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Electrophysiological Features of Taxane-Induced Polyneuropathy in Patients With Breast Cancer
Abstract
Fifty-five patients with breast cancer were analyzed for electrophysiological characteristics of taxane-induced polyneuropathy. Based on the electrodiagnostic criteria, sensory motor polyneuropathy was found in 67% (37/55) of patients ranging between mild degree and moderate to severe degree. The polyneuropathy is predominantly axonal with three unique features: (1) frequent asymmetry, (2) high sural and radial sensory amplitude ratio in patients with mild polyneuropathy, and (3) slow conduction velocity seen only at the common entrapment sites, such as the carpal tunnel. The severity of polyneuropathy correlated positively with the cumulative dose received. Our study supports the clinical utility of electrodiagnostic study in both diagnosis and monitoring of taxane-induced polyneuropathy.
... The relationship between different assessments was determined using Pearson's correlations. Wilcoxon signed rank test was used to determine difference between digit 2 and digit 5 in mechanical detection thresholds for each patient with the most affected limb being utilized for analysis (Bland, 2000;England et al., 2005;Chen et al., 2013). Differences between patients with and without median and sural nerve abnormalities were analyzed using Mann-Whitney U tests, with Chi-square tests of independence being performed to examine the relationship with patient reported neuropathy symptoms. ...
... A retrospective analysis of NCS from taxane-treated patients referred for severe neuropathy revealed similar median nerve abnormalities (Chen et al., 2013). The authors suggested that electrodiagnostic features indicative of median nerve abnormalities might reflect a mononeuropathy that may manifest with taxane treatment. ...
Objective
To comprehensively describe patient-reported, functional and neurophysiological outcomes to elucidate the phenotypic profile of taxane-induced neuropathy.
Methods
Taxane-treated patients (n=47) completed cross-sectional bilateral clinical and sensory assessments and nerve conduction studies. Patients reported symptom severity via Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-
Neurotoxicity (FACT/GOG-Ntx13) questionnaire.
Results
Symptoms of neuropathy were reported by 81% of patients. On clinical examination, 62% had 2 or more abnormalities, with 20% indicating significant symptomatic and objective neuropathy. Nerve conduction studies were consistent with a sensory predominant axonal neuropathy. However, features more typical of entrapment neuropathy were also present in >50%, which were not associated with overall severity of chemotherapy-induced peripheral neuropathy (CIPN) or clinical risk factors.
Conclusions
There is considerable variation in CIPN phenotypes associated with taxane-treatment. Understanding their clinical associations may assist in identification of patients at risk of severe neurotoxicity. This would enable treatment modification decisions but also limit early cessation of effective anti-cancer treatment in patients with less severe neurological sequelae.
Significance
Understanding the CIPN phenotype may inform treatment decisions which could impact clinical and survival outcomes.
... 8,9 Nerve conduction studies (NCSs) are insensitive to small fiber changes; typical findings include mild conduction velocity slowing at sites of entrapment or reduction of sural sensory responses. [10][11][12] Skin biopsy for measuring intraepidermal nerve fiber density (IENFD) is the gold standard for the diagnosis of sensory-predominant small fiber neuropathy but is not an ideal test due to its invasive nature. 3,6 Studies have found that neuromuscular ultrasound (NMUS) can detect peripheral nerve lesions generally with enlargement of CSA in patients with demyelinating hereditary, 13,14 inflammatory, 15,16 entrapment, 17 and diabetic neuropathies 18 though reduction of CSA has also been reported (eg, amyotrophic lateral sclerosis [ALS], 19 spinocerebellar ataxia syndrome [20][21][22][23]. ...
... 36 These findings suggest that, at compression sites, CIPN may aggravate nerve entrapment and cause an increase in CSA of peripheral nerves. This discrepancy in the effects of CIPN between compression and noncompression anatomic sites has been described in NCS 11 and was suggested in a prior study of oxaliplatin CIPN. 27 The finding of decreased peripheral nerve CSA is uncommon and has been reported in ALS 19 and spinocerebellar ataxia syndrome. ...
Introduction:
Our study aim was to evaluate NMUS for the assessment of taxane chemotherapy-induced peripheral neuropathy (CIPN), the dose-limiting toxicity of this agent.
Methods:
This cross-sectional study of breast cancer patients with taxane CIPN measured nerve cross-sectional area (CSA) by NMUS and compared to healthy historical controls. Correlations were determined between CSA and symptom scale, nerve conduction studies, and intraepidermal nerve fiber density (IENFD).
Results:
20 participants reported moderate CIPN symptoms at a median of 3.8 months following last taxane dose. Sural nerve CSA was 1.2 mm2 smaller than healthy controls (p<0.01). Older age and time since taxane were associated with smaller sural nerve CSA. For each 1 mm2 decrease in sural nerve CSA, distal IENFD decreased by 2.1 nerve/mm (R2 0.30, p=0.04).
Discussion:
These data support a sensory predominant taxane neuropathy or neuronopathy and warrant future research on longitudinal NMUS assessment of CIPN. This article is protected by copyright. All rights reserved.
... The neuropathy severity was graded according to the previously published electrodiagnostic criteria for evaluation of chemotherapy-induced polyneuropathy at our institution (Chen et al., 2013): no neuropathy when sural SNAP and other parameters are normal; mild when sural SNAP is less than 10 lV but present; moderate when sural SNAP is absent and SNAPs in upper extremities are also affected; and severe when radial SNAP is abnormal or absent and all the lower extremity CMAPs and SNAPs are absent. ...
... For these reasons, it is important that consulting neurologists can recognize these syndromes early and provide the best management for these complications. As demyelination polyneuropathy is not the typical presentation of chemotherapy-induced polyneuropathy (Chen et al., 2013), our result suggests that electrophysiological evidence of acute demyelination in addition to clinical evidence for other autoimmune disorders including myositis and myasthenia gravis might have a high predictive value for ICIrelated neuropathy in cancer patients. ...
Objective:
To report the electrodiagnostic features of immune checkpoint inhibitor (ICI)-related neuropathy.
Methods:
We retrospectively reviewed clinical presentations and electrodiagnostic features of 23 patients studied after receiving immune checkpoint inhibitors (ICIs). The presentations for electrodiagnostic evaluation included an acute neuropathy or neuromuscular junction disorder. We applied established electrodiagnostic criteria for polyneuropathy and acute demyelinating neuropathy.
Results:
We identified acute demyelinating neuropathy (13 cases), axonal sensory motor neuropathy (5), pure sensory neuropathy (4) and mononeuropathy (1). 13 patients had acute demyelinating neuropathy confirmed by demonstrating demyelination in 2 or more nerves; 3 additional patients had demyelination in only one nerve. Analysis of motor nerve conduction parameters revealed demyelination involving median and ulnar nerve distal motor latencies as well as median, ulnar and peroneal nerve conduction velocities. Conduction block was found in median, ulnar and peroneal nerves. The remaining one-third patients without demyelination had acute painful axonal neuropathy. Coexisting myopathic changes (6) and neuromuscular junction dysfunction (4) were also identified.
Conclusions:
Our findings suggest that, while immune-mediated motor nerve demyelination is the primary underlying mechanism of ICI-related neuropathy, axonal painful neuropathy can also be an important presentation. Early recognition and effective intervention may reduce morbidity and permanent disability.
Significance:
Electrophysiological studies might be useful in the evaluation of ICI-related neuropathy.
... In the present study, the clinical examination revealing progressive distal symmetrical sensory symptoms with predominant hypoesthesia and NCS yielding a decrease mainly in SNAPs and less pronounced in CMAPs with preserved NCVs and F-wave latencies are compatible with a predominantly sensory, length-dependent axonal character of TIPN[27]. Slight CSA enlargements in distal nerves and at compression sites combined with a constant INV in HRUS can be interpreted as typical signs ...
Background and purpose
The role of high‐resolution nerve ultrasound (HRUS) and corneal confocal microscopy (CCM) in the early detection of taxane‐induced polyneuropathy (TIPN) is unclear. The present prospective longitudinal controlled observational pilot study estimates the role of HRUS and CCM in the early diagnosis of TIPN in breast cancer patients.
Methods
Fifteen breast cancer patients receiving paclitaxel and 15 healthy age matched controls were included. Visits before and 3 weeks, 8 weeks and 6 months after treatment included clinical examination, the total neuropathy score, nerve conduction studies (NCS), monocular CCM including corneal nerve fibre length, density and branching and HRUS of bilateral median, ulnar, radial, tibial, peroneal and sural nerves. Patients were compared between different visits and to healthy controls.
Results
Total neuropathy score increased from 2.2 at baseline to 5.8 ( p < 0.001) at week 8. NCS showed a decreased sensory amplitude in the sural, radial, ulnar and median nerve after 6 months ( p < 0.001). HRUS revealed a significant increase of cross‐sectional area in the sural nerve ( p = 0.004), the median nerve ( p = 0.003) at the carpal tunnel and the ulnar nerve in the forearm ( p = 0.006) after 6 months. CCM showed no changes at different visits.
Conclusions
Corneal confocal microscopy and HRUS do not detect early signs of TIPN during the paclitaxel treatment period. HRUS and NCS might detect congruent signs of an axonal, predominantly sensory polyneuropathy after 6 months. The clinical examination remains the most sensitive tool in the early detection of TIPN in breast cancer patients.
... However, the median values of SRAR were higher than the suggested LLN (0.21) in our cohorts and tended to increase from baseline to the end of chemotherapy, indicating that the nerves in the upper limbs may be more susceptible to neurotoxic agents during chemotherapy. Therefore, SRAR is not a well-suited indicator for evaluating CIPN (Chen et al., 2013). Moreover, the diagnostic criterion for diabetic neuropathy that "sural nerve must be abnormal" (Dyck et al., ...
Purpose
Nerve conduction studies (NCS) have been suggested as gold standard for diagnosing and monitoring peripheral neuropathies. However, its value in measuring chemotherapy-induced peripheral neuropathy (CIPN) is not clearly understood. Our study aimed to examine the role and performance of NCS in CIPN assessment through a secondary analysis.
Methods
Pooled data pertaining to NCS, clinical examination, symptoms, and quality of life from patients with cancer enrolled in five studies were used. These patients had received taxane- or oxaliplatin-based chemotherapy. The data were grouped in cohorts of before initiation of chemotherapy, during chemotherapy, at the end of chemotherapy, and at recovery stage according to the time points of assessment in the original studies.
Results
Data was available from a total of 84 patients (74 females and 10 males) and a total of 160 NCS assessments. NCS results confirmed that damage of sensory nerves is more profound than motor nerves in patients at different stages of neurotoxic chemotherapy. No strong correlation was identified between NCS parameters and clinical examination outcomes as well as patient-reported symptoms and quality of life. NCS did not perform well in discriminating clinically relevant CIPN (area under the curve [AUC] = 0.51–0.77).
Conclusions
Our findings suggest that NCS may have limited value in diagnosing CIPN. Future prospective studies with baseline values are needed to clarify our tentative conclusions.
... Slowing seems to be a consequence of axonal degeneration rather than primary demyelinating neuropathy. Despite decreased CMAPs, the absence of significant prolongation in distal latencies also suggested primarily axonal involvement of the peripheral nerves, corroborating the predominantly axonal involvement reported in previous studies [30][31][32][33]. Treatment with platinum-based compounds resulted in a greater decrease in motor ulnar and tibial nerve CMAPs in comparison to taxanebased chemotherapy regimens; this finding has not been reported by other studies involving treatment with both options in their cohort [26,28,30]. ...
Background
Chemotherapy-induced peripheral neuropathy (CIPN) is most commonly associated with platinum-based drugs, taxanes, and vinca alkaloids. This prospective study from a single center in Kosovo aimed to evaluate CIPN in 120 patients receiving 4–6 cycles of platinum-based and taxane-based chemotherapy.
Material/Methods
One hundred twenty patients underwent neurological examination and nerve conduction studies (NCS) before chemotherapy, and after 4 to 6 cycles of treatment. Sixty patients were treated with platinum-based chemotherapy, 30 were treated with taxane-based chemotherapy, and 22 patients received a combination of platinum- and taxane-based chemotherapy. The most commonly used platinum-based compounds were oxaliplatin and carboplatin, whereas the most commonly used taxane medications were paclitaxel and docetaxel. Presence of neuropathy was confirmed with neurological examination of electrophysiological criteria applicable for polyneuropathies. Total Neuropathy Score (TNSr) was used to combine clinical and electrophysiological values.
Results
Around 90% of patients self-reported neuropathic symptoms, and in 60% of them polyneuropathy was present in NCS. All sensory and motor nerves had significantly lower amplitudes (P<0.01). Platinum-based agents caused more pronounced decrease in ulnar nerve compound motor action potential (CMAP) (P<0.05); when used solely or in combination with taxanes, they caused significant decrease in tibial nerve CMAP (P<0.01). TNSr did not reach statistical significance between groups; only clinical muscle strength showed pronounced weakness in the combined protocol (P<0.05).
Conclusions
These findings support previous studies and show that CIPN, including sensory and motor symptoms, is commonly associated with chemotherapy. Platinum-based chemotherapy agents were more commonly associated with ulnar and tibial nerve damage in this study population.
... However, in some cases, NCS does not travel parallel to the clinical course and may not change later in the course of treatment [98]. Furthermore, some clinical symptoms (particularly pain) may be seen without abnormalities in NCS [99]. Other literature data, conversely, reported a significant compound sensory nerve action potential amplitude reduction developing prior to clinical symptoms [100]. ...
Peripheral neuropathy is a well described complication in children with cancer. Oncologists are generally well aware of the toxicity of the main agents, but fear the side effects of new drugs. As chemotherapeutic agents have been correlated with the activation of the immune system such as in Chemotherapy Induced Peripheral Neuropathy (CIPN), an abnormal response can lead to Autoimmune Peripheral Neuropathy (APN). Although less frequent but more severe, Radiation Induced Peripheral Neuropathy may be related to irreversible peripheral nervous system (PNS). Pediatric cancer patients also have a higher risk of entering a Pediatric Intensive Care Unit for complications related to therapy and disease. Injury to peripheral nerves is cumulative, and frequently, the additional stress of a malignancy and its therapy can unmask a subclinical neuropathy. Emerging risk factors for CIPN include treatment factors such as dose, duration and concurrent medication along with patient factors, namely age and inherited susceptibilities. The recent identification of individual genetic variations has advanced the understanding of physiopathological mechanisms and may direct future treatment approaches. More research is needed on pharmacological agents for the prevention or treatment of the condition as well as rehabilitation interventions, in order to allow for the simultaneous delivery of optimal cancer therapy and the mitigation of toxicity associated with pain and functional impairment. The aim of this paper is to review literature data regarding PNS complications in non-primary pediatric cancer.
... There are data supporting that nerve conduction studies in asymptomatic patients who are receiving neurotoxic chemotherapy can predict the development or worsening of chemotherapy-induced peripheral neuropathy (CIPN). [8][9][10] These tests, however, are not routinely used. ...
PURPOSE
To update the ASCO guideline on the recommended prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy (CIPN) in adult cancer survivors.
METHODS
An Expert Panel conducted targeted systematic literature reviews to identify new studies.
RESULTS
The search strategy identified 257 new references, which led to a full-text review of 87 manuscripts. A total of 3 systematic reviews, 2 with meta-analyses, and 28 primary trials for prevention of CIPN in addition to 14 primary trials related to treatment of established CIPN, are included in this update.
RECOMMENDATIONS
The identified data reconfirmed that no agents are recommended for the prevention of CIPN. The use of acetyl-l-carnitine for the prevention of CIPN in patients with cancer should be discouraged. Furthermore, clinicians should assess the appropriateness of dose delaying, dose reduction, substitutions, or stopping chemotherapy in patients who develop intolerable neuropathy and/or functional impairment. Duloxetine is the only agent that has appropriate evidence to support its use for patients with established painful CIPN. Nonetheless, the amount of benefit from duloxetine is limited. Additional information is available at www.asco.org/survivorship-guidelines .
... 9 The surgical procedures may cause an accessory spinal nerve injury, with a consequent shoulder dysfunction, especially in the upper limb abduction movement. 10 In cancer patients, sensory and motor impairments were observed, which affect the nerve impulse conduction velocity, 11 resulting in loss of muscle strength. 12 Thus, these conditions may compromise the shoulder ability to perform daily life activities, especially caused by the decline of the middle deltoid muscle force, which has increased its activation in the first 90°of shoulder abduction. ...
Objective:
To compare the strength of the middle deltoid muscle by means of dynamometry and the Shoulder Pain and Disability Index (SPADI) in participants in treatment for cancer after the practice of an exergaming protocol.
Materials and Methods:
We conducted a randomized controlled clinical trial. Thirty-eight voluntary participants were divided into two groups: cancer group (n = 19; age = 61.46 ± 8.79 years; body mass index [BMI] = 28.36 ± 4.94 kg/m3) and control group (n = 19; age = 57.62 ± 7.57 years; BMI = 28.06 ± 3.74 kg/m3), and they participated in the study. All participants performed an exergame protocol by using Xbox 360 Kinect® (Microsoft, Redmond) with the game Your Shape Fitness Evolved 2012 two to three times per week for 20 sessions. They were evaluated through the isometric dynamometer in the middle deltoid muscle and the SPADI at three moments: preintervention (EV1), after 10 sessions (EV2), and after 20 sessions (EV3).
Results:
The cancer group scored higher on both the disability index, in all three evaluations, and the pain index, in EV2 and EV3, when compared with the control group. There was a significant reduction in the disability score in EV2 and EV3 when compared with EV1 in the cancer group, whereas pain was lower in EV2 and EV3 when compared with EV1 in the control group. There were no significant interevaluation or intergroup differences in the maximal isometric voluntary contraction of the deltoid muscle of both upper limbs.
Conclusion:
At the end of the exergaming, protocol reduced the disability of the shoulder joint of the cancer group and decreased the differences between the groups for disability and pain scores, without changing isometric force.
... However, objective evidence of asymmetry was not identified in clinical or neurophysiological assessments in those reporting asymmetrical side-to-side symptoms. Asymmetric NCS responses have previously been observed in taxane-treated patients [25]. ...
Purpose:
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side-effect of neurotoxic cancer treatment impacting on long-term quality of life. Symptoms include numbness, tingling, and pain, affecting the distal extremities. However, patients often report symptoms discrepant from the expected symmetrical distribution and the degree of concurrence with objective assessment remains ill-defined. This study aimed to investigate severity and symmetry of neuropathy symptoms to enable comparison of objective measures and patient report.
Methods:
Forty-five taxane-treated patients (F = 43, 66 ± 1.5 years, 19 months post-treatment) completed bilateral neuropathy assessments via clinical examination, sensory nerve conduction studies (NCS), and patient questionnaires. The laterality index (LI) was calculated as a ratio of smaller to larger side-to-side differences.
Results:
Neuropathy was reported by 89% of the cohort. On clinical examination, 83% had ≥ 2 abnormalities, with 38-35% having upper or lower limb sensory amplitudes below normative range. Thirty-five percent indicated side-to-side symptom asymmetry; however, there was no significant asymmetry evident on clinical examination (LI Asym = .60 ± .10, Sym = .76 ± .05, NS) and no difference in side-to-side NCS (median LI:Asym = .69 ± .06, Sym = .81 ± .04, NS; Sural LI:Asym = .80 ± .04, Sym = .81 ± .04, NS). Accordingly, there was no statistical association between patient-reported and objective assessment of side-to-side asymmetry, suggesting discordance between patient experience and objective assessment. Similarly, discrepancies in symptom severity between hands and feet were reported by 32% of the cohort. However, patients reporting differences in symptom severity between the hands and feet were just as likely to present with comparable assessments as to demonstrate objective discrepancies.
Conclusions:
Discrepancies may exist between the patient experience of CIPN and objective assessments. Understanding these discrepancies may help to elucidate underlying mechanisms and better inform treatment strategies.
... If confirmed at individual level, this gap could warrant a specific neuroprotective approach, whenever available. The involvement of motor nerves in TIN is a matter of debate [3,12]. In the present study, the peroneal nerve was the only trunk nerve to be involved (T2). ...
Objective:
Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling complication related to taxanes. Underlying mechanisms are not completely understood and no specific treatment exists. We investigated the role of nerve conduction studies (NCS) and of serum osteopontin (OPN) measurement as a means to stratify the risk of developing taxane-induced neuropathy (TIN).
Methods:
We enrolled 50 women with breast cancer treated with taxanes (docetaxel or paclitaxel) in a 3-month prospective study. They were evaluated before chemotherapy (time-point T0) and followed up at 1 (T1) and 3 (T2) months with clinical examinations/scales, quality of life (QoL) questionnaires, NCS, and serum OPN dosages.
Results:
A reduction of sural and superficial peroneal sensory action potentials was seen at T1, with a progression at T2 (P<0.001). In contrast, a significant impact of neuropathic symptoms on QoL only occurred at T2 (P<0.01). OPN levels at T0 inversely correlated to axonal loss in the sural nerve (T0-T2, P<0.01). OPN levels at T0 were lower in the intermediate and poor outcome patient subgroups, compared to the good outcome subgroup, as specifically defined (P<0.05).
Conclusion:
Lower limb NCS changes occurred earlier than the detrimental effects of TIN on patients' QoL. Low serum OPN levels before chemotherapy may represent a novel biomarker of TIN risk.
... 16 Corresponding to the two main pathogenic mechanisms above, NCS findings in CIPN reveal either a sensory neuronopathy affecting DRGs with a diffuse amplitude decrease or abolishment of sensory action potential (SAP) and normal sensory conduction velocities, or a length-dependent distal, dying-back, axonal degeneration with a reduction of SAP amplitudes in a distal predominant pattern starting in the legs and then involving the arms. Neuronopathy is primarily seen in cisplatin, 17 oxaliplatin 18 19 and cisplatin plus paclitaxel combination-treated patients, 20 while a length-dependent axonal sensory neuropathy is the characteristic neurophysiological pattern in taxane, 21 bortezomib, 22 thalidomide 23 and vincristine-exposed patients. 24 Abnormal SAP have been reported in patients treated with these drugs prior to the symptoms onset, particularly in haematological malignancies, suggesting that they may represent preclinical markers of CIPN. 25 Primary demyelination with evidence of slowing of motor conduction velocities or F-waves abnormalities is occasionally seen. ...
... 16 Corresponding to the two main pathogenic mechanisms above, NCS findings in CIPN reveal either a sensory neuronopathy affecting DRGs with a diffuse amplitude decrease or abolishment of sensory action potential (SAP) and normal sensory conduction velocities, or a length-dependent distal, dying-back, axonal degeneration with a reduction of SAP amplitudes in a distal predominant pattern starting in the legs and then involving the arms. Neuronopathy is primarily seen in cisplatin, 17 oxaliplatin 18 19 and cisplatin plus paclitaxel combination-treated patients, 20 while a length-dependent axonal sensory neuropathy is the characteristic neurophysiological pattern in taxane, 21 bortezomib, 22 thalidomide 23 and vincristine-exposed patients. 24 Abnormal SAP have been reported in patients treated with these drugs prior to the symptoms onset, particularly in haematological malignancies, suggesting that they may represent preclinical markers of CIPN. 25 Primary demyelination with evidence of slowing of motor conduction velocities or F-waves abnormalities is occasionally seen. ...
Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common dose-limiting side effect of several anticancer medications. CIPN may involve multiple areas of the peripheral nervous system from the autonomic and dorsal root ganglia (DRG) to the axon and any peripheral nerve fibre type. Large diameter sensory myelinated (Aβ) fibres are more frequently involved, but motor, small myelinated (Aδ), unmyelinated (C) or autonomic fibres may also be affected. Here, we review the current evidence on techniques for the CIPN assessment in the clinical and experimental settings. Nerve conduction studies (NCS) may be used at the subclinical and early CIPN stage, to assess the extent of large nerve fibre damage and to monitor long-term outcomes, with the sural or dorsal sural nerve as the most informative. The quantitative sensory neurological examination provides valuable data alongside NCS. Quantitative sensory testing and nerve excitability studies add information regarding pathophysiology. Nerve MRI and ultrasound may provide information on enlarged nerve, increased nerve signal intensity and DRG or spinal cord changes. Skin biopsy, corneal confocal microscopy, laser-evoked potentials, contact heat-related potentials and microneurography may reveal the extent of damage to small unmyelinated nerve fibres that go undetected by NCS. The information on the role of these latter techniques is preliminary. Hence, the use of multimodal testing is recommended as the optimal CIPN assessment strategy, employing objective NCS and other specialised techniques together with subjective patient-reported outcome measures.
... Myelinated and unmyelinated sensory fibers are predominately damaged by chemotherapeutic agents including vinca alkaloids, platinum-based compounds, and taxanes such as paclitaxel in patients [50,51] and rodents [43,46,52,53]. Reduction of NCV has been reported in paclitaxel-treated patients which suggested the occurrence of peripheral nerve demyelination [54][55][56]. We first quantify the diameter of myelinated axons in toluidine bluestained semi-thin cross sections of sciatic nerves 1 month after paclitaxel treatment (Fig. 4a). ...
Chemotherapy-induced peripheral neuropathy (CIPN) is an irreversible off-target adverse effect of many chemotherapeutic agents such as paclitaxel, yet its mechanism is poorly understood and no preventative measure is available. CIPN is characterized by peripheral nerve damages resulting in permanent sensory function deficits. Our recent unbiased genome-wide analysis revealed that heat shock protein (Hsp) 27 is part of a transcriptional network induced by axonal injury and highly enriched for genes involved in adaptive neuronal responses, particularly axonal regeneration. To examine if Hsp27 could prevent the occurrence of CIPN, we first demonstrated that paclitaxel-induced allodynia was associated directly with axonal degeneration in sensory neurons in a mouse model of CIPN. We therefore hypothesize that by preventing axonal degeneration could prevent the development of CIPN. We drove expression of human Hsp27 (hHsp27) specifically in neurons. Development of mechanical and thermal allodynia was prevented completely in paclitaxel-treated hHsp27 transgenic mice. Strikingly, hHsp27 protected against paclitaxel-induced neurotoxicity in vivo including degeneration of afferent nerve fibers, demyelination, mitochondrial swelling, apoptosis, and restored sensory nerve action potential. Finally, we delineated signaling cascades that link CIPN development to caspase 3 and RhoA/cofilin activation in sensory neurons and peripheral nerves. hHsp27 exerted anti-apoptotic effect and maintained axon integrity by restoring caspase 3 and RhoA expression to basal levels. Taken together, our data suggest that by preventing axonal degeneration might prove beneficial as anti-CIPN drugs, which represents an emerging research area for therapeutic development.
... Using our diagnostic criteria, 80% of the patients in the oxaliplatin group and 28% in the docetaxel group had polyneuropathy defined by NCSs, with the neuropathy being mainly an axonal sensory polyneuropathy consistent with other studies [5,22,42]. We used a conventional surface electrode technique including examination of distal nerves, but it is possible that using the nearnerve technique would have increased the number of patients with neurophysiologically defined polyneuropathy [43]. ...
Objective:
To determine symptoms and characteristics of chronic sensory neuropathy in patients treated with oxaliplatin and docetaxel, including patterns of somatosensory abnormalities, pain descriptors, and psychological functioning.
Design:
A retrospective cross-sectional study.
Setting:
A chronic pain research center.
Subjects:
Thirty-eight patients with chronic peripheral pain and/or dysesthesia following chemotherapy.
Methods:
Sensory profiles, psychological functioning, and quality of life were assessed using standardized questionnaires. In addition, standardized quantitative sensory testing and nerve conduction studies were carried out.
Results:
The sensory profiles and clinical symptoms were very similar in the two groups. Pricking, numbness, and burning were common descriptors in both groups, and the predominant finding was sensory loss to A beta-mediated sensory modalities with decreased mechanical and vibration detection thresholds. A high frequency of abnormalities in thermal sensory limen and the presence of paradoxical heat sensation seem to be sensitive markers of small fiber loss. Both groups had mainly sensory, axonal large fiber or mixed fiber polyneuropathy, which tended to be most severe in the oxaliplatin group.
Conclusions:
Both oxaliplatin-induced and docetaxel-induced polyneuropathies represent a significant problem that affects the daily life of the patients. Our results, defining the somatosensory phenotype, can improve the understanding of the pathophysiological mechanisms useful for future studies in the tailored treatment of prevention of chemotherapy-induced peripheral neuropathy and pain.
... Prolonged Hreflex latency and its correlation to sensory symptoms have been reported in conjunction with other types of neuropathy (Bertelsmann et al., 1986;Guo et al., 2014;Marya et al., 1986;Millán-Guerrero et al., 2012). There is evidence that decelerated nerve conduction velocity preferentially represents demyelinating lesions (Chen et al., 2013) and may lead to a delayed response to a postural task, i.e. postural instability. In our study, this may be represented by the PATs augmented COP sway path. ...
Balance impairment is associated with neuromuscular dysfunction in breast cancer patients with chemotherapy-induced peripheral neuropathy
Ritzmann Ramona1, Kneis Sarah1,2, Wehrle Anja1,3, Freyler Kathrin1, Lehmann Katrin1, Rudolphi Britta4, Hildenbrand Bernd4, Bartsch Hans Helge4, Bertz Hartmut2, Gollhofer Albert1
1Institute of Sport and Sport Science, University of Freiburg, Germany
2Department Medicine I, Haematology, Oncology and Stem Cell Transplantation, University
Medical Centre Freiburg, Germany
3Department of Exercise Medicine and Sport, University Medical Centre Freiburg, Germany
4Tumor Biology Centre Freiburg, Germany
HISTORY: A clinically relevant side-effect of chemotherapy in cancer treatment is peripheral neuropathy. Peripheral neuropathy causes balance and gait problems limiting the patient’s daily life. The neuromuscular mechanisms underlying these impairments are poorly understood.
PHYSICAL EXAMINATION: This study aimed to assess balance performance of patients with chemotherapy-induced peripheral neuropathy (CIPN) vs. healthy controls (CON) and to determine differences in the underlying neuromuscular mechanisms.
DIFFERENTIAL DIAGNOSIS: 20 breast cancer patients with CIPN (PAT) were compared to 16 matched CON: in a cross-sectional study design, center of pressure displacement (COP) and electromyographic (EMG) activity of M. tibialis anterior (TA), soleus (SOL), gastrocnemius (GM), rectus femoris (RF) and biceps femoris (BF) were recorded in a single leg balance task. Co-contraction index (CCI) of TA/SOL, TA/GM and RF/BF was calculated. To evaluate changes in the excitability of spinal reflex circuitry SOL H-reflexes were elicited.
TEST AND RESULTS: In PAT, COP displacement was greater than in CON (+12%, p=0.013) and correlated significantly with an increased level of CCI for TA/SOL (+ +33%, p=0.047). Moreover, PAT revealed a prolonged H-reflex latency (+5%, p=0.021) and a decreased H-reflex sensitivity (-71%, p=0.001).
FINAL WORKING DIAGNOSIS: CIPN is associated with decreased spinal excitability, prolonged nerve conduction velocity and impaired ability to modulate spinal reflex activity, resulting in an extensively diminished ability to keep postural equilibrium. As a consequence, to compensate for the neuromuscular degradation and secure postural stability, increased simultaneous antagonistic muscle activation is used.
TREATMENT AND OUTCOMES: To counteract these postural degradation sensorimotor training could serve as a training modality and thus should be considered when treating CIPN patients to improve their balance.
... In a study of 55 breast cancer patients with prior exposure to taxanes who were referred for electrodiagnostic studies for possible polyneuropathy based on their symptoms, only 67% had a large fiber polyneuropathy. The remaining 33% did not have electrophysiological evidence of polyneuropathy or showed only focal entrapment neuropathy (carpal tunnel) [11]. Thus, neurologic evaluation can clarify when symptoms are unrelated to CIPN, allowing full oncologic treatment to continue Usually the patient is referred to the neurologist only if the neuropathy symptoms persist for more than 6 months. ...
Chemotherapy-induced peripheral neuropathy (CIPN) is a common treatment-related side effect of several widely used drugs. Agents known to cause CIPN include platinum analogs, antitubulins, proteasome inhibitors, immunomodulatory agents, and some of the newer biologics. © 2016, UBM Medica Healthcare Publications. All rights reserved.
... Prolonged Hreflex latency and its correlation to sensory symptoms have been reported in conjunction with other types of neuropathy (Bertelsmann et al., 1986;Guo et al., 2014;Marya et al., 1986;Millán-Guerrero et al., 2012). There is evidence that decelerated nerve conduction velocity preferentially represents demyelinating lesions (Chen et al., 2013) and may lead to a delayed response to a postural task, i.e. postural instability. In our study, this may be represented by the PATs augmented COP sway path. ...
Objective:
Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment. Resulting sensory and motor dysfunctions often lead to functional impairments like gait or balance disorders. As the underlying neuromuscular mechanisms are not fully understood, we compared balance performance of CIPN patients with healthy controls (CON) to specify differences responsible for postural instability.
Methods:
20 breast cancer patients with CIPN (PAT) and 16 matched CONs were monitored regarding centre of pressure displacement (COP) and electromyographic activity of M. soleus, gastrocnemius, tibialis anterior, rectus femoris and biceps femoris. We calculated antagonistic co-contraction indices (CCI) and elicited soleus H-reflexes to evaluate changes in the elicitability and sensitivity of spinal reflex circuitry.
Results:
PAT's COP displacement was greater than CON's (p=.013) and correlated significantly with the level of CCIs and self-reported CIPN symptoms. PAT revealed prolonged H-wave latency (p=.021), decreased H-reflex elicitability (p=.001), and increased H-reflex sensitivity from bi- to monopedal stance (p=.004).
Conclusions:
We summarise that CIPN causes balance impairments and leads to changes in elicitability and sensitivity of spinal reflex circuitry associated with postural instability. We assume that increased simultaneous antagonistic muscle activation may be used as a safety strategy for joint stiffness to compensate for neuromuscular degradation.
Significance:
Sensorimotor training has the potential to influence neuromuscular mechanisms in order to improve balance performance. Therefore, this training modality should be evaluated as a possible treatment strategy for CIPN.
Enfortumab vedotin is a novel antibody–drug conjugate used as a third-line therapy for the treatment of urothelial cancer. We aimed to elucidate the effect of enfortumab vedotin-related peripheral neuropathy on its efficacy and whether enfortumab vedotin-induced early electrophysiological changes could be associated with peripheral neuropathy onset.
Our prospective multicenter cohort study enrolled 34 patients with prior platinum-containing chemotherapy and programmed cell death protein 1/ligand 1 inhibitor-resistant advanced urothelial carcinoma and received enfortumab vedotin. The best overall response, progression-free survival, overall survival, and safety were assessed. Nerve conduction studies were also performed in 11 patients.
The confirmed overall response rate and disease control rate were 52.9% and 73.5%, respectively. The median overall progression-free survival and overall survival were 6.9 and 13.5 months, respectively, during a median follow-up of 8.6 months. The patients with disease control had significantly longer treatment continuation and overall survival than did those with uncontrolled disease. Peripheral neuropathy occurred in 12.5% of the patients. The overall response and disease control rates were 83.3% and 100%, respectively: higher than those in patients without peripheral neuropathy (p = 0.028 and p = 0.029, respectively). Nerve conduction studies indicated that enfortumab vedotin reduced nerve conduction velocity more markedly in sensory nerves than in motor nerves and the lower limbs than in the upper limbs, with the sural nerve being the most affected in the patients who developed peripheral neuropathy (p = 0.011).
Our results indicated the importance of focusing on enfortumab vedotin-induced neuropathy of the sural nerve to maximize efficacy and improve safety.
This article discusses chemotherapy-induced peripheral neuropathic pain (CIPNP) and its associated neuropathic pain syndrome that occurs in patients with malignant neoplasms (MN) during cytostatic therapy. The overall prevalence of CIPNP in patients with malignant neoplasms associated with chemotherapy with neurotoxic drugs is estimated, according to various sources, to be about 70%. The pathophysiological mechanisms of CIPNP have not been fully studied, but it is known that they are based on: impaired axonal transport, oxidative stress, induction of apoptosis, DNA damage, dysfunction of voltage-gated ion channels, and central mechanisms. It is important to recognize CIPNP in the clinical symptoms of patients with cancer treated with cytostatics, since these disorders can lead to serious restrictions in the motor, sensory and autonomic functions of the upper and lower extremities, as well as reduce the quality of life and daily functioning of such patients, forcing them to adjust the dose of chemotherapy drugs, transfer the next cycles and even interrupt the treatment of cancer carried out according to vital needs. In addition to the clinical examination, scales and questionnaires have been developed to identify symptoms of CIPNP, but it is most important for neurological and oncological specialists to know and be able to recognize such symptoms in patients. The mandatory research methods for identifying the symptoms of polyneuropathy include electroneuromyography (ENMG), which allows you to assess muscle activity, functional characteristics and the state of the function of peripheral nerves. The methods used to reduce symptoms are screening patients for the development of CIPNP and identifying patients at high risk of CIPNP and, if necessary, reducing the dose or changing cytostatics. Methods for correcting this disorder using different classes of drugs require more detailed study and further research.
Neuromuscular ultrasound (NMUS) is a valuable tool in establishing a diagnosis of carpal tunnel syndrome (CTS), and can be particularly helpful in patients with clinical CTS but normal nerve conduction studies (NCS). This case involves the uncommon presentation of enlarged median nerves on NMUS with normal NCS in a breast cancer patient who developed chemotherapy induced peripheral neuropathy (CIPN) and CTS following taxane treatment. This case demonstrates that CTS should not be excluded based on electrodiagnostic studies alone, and comorbid CTS should be considered in patients receiving neurotoxic chemotherapy, even in the setting of normal NCS.
IntroductionPaclitaxel-induced peripheral neurotoxicity (PIPN) typically manifests as a predominantly sensory axonopathy. Nerve conduction studies (NCS) represent the gold standard method to quantify axonal impairment in PIPN. Serum neurofilament light chain (sNfL) levels are emerging biomarkers for quantifying axonal damage in peripheral neuropathies. To date, the association between NCS abnormalities and sNfL levels during paclitaxel-based chemotherapy has not been specifically addressed.Methods
We prospectively conducted longitudinal measurement of sNfL levels in 27 chemotherapy-naïve breast cancer patients and correlated conventional NCS recordings with sNfL in 22 of them, before (T0) and after (T1) 12 cycles of weekly paclitaxel-based therapy.ResultsPIPN was diagnosed in 24/27 patients (88%) after completion of the 12-week paclitaxel-based chemotherapy regimen. Serum NfL levels (pg/mL) were significantly higher at T1 compared to T0 (T0: 18.50 ± 12.88 vs T1: 255.80 ± 194.16; p < 0.001). The increase of sNfL levels at T1 significantly correlated with the decrease or abolishment of amplitudes recorded from the sural nerve (r = 0.620; p = 0.0035), sensory radial (r = 0.613; p = 0.005), sensory ulnar (r = 0.630; p = 0.005), and peroneal motor (r = 0.568; p = 0.024) nerves.Conclusions
NfL levels proportionally increase during chemotherapy administration and significantly correlate with NCS axonal abnormalities in patients with PIPN. A multimodal testing approach employing both sNfL and NCS might improve the PIPN diagnostic accuracy.
Background:
For patients with breast cancer who receive docetaxel chemotherapy, taxane-associated acute pain syndrome (T-APS), considered a form of neural pathology, is a significant clinical problem. We evaluated the effect of prophylactic etoricoxib on T-APS in patients with breast cancer.
Materials and methods:
We conducted a phase II randomised trial including 144 patients with breast cancer receiving four cycles of docetaxel-based chemotherapy. Patients were randomised in the ratio 1:1 to receive prophylactic etoricoxib (60 mg, Day 1 to Day 8) or no prophylactic treatment. The primary end-point was the overall incidence of T-APS across all cycles. Secondary end-points included the incidence of severe pain (greater than 5 on a scale 0-10); severity and duration of T-APS; Functional Assessment of Cancer Therapy-Breast subscale; chronic sensory and motor neurotoxicity and adverse events.
Results:
The overall incidence of T-APS across all cycles of chemotherapy in the etoricoxib group was 57.1%, while that in the control group was 91.5% (P < 0.001). The incidences of severe T-APS were 11.4% and 54.9% for the etoricoxib and control groups, respectively (P < 0.001). The mean Functional Assessment of Cancer Therapy-Breast subscale score of the etoricoxib group (103.79-107.24) was significantly higher than that of the control group (93.88-96.71) (P = 0.001 at cycle 1 and P < 0.001 at cycles 2-4). After four cycles of docetaxel chemotherapy, the etoricoxib group demonstrated a significantly higher mean Functional Assessment of Cancer Treatment Neurotoxicity subscale score than the control group (38.46, 95% CI: 37.63-39.29; 34.59, 95% CI: 33.73-35.45, respectively; P < 0.001). Electromyography showed that most peripheral sensory nerves in the etoricoxib group had significantly improved action potential amplitudes and conduction velocities compared with those in the control group.
Conclusion:
Prophylactic use of etoricoxib could significantly reduce the incidence and severity of docetaxel-induced acute pain syndrome and potentially decrease docetaxel-induced peripheral neuropathy.
Trial registration:
ClinicalTrials.gov, NCT04565600.
The increased survival of cancer patients has raised growing public health concern on associated long-term consequences of antineoplastic treatment. Chemotherapy-induced peripheral neuropathy (CIPN) is a primarily sensory polyneuropathy, which may be accompanied by pain, autonomic disturbances, and motor deficit. About 70% of treated cancer patients might develop CIPN during or after the completion of chemotherapy, and in most of them such complication persists after six months from the treatment. The definition of the potential risk of development and resolution of CIPN according to a clinical and biochemical profile would be certainly fundamental to tailor chemotherapy regimen and dosage on individual susceptibility. In recent years, patient-reported and clinician-related tools along with quality of life instruments have been featured as primary outcomes in clinical setting and randomized trials. New studies on metabolomics markers are further pursuing accurate and easily accessible indicators of peripheral nerve damage. The aim of this review is to outline the strengths and pitfalls of current knowledge on CIPN, and to provide a framework for future potential developments of standardized protocols involving clinical and biochemical markers for CIPN assessment and monitoring.
The leptomeninges, spinal fluid and peripheral nerves can serve as sanctuary sites for leukemia. Neurologic complications arise from direct leukemic infiltration of the central and peripheral nervous system, indirect leukemic effects (for example, cerebral leukostasis, cerebrovascular accidents, paraneoplastic syndromes), effect from treatments or stem cell transplant (for example, graft versus host disease, immune reconstitution inflammatory syndrome) or immune compromise. This review discusses the clinical manifestations of neurologic complications in leukemia patients, and reviews the recent advances in their diagnosis and management.
Chemotherapy induced peripheral neuropathy (CIPN) is a significant toxicity of cancer treatment, with the potential to affect long-term function and quality of life in cancer survivors. There remains a lack of consensus around optimal assessment techniques. While current approaches to CIPN assessment are focused on clinical grading scales, it is becoming increasingly evident that a more comprehensive multimodal assessment package is necessary to accurately characterise the impact of CIPN as well as gauge the utility of neuroprotective mechanisms. Neurophysiological techniques provide objective biomarkers and may enable early detection of toxicity while patient reported outcomes are necessary to determine the significance of symptoms to individual patients. In addition to providing an objective assessment, clinical neurophysiological techniques provide important insights into the contributory pathophysiological mechanisms of CIPN with different chemotherapy agents.
The aim of this retrospective study was to evaluate common causes of upper extremity sensory disturbance in breast cancer patients. Breast cancer patients who received surgery and taxane chemotherapy (CTx) with upper extremity sensory disturbance that began after CTx were included. With comprehensive clinical history, physical examination and electrodiagnostic results, diagnosis for each patient was made. Fifty-two patients were included: 23 (44.2%) were diagnosed with chemotherapy-induced peripheral neuropathy (CIPN), 7 (13.5%) with myofascial pain syndrome (MPS), six (11.5%) with carpal tunnel syndrome (CTS), four (7.7%) with CIPN and MPS, and three (5.8%) with CIPN and CTS. CIPN was more correlated with sensory symptoms at upper and lower extremities, a shorter time from CTx start, and adriamycin and cytoxan (AC) plus paclitaxel, than with AC plus docetaxel and fluorouracil, epirubicin and cyclophosphamide plus taxanes. MPS was correlated with longer duration of CTx and use of hormone therapy. CTS was correlated with wrist trauma history. Patients with CIPN showed similar degrees of pain even after 3 months of treatment, in comparison to the patients with MPS and CTS. When breast cancer patients complain of upper extremity sensory disturbance, various causes, especially referred symptom from MPS, should be considered for effective treatment.
Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent adverse event. Nutritional status can become impaired in cancer patients, potentially contributing to neuropathy's evolution. Our aim was to evaluate serum micronutrients and prealbumin in a cohort of 113 solid-cancer patients receiving platinum and taxane compounds during the development and recovery of neuropathy, up to one year after finishing treatment. CIPN was graded according with Total Neuropathy Score(©) and NCI.CTCv3, at T0 (baseline), T1 (1-3 months) and T12 (12 months) after chemotherapy. CIPN was classified as asymptomatic (< grade 2) or symptomatic (≥2). CIPN recovery was defined as ≥1 grade improvement at T12. Symptomatic CIPN developed in 52% of patients. Symptomatic patients presented a higher increase in TNSc(©) (p < 0.001), in TNSr(©) (p < 0.001), and decrease in sural (p < 0.001) and radial nerve conduction (p < 0.001). No significant differences with any of the micronutrients were observed along T0-T1 period between severity or chemotherapy groups. By T12, symptomatic patients without recovery had a lowering in vitamin E levels (p = 0.019) and prealbumin (p = 0.062) compared to those symptomatic that improved. A correlation between the variation of vitamin E and prealbumin at T0-T1 (r = 0.626, p = 0.001) and T1-T12 (r = 0.411, p = 0.06) was observed. After chemotherapy treatment, the improvement of patients displaying symptomatic neuropathy is related with vitamin E and prealbumin serum levels. Our results suggest that nutritional status can play a role in CIPN recovery.
Taxol, a plant alkaloid with promise as an antineoplastic agent, produced a predominantly sensory neuropathy in 16 of 60 patients treated in two phase I trials. This neuropathy occurred only at taxol doses greater than 200 mg/m2. Symptoms typically started 1 to 3 days following treatment, beginning in the hands and feet simultaneously in most patients. Electrophysiologic data suggests both axonal degeneration and demyelination. This previously undefined neurotoxic neuropathy most likely results from taxol's unique ability to produce microtubule aggregation in dorsal root ganglion cells, axons, and Schwann cells.
Docetaxel, a semi-synthetic taxane may cause a usually mild sensory neuropathy. We describe the clinical characteristics of five patients who developed a more severe neuropathy following treatment with docetaxel.
All patients were treated in phase II studies with 100 mg/m2 docetaxel in three weekly cycles, without steroid administration.
The clinical picture in these patients was dominated by a sensory neuropathy, but in one case severe weakness was present. Another patient developed Lhermitte's sign. Signs and symptoms are usually reversible after discontinuation of docetaxel administration, but in three patients symptoms worsened for some time after the end of treatment before improvement occurred.
Severe docetaxel neuropathy may especially occur following treatment with cumulative dosage over 600 mg/m2; in patients treated with this dosage a moderate or severe neuropathy may not be rare.
Carpal tunnel syndrome (CTS) is a cause of pain, numbness, and tingling in the hands and is an important cause of work disability. Although high prevalence rates of CTS in certain occupations have been reported, little is known about its prevalence in the general population.
To estimate the prevalence of CTS in a general population.
General health mail survey sent in February 1997, inquiring about symptoms of pain, numbness, and tingling in any part of the body, followed 2 months later by clinical examination and nerve conduction testing of responders reporting symptoms in the median nerve distribution in the hands, as well as of a sample of those not reporting these symptoms (controls).
A region in southern Sweden with a population of 170000.
A sex- and age-stratified sample of 3000 subjects (age range, 25-74 years) was randomly selected from the general population register and sent the survey, with a response rate of 83% (n = 2466; 46% men). Of the symptomatic responders, 81% underwent clinical examination.
Population prevalence rates, calculated as the number of symptomatic responders diagnosed on examination as having clinically certain CTS and/or electrophysiological median neuropathy divided by the total number of responders.
Of the 2466 responders, 354 reported pain, numbness, and/or tingling in the median nerve distribution in the hands (prevalence, 14.4%; 95% confidence interval [CI], 13.0%-15.8%). On clinical examination, 94 symptomatic subjects were diagnosed as having clinically certain CTS (prevalence, 3.8%; 95% CI, 3.1%-4.6%). Nerve conduction testing showed median neuropathy at the carpal tunnel in 120 symptomatic subjects (prevalence, 4.9%; 95% CI, 4.1%-5.8%). Sixty-six symptomatic subjects had clinically and electrophysiologically confirmed CTS (prevalence, 2.7%; 95% CI, 2.1%-3.4%). Of 125 control subjects clinically examined, electrophysiological median neuropathy was found in 23 (18.4%; 95% CI, 12.0%-26.3%).
Symptoms of pain, numbness, and tingling in the hands are common in the general population. Based on our data, 1 in 5 symptomatic subjects would be expected to have CTS based on clinical examination and electrophysiologic testing.
The shortening of infusion time from 3 to 1 hour decreases the systemic exposure (area under the curve, AUC) of total and unbound paclitaxel but increases the AUC of its vehicle Cremophor EL, whereas the time above total paclitaxel concentrations of 0.05 micromol/L (T >0.05) remains almost constant. As both Cremophor EL and paclitaxel are neurotoxic, we evaluated their pharmacodynamic effects on the development of peripheral neuropathy as the most important nonhematologic toxicity.
Patients with advanced cancer of different origin were randomized to receive a maximum of 12 weekly-given 1- or 3-hour infusions of 100 mg/m2 paclitaxel (Taxol). Twenty-four patients were assessable for both pharmacokinetics and peripheral neuropathy development evaluated by a clinical scoring system including sensory symptoms, strength, tendon reflexes, and vibratory sense.
Patients with peripheral neuropathy development (n=14) received more weeks of therapy (P=0.056) and showed significantly higher T(>0.05) (P=0.022) and overall systemic drug exposures (weeks of therapy x AUC) for total paclitaxel (P=0.002) and unbound paclitaxel (P=0.003) than those without peripheral neuropathy. In Kaplan-Meier analyses, T(>0.05) > or = 10.6 hours (P=0.023), AUC of total paclitaxel > or = 4.7 microg/mL x hour (P = 0.047), and AUC of unbound paclitaxel > or = 0.375 microg/mL x hour (P = 0.095) were identified as being potential factors for peripheral neuropathy development. In a Cox regression analysis, only T(>0.05) > or = 10.6 hours remained as an independent risk factor (relative risk, 18.43; P = 0.036) after adjusting for prior vincamycin (relative risk, 11.28; P = 0.038).
From the results obtained in this study, it is concluded that exposure to paclitaxel but not Cremophor EL is associated with peripheral neuropathy development.
Context Carpal tunnel syndrome (CTS) is a cause of pain, numbness, and tingling
in the hands and is an important cause of work disability. Although high prevalence
rates of CTS in certain occupations have been reported, little is known about
its prevalence in the general population.Objective To estimate the prevalence of CTS in a general population.Design General health mail survey sent in February 1997, inquiring about symptoms
of pain, numbness, and tingling in any part of the body, followed 2 months
later by clinical examination and nerve conduction testing of responders reporting
symptoms in the median nerve distribution in the hands, as well as of a sample
of those not reporting these symptoms (controls).Setting A region in southern Sweden with a population of 170,000.Participants A sex- and age-stratified sample of 3000 subjects (age range, 25-74
years) was randomly selected from the general population register and sent
the survey, with a response rate of 83% (n=2466; 46% men). Of the symptomatic
responders, 81% underwent clinical examination.Main Outcome Measures Population prevalence rates, calculated as the number of symptomatic
responders diagnosed on examination as having clinically certain CTS and/or
electrophysiological median neuropathy divided by the total number of responders.
Results Of the 2466 responders, 354 reported pain, numbness, and/or tingling
in the median nerve distribution in the hands (prevalence, 14.4%; 95% confidence
interval [CI], 13.0%-15.8%). On clinical examination, 94 symptomatic subjects
were diagnosed as having clinically certain CTS (prevalence, 3.8%; 95% CI,
3.1%-4.6%). Nerve conduction testing showed median neuropathy at the carpal
tunnel in 120 symptomatic subjects (prevalence, 4.9%; 95% CI, 4.1%-5.8%).
Sixty-six symptomatic subjects had clinically and electrophysiologically confirmed
CTS (prevalence, 2.7%; 95% CI, 2.1%-3.4%). Of 125 control subjects clinically
examined, electrophysiological median neuropathy was found in 23 (18.4%; 95%
CI, 12.0%-26.3%).Conclusion Symptoms of pain, numbness, and tingling in the hands are common in
the general population. Based on our data, 1 in 5 symptomatic subjects would
be expected to have CTS based on clinical examination and electrophysiologic
testing.
STANDARD CRITERIA FOR TOXICITY and for response to treatment are important prerequisites to the conduct of cancer trials. The Eastern Cooperative Oncology Group criteria for toxicity and response are presented to facilitate future reference and to encourage further standardization among those conducting clinical trials.
(C) Lippincott-Raven Publishers.
Paclitaxel is used in the adjuvant treatment of breast cancer. It induces disabling and potentially long-lasting sensory neuropathy. This study systematically and prospectively investigated sensory function, using clinical grading scales, quantitative sensory testing, and neurophysiological and nerve excitability studies in 28 patients with early-stage breast cancer. After administration of 529 ± 41 mg/m2 paclitaxel, 71% of patients developed neuropathic symptoms by 6 weeks of treatment. Early and progressive increases in stimulus threshold (P < 0.05) and reduction in sensory amplitudes from 47.0 ± 3.3 μV to 42.4 ± 3.4 μV (P < 0.05) occurred by 4 weeks, with a further reduction by final treatment (33.7 ± 3.0 μV, P < 0.001). The majority of patients (63%) did not experience recovery of neuropathic symptoms at follow-up. Axonal disruption did not relate to membrane conductance dysfunction. We found that paclitaxel produces early sensory dysfunction and leads to persistent neuropathy. Importantly, significant axonal dysfunction within the first month of treatment predated symptom onset, suggesting a window for neuroprotective therapies. Muscle Nerve, 2011
As proximal nerves are relatively spared in length-dependent, axonal polyneuropathy, we theorized that a sural/radial amplitude ratio (SRAR) might be a sensitive indicator of mild polyneuropathy. In this study, sural amplitudes and SRARs in patients with signs of mild axonal polyneuropathy were compared to those of normal, age-matched control subjects. Sural and radial sensory responses were measured in a standard fashion in all subjects. Thirty polyneuropathy patients had an average SRAR of 0.29 as compared to 0.71 for the 30 normal subjects. An SRAR of less than 0.40 was a strong predictor of axonal polyneuropathy, with 90% sensitivity and 90% specificity, as compared to an absolute sural amplitude of less than 6.0 μV, which had sensitivity of only 66%. Additionally, unlike the sural amplitude, the ratio did not vary significantly with age. We conclude that the SRAR is a sensitive, specific, age-independent electrodiagnostic test for mild axonal polyneuropathy. © 1997 John Wiley & Sons, Inc. Muscle Nerve20: 1236–1241, 1997
Taxol, an antimicrotubule agent, has shown promise for efficacy in treatment of breast cancer, but severe hypersensitivity reactions led to cessation of many phase I clinical trials. Consequently, investigators and the National Cancer Institute recommended that phase I and II studies of this agent use 24-hour infusions and antiallergic medications. Using a premedication regimen effective in preventing hypersensitivity reactions, we have performed a phase II trial of taxol in patients with metastatic breast cancer. Taxol was administered to 25 patients at a dose of 250 mg/m2 by 24-hour infusion every 21 days. These patients had received only one prior chemotherapy regimen, either adjuvant to surgery or for metastatic disease; all but two had received doxorubicin. In 60% of the patients, the dominant site of disease was the viscera. All patients were assessable. In April 1991, at a median time on study of 9 months (range, 5–13+months), the objective response rate was 56% (12% complete and 44% partial; 95% confidence interval, 35%–76%). Disease progressed in only 8% of the patients. The median number of courses of therapy was 11. Granulocytopenia was the dose-limiting toxic effect, but neutropenia with fever occurred in only 5% of 232 courses. A chronic glove-and-stocking neuropathy developed in most patients, but no altergic reactions occurred. We conclude that taxol is an active agent in the treatment of metastatic breast cancer and that it warrants continued study. Currently, we are conducting a phase I trial of taxol plus doxorubicin. Future trials should address the optimal effective dose, the optimal sequencing of combinations, mechanisms of drug resistance in tumors, and dose-limiting toxic effects (particularly cardiac toxic effects of taxol given as a single agent or in drug combinations).
Electrodiagnostic evaluation of patients with suspected polyneuropathy is useful for detecting and documenting peripheral abnormalities, identifying the predominant pathophysiology, and determining the prognosis for certain disorders. The electrodiagnostic classification of polyneuropathy is associated with morphologic correlates and is based upon determining involvement of sensory and motor fibers and distinguishing between predominantly axon loss and demyelinating lesions. Accurate electrodiagnostic classification leads to a more focused and expedient identification of the etiology of polyneuropathy in clinical situations.
Taxol, selected for clinical trial because of its animal antitumor activity and unique structure and mechanism of action, was administered in Cremophor by i.v. infusion over 6 h in a phase I study. Eastern Cooperative Oncology Group toxicity grading was used. Eighty-three taxol courses were administered to 34 patients. Grade 3-4 hypersensitivity reactions occurred in 4 of 13 courses at the first 2 dose levels, but premedication with dexamethasone, diphenhydramine, and cimetidine resulted in only 3 additional Grade 2 reactions in the next 70 courses. Neurotoxicity, which resolved or improved after stopping therapy, was Grade 1 with 2 of 10 courses of 230 mg/m2 and Grades 1-3 after 11 of 12 courses of 275 mg/m2. Leukopenia, first seen (Grade 1) after 1 of 8 75 mg/m2 courses, was Grades 3-4 after 10 of 34 courses of 175-230 mg/m2 and 10 of 12 courses of 275 mg/m2. The WBC nadir occurred at a median of 10 days and the median time required for normalization of the WBC was 18 days. Alopecia began 2-3 weeks posttaxol in 2 of 9 patients treated with 75-135 mg/m2 and in all 16 patients (Grade 3) treated with 175-275 mg/m2. Grades 1-2 nausea and vomiting occurred in about one-third of the patients treated at a dose of 105 mg/m2 or more. Taxol disappearance from plasma was biphasic; half-lives of the first and second phases after a 275 mg/m2 dose were 0.32 and 8.6 h, respectively. The apparent volume of distribution was 55 liters/m2, and the peak plasma concentration with a dose of 275 mg/m2, which occurred immediately postinfusion, was approximately 8 microM. Only 5% of parent drug was excreted in the urine within 24 h. Minor objective responses were noted in one patient with gastric cancer and another with ovarian carcinoma. In addition, one patient with massive ascites due to metastatic adenocarcinoma from an unknown primary had only minimal sonographic evidence of ascites for 6 months posttreatment. Neurotoxicity and leukopenia were dose limiting in this schedule. The recommended phase II trial dose is 250 mg/m2, with premedication.
On the initiative of the World Health Organization, two meetings on the Standardization of Reporting Results of Cancer Treatment have been held with representatives and members of several organizations. Recommendations have been developed for standardized approaches to the recording of baseline data relating to the patient, the tumor, laboratory and radiologic data, the reporting of treatment, grading of acute and subacute toxicity, reporting of response, recurrence and disease-free interval, and reporting results of therapy. These recommendations, already endorsed by a number of organizations, are proposed for international acceptance and use to make it possible for investigators to compare validly their results with those of others.
Taxol is a novel antineoplastic agent that has demonstrated impressive clinical activity in breast, ovarian, lung, and head and neck cancers. This broad antitumor activity of taxol in cisplatin-sensitive tumors suggests that the combination of taxol and cisplatin may become one of the most commonly used taxol-based chemotherapeutic regimen in the treatment of solid tumors. Both taxol and cisplatin, however, are neurotoxic. To study the neurotoxic effects of these two agents when used in combination, we prospectively evaluated neurological function at baseline, during, and following treatment, in 21 cancer patients treated with taxol (135-350 mg/m2), cisplatin (75-100 mg/m2), and granulocyte-colony stimulating factor (5 micrograms/kg). Twenty of the 21 patients (95%) developed a sensory-motor neuropathy 1 to 21 weeks after the initiation of therapy, that was progressive with each additional course of chemotherapy. The neuropathy was symmetrical, length dependent, axonal in nature by physiological studies, and more pronounced in those patients who received higher doses of taxol. The neuropathy appeared earlier and at lower taxol doses in those patients with preexisting neuropathies. We conclude that sensory-motor neuropathy is a frequent dose-dependent toxicity of combined cisplatin and taxol use. Peripheral neuropathy is likely to become the major dose-limiting toxicity of taxol-cisplatin combination chemotherapy when higher doses of these agents are administered with granulocyte-colony stimulating factor.
Neurotoxicity, manifested primarily by a motor and sensory polyneuropathy, is the principal nonhematological side effect of Taxol. Available evidence suggests that Taxol produces a toxic effect involving either axons or ganglion cell bodies, or both, rather than a myelinopathy. As with other toxic polyneuropathies, patients with preexisting peripheral neuropathies, such as those caused by diabetes mellitus or ethanol, appear to be particularly predisposed to developing neurological toxicity. The incidence and severity of the neuropathic manifestations also appear to be related to the Taxol dose level, the cumulative dose of Taxol, and possibly to the use of Taxol in combination with cisplatin. Rarely, manifestations of autonomic and central nervous system dysfunction occur. Taxol also induces myalgias in the peri-treatment period, especially when used in high doses, and a myopathy has been noted in patients treated with high doses of Taxol administered alone and in combination with cisplatin. Although dose-response relationships for Taxol have not been clearly established, these neuromuscular effects are likely to become a significant clinical problem if higher doses of Taxol are used with hematopoietic colony-stimulating factors. The neuromuscular effects of Taxol, including symptoms, physical and electrophysiological manifestations, and predisposing factors, as well as agents that may be used for neuroprotection, are discussed in this report.
Taxol has recently been approved for the treatment of ovarian cancer that has failed to respond to other chemotherapeutic agents. A predominantly sensory neuropathy has been reported in patients receiving taxol, but corresponding nerve changes have not been described. The patient described herein received taxol at a dose of 275 mg/m2 every 21 days. The sural nerve biopsy performed after 17 courses of taxol (cumulative dose, 6603 mg) showed severe nerve fiber loss, axonal atrophy, and secondary demyelination. Axonal regeneration was absent. The findings are compatible with a cell body disease or a length-dependent, distal neuropathy with failure of axonal regeneration. The findings observed in taxol-induced neuropathy are important to document for comparison with other neoplastic and paraneoplastic neuropathies affecting patients with cancer.
Docetaxel (Taxotere), a semisynthetic analogue of the antitumor agent paclitaxel, inhibits tubulin depolymerization. Paclitaxel produces a peripheral neuropathy. This study delineates clinically and electrophysiologically the characteristics of a peripheral neuropathy due to docetaxel. In 186 patients receiving docetaxel in phase I or phase II protocols, we performed serial neurologic exams. As patients became symptomatic, quantitative sensory testing and nerve conduction studies were done. Twenty-one patients developed mild to moderate sensory neuropathy on taxotere at a wide range of cumulative doses (50 to 750 mg/m ² ) and dose levels (10 to 115 mg/m ² ). Ten of these patients also developed weakness of varying degree in proximal and distal extremities. Nine of the 21 patients had received neurotoxic chemotherapy before; 16 were treated with docetaxel at a dose level of 100 to 115 mg/m ² . In summary, docetaxel produced a sensorimotor peripheral neuropathy in 11% of our patient population.
NEUROLOGY 1996;46: 108-111
A retrospective review was undertaken to obtain more precise information about neurotoxicity, nephrotoxicity, and the effects of dexamethasone on the frequency and severity of hyperglycemia in diabetic patients with epithelial ovarian cancer treated with paclitaxel and/or cisplatin. Thirty-three patients were identified from 1254 patients over a 10-year period. In the cisplatin-treated patients, 21 of 24 (67%) had progression of neurological symptoms, three experienced grade 3 sensory neuropathy, and two had ototoxicity. Four patients had evidence of mild nephrotoxicity and two required a 50% dose reduction. In the group of patients treated with paclitaxel, 9 of the 18 (50%) had progression of symptoms, 2 to grade 3, and 2 had ototoxicity. No discontinuation of therapy due to neuropathy was required and no patient had evidence of drug-induced autonomic nervous system dysfunction. Hyperglycemia was frequently exacerbated, and 5 patients required treatment change, but no patient was hospitalized in relation to this. Our results indicate that the paclitaxel/cisplatin combination regimen or paclitaxel alone could be safely administered in diabetic patients at standard doses, with concurrent glucose and creatinine monitoring, as well as history of neurological symptoms and physical examination.
Paclitaxel and docetaxel are novel chemotherapeutic agents that promote the polymerization and inhibit the depolymerization of microtubules.Sensory neuropathy is common with these agents, particularly paclitaxel. We evaluated 64 patients treated with these drugs; 54 were followed prospectively. Eleven (17%, including six of the 54 prospectively followed patients) developed muscle weakness that was predominantly proximal. The weakness was idiosyncratic, occurring at any stage of treatment, had a variable course, and was reversible upon cessation of drug. All patients developed symptoms or signs of taxane-induced sensory neuropathy. Weakness was likely neuropathic in origin; electrodiagnostic studies suggested a distal axonopathy in some patients and proximal denervation (anterior horn cell or nerve root) in others.
NEUROLOGY 1996;47: 115-118
The WldS mouse is a spontaneous mutant that is characterized by the phenotype of delayed degeneration of transected nerves (slow Wallerian degeneration). Molecular genetic analysis identified a mutation in this animal that codes for a unique protein expressed in brain tissue of WldS mice. We asked whether the WldS phenotype, in addition to delaying axonal degeneration after axotomy, might provide neuroprotection against toxic neuropathy. In dorsal root ganglia (DRG) cultures, neurites from WldS transiently exposed to vincristine not only resisted axonal degeneration but resumed growth after withdrawal of the toxin. Neurites from wild type mice died rapidly and did not recover. To prove that the identified mutation and its protein product are responsible for the WldS phenotype, we used an adenoviral gene transfer system to deliver the WldS to rat DRG neurons. Rat neurons expressing the WldS protein were resistant to vincristine-induced axonal degeneration, confirming the functional significance of the identified gene mutation. These data provide evidence that the WldS protein can be neuroprotective against vincristine neuropathy, and possibly other disorders characterized by axonal degeneration. In addition, delivery of this gene to wild type cells can transfer the WldS phenotype, providing the possibility of "gene therapy" for peripheral neuropathy.
The WldS mouse is a unique mutant strain that demonstrates the remarkable phenotype of prolonged survival of transected axons ("slow Wallerian degeneration"). In these studies, we tested whether this neuroprotective phenotype extends to axonal degeneration seen in a progressive peripheral neuropathy. WldS and wild-type mice were intoxicated with the cancer chemotherapeutic agent paclitaxel (Taxol). The severity of the resultant sensory neuropathy was compared with behavioral, physiological, and pathological measures. WldS mice were resistant to paclitaxel neuropathy by all measures, and the resistance was because of protection against axonal degeneration. These studies demonstrate for the first time that the WldS mouse is more than a slow Wallerian degeneration phenotype, emphasizing the mechanistic link between Wallerian degeneration and peripheral neuropathy. Understanding how this mutant gene confers protection against axonal degeneration will provide important clues toward prevention of axonal degeneration in several human neurological disorders.
Although not very common, medication-induced neuropathy is a treatable condition and, therefore, is important to identify. Medications continue to grow in number and expand in usage; consequently, toxic neuropathy continues to be relevant to neurologists. Many agents have toxicities that are tolerated because the treatments are necessary, such as therapies for HIV and malignancy. Additional agents to prevent or ameliorate the toxic neuropathy are being sought and trials are ongoing. Certain patients, however, may be at high risk for peripheral nerve toxicity due to genetic factors or another underlying neuropathy. Newer drug-delivery methods, such as viral transfection, may produce less toxicity in the future. The underlying pathomechanisms remain incompletely elucidated; however, apoptosis is emerging as an important final pathway in some forms of toxic neuropathy. Although most cases demonstrate acute or subacute onset after exposure, recent experiences with statin drugs raise the possibility of occult toxic causes of chronic idiopathic neuropathy.
The Cancer and Leukemia Group B conducted a Phase II trial to evaluate the efficacy, toxicity, and pharmacokinetics of paclitaxel administered at a maximum dose density for patients with chemotherapy-naïve, advanced-stage non-small cell lung carcinoma (NSCLC).
Patients with Stage IIIB/IV or recurrent NSCLC, a performance status (PS) score of 0-1, and no history of chemotherapy exposure were eligible. Paclitaxel, 150 mg/m(2), was administered over 3 hours during Weeks 1-6 of an 8-week cycle. Doses were modified for ANC < 1500/microL or for >or= Grade 2 neuropathy on the day of therapy. Treatment continued until toxicity or disease progression. Pharmacokinetics were assessed at Weeks 1, 3, and 5 of Cycle 1.
Thirty-eight patients (median age, 64 years; range, 31-81 years) were treated. There were 21 males (PS = 0 for 17). Eleven patients had received previous radiation, 2 had brain metastases, 25 had adenocarcinoma, 23 had Stage IV disease, 6 had StageIIIB disease, and 9 had recurrent disease. Grade 3-4 granulocytopenia occurred in 39% of patients. There were no deaths due to toxicity. Grade 2 or 3 neuropathy occurred in 29% and 24% of patients, respectively. Ten (27%) patients had Grade 3 hyperglycemia (glucose concentration > 250 mg/dL). There were 16 partial responses (42%; 95% confidence interval [CI], 26-59%). The median survival period was 12.3 months (95% CI, 7.9-19.6%), and the 1-year and 2-year survival rates were 52% (95% CI, 39-71%) and 26% (95% CI, 15-45%), respectively. Paclitaxel pharmacokinetics were consistent with published values and clearance was not induced. Older age and hyperglycemia were associated with greater neurotoxicity.
Paclitaxel at 150 mg/m(2) per week x 6 every 8 weeks can be administered safely in the cooperative group setting. These Phase II data are comparable to those associated with combination therapy. The weekly dose-dense schedule may be more active than conventional schedules.
Acute lymphoblastic leukaemia (ALL) is the most common paediatric cancer with a cure rate of approximately 80%. Relapse occurs despite treatment stratification based on clinical criteria. Relapse risk in ALL may be related to simple nucleotide polymorphisms (SNPs) of enzymes that metabolize chemotherapeutic agents. We evaluated whether SNPs in the cytochrome P450 3A family (CYP3A4*1B, CYP3A5*3 and CYP3A5*6) were associated with relapse risk on a national Children's Cancer Group (CCG) paediatric ALL trial (CCG-1891). CCG-1891 enrolled 1204 patients, and obtained both relapse and toxicity data prospectively. One hundred and twenty-four relapsed patients and 409 non-relapsed patients were assayed for each SNP. CYP3A variants were not associated with an increased risk of relapse. However, patients with the CYP3A4*1B and CYP3A5*3 genotypes had a decreased risk of peripheral neuropathy that was statistically significant on univariate analysis. After correction for multiple comparisons, the association between CYP3A*1B and CYP3A5*3 genotypes approached, but did not reach, statistical significance. CYP3 genotypes may not significantly modify the risk of relapse in childhood ALL, but may modify the risk of toxicity.
Cancer and Leukemia Group B Protocol 9342 was initiated to determine the optimal dose of paclitaxel administered as a 3-hour infusion every 3 weeks to women with metastatic breast cancer.
Four hundred seventy-four women with metastatic breast cancer who had received one or no prior chemotherapy regimens were randomly assigned to one of three paclitaxel dosing regimens-175 mg/m(2), 210 mg/m(2), or 250 mg/m(2)-each administered as a 3-hour infusion every 3 weeks. Women completed self-administered quality of life and symptom assessment questionnaires at baseline and after three cycles of treatment.
No evidence of a significant dose-response relationship was demonstrated over the dose range assessed. Response rates were 23%, 26%, and 21% for the three regimens, respectively. A marginally significant association (P =.04) was seen between dose and time to progression; however, in a multivariate analysis, the difference was even less apparent. No statistically significant difference was seen in survival. Neurotoxicity and hematologic toxicity were more severe on the higher dose arms. There was no significant difference in quality of life on the three arms.
Higher doses of paclitaxel administered as a 3-hour infusion to women with metastatic breast cancer did not improve response rate, survival, or quality of life. There was a slight improvement in time to progression with higher dose therapy, which was offset by greater toxicity. When a 3-hour infusion of paclitaxel is administered every 3 weeks, 175 mg/m(2) should be considered the optimal dose.
The objective of this report was to develop a case definition of distal symmetric polyneuropathy to standardize and facilitate clinical research and epidemiologic studies. A formalized consensus process was employed to reach agreement after a systematic review and classification of evidence from the literature. The literature indicates that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of polyneuropathy; signs are better predictors of polyneuropathy than symptoms; and single abnormalities on examination are less sensitive than multiple abnormalities in predicting the presence of polyneuropathy. The combination of neuropathic symptoms, signs, and electrodiagnostic findings provides the most accurate diagnosis of distal symmetric polyneuropathy. A set of case definitions was rank ordered by likelihood of disease. The highest likelihood of polyneuropathy (useful for clinical trials) occurs with a combination of multiple symptoms, multiple signs, and abnormal electrodiagnostic studies. A modest likelihood of polyneuropathy (useful for field or epidemiologic studies) occurs with a combination of multiple symptoms and multiple signs when the results of electrodiagnostic studies are not available. A lower likelihood of polyneuropathy occurs when electrodiagnostic studies and signs are discordant. For research purposes, the best approach to defining distal symmetric polyneuropathy is a set of case definitions rank ordered by estimated likelihood of disease. The inclusion of this formalized case definition in clinical and epidemiologic research studies will ensure greater consistency of case selection.
We prospectively performed sural and radial sensory nerve conduction studies in 92 healthy subjects, aged between 21 and 88 years, both to determine the lower limits of normal (LLN) and to assess the effects of age and body mass index (BMI) on the sural and radial sensory nerve action potential (SNAP) amplitudes and on the sural/radial amplitude ratio (SRAR). Using the nonparametric bootstrap method to calculate 95% confidence intervals, we found that the 5% LLN values for sural and radial SNAPs were 14 microV and 25.5 microV in subjects aged < or =39 years, 7 microV and 17.4 microV in subjects aged 40-59 years, and 3 microV and 12 microV in subjects aged > or =60 years. The 5% LLN for SRAR for all patients was 0.21. Sural and radial SNAP amplitudes but not SRAR were strongly and inversely correlated with age and BMI. These age-adjusted normal values and revised SRAR will aid in the electrodiagnosis of polyneuropathy.
This randomized, controlled, multicenter, open-label, phase III study compared docetaxel versus paclitaxel in patients with advanced breast cancer that had progressed after an anthracycline-containing chemotherapy regimen.
Patients (n = 449) were randomly assigned to receive either docetaxel 100 mg/m2 (n = 225) or paclitaxel 175 mg/m2 (n = 224) on day 1, every 21 days until tumor progression, unacceptable toxicity, or withdrawal of consent.
In the intent-to-treat population, both the median overall survival (OS, 15.4 v 12.7 months; hazard ratio [HR], 1.41; 95% CI, 1.15 to 1.73; P = .03) and the median time to progression (TTP, 5.7 months v 3.6 months; HR, 1.64; 95% CI, 1.33 to 2.02; P < .0001) for docetaxel were significantly longer than for paclitaxel, and the overall response rate (ORR, 32% v 25%; P = .10) was higher for docetaxel. These results were confirmed by multivariate analyses. The incidence of treatment-related hematologic and nonhematologic toxicities was greater for docetaxel than for paclitaxel; however, quality-of-life scores were not statistically different between treatment groups over time.
Docetaxel was superior to paclitaxel in terms of OS and TTP. ORR was higher for docetaxel. Hematologic and nonhematologic toxicities occurred more frequently in the docetaxel group. The global quality-of-life scores were similar for both agents over time.
ABI-007, the first biologically interactive albumin-bound paclitaxel in a nanameter particle, free of solvents, was compared with polyethylated castor oil-based standard paclitaxel in patients with metastatic breast cancer (MBC). This phase III study was performed to confirm preclinical studies demonstrating superior efficacy and reduced toxicity of ABI-007 compared with standard paclitaxel.
Patients were randomly assigned to 3-week cycles of either ABI-007 260 mg/m(2) intravenously without premedication (n = 229) or standard paclitaxel 175 mg/m(2) intravenously with premedication (n = 225).
ABI-007 demonstrated significantly higher response rates compared with standard paclitaxel (33% v 19%, respectively; P = .001) and significantly longer time to tumor progression (23.0 v 16.9 weeks, respectively; hazard ratio = 0.75; P = .006). The incidence of grade 4 neutropenia was significantly lower for ABI-007 compared with standard paclitaxel (9% v 22%, respectively; P < .001) despite a 49% higher paclitaxel dose. Febrile neutropenia was uncommon (< 2%), and the incidence did not differ between the two study arms. Grade 3 sensory neuropathy was more common in the ABI-007 arm than in the standard paclitaxel arm (10% v 2%, respectively; P < .001) but was easily managed and improved rapidly (median, 22 days). No hypersensitivity reactions occurred with ABI-007 despite the absence of premedication and shorter administration time.
ABI-007 demonstrated greater efficacy and a favorable safety profile compared with standard paclitaxel in this patient population. The improved therapeutic index and elimination of corticosteroid premedication required for solvent-based taxanes make the novel albumin-bound paclitaxel ABI-007 an important advance in the treatment of MBC.
Microtubule-stabilizing agents (MTSAs), including the taxanes and epothilones, are effective chemotherapeutic agents for the treatment of many cancers. Neuropathy is a major adverse effect of MTSA-based chemotherapy, with severe peripheral neuropathy (grade 3 or 4) occurring in as many as 30% of patients treated with a MTSA. MTSA-induced neuropathy usually resolves gradually after cessation of the treatment. The most reliable method to accurately assess MTSA-induced neuropathy is by clinical evaluation, although additional techniques are being developed and evaluated. Among MTSA-induced neuropathy, the most extensively studied is that induced by taxanes; such a neuropathy usually presents as sensory neuropathy and is more common with paclitaxel than docetaxel. The incidence of MTSA-induced neuropathy seems to depend on the MTSA dose per treatment cycle, the schedule of treatment, and the duration of the infusion. Although there have been several small clinical trials with neuroprotective agents, early recognition and supportive care are the best approaches for prevention and management of MTSA-induced neuropathy. In the future, research should focus on elucidating the mechanism of MTSA-induced neuropathy, developing reliable in vivo and in vitro preclinical models to study MTSA-induced neuropathy, developing a more reliable grading system for MTSA-induced neuropathy, developing more reliable methods for evaluating MTSA-induced neuropathy, and evaluating the efficacy of potential neuroprotective agents in clinical trials.
Peripheral neuropathy (PN) is one of the most common and dose-limiting side effects of paclitaxel, a chemiotherapeutic drug of proven efficacy in various tumours. We investigated the pathophysiological features of the PN and the temporal relationships between the development of the symptoms and signs associated with paclitaxel administration in two groups of patients with breast cancer: group A received paclitaxel alone (total cumulative dose range: 950-2,475 mg/m2), and group B paclitaxel and adriamycin (total cumulative dose range: 700-2,800 mg/m2). A codified assessment scoring clinical sensory and motor functions according to the Common Toxicity Scale and neurophysiological measurements were made before treatment, after the third and sixth cycles, and at the end of therapy. A total neuropathy score (TNS) included selected clinical and neurophysiological parameters. Both positive and negative sensory and motor symptoms and signs of PN developed during therapy, the most common being painful paresthesias, global areflexia and distal weakness. The neurophysiological study showed an early onset, length-independent and progressive sensory defect, and delayed, distal and length-dependent motor deficits. The neuropathy progressed faster in group A than in group B but, after therapy, most of the patients were TNS grade 2 regardless of their group. The temporal relationships between the PN and paclitaxel were robustly characterised, and thus provide reference data and a model for testing the efficacy of drugs designed to provide neuroprotection.
Phase II trials suggested that weekly paclitaxel might be more effective and less toxic than every-3-weeks administration for metastatic breast cancer (MBC). Cancer and Leukemia Group B (CALGB) protocol 9840 was initiated to address this question. Subsequently trastuzumab was demonstrated to improve outcomes of paclitaxel therapy for human epidermal growth factor receptor-2 (HER-2)-positive patients, and was therefore incorporated. Because inhibition of HER-family signaling had potential efficacy even without HER-2 overexpression, we randomly assigned for trastuzumab in this population.
Patients were randomly assigned to paclitaxel 175 mg/m(2) every 3 weeks or 80 mg/m(2) weekly. After the first 171 patients, all HER-2-positive patients received trastuzumab; HER-2 nonoverexpressors were randomly assigned for trastuzumab, in addition to paclitaxel schedule. A total of 577 patients were treated on 9840. An additional 158 patients were included in analyses, for combined sample of 735. The primary end point was response rate (RR); secondary end points were time to progression (TTP), overall survival, and toxicity. Primary comparisons were between weekly versus every-3-weeks paclitaxel, and trastuzumab versus no trastuzumab in HER-2 nonoverexpressors.
In the combined sample, weekly paclitaxel was superior to every-3-weeks administration: RR (42% v 29%, unadjusted odds ratio [OR] = 1.75; P = .0004), TTP (median, 9 v 5 months; adjusted HR = 1.43; P < .0001), and survival (median, 24 v 12 months; adjusted HR = 1.28; P = .0092). For HER-2 nonoverexpressors, trastuzumab did not improve efficacy. Grade 3 neuropathy was more common with weekly dosing (24% v 12%; P = .0003).
Weekly paclitaxel is more effective than every-3-weeks administration for MBC. Trastuzumab did not improve efficacy for HER-2 nonoverexpressors. Neurotoxicity is a treatment-limiting toxicity for weekly paclitaxel.
Reporting results of cancer treatment.
- Miller
. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer.
- Gradishar