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February 2013, Supplement to Volume 17, Number 1
Current Methods for the Assessment and Management of Taxane-Related Neuropathy
Ellen M. Lavoie Smith, PhD, ANP-BC, AOCN®
Taxane-induced peripheral neuropathy (TIPN) affects a number of patients with breast cancer. To properly manage these patients, nurses must be able to identify and assess TIPN, as well as educate patients on TIPN as a side effect of taxane therapy. This article provides practical suggestions regarding how nurses can incorporate clinically feasible measurement approaches into practice and includes examples of grading TIPN that illustrate the limitations of the current tools and techniques for assessment. For example, a shortened and revised version of the Total Neuropathy Score and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity subscale should be considered for future use. In addition, neuropathy-related results from numerous phase III trials in breast cancer are discussed, and the latest evidence regarding pharmacologic interventions for TIPN is briefly summarized.
Taxane-induced peripheral neuropathy (TIPN) significantly compromises the quality of life of breast cancer survivors. TIPN is an underrecognized problem because of continued reliance on suboptimal assessment approaches. Emerging empirical evidence suggests that more reliable, valid, sensitive, and clinically feasible TIPN measurement approaches should be used to quantify TIPN in clinical and research settings (Cavaletti et al., 2010; Griffith, Merkies, Hill, & Cornblath, 2010). Oncology nurses know that TIPN poses significant problems for patients with breast cancer. Although most oncology nurses are well versed regarding TIPN signs, symptoms, and related adverse outcomes, this knowledge does not necessarily translate into knowing what to do about it. Measurement approaches should include objective assessment of peripheral neuropathy signs and symptoms using history taking and simple physical examination approaches. TIPN signs and symptoms can be quantified using a composite measure such as the revised and shortened Total Neuropathy Score (TNS) (Chaudhry, Rowinsky, Sartorius, Donehower, & Cornblath, 1994; Cornblath et al., 1999; Lavoie Smith, Cohen, Pett, & Beck, 2011; Smith, Beck, & Cohen, 2008; Smith, Cohen, Pett, & Beck, 2010). In addition, patient-reported outcome measures should be used to assess the patient’s experience and the short 11-item Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity (FACT/GOG-Ntx) subscale often is used because of its excellent psychometric properties (Griffith et al., 2010). To date, duloxetine is the only pharmacologic intervention tested via a large phase III trial that has been shown to be effective in diminishing TIPN-related pain. Future testing of additional pharmacologic and nonpharmacologic interventions is needed.
Taxane chemotherapy (paclitaxel, docetaxel, and nab-paclitaxel) has led to significant improvements in breast cancer survival in patients with metastatic breast cancer. However, in addition to killing cancer cells, taxanes cause unwanted damage to the nerve cell axon and surrounding myelin sheath and the cell body within the dorsal root ganglion (Argyriou, Koltzenburg, Polychronopoulos, Papapetropoulos, & Kalofonos, 2008). Although the precise TIPN pathophysiologic mechanism is unknown, taxanes are believed to exert their neurotoxic effects on peripheral nerves by stabilizing the microtubule system critical for mitosis and intracellular transport of proteins and other substances between the axon and the cell body (Argyriou et al., 2008; Carlson & Ocean, 2011; Swain & Arezzo, 2008; Theiss & Meller, 2000). Once the microtubule transport system becomes damaged, the cell undergoes apoptosis (programmed cellular death) (Carlson & Ocean, 2011). Mitochondrial swelling, damage to peripheral nerve support structures, and various immune mechanisms have been implicated in the development of painful TIPN (Flatters & Bennett, 2006; Peters et al., 2007; Polomano, Mannes, Clark, & Bennett, 2001; Siau, Xiao, & Bennett, 2006; Zheng, Xiao, & Bennett, 2011). In addition, the Cremophor® EL (polyoxyethylated castor oil; now renamed as Kolliphor® EL) solvent used to formulate paclitaxel may contribute to TIPN, but a definitive causal relationship has not been established (Authier, Gillet, Fialip, Eschalier, & Coudore, 2000; Gradishar et al., 2005; Hausheer, Schilsky, Bain, Berghorn, & Lieberman, 2006; Swain & Arezzo, 2008).
TIPN is generally described as a symmetrical “dying back” phenomenon, meaning that the tips of the longest nerves are affected first. That explains why most patients initially report TIPN symptoms in their toes. As an individual receives higher cumulative taxane doses, symptoms extend up the feet to the ankles and lower legs and eventually appear in the fingertips, hands, wrists, and arms. Although all peripheral nerve types (sensory, motor, and autonomic) can be damaged as a result of taxane therapy, large, myelinated sensory nerve fibers are the most vulnerable (Argyriou et al., 2008; Carlson & Ocean, 2011). Common sensory symptoms include numbness, tingling, electric shock-like sensations, neuropathic pain, and impaired balance from diminished plantar sensation and resultant altered proprioception (Kuroi & Shimozuma, 2004; Swain & Arezzo, 2008; Wickham, 2007). Patients typically compensate for balance impairment by broadening their gate and using visual, rather than sensory, clues when monitoring foot placement. Impaired sensation in the fingertips can compromise the ability to manipulate small objects, button or zip clothing, or perform other daily tasks. Patients occasionally report mechanical or temperature-induced injuries. Those injuries occur when TIPN-related numbness impairs the patient’s ability to sense sharp objects or extremely hot or cold temperatures. Occurring in about 25%–30% of patients, painful peripheral neuropathy can be particularly distressing (Loprinzi et al., 2011; Smith et al., 2010). One type of neuropathy-related pain, allodynia, occurs when pain results from nonpainful stimuli. For example, patients may report pain when bed sheets touch their feet or when attempting to wear common clothing items, such as socks, shoes, or gloves.
TIPN signs include diminished or absent reflexes as well as altered vibration, temperature, and pin sensibility. Those TIPN signs are detectable only via physical examination and may appear earlier than subjective symptoms. As such, patients may not notice these TIPN signs before a clinician detects the deficit during a physical examination. This emphasizes the importance of the clinical examination because detection of preclinical signs (occurring early and before the emergence of patient-reported symptoms) can provide evidence that TIPN is worsening before the patient is aware that a problem exists. Although less common, upper and lower extremity motor weakness can occur. Motor weakness is typically evidenced when the patient is, for example, unable to turn on or off sink faucets, reports frequent tripping and falls, has difficulty managing a vehicle’s gas and brake pedals, or when a foot drop becomes noticeable. Autonomic neuropathy symptoms (e.g., constipation, erectile dysfunction, orthostatic hypotension, urinary retention) also occur, albeit infrequently. Autonomic symptoms are more difficult to attribute to TIPN because of the presence of other comorbid conditions or concurrent mediations that can lead to similar problems. Lastly, paclitaxel acute pain syndrome is characterized by moderate to severe pain in the back, hips, shoulders, thighs, and legs occurring during the first week following paclitaxel administration (Loprinzi et al., 2011). The symptoms of paclitaxel acute pain syndrome have been described as affecting the muscles and joints, but evidence suggests that this pain is instead because of taxane-related nerve injury (Loprinzi et al., 2011).
TIPN incidence data from breast cancer phase III studies are quite variable. Table 1 presents data demonstrating that TIPN incidence rates reported in phase III trials of metastatic and adjuvant populations conducted since the mid-2000s range from 8%–83%. The majority of patients with metastatic breast cancer included in these trials had previously received a neurotoxic agent. Unless otherwise indicated, TIPN was quantified using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI CTCAE) (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). Higher TIPN incidence and severity are generally associated with more frequent taxane administration and higher cumulative dosages. However, incidence rates vary greatly across studies when comparisons are made of TIPN caused by the same taxane with the same dose and treatment schedules. What might explain these discrepancies? The wide range in reported incidence is partially attributable to the presence or absence of various factors known to influence the risk of developing TIPN, such as taxane type, the dose administered (M2), cumulative dosage, and dose density, as well as demographic, genetic, and comorbid variables (Bergmann et al., 2011; Hausheer et al., 2006; Hertz et al., 2012; Kroetz et al., 2010; Schneider et al., 2011; Sissung et al., 2006; Visovsky, Meyer, Roller, & Poppas, 2008; Windebank & Grisold, 2008). However, another important factor influencing the imprecise understanding regarding the scope of the problem relates to inadequate attention to TIPN measurement. Many clinicians believe that TIPN poses only a minor problem because, in most published reports, only the rates of moderate and severe (grades 3 or 4) TIPN are reported. The reporting patterns illustrate clinician bias regarding the degree of clinically important TIPN and discount the discomfort and distress potentially caused by any degree of peripheral neuropathy.
Another problem is that, in phase III studies, TIPN is most often quantified using toxicity grading scales, and these scales are known to have suboptimal reliability and validity as well as suboptimal sensitivity reflected by floor effects (low scores), leading to underrepresentation of TIPN incidence and severity (Cavaletti et al., 2010; Griffith et al., 2010; Kuroi et al., 2009; Postma et al., 1998). To illustrate the main limitations, grading of two patient examples is described here.
The first patient has reduced ankle reflexes as the only sign of peripheral neuropathy. The second patient reports paresthesias that do not interfere with activity, plus all reflexes are absent. Per NCI CTCAE, version 4, paresthesias and tendon reflex loss define grade 1 sensory neuropathy, and grades 2–4 are defined by moderate, severe, and life-threatening interference with activities of daily living. Grade 5 equates to death from peripheral neuropathy, an extremely rare event. Both patients have grade 1 TIPN according to the NCI CTCAE, but the second patient’s neuropathy is more severe. This example illustrates the lack of sensitivity associated with the NCI CTCAE grading system because signs and symptoms representing a broad range of TIPN severity each fall within the same low-scoring category and very few patients receive the highest score.
To illustrate another grading scale limitation, consider how several different oncology providers might define moderate, severe, and life-threatening neuropathy. Because no operational definitions are provided for the various grades, each provider may define these grades differently, leading to lack of consistency and poor reliability across providers.
Based on these examples, it is easy to see why grading scales are problematic. However, grading scale use is deeply embedded within clinical and research practice. Mounting evidence supports the stance that grading scales should no longer be used or, at the very least, should be used alongside other patient-reported outcome measures (Atkinson et al., 2011; Basch et al., 2009; Kuroi et al., 2009; Shimozuma et al., 2009; Sloan et al., 2007). Shimozuma et al. (2009) compared several validated patient-reported outcome measure scores with provider-obtained NCI CTCAE scores and found that TIPN was consistently reported to be more prevalent and severe when quantified using patient-reported outcome measures. In another large cooperative group study in which 696 patients received oxaliplatin for colorectal cancer, neuropathy was quantified using both the NCI CTCAE and a patient-reported numeric rating scale (NRS) (Goldberg et al., 2004). In that study, neuropathy onset was detected several months sooner when the NRS was used versus the NCI CTCAE, allowing timelier oxaliplatin dose modifications (Morton et al., 2005; Sloan et al., 2007). This evidence supports the position that patient-reported outcome measures should be integrated into clinical trials because grading scales alone do not adequately quantify dose-limiting adverse events.
Table 2 provides a summary of selected TIPN measures that have been tested in patients receiving taxanes. In addition, two reviews (Cavaletti et al., 2010; Griffith et al., 2010) have summarized the available literature regarding the development of instruments to measure chemotherapy-induced peripheral neuropathy. Griffith et al. (2010) used a meticulous process to identify and evaluate published research and recommended two measures for future use: the FACT/GOG-Ntx (Calhoun et al., 2003) and a shortened version of the TNS (Chaudhry et al., 1994; Cornblath et al., 1999; Griffith et al., 2010; Lavoie Smith et al., 2011; Smith et al., 2010). Several advantages in routinely assessing TIPN using those two measures exist. First, the measures have undergone more extensive testing in patients with TIPN compared with other measures and have been shown to have strong psychometric properties. This combined subjective/objective measurement approach will enhance the understanding of TIPN prevalence and severity because subtle differences in TIPN will be more detectable and patients (not physicians or nurses) will have an opportunity to describe their symptoms and related functional limitations.
In addition to being reliable and valid, the FACT/GOG-Ntx and the shortened TNS instruments are relatively easy to use. The FACT/GOG-Ntx subscale consists of only 11 items and can be given to patients to complete while they wait to receive each taxane treatment. The form is written at a sixth-grade reading level and takes only a few minutes to complete (Calhoun et al., 2003). Table 3 provides information regarding the TNS scoring criteria (modified). Clinicians would likely need to keep these criteria nearby; however, this should not be a barrier to its use because many clinicians also need to frequently refer to the NCI CTCAE scoring criteria when grading neuropathy and a variety of other adverse events. The shortened TNS has been shown to be feasible for use by advanced practice nurses, and an ongoing study has demonstrated that staff nurses are capable of using the TNS when measuring vincristine-induced neuropathy in children with leukemia (Smith, Renbarger, et al., 2012). With the shortened version, a TNS-based assessment can be completed in about five minutes. Subjective numbness, tingling, and neuropathic pain scores are obtained by asking the patient to describe the distal to proximal extension of these symptoms. For example, a nurse would ask the patient whether his or her symptoms are present only in the toes or if they extend further up the foot to the ankle and beyond. More severe TIPN is associated with greater proximal extension of symptoms. Hand symptoms typically appear after feet symptoms have already developed because the upper extremity nerve fibers are more proximal to the spinal cord. One limitation of the TNS scoring criteria is that symptom severity cannot be adequately assessed. Therefore, use of a 0–10 NRS should be considered, particularly when assessing neuropathic pain severity (Lavoie Smith et al., 2009; Smith et al., 2008).
The most difficult aspect of performing the TNS-based assessment is learning how to obtain tendon reflex scores; however, if nurses need assistance, they can seek it from an experienced nurse practitioner or physician colleagues. Reflex assessment provides a measure of both motor and sensory function. The Achilles reflex should be tested first; if the reflex is diminished or absent, other reflexes should be assessed, such as patellar, brachioradialis, bicep, and tricep. However, if the Achilles reflex is normal, no additional reflex testing is needed. If asymmetrical findings are discovered (for any TNS item), the most severe finding is used for scoring.
Gaining competence in assessing vibration sensibility testing using a basic 128 Hz weighted tuning fork is not difficult, and nurses and patients seem to enjoy conducting and undergoing these assessments, respectively. The tuning fork should be firmly tapped on the palm of the hand to initiate vibration. The vibrating tuning fork is first placed on the interphalangeal joint of the great toe (see Figure 1A). The nurse places a finger under the patient’s toe to compare the patient’s vibration sensibility with the nurse’s (control). The nurse should feel the vibration through the patient’s toe for at least as long as the patient. The patient is instructed to report when vibration is no longer detected. If the patient feels the vibration longer than the nurse, this is defined as normal. If vibration sensation is normal at the great toe, it will be normal elsewhere (more proximally), and additional assessments are not needed. However, if vibration sensation is diminished or absent in the great toe, the nurse then conducts the testing at the middorsal foot and medial malleolus (ankle) areas (see Figures 1B and 1C), followed by the midfibular and patellar regions (see Figures 1D and 1E). Upper extremity vibration sensibility is first tested at the distal interphalangeal joint of the index finger (see Figure 2A) and then the ulnar styloid (wrist) (see Figure 2B) and lateral epicondyle (elbow) (see Figure 2C). Once the patient is no longer able to sense vibration, the nurse determines whether vibration was still detectable by quickly moving the tuning fork to his or her own ankle, knee, or wrist. However, one limitation is that nurses with impaired vibration sensation are less able to obtain valid scores. An alternative approach is to record how long (in seconds) the patient feels the vibration. Feeling the vibration for about 15 seconds is considered to be normal for all testing locations except for the patella (10 seconds) and index finger (25 seconds) (Ohsumi & Sunada, 2004). Variability will exist based on how hard the tuning fork is tapped. A specialized tuning fork (Rydel-Seiffer) is available to facilitate vibration assessment, but these generally are not available in oncology clinical settings (Pestronk et al., 2004). Although this low-tech approach to vibration assessment is imperfect, it has been shown to be reliable, valid, and more sensitive to change over time than grading scale scoring (Lavoie Smith et al., 2011; Smith, Renbarger, et al., 2012).
Treating Taxane-Induced Peripheral Neuropathy
Despite escalating attempts to find effective treatments for TIPN, little progress has been made (Pachman, Barton, Watson, & Loprinzi, 2011; Visovsky, Collins, Abbott, Aschenbrenner, & Hart, 2007; Wolf, Barton, Kottschade, Grothey, & Loprinzi, 2008). Ineffective drugs for treating TIPN include amitriptyline (Kautio et al., 2009), gabapentin (Rao et al., 2007), and lamotrigine (Rao et al., 2008). Barton et al. (2011) tested the efficacy of topical baclofen, amitriptyline, and ketamine (BAK) gel. The researchers reported that BAK was only marginally effective, possibly because of subtherapeutic dosing. One phase III trial testing the efficacy of acetyl-L-carnitine revealed unexpected findings in that the drug worsened TIPN symptoms compared with placebo (Hershman et al., 2012). Positive findings came from a large, phase III placebo-controlled study conducted by the Cancer and Leukemia Group B, which demonstrated that oral duloxetine 60 mg daily was effective in diminishing taxane-related painful neuropathy (Smith, Pang, et al., 2012). With only one positive phase III trial to date, continued research examining new interventions to prevent or diminish TIPN is needed.
Nurses can play a role in diminishing some of the negative consequences of TIPN by educating patients on the importance of reporting symptoms. By encouraging patients to report their symptoms and taking a more active role in TIPN assessment, nurses can help ensure that taxane treatment is modified sooner. Impaired foot and hand sensation places patients at increased risk for mechanical or thermal injury. Nurses should counsel patients regarding strategies to minimize injury risk. Such strategies include turning down the temperature settings on home water heaters, using gloves when washing dishes or gardening, and always wearing shoes with soles, particularly when outdoors. Tofthagen, Overcash, and Kip (2012) reported that patients receiving taxanes may be more likely to fall than those receiving platinums, and that a higher cumulative chemotherapy dose, impaired balance, muscle weakness, more severe TIPN symptoms, and impaired walking and driving ability are predictive of increased fall risk. Nurses should advise patients who are at high risk for tripping or falling to remove clutter and scatter rugs in their homes. Because patients with TIPN need to rely more heavily on visual clues when monitoring the location of their feet on the ground, patients should avoid walking in poorly lighted areas. A referral to an occupational or physical therapist may be necessary in cases of severely impaired balance, foot drop, or extremity weakness. Adaptive equipment, such as large-handled eating utensils, foot braces, walkers, or canes can be helpful to optimize functional capacity and safety. In addition, muscle-strengthening exercises may help to minimize weakness. Patients with severely impaired plantar foot sensation or foot drop should be advised not to drive. Lastly, because orthostatic hypotension can occur because of autonomic neuropathy, nurses should teach patients to change positions slowly so as to avoid syncopal episodes.
Studies are beginning to suggest that taxane neurotoxicity may be directly related to individual variations in neurotoxic drug metabolism, distribution, and elimination; however, the results, to date, are inconclusive (Bergmann et al., 2011; Sissung et al., 2006). Three large studies have identified genetic polymorphisms associated with TIPN (Hertz et al., 2012; Kroetz et al., 2010; Schneider et al., 2011). If detection of genetic predictors becomes the standard of care, this could lead to a significant paradigm shift in how TIPN is managed. Patients determined to be at high risk via a genetic test performed prior to receiving taxane therapy might be offered alternative treatments or altered dosing schedules. As one example, it may be possible to individualize taxane dosing so that those with genetic polymorphisms leading to more efficient taxane metabolism would receive higher doses, whereas slow metabolizers would receive lower doses. That approach could ultimately result in improved taxane efficacy while minimizing severe and disabling peripheral neuropathy for long-term cancer survivors.
TIPN is an underrecognized problem that significantly compromises quality of life for patients with breast cancer. TIPN is underrecognized because of continued reliance on suboptimal assessment approaches. Emerging empirical evidence suggests that more reliable, valid, sensitive, and clinically feasible TIPN measurement approaches should be used to quantify TIPN in clinical and research settings. However, implementing practice change based on this evidence continues to be challenging. This article provides practical suggestions for how nurses can take the lead in improving TIPN measurement practices. In addition, the search must continue for effective interventions that will ameliorate or even prevent distressing and disabling TIPN symptoms for breast cancer survivors receiving taxane therapy.
Implications for Practice
Ø Taxane-induced peripheral neuropathy should be quantified by determination of the distal to proximal extension of numbness, tingling, and neuropathic pain, as well as vibration sensibility and tendon reflexes.
Ø Neuropathic pain severity should be assessed using a 0–10 numeric rating scale.
Ø Validated assessment tools should be administered to patients prior to each taxane treatment.
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Ellen M. Lavoie Smith, PhD, ANP-BC, AOCN®, is an assistant professor in the School of Nursing at the University of Michigan in Ann Arbor. The author received editorial support from Christopher Carter, PhD, of MediTech Media, which was funded by Celgene Corporation. The author is fully responsible for the content of and editorial decisions about this article and received no honorarium for its development. Celgene Corporation provided funding for the publication of this article and provided a medical accuracy review of content for author consideration. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers or editorial staff. Mention of specific products and opinions related to those products do not indicate or imply endorsement by the Clinical Journal of Oncology Nursing or the Oncology Nursing Society. Lavoie Smith can be reached at email@example.com, with copy to editor at CJONEditor@ons.org. (First submission October 2012. Revision submitted November 2012. Accepted for publication November 16, 2012.)