Measures Used

TNS mTNS MDNS TT VT

providers then could use it to identify patients who may benet from further assessment and treatment for pain, balance, or physical performance problems associated with taxane-induced peripheral neuropathy.

Patient report of motor and sensory symptoms Pin sensibility Vibration examination Strength Deep tendon reexes Nerve conduction studies Touch examination

+ + + + + +

+ + + + + + + + + + +

Participants and Methods

PATIENT POPULATION

Although many of these scales share common qualities, such as vibration examination, the actual technique may differ among scales. The methods for each scale are described in detail in the text. Abbreviations: TNS = Total Neuropathy Score; mTNS = Modied Total Neuropathy Score; MDNS = Michigan Diabetic Neuropathy Score; TT = touch threshold; VT = vibration threshold

is unfortunateexercise-based interventions may provide signicant improvements in balance and physical mobility in patients with peripheral somatosensory problems.23,24 More importantly, effective treatments for neuropathic pain are available.2527 However, controlled trials for the treatment of chemotherapy-induced neuropathic pain are lacking. No clear consensus exists regarding the most useful clinical measure of chemotherapy-induced peripheral neuropathy. The World Health Organization (WHO),28 Eastern Cooperative Group (ECOG),29 or Ajani30 criteria for peripheral neuropathy often are used in large clinical trials, because they are easy to administer. Each of these scales uses a 4-point rating system, in which grade 0 indicates no neuropathy and grade 4 indicates debilitating paresthesias or paralysis. These scales are limited, because they use broad categories that are not sensitive to small changes in peripheral neuropathy severity, and they have low-to-moderate intraclass correlation (ICC) values: 0.55 (WHO), 0.75 (ECOG), and 0.37 (Ajani).31 Methods to monitor peripheral neuropathy in diabetics may be more useful than are common toxicity scores. The San Antonio Consensus Statement on diabetic peripheral neuropathy states that the best assessment tools for peripheral neuropathy are those that combine testing of quantitative touch thresholds, quantitative vibration thresholds, nerve conduction studies, and patient reports of symptoms.32 The Total Neuropathy Score (TNS) is a composite instrument to assess chemotherapy-induced peripheral neuropathy9; it has been found to be a reliable (interrater reliability, .94; intrarater reliability, .97) and valid instrument.33 Unfortunately, the TNS is time-consuming and expensive to perform, because it requires nerve conduction studies and the use of specialized equipment to measure vibration sense. This prospective, correlational study sought to identify a clinically feasible, valid measure of taxane-induced peripheral neuropathy that correlated with impairments in balance, physical performance, pain, and QOL. This type of measure would benet women with breast cancer, because healthcare

In all, 20 women with breast cancer who received either paclitaxel or docetaxel were recruited from a comprehensive cancer center; another 20 healthy women were recruited from the community and a university-based medical center. The two groups were matched, because age, height, and weight are associated with the outcome variables balance and vibration thresholds.34,35 Stringent inclusion and exclusion criteria were applied to both groups. Women were included if they were 3060 years of age, had completed taxane chemotherapy treatment for breast cancer within the previous 30 days, and had a corrected low-contrast visual acuity better than 20/60 and a corrected high-contrast visual acuity better than 20/40. Women were excluded if they had a history of neurotoxic chemotherapy treatment, central or peripheral neurologic disease, brain or spinal cord metastases, orthopedic problems that affected balance, or vestibular or visual disease. These criteria were chosen because balance is correlated with visual acuity, orthopedic problems, neurologic problems, and vestibular problems.3639 The Human Subjects Committee at the University of California, San Francisco, approved the study, and all of the participants signed a written informed consent prior to study participation.
PATIENT ASSESSMENT

Participants in the taxane group underwent a battery of quantitative peripheral nerve function tests, including nerve conduction studies, quantitative balance tests, physical performance tests, pain questionnaires, and a QOL questionnaire within 30 days following their nal infusion of paclitaxel or docetaxel. Participants in the control group underwent the same battery of tests, excluding the nerve conduction studies. Nerve conduction studies were performed by an experienced neurologist; all other testing was completed by a licensed physical therapist at the Movement Analysis Laboratory (MAL). Nerve conduction studies were completed within 48 hours of testing at the MAL.
MEASURES OF PERIPHERAL NEUROPATHY

Peripheral neuropathy was measured using the TNS.33 In addition, four other measures of peripheral neuropathy were used the Modied Total Neuropathy Score (mTNS), the Michigan Diabetic Neuropathy Score (MDNS), quantitative touch thresholds, and quantitative vibration thresholds. These measures are valid in other populations and, in comparison with the TNS, are simple to administer.18,33,40 Table 1 highlights the common qualities of the measures of peripheral neuropathy. For all measures of peripheral neuropathy, a higher score indicates a more severe peripheral neuropathy.

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The TNS is a composite scale (032 points) that includes patient report of sensory and motor symptoms (08 points), pin sensibility (04 points), quantitative vibration thresholds using a biothesiometer (Bio-Medical Instrument Company; Newbury, Ohio; 04 points), strength using manual muscle tests (04 points), deep tendon reexes (04 points), and nerve conduction studies that compare the amplitude of sural and peroneal nerves with lower limits of normal values (08 points). The neurologist followed standard nerve conduction study procedures.41 The TNS was obtained only for women in the taxane group, because the neurology clinic had normative values by age that were obtained using the same equipment and nerve conduction study testing techniques used in this study. Therefore, valid normative values were available to determine the TNS for the breast cancer group. The four remaining measures of peripheral neuropathy obtained for the two groups included the mTNS (024 points; the TNS excluding nerve conduction studies); quantitative touch thresholds of the right and left great toes and index ngers using Semmes Weinstein monolaments18 in a forced choice protocol42; quantitative vibration thresholds of the right and left pads of the great toes, medial malleolus, pad of the thumb, and head of the ulna using a biothesiometer35 in a method-of-limits protocol43 and the MDNS.40 The MDNS is a composite scale (046 points) that includes a pin sensibility test (04 points), a vibration examination using a tuning fork (04 points), a strength examination using a manual muscle test of distal muscles (018 points), a deep-tendon reex test (016 points), and a touch examination using a 10-g Semmes Weinstein monolament (04 points).
MEASURES OF BALANCE, PHYSICAL PERFORMANCE, PAIN, AND QOL

Table 2

Demographic and Treatment Characteristics of Patients With Breast Cancer

CHARACTERISTIC BREAST CANCER GROUP (n = 20)

Age, y Height, m Weight, kg Stage of breast cancer, n (%) I II III IV Neoadjuvant taxane therapy, n (%) Adjuvant taxane therapy, n (%) Type of taxane received Paclitaxel, n (%) Mean dose, mg/m2 Docetaxel, n (%) Mean dose, mg/m2 Dose schedule, n (%) Dose dense (every 2 weeks or weekly) Every 3 weeks Pain and sedative medications, n (%)a None Analgesics Sedatives
a

50.35 9.34 1.65 .06 68.19 9.39 0 13 (65%) 6 (30%) 1 (5%) 6 (30%) 14 (70%) 15 (75%) 836 248.9 5 (25%) 432 71.6 13 (65%) 7 (35%) 11 (55%) 9 (45%) 7 (35%)

Several women were taking multiple medications; therefore, the total percentage for this characteristic is over 100%.

Functional Assessment Cancer TherapyTaxane (FACTTaxane, 0172 points)17; a higher score indicated a better QOL.
DATA ANALYSIS

Balance was quantied using the equilibrium score from the Sensory Organization Test (NeuroCom Smart Balance; Portland, Ore). 44 Participants were asked to remain as steady as possible during six challenges. Equilibrium scores ranged from 0100, with lower scores indicating poorer balance. Physical performance was quantied using the Timed Up and Go test (TUG)45 and the Ayers Kinesthesia46 test. The TUG is a timed test, in which participants stand from a chair without using their arms, walk 3 meters, turn, and return to a seated position. The Ayers Kinesthesia test quanties patients upper extremity position sense. A higher score for each of these instruments indicates poorer performance. Pain was quantied using the Pain Quality Assessment Scale (PQAS),47 a questionnaire that asks participants to rate the intensity of 20 different pain descriptors (eg, electrical, numbness) on a 10-point, Likert-type scale; a higher score indicates more pain. The 20 items were summed to form a total score of 0200 points. To attempt to control for myalgias, arthralgias, and postsurgical pain, participants were asked to limit answers about discomfort to pain experienced below the elbow over the past week. Participants completed a separate PQAS to describe pain experienced below the knee. QOL was quantied using the

Descriptive statistics and frequency distributions were generated for participant demographic and disease-related characteristics. Paired t-tests were performed to determine differences between groups for each measure of peripheral neuropathy, because the two groups were matched one by one for age, height, and weight. A conservative Bonferroni correction (family = 0.05; 8 comparisons; P < 0.006 to be considered signicant) was applied to this analysis to reduce the chance of a type II error during comparison of multiple measures of the same construct, peripheral neuropathy. Pearson product moment correlations were used to determine the relationship between the TNS and other measures of peripheral neuropathy as well as for correlations between peripheral neuropathy and measures of balance, physical mobility, QOL, and pain in the breast cancer cohort. Among the breast cancer cohort, frequency distributions were performed to determine the proportion of women who reported neuropathic pain and received treatment for pain. Paired t-tests were used to discern differences between upper extremity and lower extremity total pain scores and individual item pain scores. All calculations were performed using a Minitab statistical package (State College, Pennsylvania). A P value < 0.05 was considered statistically signicant.

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Table 3 Peripheral Nerve Function Measures for Breast Cancer and Control Groups
PERIPHERAL NERVE FUNCTION MEASURE BREAST CANCER GROUP (n = 20) CONTROL GROUP (n = 20) P VALUE

Total Neuropathy Score, 032 points Modied Total Neuropathy Score, 024 points Michigan Diabetic Neuropathy Score, 046 points Touch threshold, log score Great toe Index nger Vibration threshold, V Great toe Ankle Thumb Wrist

73 73 13 7 3.91 0.34 3.07 0.48 13 9 17 8 42 73

ND 11 22 3.48 0.56 2.50 0.19 53 13 5 32 52

N/A < 0.001 < 0.001 0.003 < 0.001 0.001 0.047 0.333 0.024

Data reported are means standard deviations. mTNS includes all items from the TNS except for nerve conduction study scores. Abbreviations: ND = no data because nerve conduction studies were not performed for women in the healthy group; N/A = not applicable

Results
SAMPLE DEMOGRAPHICS AND TREATMENT CHARACTERISTICS

Table 2 summarizes the mean age, height, and weight of the 20 breast cancer patients. No signicant differences in age, height, or weight were found between the breast cancer group and the healthy control group. All women in the breast cancer group were diagnosed with invasive breast cancer and received four cycles of doxorubicin and cyclophosphamide before receiving taxane therapy. Table 2 describes the types of taxane chemotherapy regimens and the number of women taking analgesic and sedative medications.
DISCRIMINATING BETWEEN THE GROUPS

used for all further statistical analyses. All of the measures of peripheral neuropathy, except for vibration thresholds of the ankle, thumb, and wrist, discriminated between the breast cancer and control group (see Table 3). The TNS for the breast cancer group was not compared with that of the control group, because the TNS could not be calculated in the control group without nerve conduction study values.
mTNS CORRELATED STRONGLY WITH TNS

No statistically signicant differences were found between right and left mean values of touch or vibration thresholds for each participant. Therefore, values from the right side were

For women in the breast cancer group, the mTNS, MDNS, and vibration threshold at the wrist were signicantly correlated with the TNS (see Table 4). The mTNS had the strongest correlation coefcient with the TNS (r = .99; P < 0.001). Of particular note, only two participants in the breast cancer group presented with sural amplitudes below the lower limit of normal for their age (see Table 5). All other nerve conduction studies were above the lower limits of normal amplitude and conduction velocity.
THE mTNS CORRELATED WITH ALL MEASURES BUT PAIN

Table 4

Correlations of Clinical Measures of Peripheral Neuropathy With Total Neuropathy Score for the Breast Cancer Group
TOTAL NEUROPATHY SCORE r P

mTNS MDNS VT Great toe VT Ankle VT Thumb VT Wrist TT Great toe TT Index nger

0.990 0.715 0.318 0.344 0.228 0.554 0.291 0.239

< 0.001 < 0.001 0.171 0.138 0.335 0.011 0.213 0.310

The mTNS was moderately correlated with the sensory organization test, TUG, and QOL scores (see Table 6). The correlation coefcient was negative for balance and QOL, indicating that those with more severe peripheral neuropathy had poorer balance and lower QOL scores. The correlation coefcient was positive for TUG, indicating that subjects who had more severe peripheral neuropathy took longer to perform the task. The mTNS was not signicantly correlated with pain scores. The MDNS and vibration threshold at the wrist were not associated with any measure of balance, physical performance, QOL, or pain.
CHARACTERISTICS OF TAXANEINDUCED NEUROPATHIC PAIN

Abbreviations: mTNS = Modied Total Neuropathy Score; MDNS = Michigan Diabetic Neuropathy Score; VT = vibration threshold; TT = touch threshold

Pain was not universally experienced by the women in the breast cancer group. One woman (5%) experienced only upper-

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Table 5

Nerve Conduction Study Results for Women in the Breast Cancer Group
SUBJECT NUMBER AGE (y) SURAL CV (m/sec) SURAL AMP (V) PERONEAL CV (m/sec) PERONEAL AMP (mV)

1 43 2 54 3 44 4 57 5 45 6a 54 7 46 8b 60 9 56 10 59 11 56 12 57 13 41 14 54 15 35 16 33 17 50 18a 37 19 67 20 59 Lower limits of normal (age, 540 y) Lower limits of normal (age, 4160 y)
a

45 51 52 50 45 47 45 ND 42 44 47 40 44 50 48 48 55 50 44 45 42 36

7.80 21.30 10.21 5.70 15.00 4.12 5.40 ND 6.03 9.97 11.60 7.10 18.00 15.00 15.29 16.00 15.10 4.50 8.20 5.60 6.0 5.0

47 51 48 47 45 48 49 42 51 55 47 43 52 52 52 50 47 45 43 41 38 34

3.70 3.50 6.00 2.80 2.70 1.50 5.30 4.02 2.60 8.98 2.00 3.50 5.10 2.30 5.90 5.50 3.90 3.30 4.10 1.60 2.0 1.5

Abnormal nerve conduction values are shown in bold. b One participant refused to complete nerve conduction studies because it was too uncomfortable. Abbreviations: CV = conduction velocity; AMP = amplitude; ND = no data

extremity pain. Three women (15%) experienced only lowerextremity pain. Ten women (50%) experienced both upper- and lower-extremity pain. Whereas 14 women (70%) reported pain, only 9 (45%) were receiving analgesics (see Table 2). No differences were found in total PQAS for the upper extremities as compared with the lower extremities (upper extremities = 33.79 36.55; lower extremities = 47.43 31.59; P = .152). Aching, tingling, numbness, unTable 6

pleasant, and intense were descriptions given for the most severe pain qualities reported (see Figure 1). The scores for these items each reached 2 points or more for both upper and lower extremities.

Discussion
This study was the rst to identify a clinically feasible and valid measure of taxane-induced peripheral neuropathy that

Correlation of mTNS, MDNS, and VT at the Wrist with Measures of Balance, Physical Performance, Quality of Life, and Pain in the Breast Cancer Group (n = 20)
mTNS r P r MDNS P r VT WRIST P

Balance Sensory organization test Physical performance Upper extremity kinesthesia Timed Up and Go Quality of life FACTTaxane Taxane subscale Pain Upper extremity pain Lower extremity pain

0.638 0.038 0.654 0.615 0.691 0.309 0.315

0.002 0.874 0.002 0.004 0.001 0.184 0.176

0.388 0.046 0.404 0.145 0.330 0.049 0.063

0.091 0.846 0.077 0.541 0.156 0.836 0.792

0.404 0.042 0.209 0.437 0.547 0.118 0.078

0.077 0.859 0.376 0.054 0.013 0.619 0.742

Abbreviations: mTNS = Modied Total Neuropathy Score; MDNS = Michigan Diabetic Neuropathy Score; VT = vibration threshold; FACT = Functional Assessment Cancer Therapy

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Heavy Aching Throbbing Radiating Cramping Tingling

Lower extremity Upper extremity

Items from Pain Quality Assessment Score

Electrical Numb Shooting Itchy Tender Sensitive Cold Dull Hot Sharp Surface Deep Unpleasant Intense *

10

Mean item score

Figure 1

Mean Pain Quality Assessment Scale Scores by Item for Women With Breast Cancer

Mean and standard deviation for each item of the Pain Quality Assessment Score are shown separately for lower extremity and upper extremity (n = 14). *Only Deep had a signicant difference between lower extremity and upper extremity item scores (P < 0.05).

correlated with impairments in balance, physical performance, and QOL in women with breast cancer. The mTNS may be performed in 10 minutes; it is relatively inexpensive and well tolerated by patients, because it excludes nerve conduction studies. This test could discriminate between healthy women and those who completed taxane therapy for breast cancer. In addition, the mTNS was highly correlated with the TNS. Finally, the mTNS correlated moderately with measures of balance, physical mobility, and QOL. The MDNS may be a quick, inexpensive alternative measure of peripheral neuropathy. It also was signicantly correlated with the TNS and showed a trend toward signicant cor-

relations with measures of balance and physical performance. A tuning fork is used to perform the vibration examination, making it a feasible and useful tool for clinicians who do not have access to a quantitative vibration threshold instrument required for the mTNS. However, the limited sample size of our study made clear identication of the mTNS or MDNS as the most meaningful tool difcult. Our data suggested that nerve conduction studies may not provide additive information for clinicians who use the TNS. Nerve conduction studies were above the lower limits of normal in all but two participants. Because the TNS is scored by comparing tested peroneal and sural amplitude values with normative valuesnot baseline valuesthe mTNS equaled the TNS for most participants. This observation may explain the high correlation between the mTNS and TNS that is not unique to our cohort. In previously published data of cancer patients that were used to calculate mTNS and TNS scores,9 the correlation between mTNS and TNS also was high (r = 0.95; P < 0.001). Serial nerve conduction studies may provide important information to clinicians; several studies have reported a signicant decrease in sural nerve amplitudes between baseline and postchemotherapeutic measures.9,48 The peripheral neuropathy experienced by women in the breast cancer group was relatively mild; of 32 possible points, the mean TNS score was 7 3. In comparison, the mean TNS for patients following treatment with paclitaxel/cisplatin was 11 5 points, indicating that combined use of two neurotoxic chemotherapeutic agents may cause a slightly more severe neuropathy.9 In contrast, patients with severe diabetic peripheral neuropathy had a mean TNS of 25 7.33 However, even though peripheral neuropathy was mild, the mTNS signicantly correlated with changes in balance, physical mobility, and QOL in breast cancer patients, suggesting the neuropathy is clinically important. Pain did not correlate with peripheral neuropathy in this cohort; however, clinicians must identify neuropathic pain, because it may become chronic and debilitating.15,49,50 Unfortunately, taxane-induced neuropathic pain may be undertreated in breast cancer patients. Although 70% of the women in this study reported neuropathic pain, only 45% received analgesics. Instruments such as the PQAS that include items about aching, tingling, numbness, unpleasantness, and intenseness may help to identify neuropathic pain so that management interventions to afford relief may begin.51,52 This study had several limitations. Insufcient resources did not allow for a longitudinal study, in which participants underwent testing before and after chemotherapy. This type of design would have controlled for confounding variables related to outcome measures by having women serve as their own controls. The team attempted to control for confounding variables by imposing strict entry criteria and matching the groups by age, height, and weight. The other limitation was the small sample size. However, there was adequate power to achieve the correlational aims of this study. With 20 participants, there was 83% power to detect

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Pearson correlations of .60 or higher.53 Correlations below .60 were not of interest; the primary aim was to identify a measure of peripheral neuropathy that correlated highly with the TNS. Similarly, only robust correlations (> .60) among peripheral neuropathy and balance, physical mobility, and QOL were of interest. Correlations less than .60 would dilute the ability of the measure of peripheral neuropathy to serve as a surrogate measure of problems in balance, mobility, and QOL.

Conclusion
Oncologists need to be cognizant of taxane-induced peripheral neuropathy in women being treated for breast cancer. The mTNS may provide important information about the severity of peripheral neuropathy. Further, it may raise clini-

cians sensitivity to patient problems with balance, physical mobility, and QOL. Tools such as the PQAS may provide clinicians with a method to identify patients who are experiencing taxane-induced painful peripheral neuropathy. By monitoring these phenomena, patients can be directed to pain management and rehabilitative services that could positively impact their QOL. Acknowledgments We are grateful to all of the participants who participated in this study. We acknowledge the support and assistance of the physicians and nurses at the UCSF Carol Franc Buck Breast Care Center who helped recruit participants for this study. We thank Jeffrey Ralph, MD, who performed all of the nerve conduction studies.

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