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Evaluation and monitoring of peripheral nerve function
Handbook of Clinical Neurology, Vol. 104 (3rd series) Neuro-oncology W. Grisold and R. Soffietti, Editors # 2012 Elsevier B.V. All rights reserved
Chapter 13
Evaluation and monitoring of peripheral nerve function G. CAVALETTI* AND P. MARMIROLI Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, Monza, Italy
INTRODUCTION The peripheral nervous system may be involved in several pathological events in cancer patients and, in some cases, the evaluation and monitoring of nerve damage can be difficult (Paice, 2009; Cavaletti et al., 2010; Gutierrez-Gutierrez et al., 2010). Cancer can directly infiltrate or compress individual nerves, roots, ganglia, or parts of a nerve plexus, causing sensory and/motor impairment depending on the site of the damage. Only rarely do these cases represent a diagnostic challenge and the site of the lesion can be detected using imaging and neurophysiological methods. Occasionally, biopsy of the lesion may be necessary to confirm the results of noninvasive investigations. Some years ago, indirect (‘paraneoplastic’) involvement of dorsal root ganglia neurons and peripheral nerves, possibly due to an immune-mediated mechanism, was suggested. The recognition of a number of ‘classical’ antibodies directed against cancer and peripheral nervous system antigens is currently a very useful additional tool for a correct diagnosis in well-defined neurological paraneoplastic syndromes (Graus et al., 2004). The use of advanced imaging techniques (e.g., positron emission tomography) enhances the possibility of detecting an occult cancer. From a clinical viewpoint, sensory and autonomic impairment are the most common symptoms of neurological paraneoplastic syndromes (Freeman, 2005; Rudnicki and Dalmau, 2005). A more challenging issue in patients with cancer is the recognition and monitoring of iatrogenic damage. Although surgery and radiation therapy may be the cause of mononeuropathy or plexopathy, polyneuropathy is definitely much more frequent as a result of the toxic action of several drugs (Cavaletti and Marmiroli, 2004). The target of drug-induced neurotoxicity is most dependent on the type and distribution of each substance that
can act predominantly on the nerve fibers (axon or myelin) or on the neuronal body (dorsal root ganglia primary sensory neurons or, very occasionally, motor neurons). Accordingly, the clinical features of druginduced neuropathy are also dependent on the type of agent involved, inducing exclusively sensory or sensorimotor neuropathy, with or without autonomic impairment and pain. Neurotoxic antineoplastic agents represent a major clinical problem given their widespread use, the potential severity of their toxicity, and the obvious reluctance of oncologists to change effective schedules of treatment despite the occurrence of side-effects. Nevertheless, chemotherapy-induced peripheral neurotoxicity (CIPN) is frequently a dose-limiting side-effect in the treatment of cancer and, even when this is not the case, its onset may severely affect the quality of life of patients with cancer and cause permanent or long-lasting discomfort, a fact particularly relevant in patients with a good prognosis (Fossa et al., 2003). Another peculiar aspect of CIPN is that the effects of several very effective drugs not only may appear during chemotherapy, but they may even worsen after treatment withdrawal (the ‘coasting’ phenomenon), thus representing a considerable challenge in their monitoring and reporting. Finally, it is worth noting that not only the oldest drugs (e.g., platinum-derived compounds, vinca alkaloids, and taxanes) but also several of the most recent and effective agents, such as the first-in-class proteasome inhibitors and epothilones, evidenced considerable peripheral neurotoxicity in the earliest clinical trials. Given their mechanism of antineoplastic action, it is unlikely that their derivates will be devoid of this side-effect (Cavaletti and Marmiroli, 2004). In view of the above, it is clear that CIPN should be assessed carefully and reliably. The most suitable tool for assessing and monitoring the neurotoxic effect of
*Correspondence to: G. Cavaletti, Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, Via Cadore 48, 20052 Monza, Italy. Tel: þ 39 02 6448 8039, Fax: þ39 02 6448 8250, E-mail: [email protected]
164 G. CAVALETTI AND P. MARMIROLI antineoplastic agents should be clinically relevant, assessment of a given compound may be markedly fast and easy to use, reliable and reproducible, specific different when performed by oncologists or neuroloand sensitive to severity changes, formally validated, gists, and that different agents are frequently evaluated and universally accepted, and patients should be highly with ‘dedicated’ scales that have never been formally compliant with its items. All of these problems have compared with other, more widely used, scales. already been faced, as demonstrated by the studies on The issue of the best method for investigating and diabetic patients for whom, since the 1980s, different reporting the type and severity of CIPN has been clinical or composite (clinical plus instrumental) scales reviewed extensively by several authors in recent years. have been proposed, validated, and, finally, used in Postma and Heimans (2000), after a very thorough anaclinical trials and daily practice (Dyck et al., 1985). lysis of the results obtained using some of the most In contrast, despite the fact that, also in the 1980s, widely used clinically based oncological scales for neurophysicians started to investigate common neurotoxicity toxicity, demonstrated that disagreement was frequent criteria (Miller et al., 1981) and given that different clinamong examiners and that this effect was due partially ically based scales are currently available, the accurate to different interpretations of scale parameters. The grading of CIPN still represents an unsolved issue authors noted that several pitfalls can be identified when (Postma and Heimans, 2000). This is largely due to examining CIPN, mostly because accurate neurological the lack of sensitivity of most of the proposed scales. examination results are ‘subject to patients’ cooperation Moreover, grading may differ between different examand investigators’ skill and judgment’. iners (Postma et al., 1998). When neurophysiological The ‘common toxicity scales’ (CTS) are the most and semiquantitative testing or composite scores have widely used clinical tools for examining and reporting been used in order to enhance the sensitivity of the the course and severity of CIPN by oncologists; Table 13.1 scales, their results have been strongly influenced by shows some examples. These CTS have several evident the personal expertise of the examiners, by the technical advantages: they are quick to be administered, can be facilities available, and by neurologically or oncologigeneralized to most antineoplastic agents, are well cally based education and practice (Zaslansky and known by oncologists, and do not require any instruYarnitsky, 1998, Krarup, 1999). mental examination. Their simplicity in scoring has also Over the past few years, the evaluation and monitorbeen advocated as another major advantage, although, ing of CIPN have been performed using clinical assessby contrast, it may be an issue that disagreement in ment, semiquantitative methods, neurophysiological scoring is not infrequent for some of their items due tests, and even with neuroimaging techniques or with to different interpretations, particularly in the interthe pathological examination of nerve or skin biopsies. mediate grades of severity (which are frequently the The use of these different tools makes comparison very most clinically relevant) (Postma et al., 1998). An objecdifficult. Moreover, in the vast majority of cases, CIPN tive limitation in CTS use is represented by their reduced evaluation is focused on the sensory and motor scoring range (generally from 0 to 4 or 5), which does not impairment induced by the neurotoxic agents, so that allow a fine graduation of the impairment and may the incidence of autonomic changes and pain has result in a kind of ‘ceiling’ effect around mildnever been clearly established, except in a few cases to-moderate grading of involvement with the most (Quasthoff and Hartung, 2002). neurotoxic agents (Cavaletti et al., 2006). Another negaThe major advantages and limitations of the difftive feature of CTS is the relatively poor information erent methods used to evaluate and monitor peripheral that can be obtained regarding the quality, in addition nerve function in patients with cancer will be discussed to the severity, of the nervous system impairment. For in the following sections, with particular reference to instance, sensory impairment may be located in the the features of CIPN. same parts of the body and may be equally disabling, thus resulting in the same CTS score, although pain– thermal hypoesthesia or ataxia with joint position CLINICAL ASSESSMENT impairment reflect the involvement of two different Examination of the peripheral nervous system is types of fiber. However, the correct identification of a performed routinely in daily practice and clinical trials different quality of sensory impairment is important in in patients with cancer, but it should be acknowledged understanding the pathogenesis of the damage, as it that, at the moment, none of the various tools that has may reflect different sites of neurotoxic action. Morebeen used is accepted universally and fulfills the strict over, in most of these CTS, symptoms, signs, and daily criteria required by a reliable and validated method life activity impairment are grouped within the same (Postma et al., 1998; Postma and Heimans, 2000). For score, thus making it difficult to understand the relative instance, it is significant that the methods used in CIPN importance of each aspect in a given severity grade.
Table 13.1 Summary of some of the most used common toxicity scales
Toxicity scale
0
1
No change
Paresthesias and/or decreased DTR
Severe paresthesias and/or mild weakness
Intolerable paresthesias and/or marked motor loss
Paralysis
None or no change
Mild paresthesias; loss of DTR
Mild or moderate objective sensory loss; moderate paresthesias
–
None or no change
Subjective weakness; no objective findings
Mild objective weakness without significant impairment of function
Severe objective sensory loss or paresthesias that interfere with function Objective weakness with impairment of function
Ajani’s scale (Ajani et al., 1990) Sensory neuropathy
None
Paresthesias and decreased DTR
Motor neuropathy
None
Severe paresthesias; moderate objective abnormality; severe functional abnormality Unable to ambulate
Complete sensory loss, loss of function Complete paralysis
NCI-CTC (version 3.0)*{ Neuropathy – sensory
Mild transient muscle weakness
Mild objective abnormalities; absent DTR; mild to moderate functional abnormality Persistent moderate weakness, but ambulatory
None
Normal
Sensory alterations or paresthesias interfering with function but not with activities of daily living Symptomatic weakness interfering with function but not with activities of daily living
Sensory alterations or paresthesias interfering with activities of daily living Weakness interfering with activities of daily living; bracing or assistance to walk indicated
Disabling
Neuropathy – motor
Asymptomatic; loss of DTR or paresthesias but not interfering with function Asymptomatic; weakness detected on examination or testing only
WHO (Miller et al., 1981) ECOG{ Neurosensory
Neuromotor
2
3
4
Paralysis
Life-threatening, disabling
DTR, deep tendon reflexes; ECOG, Eastern Cooperative Oncology Group; NCI-CTC, National Cancer Institute – Common Terminology Criteria; WHO, World Health Organization. *For all neuropathy items a score of 5 ¼ death (absent in NCI-CTC 2.0) has been included. { Available at http://www.ecog.org/. { Available at http://ctep.cancer.gov/.
EVALUATION AND MONITORING OF PERIPHERAL NERVE FUNCTION
Score
165
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G. CAVALETTI AND P. MARMIROLI
In an attempt to overcome these CTS limitations and to improve CIPN monitoring, several other clinical scales have been developed. These tools are frequently ‘tailored’ to specific drugs or to a class of agents. Although the quality of the neurological information that can be obtained using these scales is generally much higher than when using CTS, because the items are focused on the most frequent symptoms and signs of the compound under investigation, several disadvantages cannot be denied: they take more time to be administered than CTS, specific training is frequently required for their reliable use, and they have never been formally validated in comparison with CTS (it is for this reason that oncologists are reluctant to accept their results and also they cannot be compared with the data generated by other trials). Occasionally CIPN has been investigated using clinical tools originally developed for other neurological diseases. With these instruments, manual dexterity or walking ability, as well as other common functions, can be scored reliably (Lee et al., 2006). However, these functional scales, although objective and reproducible, give only rather general information regarding the neurological changes induced by treatment and, in any case, they have not been validated for use in CIPN. Another major issue of CIPN, which has been recognized clearly only in recent years, is the occurrence of neuropathic pain during or after treatment. In the context of patients with cancer, it is mandatory clearly to distinguish neuropathic pain secondary to toxic damage from cancer pain (e.g., due to direct root or peripheral nerve neoplastic infiltration/compression, paraneoplastic syndrome, bone metastasis). No scales specific for the painful aspects of CIPN have been developed. Up to now, scales used to ascertain the occurrence of neuropathic pain or pain questionnaires (Table 13.2), as well as the older visual analog scales (VAS) for pain, have been used, but they have never been formally validated in this clinical setting. Recently, the ‘patient-oriented’ evaluation of symptoms and functional impairment has also become a major concern in the assessment of patients with cancer. This attitude follows recent increased attention to the quality of life of patients, particularly in view of the increasing number of long-term cancer survivors. Several questionnaires and scales based on the perception of the quality of life and on functional limitations in daily activities have been developed. Some of them have been validated in their ‘basic’ version for general use and, subsequently, have been adapted to assess the most frequent symptoms and signs of specific compounds (Table 13.3 shows some examples) and have also been used to assess the severity of CIPN.
Table 13.2 The DN4 questionnaire for neuropathic pain Interview of the patient Question 1: Does the pain have one or more of the following characteristics? Yes No 1. burning 2. painful cold 3. electric shocks Question 2: Is the pain associated with one or more of the following symptoms in the same area? Yes No 4. tingling 5. pins and needles 6. numbness 7. itching Examination of the patient Question 3: Is the pain located in an area where the physical examination may reveal one or more of the following characteristics? Yes No 8. hypoesthesia to touch 9. hypoesthesia to prick Question 4: In the painful area, can the pain be caused or increased by Yes No 10. brushing Note: A cut-off score of 4 resulted in the highest percentage of correctly identified patients, sensitivity, and specificity (Bouhassira et al., 2005).
SEMIQUANTITATIVE ASSESSMENT The use of devices that can allow physicians to determine, in a semiquantitative way, the extent of sensory and motor impairment can improve the accuracy of peripheral neuropathy assessment. The use of semiquantitative methods in CIPN is derived from the experience accumulated in the evaluation of other neuropathies (Shy et al., 2003). In addition to impaired deep tendon reflexes, reduced vibration sensation (Cavaletti et al., 2004; Hausheer et al., 2006), and impaired epicritic (two-point discrimination) touch perception are among the most common neurological signs of CIPN. Vibration perception threshold (VPT) testing (direct measurement of the objective impairment in these sensory parameters) and thermal threshold (Forsyth et al., 1997) have been used only occasionally as an endpoint for clinical trials, and are rarely used in clinical practice. There are several reasons for the limited use of quantitative sensory testing (QST) methods, including the reduced availability of the instruments, their cost,
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Table 13.3 Examples of questionnaires designed to assess chemotherapy-induced peripheral neurotoxicity Scale
Domains or factors
FACT/GOG-Ntx (Calhoun et al., 2003)
Functional assessment of cancer therapy – taxane* (version 4) (Cella et al., 2003) Functional assessment of cancer therapy – oxaliplatin EORTC QLC-C30
EORTC QLC-CIPN20 (Postma et al., 2005)
No. of items
Scaling
Physical wellbeing Social wellbeing Emotional wellbeing Functional wellbeing Additional concerns (related to neuropathy) Neuropathy symptoms
7 7 7 6 11 16
0–4 0–4 0–4 0–4 0–4 0–4
Neuropathy symptoms
13
0–4
Current symptoms Symptoms present during the last week Overall health Overall quality of life Symptoms present during the last week Car driving (if applicable) Sexual activity (men only)
5 23 1 1 18 1 1
0–4 0–4 0–7 0–7 0–4 0–4 0–4
*Based on the ‘Additional concerns’ (related to neuropathy) of the FACT/GOG-Ntx, with specific modification. FACT/GOG-Ntx, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity. EORTC QLC-C30, European Organization for Research and Treatment of Cancer – Quality of Life Questionnaire Core 30. EORTC QLC-CIPN20, supplement module to EORTC QLC-C30 to assess Chemotherapy-Induced Peripheral Neurotoxicity.
variability in the results obtained with different devices, and, for most neurotoxic drugs, the lack of a formal comparison with accepted clinical scales. Moreover, it has been recognized that QST results are highly influenced by the examiner training and expertise, and that they depend on the patient’s collaboration (Zaslansky and Yarnitsky, 1998), so that the real extent of the advantage over careful clinical examination is still being debated.
NEUROPHYSIOLOGICAL INVESTIGATION Nerve conduction studies are a cornerstone of the peripheral nervous system evaluation, and can be used reliably in clinical trials (Bird et al., 2006). However, although the neurophysiological investigation may be crucial in defining the earliest (frequently subclinical) changes and in assessing the extent of the damage, the usefulness of nerve conduction studies in daily clinical practice should always be weighed against the discomfort for the subjects and the real advantage over clinical assessment. The awareness of pitfalls and possible misinterpretations in nerve conduction studies is also particularly important in CIPN and in paraneoplastic sensory polyneuropathy, where the damage is generally due to axonal damage with fiber loss and not to primary myelin changes. The neurophysiological
counterpart of axonal loss is represented by sensory action potential (SAP) and compound motor action potential (CMAP) reduction, and the accurate and reproducible recording of these neurophysiological parameters can be biased by several technical problems, such as the method of stimulation/recording, the type of device/electrodes, the occurrence of skin temperature changes, and local edema. In general, it should always be considered that repeated measurement of SAP and CMAP can be relatively unreliable, unless well-standardized methods and appropriate reference values are used (Krarup, 1999; Bird et al., 2006). Moreover, careful assessment of the clinical relevance of any neurophysiological change is mandatory in interpreting these parameters, if they are to be really useful for daily clinical practice. In fact, poor correlation between nerve conduction studies and clinical symptoms and severity of CIPN have frequently been documented. One of the possible reasons for this discrepancy is the fact that nerve conduction studies are commonly applied to anatomical regions that are frequently proximal to the anatomical stocking–glove distribution of CIPN, and that nerve conduction studies reflect the status of the best surviving nerve fibers, so that they may remain relatively normal if only a proportion of fibers has been affected by the disease process. Another possible limitation of nerve conduction examination in patients with cancer is that it measures velocity and amplitude in the
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largest diameter and fastest conducting nerve fibers and, therefore, does not provide reliable data on the smallsized fibers, an issue of particular relevance in patients with painful CIPN or paraneoplastic involvement. At present, the use of nerve conduction studies is generally limited to clinical trials or to the examination of selected patients. The electromyographic (EMG) examination of skeletal muscles has very rarely been used in the assessment and monitoring of CIPN, and in patients with cancer in general. This is because motor impairment is only occasionally a major feature of CIPN and of the classical paraneoplastic syndromes, and because needle examination is more invasive then nerve conduction examination and can be scored and reproduced only with difficulty. The use of EMG may be useful in the clinical assessment of isolated nerve, root, or plexus damage when motor impairment is present. Other neurophysiological methods that have been used occasionally to monitor the sensory impairment in patients with cancer are the somatosensory evoked potentials (SEPs) which can be helpful for studying the pathological changes of the centripetal branch of the primary sensory afferents and of the dorsal roots (Bogliun et al., 1992; Sghirlanzoni et al., 2005).
NEUROIMAGING TECHNIQUES As mentioned above, sensory involvement is a frequent feature of CIPN and, more rarely, of classical paraneoplastic syndromes. In view of the technological advances in imaging techniques, it has been proposed that magnetic resonance imaging (MRI) could improve the accuracy of the assessment of sensory symptoms, particularly regarding the central pathway. MRI has been used to study the spinal cord pathological changes induced by cisplatin and thalidomide treatment (Giannini et al., 2003; Sghirlanzoni et al., 2005), but this technique should be considered only as an additional tool in research and in the investigation of selected patients.
PATHOLOGICAL EVALUATION Over the past few years, the examination of sural nerve biopsies and of specimens belonging to post-mortem examinations of treated patients has given some information regarding the pathological changes occurring in CIPN and in paraneoplastic syndromes. However, with reference to CIPN, in most cases the patients had been treated with more than one neurotoxic compound, specimens were obtained at different times during or after chemotherapy, and it was difficult to estimate the effects of the underlying oncological disease and of post-mortem changes. As a result, most of the
available data regarding the pathological changes induced by antineoplastic drugs have been obtained in rodent experimental models. At present there are very few (if any) indications for nerve biopsy in CIPN given the invasiveness of the procedure and the limited amount of additional information that can be obtained in most of the cases over noninvasive investigation. The experience accumulated in the investigation of neuropathic patients (Lauria et al., 2001; Polydefkis et al., 2001; Smith et al., 2001; Polydefkis, 2006) and data obtained from animal models of toxic neuropathy (Lauria et al., 2005), suggest that skin biopsy with the measurement of intraepidermal fiber density may be a possible alternative tool for obtaining useful pathological information where patients are affected by CIPN with predominant sensory impairment. In fact, skin biopsy is a minimally invasive procedure that can be performed in most centers; it could be repeated in the same patient throughout the course of treatment; it could be performed very distally (for this reason it may be more sensitive than nerve conduction studies, particularly in small-fiber neuropathies); and it allows the presence of reinnervation to be investigated (i.e., it could give an indication as to the long-term course of CIPN) (Lauria, 2005). By contrast, estimating intraepidermal fiber density is time-consuming, is dependent on the observer’s training, and, in general, its usefulness in humans should be further confirmed in CIPN.
COMPOSITE SCALES On the basis of the promising results obtained in diabetic neuropathy (Dyck et al., 1997; Cornblath et al., 1999), and in view of the already mentioned lack of validated clinical scales for CIPN, the use of new tools based on the ‘composition’ of clinical and instrumental evaluations has increasingly gained favor over the last few years in the assessment of patients with cancer (Chaudhry et al., 1994; Cornblath et al., 1999; Openshaw et al., 2004; Davis et al., 2005). In most cases, these scales include different combinations of clinical assessment of symptoms and signs, neurophysiological examinations, QST, and, sometimes, an evaluation of quality of life and activity of daily life functions. The most obvious reason for using a composite scale is the assumption that the combination of different instruments can effectively enhance the possibility of detecting and scoring CIPN symptoms and signs, particularly in comparison with the CTS. However, this assumption has never been formally validated on a large scale, and it is difficult to compare the results of different scales. In fact, the endpoints are different among scales, and scales designed for more general use are clearly different from those devoted to the precise definition of the toxicity of a given compound or
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169
Table 13.4 The Total Neuropathy Score, as an example of composite scale Score 0
1
2
3
Symptoms extend to ankle or wrist Moderate difficulty 2
Symptoms extend to knee or elbow Require help/ assistance 3
Symptoms above knees or elbow, or functionally disabling Paralysis
Reduced up to elbow/knee Reduced up to elbow/knee Severe weakness (MRC 2)
Reduced to above elbow/ knee Reduced to above elbow/ knee Paralysis (MRC 0–1)
All reflexes absent
Sensory symptoms
None
Motor symptoms
None
Symptoms limited to finger or toes Slight difficulty
Autonomic symptoms, n Pin sensibility
0
1
Normal
Reduced in fingers/toes Reduced in fingers/toes Mild weakness (MRC 4)
4
4 or 5
Vibration sensibility Strength
Normal
DTR
Normal
Ankle reflex reduced
Reduced up to wrist/ankle Reduced up to wrist/ankle Moderate weakness (MRC 3) Ankle reflex absent
Vibration sensation (QST vibration) Sural nerve SAP
Normal to 125% ULN
126—150% ULN
151—200% ULN
Ankle reflex absent, others reduced 201—300% ULN
Normal/ reduced to < 5% LLN Normal/ reduced to < 5% LLN
76—95% of LLN
51—75% of LLN
26—50% of LLN
0—25% of LLN
76—95% of LLN
51—75% of LLN
26—50% of LLN
0—25% of LLN
Peroneal nerve CMAP
Normal
> 300% ULN
Items in italics are excluded in the clinical version of the Total Neuropathy Score (Cavaletti et al., 2003, 2006). CMAP, amplitude of the compound muscular potential; DTR, deep tendon reflexes; LLN, lower limit of normal; MRC, Medical Research Council; QST, quantitative sensory test; SAP, amplitude of the sensory potential; ULN, upper limit of normal.
combination of drugs. Although the composite scales reported so far (Table 13.4 shows the Total Neuropathy Score, which has been compared to several CTS in different types of CIPN, as an example) (Cavaletti et al., 2003) allow a thorough investigation of several aspects of CIPN and their accurate scoring (and, therefore, they may be extremely useful in clinical trials), the need to perform instrumental examinations makes it difficult to use them in daily practice. For this reason, and because of the same criticisms already discussed with reference to the use of neurophysiological and QST methods in patients with cancer, it has been proposed that only the clinically based parts of these scales be used. When these reduced versions of composite scales were compared with the CTS (Cavaletti et al., 2003, 2006) their superior effectiveness in CIPN grading was hypothesized and the feasibility of their use was confirmed (Hughes, 2008).
CURRENT STATUS AND FUTURE PROSPECTS A critical revision of the current status of evaluation and monitoring of peripheral nerve function in patients with cancer has evidenced that the present situation is unsatisfactory, particularly in patients with CIPN, and that significant improvements need to be made. In fact, a thorough investigation of the features and severity of CIPN is not only important for a better understanding of its pathophysiology, but would also be the starting point for implementing reliable clinical trials aimed at investigating neuroprotective strategies. This goal could be achievable in the near future if an effective network of neurologists and oncologists, supported by international regulatory agencies and patient-oriented groups, were to focus on this topic.
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EVALUATION AND MONITORING OF PERIPHERAL NERVE FUNCTION Polydefkis M, Hauer P, Griffin JW et al. (2001). Skin biopsy as a tool to assess distal small fiber innervation in diabetic neuropathy. Diabetes Technol Ther 3: 23–28. Postma TJ, Heimans JJ (2000). Grading of chemotherapyinduced peripheral neuropathy. Ann Oncol 11: 509–513. Postma TJ, Heimans JJ, Muller MJ et al. (1998). Pitfalls in grading severity of chemotherapy-induced peripheral neuropathy. Ann Oncol 9: 739–744. Postma TJ, Aaronson NK, Heimans JJ et al. (2005). The development of an EORTC quality of life questionnaire to assess chemotherapy-induced peripheral neuropathy: the QLQ-CIPN20. Eur J Cancer 41: 1135–1139. Quasthoff S, Hartung HP (2002). Chemotherapy-induced peripheral neuropathy. J Neurol 249: 9–17.
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Rudnicki SA, Dalmau J (2005). Paraneoplastic syndromes of the peripheral nerves. Curr Opin Neurol 18: 598–603. Sghirlanzoni A, Pareyson D, Lauria G (2005). Sensory neuron diseases. Lancet Neurol 4: 349–361. Shy ME, Frohman EM, So YT et al. (2003). Quantitative sensory testing: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 60: 898–904. Smith AG, Ramachandran P, Tripp S et al. (2001). Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy. Neurology 57: 1701–1704. Zaslansky R, Yarnitsky D (1998). Clinical applications of quantitative sensory testing (QST). J Neurol Sci 153: 215–238.
Chapter 13
Evaluation and monitoring of peripheral nerve function G. CAVALETTI* AND P. MARMIROLI Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, Monza, Italy
INTRODUCTION The peripheral nervous system may be involved in several pathological events in cancer patients and, in some cases, the evaluation and monitoring of nerve damage can be difficult (Paice, 2009; Cavaletti et al., 2010; Gutierrez-Gutierrez et al., 2010). Cancer can directly infiltrate or compress individual nerves, roots, ganglia, or parts of a nerve plexus, causing sensory and/motor impairment depending on the site of the damage. Only rarely do these cases represent a diagnostic challenge and the site of the lesion can be detected using imaging and neurophysiological methods. Occasionally, biopsy of the lesion may be necessary to confirm the results of noninvasive investigations. Some years ago, indirect (‘paraneoplastic’) involvement of dorsal root ganglia neurons and peripheral nerves, possibly due to an immune-mediated mechanism, was suggested. The recognition of a number of ‘classical’ antibodies directed against cancer and peripheral nervous system antigens is currently a very useful additional tool for a correct diagnosis in well-defined neurological paraneoplastic syndromes (Graus et al., 2004). The use of advanced imaging techniques (e.g., positron emission tomography) enhances the possibility of detecting an occult cancer. From a clinical viewpoint, sensory and autonomic impairment are the most common symptoms of neurological paraneoplastic syndromes (Freeman, 2005; Rudnicki and Dalmau, 2005). A more challenging issue in patients with cancer is the recognition and monitoring of iatrogenic damage. Although surgery and radiation therapy may be the cause of mononeuropathy or plexopathy, polyneuropathy is definitely much more frequent as a result of the toxic action of several drugs (Cavaletti and Marmiroli, 2004). The target of drug-induced neurotoxicity is most dependent on the type and distribution of each substance that
can act predominantly on the nerve fibers (axon or myelin) or on the neuronal body (dorsal root ganglia primary sensory neurons or, very occasionally, motor neurons). Accordingly, the clinical features of druginduced neuropathy are also dependent on the type of agent involved, inducing exclusively sensory or sensorimotor neuropathy, with or without autonomic impairment and pain. Neurotoxic antineoplastic agents represent a major clinical problem given their widespread use, the potential severity of their toxicity, and the obvious reluctance of oncologists to change effective schedules of treatment despite the occurrence of side-effects. Nevertheless, chemotherapy-induced peripheral neurotoxicity (CIPN) is frequently a dose-limiting side-effect in the treatment of cancer and, even when this is not the case, its onset may severely affect the quality of life of patients with cancer and cause permanent or long-lasting discomfort, a fact particularly relevant in patients with a good prognosis (Fossa et al., 2003). Another peculiar aspect of CIPN is that the effects of several very effective drugs not only may appear during chemotherapy, but they may even worsen after treatment withdrawal (the ‘coasting’ phenomenon), thus representing a considerable challenge in their monitoring and reporting. Finally, it is worth noting that not only the oldest drugs (e.g., platinum-derived compounds, vinca alkaloids, and taxanes) but also several of the most recent and effective agents, such as the first-in-class proteasome inhibitors and epothilones, evidenced considerable peripheral neurotoxicity in the earliest clinical trials. Given their mechanism of antineoplastic action, it is unlikely that their derivates will be devoid of this side-effect (Cavaletti and Marmiroli, 2004). In view of the above, it is clear that CIPN should be assessed carefully and reliably. The most suitable tool for assessing and monitoring the neurotoxic effect of
*Correspondence to: G. Cavaletti, Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, Via Cadore 48, 20052 Monza, Italy. Tel: þ 39 02 6448 8039, Fax: þ39 02 6448 8250, E-mail: [email protected]
164 G. CAVALETTI AND P. MARMIROLI antineoplastic agents should be clinically relevant, assessment of a given compound may be markedly fast and easy to use, reliable and reproducible, specific different when performed by oncologists or neuroloand sensitive to severity changes, formally validated, gists, and that different agents are frequently evaluated and universally accepted, and patients should be highly with ‘dedicated’ scales that have never been formally compliant with its items. All of these problems have compared with other, more widely used, scales. already been faced, as demonstrated by the studies on The issue of the best method for investigating and diabetic patients for whom, since the 1980s, different reporting the type and severity of CIPN has been clinical or composite (clinical plus instrumental) scales reviewed extensively by several authors in recent years. have been proposed, validated, and, finally, used in Postma and Heimans (2000), after a very thorough anaclinical trials and daily practice (Dyck et al., 1985). lysis of the results obtained using some of the most In contrast, despite the fact that, also in the 1980s, widely used clinically based oncological scales for neurophysicians started to investigate common neurotoxicity toxicity, demonstrated that disagreement was frequent criteria (Miller et al., 1981) and given that different clinamong examiners and that this effect was due partially ically based scales are currently available, the accurate to different interpretations of scale parameters. The grading of CIPN still represents an unsolved issue authors noted that several pitfalls can be identified when (Postma and Heimans, 2000). This is largely due to examining CIPN, mostly because accurate neurological the lack of sensitivity of most of the proposed scales. examination results are ‘subject to patients’ cooperation Moreover, grading may differ between different examand investigators’ skill and judgment’. iners (Postma et al., 1998). When neurophysiological The ‘common toxicity scales’ (CTS) are the most and semiquantitative testing or composite scores have widely used clinical tools for examining and reporting been used in order to enhance the sensitivity of the the course and severity of CIPN by oncologists; Table 13.1 scales, their results have been strongly influenced by shows some examples. These CTS have several evident the personal expertise of the examiners, by the technical advantages: they are quick to be administered, can be facilities available, and by neurologically or oncologigeneralized to most antineoplastic agents, are well cally based education and practice (Zaslansky and known by oncologists, and do not require any instruYarnitsky, 1998, Krarup, 1999). mental examination. Their simplicity in scoring has also Over the past few years, the evaluation and monitorbeen advocated as another major advantage, although, ing of CIPN have been performed using clinical assessby contrast, it may be an issue that disagreement in ment, semiquantitative methods, neurophysiological scoring is not infrequent for some of their items due tests, and even with neuroimaging techniques or with to different interpretations, particularly in the interthe pathological examination of nerve or skin biopsies. mediate grades of severity (which are frequently the The use of these different tools makes comparison very most clinically relevant) (Postma et al., 1998). An objecdifficult. Moreover, in the vast majority of cases, CIPN tive limitation in CTS use is represented by their reduced evaluation is focused on the sensory and motor scoring range (generally from 0 to 4 or 5), which does not impairment induced by the neurotoxic agents, so that allow a fine graduation of the impairment and may the incidence of autonomic changes and pain has result in a kind of ‘ceiling’ effect around mildnever been clearly established, except in a few cases to-moderate grading of involvement with the most (Quasthoff and Hartung, 2002). neurotoxic agents (Cavaletti et al., 2006). Another negaThe major advantages and limitations of the difftive feature of CTS is the relatively poor information erent methods used to evaluate and monitor peripheral that can be obtained regarding the quality, in addition nerve function in patients with cancer will be discussed to the severity, of the nervous system impairment. For in the following sections, with particular reference to instance, sensory impairment may be located in the the features of CIPN. same parts of the body and may be equally disabling, thus resulting in the same CTS score, although pain– thermal hypoesthesia or ataxia with joint position CLINICAL ASSESSMENT impairment reflect the involvement of two different Examination of the peripheral nervous system is types of fiber. However, the correct identification of a performed routinely in daily practice and clinical trials different quality of sensory impairment is important in in patients with cancer, but it should be acknowledged understanding the pathogenesis of the damage, as it that, at the moment, none of the various tools that has may reflect different sites of neurotoxic action. Morebeen used is accepted universally and fulfills the strict over, in most of these CTS, symptoms, signs, and daily criteria required by a reliable and validated method life activity impairment are grouped within the same (Postma et al., 1998; Postma and Heimans, 2000). For score, thus making it difficult to understand the relative instance, it is significant that the methods used in CIPN importance of each aspect in a given severity grade.
Table 13.1 Summary of some of the most used common toxicity scales
Toxicity scale
0
1
No change
Paresthesias and/or decreased DTR
Severe paresthesias and/or mild weakness
Intolerable paresthesias and/or marked motor loss
Paralysis
None or no change
Mild paresthesias; loss of DTR
Mild or moderate objective sensory loss; moderate paresthesias
–
None or no change
Subjective weakness; no objective findings
Mild objective weakness without significant impairment of function
Severe objective sensory loss or paresthesias that interfere with function Objective weakness with impairment of function
Ajani’s scale (Ajani et al., 1990) Sensory neuropathy
None
Paresthesias and decreased DTR
Motor neuropathy
None
Severe paresthesias; moderate objective abnormality; severe functional abnormality Unable to ambulate
Complete sensory loss, loss of function Complete paralysis
NCI-CTC (version 3.0)*{ Neuropathy – sensory
Mild transient muscle weakness
Mild objective abnormalities; absent DTR; mild to moderate functional abnormality Persistent moderate weakness, but ambulatory
None
Normal
Sensory alterations or paresthesias interfering with function but not with activities of daily living Symptomatic weakness interfering with function but not with activities of daily living
Sensory alterations or paresthesias interfering with activities of daily living Weakness interfering with activities of daily living; bracing or assistance to walk indicated
Disabling
Neuropathy – motor
Asymptomatic; loss of DTR or paresthesias but not interfering with function Asymptomatic; weakness detected on examination or testing only
WHO (Miller et al., 1981) ECOG{ Neurosensory
Neuromotor
2
3
4
Paralysis
Life-threatening, disabling
DTR, deep tendon reflexes; ECOG, Eastern Cooperative Oncology Group; NCI-CTC, National Cancer Institute – Common Terminology Criteria; WHO, World Health Organization. *For all neuropathy items a score of 5 ¼ death (absent in NCI-CTC 2.0) has been included. { Available at http://www.ecog.org/. { Available at http://ctep.cancer.gov/.
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Score
165
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G. CAVALETTI AND P. MARMIROLI
In an attempt to overcome these CTS limitations and to improve CIPN monitoring, several other clinical scales have been developed. These tools are frequently ‘tailored’ to specific drugs or to a class of agents. Although the quality of the neurological information that can be obtained using these scales is generally much higher than when using CTS, because the items are focused on the most frequent symptoms and signs of the compound under investigation, several disadvantages cannot be denied: they take more time to be administered than CTS, specific training is frequently required for their reliable use, and they have never been formally validated in comparison with CTS (it is for this reason that oncologists are reluctant to accept their results and also they cannot be compared with the data generated by other trials). Occasionally CIPN has been investigated using clinical tools originally developed for other neurological diseases. With these instruments, manual dexterity or walking ability, as well as other common functions, can be scored reliably (Lee et al., 2006). However, these functional scales, although objective and reproducible, give only rather general information regarding the neurological changes induced by treatment and, in any case, they have not been validated for use in CIPN. Another major issue of CIPN, which has been recognized clearly only in recent years, is the occurrence of neuropathic pain during or after treatment. In the context of patients with cancer, it is mandatory clearly to distinguish neuropathic pain secondary to toxic damage from cancer pain (e.g., due to direct root or peripheral nerve neoplastic infiltration/compression, paraneoplastic syndrome, bone metastasis). No scales specific for the painful aspects of CIPN have been developed. Up to now, scales used to ascertain the occurrence of neuropathic pain or pain questionnaires (Table 13.2), as well as the older visual analog scales (VAS) for pain, have been used, but they have never been formally validated in this clinical setting. Recently, the ‘patient-oriented’ evaluation of symptoms and functional impairment has also become a major concern in the assessment of patients with cancer. This attitude follows recent increased attention to the quality of life of patients, particularly in view of the increasing number of long-term cancer survivors. Several questionnaires and scales based on the perception of the quality of life and on functional limitations in daily activities have been developed. Some of them have been validated in their ‘basic’ version for general use and, subsequently, have been adapted to assess the most frequent symptoms and signs of specific compounds (Table 13.3 shows some examples) and have also been used to assess the severity of CIPN.
Table 13.2 The DN4 questionnaire for neuropathic pain Interview of the patient Question 1: Does the pain have one or more of the following characteristics? Yes No 1. burning 2. painful cold 3. electric shocks Question 2: Is the pain associated with one or more of the following symptoms in the same area? Yes No 4. tingling 5. pins and needles 6. numbness 7. itching Examination of the patient Question 3: Is the pain located in an area where the physical examination may reveal one or more of the following characteristics? Yes No 8. hypoesthesia to touch 9. hypoesthesia to prick Question 4: In the painful area, can the pain be caused or increased by Yes No 10. brushing Note: A cut-off score of 4 resulted in the highest percentage of correctly identified patients, sensitivity, and specificity (Bouhassira et al., 2005).
SEMIQUANTITATIVE ASSESSMENT The use of devices that can allow physicians to determine, in a semiquantitative way, the extent of sensory and motor impairment can improve the accuracy of peripheral neuropathy assessment. The use of semiquantitative methods in CIPN is derived from the experience accumulated in the evaluation of other neuropathies (Shy et al., 2003). In addition to impaired deep tendon reflexes, reduced vibration sensation (Cavaletti et al., 2004; Hausheer et al., 2006), and impaired epicritic (two-point discrimination) touch perception are among the most common neurological signs of CIPN. Vibration perception threshold (VPT) testing (direct measurement of the objective impairment in these sensory parameters) and thermal threshold (Forsyth et al., 1997) have been used only occasionally as an endpoint for clinical trials, and are rarely used in clinical practice. There are several reasons for the limited use of quantitative sensory testing (QST) methods, including the reduced availability of the instruments, their cost,
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Table 13.3 Examples of questionnaires designed to assess chemotherapy-induced peripheral neurotoxicity Scale
Domains or factors
FACT/GOG-Ntx (Calhoun et al., 2003)
Functional assessment of cancer therapy – taxane* (version 4) (Cella et al., 2003) Functional assessment of cancer therapy – oxaliplatin EORTC QLC-C30
EORTC QLC-CIPN20 (Postma et al., 2005)
No. of items
Scaling
Physical wellbeing Social wellbeing Emotional wellbeing Functional wellbeing Additional concerns (related to neuropathy) Neuropathy symptoms
7 7 7 6 11 16
0–4 0–4 0–4 0–4 0–4 0–4
Neuropathy symptoms
13
0–4
Current symptoms Symptoms present during the last week Overall health Overall quality of life Symptoms present during the last week Car driving (if applicable) Sexual activity (men only)
5 23 1 1 18 1 1
0–4 0–4 0–7 0–7 0–4 0–4 0–4
*Based on the ‘Additional concerns’ (related to neuropathy) of the FACT/GOG-Ntx, with specific modification. FACT/GOG-Ntx, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity. EORTC QLC-C30, European Organization for Research and Treatment of Cancer – Quality of Life Questionnaire Core 30. EORTC QLC-CIPN20, supplement module to EORTC QLC-C30 to assess Chemotherapy-Induced Peripheral Neurotoxicity.
variability in the results obtained with different devices, and, for most neurotoxic drugs, the lack of a formal comparison with accepted clinical scales. Moreover, it has been recognized that QST results are highly influenced by the examiner training and expertise, and that they depend on the patient’s collaboration (Zaslansky and Yarnitsky, 1998), so that the real extent of the advantage over careful clinical examination is still being debated.
NEUROPHYSIOLOGICAL INVESTIGATION Nerve conduction studies are a cornerstone of the peripheral nervous system evaluation, and can be used reliably in clinical trials (Bird et al., 2006). However, although the neurophysiological investigation may be crucial in defining the earliest (frequently subclinical) changes and in assessing the extent of the damage, the usefulness of nerve conduction studies in daily clinical practice should always be weighed against the discomfort for the subjects and the real advantage over clinical assessment. The awareness of pitfalls and possible misinterpretations in nerve conduction studies is also particularly important in CIPN and in paraneoplastic sensory polyneuropathy, where the damage is generally due to axonal damage with fiber loss and not to primary myelin changes. The neurophysiological
counterpart of axonal loss is represented by sensory action potential (SAP) and compound motor action potential (CMAP) reduction, and the accurate and reproducible recording of these neurophysiological parameters can be biased by several technical problems, such as the method of stimulation/recording, the type of device/electrodes, the occurrence of skin temperature changes, and local edema. In general, it should always be considered that repeated measurement of SAP and CMAP can be relatively unreliable, unless well-standardized methods and appropriate reference values are used (Krarup, 1999; Bird et al., 2006). Moreover, careful assessment of the clinical relevance of any neurophysiological change is mandatory in interpreting these parameters, if they are to be really useful for daily clinical practice. In fact, poor correlation between nerve conduction studies and clinical symptoms and severity of CIPN have frequently been documented. One of the possible reasons for this discrepancy is the fact that nerve conduction studies are commonly applied to anatomical regions that are frequently proximal to the anatomical stocking–glove distribution of CIPN, and that nerve conduction studies reflect the status of the best surviving nerve fibers, so that they may remain relatively normal if only a proportion of fibers has been affected by the disease process. Another possible limitation of nerve conduction examination in patients with cancer is that it measures velocity and amplitude in the
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largest diameter and fastest conducting nerve fibers and, therefore, does not provide reliable data on the smallsized fibers, an issue of particular relevance in patients with painful CIPN or paraneoplastic involvement. At present, the use of nerve conduction studies is generally limited to clinical trials or to the examination of selected patients. The electromyographic (EMG) examination of skeletal muscles has very rarely been used in the assessment and monitoring of CIPN, and in patients with cancer in general. This is because motor impairment is only occasionally a major feature of CIPN and of the classical paraneoplastic syndromes, and because needle examination is more invasive then nerve conduction examination and can be scored and reproduced only with difficulty. The use of EMG may be useful in the clinical assessment of isolated nerve, root, or plexus damage when motor impairment is present. Other neurophysiological methods that have been used occasionally to monitor the sensory impairment in patients with cancer are the somatosensory evoked potentials (SEPs) which can be helpful for studying the pathological changes of the centripetal branch of the primary sensory afferents and of the dorsal roots (Bogliun et al., 1992; Sghirlanzoni et al., 2005).
NEUROIMAGING TECHNIQUES As mentioned above, sensory involvement is a frequent feature of CIPN and, more rarely, of classical paraneoplastic syndromes. In view of the technological advances in imaging techniques, it has been proposed that magnetic resonance imaging (MRI) could improve the accuracy of the assessment of sensory symptoms, particularly regarding the central pathway. MRI has been used to study the spinal cord pathological changes induced by cisplatin and thalidomide treatment (Giannini et al., 2003; Sghirlanzoni et al., 2005), but this technique should be considered only as an additional tool in research and in the investigation of selected patients.
PATHOLOGICAL EVALUATION Over the past few years, the examination of sural nerve biopsies and of specimens belonging to post-mortem examinations of treated patients has given some information regarding the pathological changes occurring in CIPN and in paraneoplastic syndromes. However, with reference to CIPN, in most cases the patients had been treated with more than one neurotoxic compound, specimens were obtained at different times during or after chemotherapy, and it was difficult to estimate the effects of the underlying oncological disease and of post-mortem changes. As a result, most of the
available data regarding the pathological changes induced by antineoplastic drugs have been obtained in rodent experimental models. At present there are very few (if any) indications for nerve biopsy in CIPN given the invasiveness of the procedure and the limited amount of additional information that can be obtained in most of the cases over noninvasive investigation. The experience accumulated in the investigation of neuropathic patients (Lauria et al., 2001; Polydefkis et al., 2001; Smith et al., 2001; Polydefkis, 2006) and data obtained from animal models of toxic neuropathy (Lauria et al., 2005), suggest that skin biopsy with the measurement of intraepidermal fiber density may be a possible alternative tool for obtaining useful pathological information where patients are affected by CIPN with predominant sensory impairment. In fact, skin biopsy is a minimally invasive procedure that can be performed in most centers; it could be repeated in the same patient throughout the course of treatment; it could be performed very distally (for this reason it may be more sensitive than nerve conduction studies, particularly in small-fiber neuropathies); and it allows the presence of reinnervation to be investigated (i.e., it could give an indication as to the long-term course of CIPN) (Lauria, 2005). By contrast, estimating intraepidermal fiber density is time-consuming, is dependent on the observer’s training, and, in general, its usefulness in humans should be further confirmed in CIPN.
COMPOSITE SCALES On the basis of the promising results obtained in diabetic neuropathy (Dyck et al., 1997; Cornblath et al., 1999), and in view of the already mentioned lack of validated clinical scales for CIPN, the use of new tools based on the ‘composition’ of clinical and instrumental evaluations has increasingly gained favor over the last few years in the assessment of patients with cancer (Chaudhry et al., 1994; Cornblath et al., 1999; Openshaw et al., 2004; Davis et al., 2005). In most cases, these scales include different combinations of clinical assessment of symptoms and signs, neurophysiological examinations, QST, and, sometimes, an evaluation of quality of life and activity of daily life functions. The most obvious reason for using a composite scale is the assumption that the combination of different instruments can effectively enhance the possibility of detecting and scoring CIPN symptoms and signs, particularly in comparison with the CTS. However, this assumption has never been formally validated on a large scale, and it is difficult to compare the results of different scales. In fact, the endpoints are different among scales, and scales designed for more general use are clearly different from those devoted to the precise definition of the toxicity of a given compound or
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169
Table 13.4 The Total Neuropathy Score, as an example of composite scale Score 0
1
2
3
Symptoms extend to ankle or wrist Moderate difficulty 2
Symptoms extend to knee or elbow Require help/ assistance 3
Symptoms above knees or elbow, or functionally disabling Paralysis
Reduced up to elbow/knee Reduced up to elbow/knee Severe weakness (MRC 2)
Reduced to above elbow/ knee Reduced to above elbow/ knee Paralysis (MRC 0–1)
All reflexes absent
Sensory symptoms
None
Motor symptoms
None
Symptoms limited to finger or toes Slight difficulty
Autonomic symptoms, n Pin sensibility
0
1
Normal
Reduced in fingers/toes Reduced in fingers/toes Mild weakness (MRC 4)
4
4 or 5
Vibration sensibility Strength
Normal
DTR
Normal
Ankle reflex reduced
Reduced up to wrist/ankle Reduced up to wrist/ankle Moderate weakness (MRC 3) Ankle reflex absent
Vibration sensation (QST vibration) Sural nerve SAP
Normal to 125% ULN
126—150% ULN
151—200% ULN
Ankle reflex absent, others reduced 201—300% ULN
Normal/ reduced to < 5% LLN Normal/ reduced to < 5% LLN
76—95% of LLN
51—75% of LLN
26—50% of LLN
0—25% of LLN
76—95% of LLN
51—75% of LLN
26—50% of LLN
0—25% of LLN
Peroneal nerve CMAP
Normal
> 300% ULN
Items in italics are excluded in the clinical version of the Total Neuropathy Score (Cavaletti et al., 2003, 2006). CMAP, amplitude of the compound muscular potential; DTR, deep tendon reflexes; LLN, lower limit of normal; MRC, Medical Research Council; QST, quantitative sensory test; SAP, amplitude of the sensory potential; ULN, upper limit of normal.
combination of drugs. Although the composite scales reported so far (Table 13.4 shows the Total Neuropathy Score, which has been compared to several CTS in different types of CIPN, as an example) (Cavaletti et al., 2003) allow a thorough investigation of several aspects of CIPN and their accurate scoring (and, therefore, they may be extremely useful in clinical trials), the need to perform instrumental examinations makes it difficult to use them in daily practice. For this reason, and because of the same criticisms already discussed with reference to the use of neurophysiological and QST methods in patients with cancer, it has been proposed that only the clinically based parts of these scales be used. When these reduced versions of composite scales were compared with the CTS (Cavaletti et al., 2003, 2006) their superior effectiveness in CIPN grading was hypothesized and the feasibility of their use was confirmed (Hughes, 2008).
CURRENT STATUS AND FUTURE PROSPECTS A critical revision of the current status of evaluation and monitoring of peripheral nerve function in patients with cancer has evidenced that the present situation is unsatisfactory, particularly in patients with CIPN, and that significant improvements need to be made. In fact, a thorough investigation of the features and severity of CIPN is not only important for a better understanding of its pathophysiology, but would also be the starting point for implementing reliable clinical trials aimed at investigating neuroprotective strategies. This goal could be achievable in the near future if an effective network of neurologists and oncologists, supported by international regulatory agencies and patient-oriented groups, were to focus on this topic.
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