J Neurooncol (2015) 121:229–237 DOI 10.1007/s11060-014-1632-x
TOPIC REVIEW
Chemotherapy-induced peripheral neuropathies in hematological malignancies Joost Louis Marie Jongen • Annemiek Broijl Pieter Sonneveld
•
Received: 26 August 2014 / Accepted: 15 October 2014 / Published online: 19 October 2014 Ó Springer Science+Business Media New York 2014
Abstract Recent developments in the treatment of hematological malignancies, especially with the advent of proteasome inhibitors and immunomodulatory drugs in plasma cell dyscrasias, call for an increased collaboration between hematologists and neurologists. This collaboration involves differentiating chemotherapy-induced peripheral neuropathies (CiPN) from disease-related neurologic complications, early recognition of CiPN and treatment of neuropathic pain. Multiple myeloma, Waldenstrom’s macroglobulinemia and light-chain amyloidosis frequently present with peripheral neuropathy. In addition, multiple myeloma, non-Hodgkin lymphomas and leukemia’s may mimic peripheral neuropathy by compression or invasion of the extra/intradural space. Platinum compounds, vinca alkaloids, proteasome inhibitors and immunomodulatory drugs may all cause CiPN, each with different and often specific clinical characteristics. Early recognition, by identifying the distinct clinical phenotype of CiPN, is of crucial importance to prevent irreversible neurological damage. No recommendations can be given on the use of neuroprotective strategies because of a lack of convincing clinical evidence. Finally, CiPN caused by vinca-alkaloids, proteasome inhibitors and immunomodulatory drugs is often painful and neurologists are best equipped to treat this kind of painful neuropathy.
Keywords Chemotherapy Neuropathic pain Hematological Prevention
Introduction Peripheral neuropathy in hematological malignancies can occur as a disease related complication or may develop in the course of treatment with chemotherapeutics. Disease related peripheral neuropathy is associated with M-protein, i.e. paraprotein produced in plasma cell dyscrasias, and peripheral neuropathy mimics may occur as a consequence of central nervous system (CNS) localization of nonHodgkin lymphoma and the leukemias. Chemotherapyinduced peripheral neuropathy (CiPN) has become an increasingly frequent complication of (new) pharmaceuticals against multiple myeloma, non-Hodgkin lymphoma and the leukemias. Drugs that are associated with CiPN in hematological malignancies include cis-platinum, vincristine, proteasome inhibitors and immunomodulatory drugs. This article will give an overview of the clinical presentation and pathophysiology of CiPN and will focus on practical issues such as monitoring, prevention and management of treatment-emergent peripheral neuropathy.
Incidence, pathophysiology and clinical presentation of chemotherapy-induced peripheral neuropathy J. L. M. Jongen (&) Department of Neurology, Erasmus MC, ‘s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands e-mail: [email protected] A. Broijl P. Sonneveld Department of Hematology, Erasmus MC Cancer Institute, ‘s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
General clinical presentation of CiPN CiPN is caused by damage to nerve fibers, more specifically the axon, or the dorsal root ganglion (DRG). Although peripheral neuropathy mostly presents as a distal, symmetrical, sensory neuropathy, motor and/or autonomic
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Table 1 Epidemiological, clinical and electrophysiological characteristics of CiPN Group
Specific drug
PN incidence 1–4 (%)
PN incidence 3–4 (%)
Clinical features
NCS/EMG features
Platinum compounds
cis-Platinum
30
NR
Dose-related, non-painful paresthesias of extremities, may progress to sensory ataxia, coasting phenomenon
Reduced amplitude of sensory nerve action potential (SNAP)
Vinca alkaloids
Vincristine
30–40
2
Dose-related sensory loss, pain, autonomic symptoms, distal muscle weakness
Proteasome inhibitors
Bortezomib
26–46
24
Subacute sensory neuropathy, often painful, partially dose related with ceiling effect
Reduced amplitude of SNAP and compound muscle action potential (CMAP) NCS may be normal, as preferentially small diameter nerve fibers are affected, reduced SNAP
Carfilzomib
14–19
2
NR
NR
Thalidomide
10–55
3–15
Dose-related sensory neuropathy, often painful, onset usually slower than for BiPN
Reduced SNAP, NCS may be normal
Lenalidomide
24
1
NR
NR
Pomalidomide \5
0
NR
NR
Immunomodulatory drugs
CiPN chemotherapy induced peripheral neuropathy, PN incidence 1–4 incidence of peripheral neuropathy grade 1–4 on the NCTC scale, i.e. all peripheral neuropathy, PN incidence 3–4 incidence of peripheral neuropathy grade 3–4 on the CTC scale, i.e. severe neuropathy, NCS/EMG nerve conduction studies/electromyography, NR not reported
nerve fibers may be affected. Motor symptoms are relatively rare in CiPN and mostly occur in the context of severe sensory peripheral neuropathy. Neuropathic pain may occur spontaneously or may be evoked by normally non-noxious stimuli such as palpation, cold or warmth and is then called allodynia. Neuropathic pain may be described as an annoying, sharp, burning, cold, numb etc. feeling, which does not resemble ‘‘normal’’ pain. Since pain is transmitted through thinly myelinated or unmyelinated nerve fibers that serve pinprick and temperature sensation, these sensory qualities are often affected at neurological examination [1]. Autonomic symptoms, such as orthostatic hypotension, bradycardia, constipation, incontinence and erectile dysfunction may occur in CiPN and are caused by damage to pre- and post-ganglionic autonomic nerve fibers. A summary of different chemotherapeutics and their associated peripheral neuropathy is shown in Table 1. Platinum compounds Platinum-induced peripheral neuropathy occurs in about 30 % of patients using cis-platinum, which results in 20 % being forced to discontinue treatment [2]. Platinum-induced peripheral neuropathy is related to the total cumulative dose but possibly not to the dose-intensity of treatment [3]. It starts at a cumulative dose of 250–350 mg/m2, while at a cumulative dose of 500–600 mg/m2 almost all patients have objective evidence of neuropathy.
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The DRG is the main target of platinum-induced peripheral neuropathy. Two mechanisms underlying platinum-induced peripheral neuropathy, which have been identified in cultured DRG neurons and experimental animals, have been put forward. The first mechanism involves platinum-induced crosslinking of DNA [4], resulting in an altered tertiary DNA structure and ultimately apoptosis of DRG neurons [5]. The second mechanism involves binding of platinum to mitochondrial DNA ultimately inducing delayed neuronal death [6]. Cis-platinum neurotoxicity typically affects large diameter sensory neurons. Even though platinum-induced peripheral neuropathy is considered a ganglionopathy, clinically patients almost invariably present with nonpainful paresthesias in hands and feet, i.e. a lengthdependent distribution. At neurological examination, a loss of sense of vibration, position and movement and reduced myotatic reflexes are found. l‘Hermitte’ phenomenon is caused by Wallerian degeneration of the central projections of the DRG. Risk factors include previous neuropathy, low magnesium levels and combination with other neurotoxic agents. Platinum-induced peripheral neuropathy may progress to painful paresthesias and ataxia for months after cessation of cis-platinum and symptoms may develop as long as 3–6 weeks after the last chemotherapy [7], called the coasting phenomenon. However, a gradual improvement following withdrawal occurs in most patients. Nerve conduction studies (NCS) consistently demonstrate sensory axonal damage with reduced amplitude of the sensory
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nerve action potential (SNAP), while conduction velocity and motor nerve conduction remain intact. Somatosensory evoked potentials may be another sensitive neurophysiologic test for platinum-induced peripheral neuropathy [8]. Vinca alkaloids Neurotoxicity due to vinca alkaloids, with vincristine being the most neurotoxic, develops in 30–40 % of patients [9]. The severity of vincristine-induced peripheral neuropathy is total cumulative dose related, occurring in most patients after administration of more than 4 mg/m2 vincristine. Sensory signs appear first; with doses [6–8 mg/m2 distal motor weakness is not uncommon [10], as well as neuropathic pain [11] and autonomic dysfunction [12]. Vinca alkaloids exert their antineoplastic effect by inhibiting microtubule formation in mitotic spindles, resulting in arrest of dividing cells at the metaphase stage and ultimately leading to cancer cell death. Microtubuli, however, are also essential for anterograde and retrograde transport in axons [13]. Neurons are dependent for their survival on retrogradely transported neurotrophic factors. In addition, because of an impairment of anterograde transport, neurofilaments and axoplasmic organelles accumulate in the cell body, thus disrupting neuronal cell function. Pathological changes that have been demonstrated in an animal model of vincristine-induced peripheral neuropathy include swelling and disorganization of microtubules in both myelinated and unmyelinated axons, evidence of impaired axonal transport in the cell bodies [14] and a reduction of intra-epidermal nerve fibers [15]. There was, however, no loss of more proximal axons, which may explain recovery in clinical vincristine-induced peripheral neuropathy. Vincristine-induced peripheral neuropathy may start with paresthesias in the fingers instead of toes, which is unusual for a dying-back neuropathy in which the longest fibers are usually affected first. Apart from sensory loss, vincristineinduced peripheral neuropathy may also cause ataxia, pain and (distal) muscle weakness, resulting in foot drop [9]. A significant proportion of patients will also develop autonomic symptoms [16], like urinary retention and erectile dysfunction. Although vincristine-induced peripheral neuropathy usually improves in months with dose reduction or discontinuation of the drug, the coasting phenomenon was present in up to 30 % of patients in one study [17]. NCS may show a reduction in both sensory nerve and compound motor nerve action potential amplitude. Proteasome inhibitors Bortezomib-induced peripheral neuropathy has been well documented from the time of the initial clinical
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introduction of bortezomib in (heavily) pretreated relapsed/ refractory multiple myeloma patients included in phase II and phase III trials [18, 19], as well as in 26 % up to 46 % of newly diagnosed multiple myeloma patients, while severe neuropathy occurred in up to 24 %. Interestingly, when bortezomib was combined with other potentially neurotoxic agents, such as thalidomide or lenalidomide, this did not further increase the rate of treatment-induced peripheral neuropathy [20]. A history of pre-existing neuropathy (caused by diabetes, previous neurotoxic chemotherapy or M-protein related) may increase the risk of developing bortezomib-induced peripheral neuropathy [21]. Previous exposure to neurotoxic chemotherapy alone, however, does not appear to affect chances of developing bortezomib-induced peripheral neuropathy. Median time to development of peripheral neuropathy in trials using 1.3 mg bortezomib/m2 biweekly and three-week dosing cycles was 6–12 weeks [18, 22]. Although at lower cumulative doses there is a dose response effect, the incidence of bortezomib-induced peripheral neuropathy reaches a plateau at cumulative doses of 30–45 mg/m2 [18, 21]. Apart from toxicity, the risk of developing bortezomib-induced peripheral neuropathy may also be determined by genetic factors. We have previously suggested that it may be dependent on genetic polymorphisms related to bortezomib metabolism and pathways of neurological disease [22, 23]. Bortezomib is a proteasome inhibitor. Proteasomes are protein complexes involved in protein degradation, including pro-apoptotic proteins that induce programmed cell death in (cancer) cells. The anti-tumor effect of bortezomib may be explained by inhibition of proteasomemediated degradation of these pro-apoptotic proteins [24]. Morphological changes in Schwann cells and satellite cells (i.e. supportive cells of the DRG) that were described in a rat model of bortezomib-induced peripheral neuropathy [25] may also be proteasome-mediated and the relative sparing of axons and DRG cells may explain the relatively good prognosis of this peripheral neuropathy. However, these findings do not explain why preferentially thinly and unmyelinated nerve fibers are affected. It was recently suggested that bortezomib-induced peripheral neuropathy occurs via a proteasome-independent mechanism [26], possibly involving mitochondrial dysfunction [27], and that agents that are protective to mitochondria or reduce oxidative stress may be promising to prevent bortezomibinduced peripheral neuropathy [28]. Bortezomib-induced peripheral neuropathy usually presents as a subacute sensory and often painful neuropathy. Neuropathic pain is a prominent feature, occurring in 25–80 % of cases [29]. This can be explained by the fact that bortezomib preferentially affects thinly or unmyelinated nerve fibers [1]. Similarly, signs and symptoms of
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autonomic dysfunction may occur, since these are also served by unmyelininated nerve fibers. Motor fibers are rarely affected. Using dose adjustment schemas developed and validated for bortezomib [18], the prognosis is generally good over a period of weeks-months, including recovery from neuropathic pain. NCS may be normal in bortezomib-induced peripheral neuropathy [18, 29], as preferentially small diameter nerve fibers are involved. Subcutaneous (SC) administration of bortezomib [30] (see also below) and novel bortezomib-like agents such as carfilzomib and ixazomib seem to give rise to much lower percentages of peripheral neuropathy, with \25 % grade B 2 CiPN with carfilzomib [31]. Immunomodulatory drugs Thalidomide was the first drug of a class of drugs of its own that was designed for nausea in pregnant woman in the 1960s. Widely known for it’s teratogenic effects, it was only until the 2000s that it was approved for the treatment of multiple myeloma. Thalidomide-induced peripheral neuropathy has already been described from it’s beginnings. The prevalence of thalidomide-induced peripheral neuropathy ranges from 10–55 %. Collected data showed a higher percentage of patients developing peripheral neuropathy following thalidomide at doses of 200 mg/day or higher in comparison to lower thalidomide doses [32]. Furthermore, an association was found between thalidomide-induced peripheral neuropathy development and duration of treatment [33]. The pathogenesis of thalidomide-induced peripheral neuropathy is poorly understood, but may involve antiangiogenetic and immunomodulatory mechanisms, resulting in partially irreversible damage to distal axons, DRG neurons and central projections of primary afferent neurons [34, 35]. This may explain why reduction of the sural SNAP is the most reliable parameter to detect early neuropathy related to thalidomide and why recovery is often slow and incomplete. A crucial event in thalidomideinduced peripheral neuropathy may be suppression of NFjB, a molecule linked to the p65 (activated by TNFa) and p75 (activated by pro-neurotrophins) receptors [36]. These receptors may induce both apoptosis and cell growth, depending on the circumstances [37]. A dual role for thalidomide is illustrated by clinical observations, which have suggested that thalidomide may be neuroprotective in patients receiving a combination with bortezomib, while being neurotoxic when given as a single agent [38]. As with bortezomib, genetic factors contribute to the risk of developing thalidomide-induced peripheral neuropathy [39] and the genetic signature of thalidomide-induced peripheral neuropathy was different from vincristineinduced peripheral neuropathy [39], alluding to a specific
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genetic underlying mechanism that may explain the distinct clinical phenotypes, i.e. a mainly sensory neuropathy in thalidomide-induced peripheral neuropathy versus a mixed neuropathy in vincristine-induced peripheral neuropathy. Like bortezomib, thalidomide-induced peripheral neuropathy presents as a sensory, often painful neuropathy [40]. It’s onset, however, is usually slower than for bortezomib. Proprioceptive sensory failure and sometimes even a mild motor neuropathy have been described in severe cases [35]. Long-term outcome of thalidomide-induced peripheral neuropathy has not yet been extensively studied, although it is suggested that also thalidomide-induced peripheral neuropathy may improve after thalidomide dose-reduction or discontinuation [16]. A reduction in the SNAP amplitude with relative sparing of the compound motor action potential and nerve conduction velocity is the typical electrophysiological finding, which is indicative of a mostly axonal, sensory neuropathy. However, NCS may be normal in thalidomide-induced peripheral neuropathy, as preferentially small diameter nerve fibers are involved. Concerning other immunomodulatory drugs, most data are available for lenalidomide. In phase I, II and III clinical trials, lenalidomide neurotoxicity concerned mainly grade 1–2 peripheral neuropathy [41]. For pomalidomide so far less than 5 % PN \ grade 2 was reported [42].
Diagnosis, measurement and management of chemotherapy induced peripheral neuropathy We have designed a diagram for the diagnosis, measurement and management of CiPN (Fig. 1). Recognizing uncomplicated CiPN usually is pretty straightforward for both neurologists and hematologists, especially when there is a strong temporal relationship with start and/or dose of chemotherapy. However, suspicion should be raised when the neuropathy does not comply with the distinctive clinical characteristics of each CiPN, as described above. Severe neuropathic pain for example is not common in platinum-induced peripheral neuropathy, a dropping foot does not fit bortezomib-induced peripheral neuropathy. A more complex situation arises in case of preexisting peripheral neuropathy (e.g. diabetic neuropathy, alcohol related neuropathy, hereditary neuropathies etc.), concomitant M-protein related peripheral neuropathy and rarely transplant- or lymphoma- associated immune neuropathy. These conditions usually present with an insidious onset and slow progression in contrast to CiPN, which is more rapidly progressive and is temporally related to dosing of chemotherapy, although coasting may occur with cis-platinum and vincristine. Furthermore, disease related peripheral neuropathy mimics like polyradiculopathy or myelopathy caused by compression or invasion of the CNS
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Fig. 1 Diagram for diagnosis, measurement and management of CiPN signs or symptoms of peripheral neuropathy
asymmetrical, mulfocal, proximal distribuon, predominantly motor
CIPN unlikely
distal, symmetrical distribuon; neuropathy typical for chemotherapy
-qualificaon of neuropathy: motor/sensory/neuropathic pain -quanficaon of neuropathy: NCI-CTC criteria
dose adjustment: -based on recommendaons: bortezomib, thalidomide -based on physician/local protocols: vincrisne decrease dose; cisplanum hold, start carboplan when recovered
-treatment of neuropathic pain -praccal recommendaons
by non-Hodgkin lymphomas or the leukemias and finally, radiation or (intrathecal) chemotherapy-induced polyradiculopathy/myelopathy may resemble CiPN. However, these CNS syndromes can usually be distinguished from peripheral neuropathy by a thorough neurological examination and additional MRI and/or cerebrospinal fluid examination.
After a diagnosis of CiPN has been established, the severity of neuropathy should be quantified, since this is essential for an appropriate intervention. One of the most widely used grading systems for assessing CiPN is the National Cancer Institute’s Common Toxicity Criteria (NCICTC) version 4.0, on which severity of motor and sensory symptoms and neuropathic pain can be scored on a 0–5 scale
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(http://evs.nci.nih.gov/ftp1/CTCAE/). Other grading systems include the 11-item functional assessment of cancer therapy neurotoxicity (Ntx-FACT/GOG) subscale [43]. More complex clinical scales such as the total neuropathy score (TNSr) [18, 44], combining assessment of clinical symptoms with electrophysiological measurements, may result in higher sensitivity for detection of peripheral neuropathy. Although the degree of peripheral neuropathy in NCI-CTC terms is subjective and dependent on patients’ reporting, a recent study reported good intra- en interobserver scores for both the NCI-CTC and TNSr [44]. The additional value of NCS/electromyography (EMG) in CiPN is still a matter of debate. NCS/EMG may appear normal in small fiber neuropathies, such as those induced by bortezomib and thalidomide [45]. Secondly, most current treatment algorithms are based on clinical criteria, i.e. NCI-CTC, rather than on NCS/EMG [18, 46]. Therefore, our personal view is that NCS/EMG should not be part of the standard work-up of CiPN, but may certainly provide valuable additional information in cases where CiPN must be differentiated from pre-existing neuropathy or from concomitant M-protein related peripheral neuropathy. In these cases, a comprehensive or even serial NCS/ EMG(s) may be very helpful and exceptionally skin biopsy or sural nerve biopsy may be considered. Early recognition and timely dose modification or even discontinuation according to guidelines (see below) is essential to prevent more serious and potentially irreversible neurologic damage. Especially, patients with preexisting or concomitant peripheral neuropathy should be watched closely during initial treatment for deterioration of neuropathy. On the other hand, the decision to take a patient off chemotherapy is complicated and should not be made lightly, since the chemotherapy may be the best or even the only treatment for the underlying malignancy. Dose-modification guidelines for the management of bortezomib-induced peripheral neuropathy have been based on experience in early clinical trials and were subsequently validated [18]. This resulted in improvement or resolution of bortezomib-induced peripheral neuropathy in up to 64 % of patients with peripheral neuropathy grade C 2 within a median time of 110 days, while survival outcome did not appear adversely affected in patients who had dose modification [18]. More recently, multi-agent studies have shown that, in addition to dose reduction, weekly dosing may prevent the progression of peripheral neuropathy and reduce severe peripheral neuropathy [47]. Weekly bortezomib dosing is therefore considered an effective strategy to prevent further worsening of peripheral neuropathy once patients have developed bortezomib-induced peripheral neuropathy grade 1. Furthermore, for patients age C 75 years, with comorbidities, frailty or disability who may be more prone to bortezomib-induced peripheral neuropathy, a
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reduced intensity strategy is recommended [48]. Finally, it was published and recently updated that subcutaneous administration of bortezomib versus intravenous administration of bortezomib resulted in non-inferiority in terms of response, but significantly lower rates of bortezomibinduced peripheral neuropathy (53 versus 38 %) as a result of lower peak-dose toxicity [30]. Subcutaneous administration therefore is now the recommended choice of administration. Guidelines for reduction of thalidomide are merely based on expert opinion [49]. Limiting the initial dose of thalidomide to a maximum of 200 mg daily is recommended to prevent rapid development of thalidomideinduced peripheral neuropathy. Because this peripheral neuropathy is correlated with the total cumulative dose, thalidomide should not be given for longer than 6–12 months [46].
Neuroprotective strategies and treatment of neuropathic pain Neuroprotective interventions mostly involve pharmacological treatment administered just before or concomitantly with chemotherapy. Molecules that have been investigated as neuroprotective in CiPN include amifostine, glutathione, calcium and magnesium infusion, glutamine, vitamins, erythropoietine, acetyl-L-carnitine, an ACTH analogue and human leukemia inhibitory factor. However, a recent review on neuroprotective strategies in CiPN concluded that clinical evidence for the efficacy of these drugs is sparse and that therefore no recommendations can be given on the use of neuroprotective agents in CiPN [50]. Our personal view is that given the lack of convincing clinical evidence these agents should not be routinely prescribed, especially when they may be associated with serious side effects, like hypotension in amifostine, or may potentially interfere with anti-neoplastic activity, like vitamin C that blocks the inhibitory effect of bortezomib on proteasome 20S activity in vitro and blocks the inhibitory effect of bortezomib on multiple myeloma growth in vivo [51]. First-line treatment of chemotherapy-induced neuropathic pain includes drugs like gabapentin and pregabalin, together called gabapentinoids; tricyclic antidepressants like amitriptyline, nortriptyline and imipramine; serotonin and norepinephrine reuptake inhibitors like duloxetine and venlafaxine and anti-epileptics like carbamazepine and oxcarbazepine [52]. A suggested order of preference and a summary of dosing-schedules is presented in Table 2. However, we would not recommend prescribing these drugs by someone who is not familiar with treating neuropathic pain, because of potential side-effects, interactions and contra-indications. Opioid analgesics are generally considered second-line treatment for neuropathic pain [53].
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Table 2 Treatment of neuropathic pain Group
Specific drug
Dose of drug
1. Gabapentinoids
Gabapentin
300–1200 mg tid
Pregabalin
75–300 mg bid
Amitriptyline
10–100 mg qd
2. Tricyclic antidepressants
3. SNRI 4. Anti-epileptics
Nortriptyline
10–100 mg qd
Imipramine
25–100 mg qd
Duloxetine
60–90 mg qd
Venlafaxine
75–150 mg qd
Carbamazepine
100–600 mg bid
Oxcarbazepine
150–900 mg bid
SNRI serotonin and norepinephrine reuptake inhibitors
The use of the aforementioned drugs in neuropathic cancer pain is mostly extrapolated from their (proven) efficacy in other neuropathic pain syndromes, such as painful diabetic neuropathy, postherpetic neuralgia and trigeminal neuralgia. Clinical evidence for the use of these compounds in neuropathic cancer pain is sparse, with only three class I (according to the classification of clinical evidence of the American Academy of Neurology) articles specifically on neuropathic cancer pain [54, 55]. Local application of lidocaine or menthol cream may temporarily alleviate chemotherapy-induced neuropathic pain. Simple emollients such as cocoa butter or transcutaneous electrical nerve stimulation (TENS) are safe and may be helpful for symptom relief. Patients may be advised to wear loose-fitting clothes and shoes and to keep feet uncovered in bed, to prevent mechanical allodynia. Patients with autonomic dysfunction should rise cautiously and avoid strenuous physical activity. Patients suffering from severe peripheral neuropathy that are disabled in the exertion of daily tasks may benefit from exercise and physical therapy.
Conclusions and recommendations for clinical practice CiPN has become a frequent dose and treatment limiting adverse event in hematological malignancies, with a major impact on quality of life. In addition, the clinical picture may be obscured by (a concomitant) M-protein related peripheral neuropathy or disease-related peripheral neuropathy mimic. CiPN may occur during and after treatment with cis-platinum, vincristine, thalidomide and bortezomib. For the latter two, dose adjustment guidelines have been developed, thus early recognition of peripheral neuropathy by adhering to these schedules is essential. Fortunately, subcutaneous bortezomib and recently developed second-generation proteasome inhibitors like carfilzomib and immunomodulatory drugs like lenalidomide and pomalidomide confer a much
lower risk on development of peripheral neuropathy. When peripheral neuropathy develops in spite of dose adjustments or treatment discontinuation, gabapentinoids, anti-depressants, SNRIs or anticonvulsants may be considered to treat neuropathic pain and/or practical supportive measures may be considered for all forms of CiPN. No compelling clinical evidence is currently available to recommend the routine use of neuroprotective drugs. Therefore, the key issue to prevent (exacerbation) of CiPN remains early recognition and timely dose modification. Acknowledgments Supported by a clinical research grant from the European Hematology Association, EMCR Translational Research Grant, Janssen Orthobiotech, and Multiple Myeloma Stem cell Network of the European Myeloma Network. Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Cata JP, Weng HR, Burton AW, Villareal H, Giralt S, Dougherty PM (2007) Quantitative sensory findings in patients with bortezomib-induced pain. J Pain 8:296–306 2. Thompson SW, Davis LE, Kornfeld M, Hilgers RD, Standefer JC (1984) Cisplatin neuropathy. Clinical, electrophysiologic, morphologic, and toxicologic studies. Cancer 54:1269–1275 3. Hilkens PH, van der Burg ME, Moll JW, Planting AS, van Putten WL, Vecht CJ, van den Bent MJ (1995) Neurotoxicity is not enhanced by increased dose intensities of cisplatin administration. Eur J Cancer 31A:678–681 4. McDonald ES, Randon KR, Knight A, Windebank AJ (2005) Cisplatin preferentially binds to DNA in dorsal root ganglion neurons in vitro and in vivo: a potential mechanism for neurotoxicity. Neurobiol Dis 18:305–313 5. Gill JS, Windebank AJ (1998) Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle. J Clin Invest 101:2842–2850 6. Podratz JL, Knight AM, Ta LE, Staff NP, Gass JM, Genelin K, Schlattau A, Lathroum L, Windebank AJ (2011) Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons. Neurobiol Dis 41:661–668 7. Mollman JE, Hogan WM, Glover DJ, McCluskey LF (1988) Unusual presentation of cis-platinum neuropathy. Neurology 38:488–490 8. Boogerd W, ten Bokkel Huinink WW, Dalesio O, Hoppenbrouwers WJ, van der Sande JJ (1990) Cisplatin induced neuropathy: central, peripheral and autonomic nerve involvement. J Neurooncol 9:255–263 9. Patchell RA, Posner JB (1985) Neurologic complications of systemic cancer. Neurol Clin 3:729–750 10. Sandler SG, Tobin W, Henderson ES (1969) Vincristine-induced neuropathy. A clinical study of fifty leukemic patients. Neurology 19:367–374 11. Dougherty PM, Cata JP, Burton AW, Vu K, Weng HR (2007) Dysfunction in multiple primary afferent fiber subtypes revealed by quantitative sensory testing in patients with chronic vincristine-induced pain. J Pain Symptom Manage 33:166–179 12. Pal PK (1999) Clinical and electrophysiological studies in vincristine induced neuropathy. Electromyogr Clin Neurophysiol 39:323–330
123
236 13. Korsching S (1993) The neurotrophic factor concept: a reexamination. J Neurosci 13:2739–2748 14. Tanner KD, Levine JD, Topp KS (1998) Microtubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat. J Comp Neurol 395:481–492 15. Siau C, Xiao W, Bennett GJ (2006) Paclitaxel- and vincristineevoked painful peripheral neuropathies: loss of epidermal innervation and activation of Langerhans cells. Exp Neurol 201:507–514 16. Argyriou AA, Bruna J, Marmiroli P, Cavaletti G (2012) Chemotherapy-induced peripheral neurotoxicity (CIPN): an update. Crit Rev Oncol Hematol 82:51–77 17. Verstappen CC, Koeppen S, Heimans JJ, Huijgens PC, Scheulen ME, Strumberg D, Kiburg B, Postma TJ (2005) Dose-related vincristine-induced peripheral neuropathy with unexpected offtherapy worsening. Neurology 64:1076–1077 18. Richardson PG, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Blade J, Boccadoro M, Cavenagh JD, Boral AL, Esseltine DL, Wen PY, Amato AA, Anderson KC, San Miguel J (2009) Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. Br J Haematol 144:895–903 19. Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM (2012) Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol 30:2946–2955 20. Dimopoulos MA, Kastritis E, Christoulas D, Migkou M, Gavriatopoulou M, Gkotzamanidou M, Iakovaki M, Matsouka C, Mparmparoussi D, Roussou M, Efstathiou E, Terpos E (2010) Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities and of previous therapies. Leukemia 24:1769–1778 21. Dimopoulos MA, Mateos MV, Richardson PG, Schlag R, Khuageva NK, Shpilberg O, Kropff M, Spicka I, Palumbo A, Wu KL, Esseltine DL, Liu K, Deraedt W, Cakana A, Van De Velde H, San Miguel JF (2011) Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalanprednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study. Eur J Haematol 86:23–31 22. Broyl A, Corthals SL, Jongen JL, van der Holt B, Kuiper R, de Knegt Y, van Duin M, el Jarari L, Bertsch U, Lokhorst HM, Durie BG, Goldschmidt H, Sonneveld P (2010) Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol 11:1057–1065 23. Corthals SL, Kuiper R, Johnson DC, Sonneveld P, Hajek R, van der Holt B, Magrangeas F, Goldschmidt H, Morgan GJ, AvetLoiseau H (2011) Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients. Haematologica 96:1728–1732 24. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Treon SP, Munshi NC, Richardson PG, Hideshima T, Anderson KC (2002) Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 99:14374–14379
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J Neurooncol (2015) 121:229–237 25. Cavaletti G, Gilardini A, Canta A, Rigamonti L, RodriguezMenendez V, Ceresa C, Marmiroli P, Bossi M, Oggioni N, D’Incalci M, De Coster R (2007) Bortezomib-induced peripheral neurotoxicity: a neurophysiological and pathological study in the rat. Exp Neurol 204:317–325 26. Arastu-Kapur S, Anderl JL, Kraus M, Parlati F, Shenk KD, Lee SJ, Muchamuel T, Bennett MK, Driessen C, Ball AJ, Kirk CJ (2011) Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res 17:2734–2743 27. Zheng H, Xiao WH, Bennett GJ (2012) Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy. Exp Neurol 238:225–234 28. Trevisan G, Materazzi S, Fusi C, Altomare A, Aldini G, Lodovici M, Patacchini R, Geppetti P, Nassini R (2013) Novel therapeutic strategy to prevent chemotherapy-induced persistent sensory neuropathy by TRPA1 blockade. Cancer Res 73:3120–3131 29. Rampen AJ, Jongen JL, van Heuvel I, Scheltens-de Boer M, Sonneveld P, van den Bent MJ (2013) Bortezomib-induced polyneuropathy. Neth J Med 71:128–133 30. Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL (2011) Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 12:431–440 31. Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, Kukreti V, Jagannath S, McDonagh KT, Alsina M, Bahlis NJ, Reu FJ, Gabrail NY, Belch A, Matous JV, Lee P, Rosen P, Sebag M, Vesole DH, Kunkel LA, Wear SM, Wong AF, Orlowski RZ, Siegel DS (2012) An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomibnaive patients with relapsed and/or refractory multiple myeloma. Blood 119:5661–5670 32. Glasmacher A, Hahn C, Hoffmann F, Naumann R, Goldschmidt H, von Lilienfeld-Toal M, Orlopp K, Schmidt-Wolf I, Gorschluter M (2006) A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma. Br J Haematol 132:584–593 33. Richardson P, Schlossman R, Jagannath S, Alsina M, Desikan R, Blood E, Weller E, Mitsiades C, Hideshima T, Davies F, Doss D, Freeman A, Bosch J, Patin J, Knight R, Zeldis J, Dalton W, Anderson K (2004) Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity. Mayo Clin Proc 79:875–882 34. Chaudhry V, Cornblath DR, Corse A, Freimer M, SimmonsO’Brien E, Vogelsang G (2002) Thalidomide-induced neuropathy. Neurology 59:1872–1875 35. Giannini F, Volpi N, Rossi S, Passero S, Fimiani M, Cerase A (2003) Thalidomide-induced neuropathy: a ganglionopathy? Neurology 60:877–878 36. Li S, Xue F, Cheng Z, Yang X, Wang S, Geng F, Pan L (2009) Effect of artesunate on inhibiting proliferation and inducing apoptosis of SP2/0 myeloma cells through affecting NFkappaB p65. Int J Hematol 90:513–521 37. Ibanez CF, Simi A (2012) p75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity. Trends Neurosci 35:431–440 38. Badros A, Goloubeva O, Dalal JS, Can I, Thompson J, Rapoport AP, Heyman M, Akpek G, Fenton RG (2007) Neurotoxicity of bortezomib therapy in multiple myeloma: a single-center experience and review of the literature. Cancer 110:1042–1049 39. Johnson DC, Corthals SL, Walker BA, Ross FM, Gregory WM, Dickens NJ, Lokhorst HM, Goldschmidt H, Davies FE, Durie
J Neurooncol (2015) 121:229–237
40.
41.
42. 43.
44.
45.
46.
BG, Van Ness B, Child JA, Sonneveld P, Morgan GJ (2011) Genetic factors underlying the risk of thalidomide-related neuropathy in patients with multiple myeloma. J Clin Oncol 29:797–804 Cavaletti G, Beronio A, Reni L, Ghiglione E, Schenone A, Briani C, Zara G, Cocito D, Isoardo G, Ciaramitaro P, Plasmati R, Pastorelli F, Frigo M, Piatti M, Carpo M (2004) Thalidomide sensory neurotoxicity: a clinical and neurophysiologic study. Neurology 62:2291–2293 Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foa R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD (2007) Multiple myeloma study I (2007) lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. New Engl J Med 357:2123–2132 Schey S, Ramasamy K (2011) Pomalidomide therapy for myeloma. Expert Opin Investig Drugs 20:691–700 Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M, Yellen SB, Winicour P, Brannon J et al (1993) The functional assessment of cancer therapy scale: development and validation of the general measure. J Clin Oncol Off J Am Soc Clin Oncol 11:570–579 Cavaletti G, Cornblath DR, Merkies IS, Postma TJ, Rossi E, Frigeni B, Alberti P, Bruna J, Velasco R, Argyriou AA, Kalofonos HP, Psimaras D, Ricard D, Pace A, Galie E, Briani C, Dalla Torre C, Faber CG, Lalisang RI, Boogerd W, Brandsma D, Koeppen S, Hense J, Storey D, Kerrigan S, Schenone A, Fabbri S, Valsecchi MG (2013) The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings. Ann Oncol 24:454–462 Richardson PG, Xie W, Mitsiades C, Chanan-Khan AA, Lonial S, Hassoun H, Avigan DE, Oaklander AL, Kuter DJ, Wen PY, Kesari S, Briemberg HR, Schlossman RL, Munshi NC, Heffner LT, Doss D, Esseltine DL, Weller E, Anderson KC, Amato AA (2009) Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. J Clin Oncol 27:3518–3525 Richardson PG, Delforge M, Beksac M, Wen P, Jongen JL, Sezer O, Terpos E, Munshi N, Palumbo A, Rajkumar SV, Harousseau JL, Moreau P, Avet-Loiseau H, Lee JH, Cavo M, Merlini G, Voorhees P, Chng WJ, Mazumder A, Usmani S, Einsele H, Comenzo R, Orlowski R, Vesole D, Lahuerta JJ, Niesvizky R,
237
47.
48. 49.
50.
51.
52.
53.
54.
55.
Siegel D, Mateos MV, Dimopoulos M, Lonial S, Jagannath S, Blade J, Miguel JS, Morgan G, Anderson KC, Durie BG, Sonneveld P (2012) Management of treatment-emergent peripheral neuropathy in multiple myeloma. Leukemia 26:595–608 Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A (2010) Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 116:4745–4753 Palumbo A, Mina R (2013) Management of older adults with multiple myeloma. Blood Rev 27:133–142 Delforge M, Blade J, Dimopoulos MA, Facon T, Kropff M, Ludwig H, Palumbo A, Van Damme P, San-Miguel JF, Sonneveld P (2010) Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol 11:1086–1095 Beijers AJ, Jongen JL, Vreugdenhil G (2012) Chemotherapyinduced neurotoxicity: the value of neuroprotective strategies. Neth J Med 70:18–25 Perrone G, Hideshima T, Ikeda H, Okawa Y, Calabrese E, Gorgun G, Santo L, Cirstea D, Raje N, Chauhan D, Baccarani M, Cavo M, Anderson KC (2009) Ascorbic acid inhibits antitumor activity of bortezomib in vivo. Leukemia 23:1679–1686 Finnerup NB, Sindrup SH, Jensen TS (2010) The evidence for pharmacological treatment of neuropathic pain. Pain 150:573–581 Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy RK, Rice AS, Stacey BR, Treede RD, Turk DC, Wallace MS (2007) Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132:237–251 Jongen JL, Huijsman ML, Jessurun J, Ogenio K, Schipper D, Verkouteren DR, Moorman PW, van der Rijt CC, Vissers KC (2013) The Evidence for Pharmacologic Treatment of Neuropathic Cancer Pain: Beneficial and Adverse Effects. J Pain Symptom Manage 46:581–590 Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, Bressler LR, Fadul CE, Knox C, Le-Lindqwister N, Gilman PB, Shapiro CL, Alliance for Clinical Trials in O (2013) Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA 309:1359–1367
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TOPIC REVIEW
Chemotherapy-induced peripheral neuropathies in hematological malignancies Joost Louis Marie Jongen • Annemiek Broijl Pieter Sonneveld
•
Received: 26 August 2014 / Accepted: 15 October 2014 / Published online: 19 October 2014 Ó Springer Science+Business Media New York 2014
Abstract Recent developments in the treatment of hematological malignancies, especially with the advent of proteasome inhibitors and immunomodulatory drugs in plasma cell dyscrasias, call for an increased collaboration between hematologists and neurologists. This collaboration involves differentiating chemotherapy-induced peripheral neuropathies (CiPN) from disease-related neurologic complications, early recognition of CiPN and treatment of neuropathic pain. Multiple myeloma, Waldenstrom’s macroglobulinemia and light-chain amyloidosis frequently present with peripheral neuropathy. In addition, multiple myeloma, non-Hodgkin lymphomas and leukemia’s may mimic peripheral neuropathy by compression or invasion of the extra/intradural space. Platinum compounds, vinca alkaloids, proteasome inhibitors and immunomodulatory drugs may all cause CiPN, each with different and often specific clinical characteristics. Early recognition, by identifying the distinct clinical phenotype of CiPN, is of crucial importance to prevent irreversible neurological damage. No recommendations can be given on the use of neuroprotective strategies because of a lack of convincing clinical evidence. Finally, CiPN caused by vinca-alkaloids, proteasome inhibitors and immunomodulatory drugs is often painful and neurologists are best equipped to treat this kind of painful neuropathy.
Keywords Chemotherapy Neuropathic pain Hematological Prevention
Introduction Peripheral neuropathy in hematological malignancies can occur as a disease related complication or may develop in the course of treatment with chemotherapeutics. Disease related peripheral neuropathy is associated with M-protein, i.e. paraprotein produced in plasma cell dyscrasias, and peripheral neuropathy mimics may occur as a consequence of central nervous system (CNS) localization of nonHodgkin lymphoma and the leukemias. Chemotherapyinduced peripheral neuropathy (CiPN) has become an increasingly frequent complication of (new) pharmaceuticals against multiple myeloma, non-Hodgkin lymphoma and the leukemias. Drugs that are associated with CiPN in hematological malignancies include cis-platinum, vincristine, proteasome inhibitors and immunomodulatory drugs. This article will give an overview of the clinical presentation and pathophysiology of CiPN and will focus on practical issues such as monitoring, prevention and management of treatment-emergent peripheral neuropathy.
Incidence, pathophysiology and clinical presentation of chemotherapy-induced peripheral neuropathy J. L. M. Jongen (&) Department of Neurology, Erasmus MC, ‘s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands e-mail: [email protected] A. Broijl P. Sonneveld Department of Hematology, Erasmus MC Cancer Institute, ‘s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
General clinical presentation of CiPN CiPN is caused by damage to nerve fibers, more specifically the axon, or the dorsal root ganglion (DRG). Although peripheral neuropathy mostly presents as a distal, symmetrical, sensory neuropathy, motor and/or autonomic
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Table 1 Epidemiological, clinical and electrophysiological characteristics of CiPN Group
Specific drug
PN incidence 1–4 (%)
PN incidence 3–4 (%)
Clinical features
NCS/EMG features
Platinum compounds
cis-Platinum
30
NR
Dose-related, non-painful paresthesias of extremities, may progress to sensory ataxia, coasting phenomenon
Reduced amplitude of sensory nerve action potential (SNAP)
Vinca alkaloids
Vincristine
30–40
2
Dose-related sensory loss, pain, autonomic symptoms, distal muscle weakness
Proteasome inhibitors
Bortezomib
26–46
24
Subacute sensory neuropathy, often painful, partially dose related with ceiling effect
Reduced amplitude of SNAP and compound muscle action potential (CMAP) NCS may be normal, as preferentially small diameter nerve fibers are affected, reduced SNAP
Carfilzomib
14–19
2
NR
NR
Thalidomide
10–55
3–15
Dose-related sensory neuropathy, often painful, onset usually slower than for BiPN
Reduced SNAP, NCS may be normal
Lenalidomide
24
1
NR
NR
Pomalidomide \5
0
NR
NR
Immunomodulatory drugs
CiPN chemotherapy induced peripheral neuropathy, PN incidence 1–4 incidence of peripheral neuropathy grade 1–4 on the NCTC scale, i.e. all peripheral neuropathy, PN incidence 3–4 incidence of peripheral neuropathy grade 3–4 on the CTC scale, i.e. severe neuropathy, NCS/EMG nerve conduction studies/electromyography, NR not reported
nerve fibers may be affected. Motor symptoms are relatively rare in CiPN and mostly occur in the context of severe sensory peripheral neuropathy. Neuropathic pain may occur spontaneously or may be evoked by normally non-noxious stimuli such as palpation, cold or warmth and is then called allodynia. Neuropathic pain may be described as an annoying, sharp, burning, cold, numb etc. feeling, which does not resemble ‘‘normal’’ pain. Since pain is transmitted through thinly myelinated or unmyelinated nerve fibers that serve pinprick and temperature sensation, these sensory qualities are often affected at neurological examination [1]. Autonomic symptoms, such as orthostatic hypotension, bradycardia, constipation, incontinence and erectile dysfunction may occur in CiPN and are caused by damage to pre- and post-ganglionic autonomic nerve fibers. A summary of different chemotherapeutics and their associated peripheral neuropathy is shown in Table 1. Platinum compounds Platinum-induced peripheral neuropathy occurs in about 30 % of patients using cis-platinum, which results in 20 % being forced to discontinue treatment [2]. Platinum-induced peripheral neuropathy is related to the total cumulative dose but possibly not to the dose-intensity of treatment [3]. It starts at a cumulative dose of 250–350 mg/m2, while at a cumulative dose of 500–600 mg/m2 almost all patients have objective evidence of neuropathy.
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The DRG is the main target of platinum-induced peripheral neuropathy. Two mechanisms underlying platinum-induced peripheral neuropathy, which have been identified in cultured DRG neurons and experimental animals, have been put forward. The first mechanism involves platinum-induced crosslinking of DNA [4], resulting in an altered tertiary DNA structure and ultimately apoptosis of DRG neurons [5]. The second mechanism involves binding of platinum to mitochondrial DNA ultimately inducing delayed neuronal death [6]. Cis-platinum neurotoxicity typically affects large diameter sensory neurons. Even though platinum-induced peripheral neuropathy is considered a ganglionopathy, clinically patients almost invariably present with nonpainful paresthesias in hands and feet, i.e. a lengthdependent distribution. At neurological examination, a loss of sense of vibration, position and movement and reduced myotatic reflexes are found. l‘Hermitte’ phenomenon is caused by Wallerian degeneration of the central projections of the DRG. Risk factors include previous neuropathy, low magnesium levels and combination with other neurotoxic agents. Platinum-induced peripheral neuropathy may progress to painful paresthesias and ataxia for months after cessation of cis-platinum and symptoms may develop as long as 3–6 weeks after the last chemotherapy [7], called the coasting phenomenon. However, a gradual improvement following withdrawal occurs in most patients. Nerve conduction studies (NCS) consistently demonstrate sensory axonal damage with reduced amplitude of the sensory
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nerve action potential (SNAP), while conduction velocity and motor nerve conduction remain intact. Somatosensory evoked potentials may be another sensitive neurophysiologic test for platinum-induced peripheral neuropathy [8]. Vinca alkaloids Neurotoxicity due to vinca alkaloids, with vincristine being the most neurotoxic, develops in 30–40 % of patients [9]. The severity of vincristine-induced peripheral neuropathy is total cumulative dose related, occurring in most patients after administration of more than 4 mg/m2 vincristine. Sensory signs appear first; with doses [6–8 mg/m2 distal motor weakness is not uncommon [10], as well as neuropathic pain [11] and autonomic dysfunction [12]. Vinca alkaloids exert their antineoplastic effect by inhibiting microtubule formation in mitotic spindles, resulting in arrest of dividing cells at the metaphase stage and ultimately leading to cancer cell death. Microtubuli, however, are also essential for anterograde and retrograde transport in axons [13]. Neurons are dependent for their survival on retrogradely transported neurotrophic factors. In addition, because of an impairment of anterograde transport, neurofilaments and axoplasmic organelles accumulate in the cell body, thus disrupting neuronal cell function. Pathological changes that have been demonstrated in an animal model of vincristine-induced peripheral neuropathy include swelling and disorganization of microtubules in both myelinated and unmyelinated axons, evidence of impaired axonal transport in the cell bodies [14] and a reduction of intra-epidermal nerve fibers [15]. There was, however, no loss of more proximal axons, which may explain recovery in clinical vincristine-induced peripheral neuropathy. Vincristine-induced peripheral neuropathy may start with paresthesias in the fingers instead of toes, which is unusual for a dying-back neuropathy in which the longest fibers are usually affected first. Apart from sensory loss, vincristineinduced peripheral neuropathy may also cause ataxia, pain and (distal) muscle weakness, resulting in foot drop [9]. A significant proportion of patients will also develop autonomic symptoms [16], like urinary retention and erectile dysfunction. Although vincristine-induced peripheral neuropathy usually improves in months with dose reduction or discontinuation of the drug, the coasting phenomenon was present in up to 30 % of patients in one study [17]. NCS may show a reduction in both sensory nerve and compound motor nerve action potential amplitude. Proteasome inhibitors Bortezomib-induced peripheral neuropathy has been well documented from the time of the initial clinical
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introduction of bortezomib in (heavily) pretreated relapsed/ refractory multiple myeloma patients included in phase II and phase III trials [18, 19], as well as in 26 % up to 46 % of newly diagnosed multiple myeloma patients, while severe neuropathy occurred in up to 24 %. Interestingly, when bortezomib was combined with other potentially neurotoxic agents, such as thalidomide or lenalidomide, this did not further increase the rate of treatment-induced peripheral neuropathy [20]. A history of pre-existing neuropathy (caused by diabetes, previous neurotoxic chemotherapy or M-protein related) may increase the risk of developing bortezomib-induced peripheral neuropathy [21]. Previous exposure to neurotoxic chemotherapy alone, however, does not appear to affect chances of developing bortezomib-induced peripheral neuropathy. Median time to development of peripheral neuropathy in trials using 1.3 mg bortezomib/m2 biweekly and three-week dosing cycles was 6–12 weeks [18, 22]. Although at lower cumulative doses there is a dose response effect, the incidence of bortezomib-induced peripheral neuropathy reaches a plateau at cumulative doses of 30–45 mg/m2 [18, 21]. Apart from toxicity, the risk of developing bortezomib-induced peripheral neuropathy may also be determined by genetic factors. We have previously suggested that it may be dependent on genetic polymorphisms related to bortezomib metabolism and pathways of neurological disease [22, 23]. Bortezomib is a proteasome inhibitor. Proteasomes are protein complexes involved in protein degradation, including pro-apoptotic proteins that induce programmed cell death in (cancer) cells. The anti-tumor effect of bortezomib may be explained by inhibition of proteasomemediated degradation of these pro-apoptotic proteins [24]. Morphological changes in Schwann cells and satellite cells (i.e. supportive cells of the DRG) that were described in a rat model of bortezomib-induced peripheral neuropathy [25] may also be proteasome-mediated and the relative sparing of axons and DRG cells may explain the relatively good prognosis of this peripheral neuropathy. However, these findings do not explain why preferentially thinly and unmyelinated nerve fibers are affected. It was recently suggested that bortezomib-induced peripheral neuropathy occurs via a proteasome-independent mechanism [26], possibly involving mitochondrial dysfunction [27], and that agents that are protective to mitochondria or reduce oxidative stress may be promising to prevent bortezomibinduced peripheral neuropathy [28]. Bortezomib-induced peripheral neuropathy usually presents as a subacute sensory and often painful neuropathy. Neuropathic pain is a prominent feature, occurring in 25–80 % of cases [29]. This can be explained by the fact that bortezomib preferentially affects thinly or unmyelinated nerve fibers [1]. Similarly, signs and symptoms of
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autonomic dysfunction may occur, since these are also served by unmyelininated nerve fibers. Motor fibers are rarely affected. Using dose adjustment schemas developed and validated for bortezomib [18], the prognosis is generally good over a period of weeks-months, including recovery from neuropathic pain. NCS may be normal in bortezomib-induced peripheral neuropathy [18, 29], as preferentially small diameter nerve fibers are involved. Subcutaneous (SC) administration of bortezomib [30] (see also below) and novel bortezomib-like agents such as carfilzomib and ixazomib seem to give rise to much lower percentages of peripheral neuropathy, with \25 % grade B 2 CiPN with carfilzomib [31]. Immunomodulatory drugs Thalidomide was the first drug of a class of drugs of its own that was designed for nausea in pregnant woman in the 1960s. Widely known for it’s teratogenic effects, it was only until the 2000s that it was approved for the treatment of multiple myeloma. Thalidomide-induced peripheral neuropathy has already been described from it’s beginnings. The prevalence of thalidomide-induced peripheral neuropathy ranges from 10–55 %. Collected data showed a higher percentage of patients developing peripheral neuropathy following thalidomide at doses of 200 mg/day or higher in comparison to lower thalidomide doses [32]. Furthermore, an association was found between thalidomide-induced peripheral neuropathy development and duration of treatment [33]. The pathogenesis of thalidomide-induced peripheral neuropathy is poorly understood, but may involve antiangiogenetic and immunomodulatory mechanisms, resulting in partially irreversible damage to distal axons, DRG neurons and central projections of primary afferent neurons [34, 35]. This may explain why reduction of the sural SNAP is the most reliable parameter to detect early neuropathy related to thalidomide and why recovery is often slow and incomplete. A crucial event in thalidomideinduced peripheral neuropathy may be suppression of NFjB, a molecule linked to the p65 (activated by TNFa) and p75 (activated by pro-neurotrophins) receptors [36]. These receptors may induce both apoptosis and cell growth, depending on the circumstances [37]. A dual role for thalidomide is illustrated by clinical observations, which have suggested that thalidomide may be neuroprotective in patients receiving a combination with bortezomib, while being neurotoxic when given as a single agent [38]. As with bortezomib, genetic factors contribute to the risk of developing thalidomide-induced peripheral neuropathy [39] and the genetic signature of thalidomide-induced peripheral neuropathy was different from vincristineinduced peripheral neuropathy [39], alluding to a specific
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genetic underlying mechanism that may explain the distinct clinical phenotypes, i.e. a mainly sensory neuropathy in thalidomide-induced peripheral neuropathy versus a mixed neuropathy in vincristine-induced peripheral neuropathy. Like bortezomib, thalidomide-induced peripheral neuropathy presents as a sensory, often painful neuropathy [40]. It’s onset, however, is usually slower than for bortezomib. Proprioceptive sensory failure and sometimes even a mild motor neuropathy have been described in severe cases [35]. Long-term outcome of thalidomide-induced peripheral neuropathy has not yet been extensively studied, although it is suggested that also thalidomide-induced peripheral neuropathy may improve after thalidomide dose-reduction or discontinuation [16]. A reduction in the SNAP amplitude with relative sparing of the compound motor action potential and nerve conduction velocity is the typical electrophysiological finding, which is indicative of a mostly axonal, sensory neuropathy. However, NCS may be normal in thalidomide-induced peripheral neuropathy, as preferentially small diameter nerve fibers are involved. Concerning other immunomodulatory drugs, most data are available for lenalidomide. In phase I, II and III clinical trials, lenalidomide neurotoxicity concerned mainly grade 1–2 peripheral neuropathy [41]. For pomalidomide so far less than 5 % PN \ grade 2 was reported [42].
Diagnosis, measurement and management of chemotherapy induced peripheral neuropathy We have designed a diagram for the diagnosis, measurement and management of CiPN (Fig. 1). Recognizing uncomplicated CiPN usually is pretty straightforward for both neurologists and hematologists, especially when there is a strong temporal relationship with start and/or dose of chemotherapy. However, suspicion should be raised when the neuropathy does not comply with the distinctive clinical characteristics of each CiPN, as described above. Severe neuropathic pain for example is not common in platinum-induced peripheral neuropathy, a dropping foot does not fit bortezomib-induced peripheral neuropathy. A more complex situation arises in case of preexisting peripheral neuropathy (e.g. diabetic neuropathy, alcohol related neuropathy, hereditary neuropathies etc.), concomitant M-protein related peripheral neuropathy and rarely transplant- or lymphoma- associated immune neuropathy. These conditions usually present with an insidious onset and slow progression in contrast to CiPN, which is more rapidly progressive and is temporally related to dosing of chemotherapy, although coasting may occur with cis-platinum and vincristine. Furthermore, disease related peripheral neuropathy mimics like polyradiculopathy or myelopathy caused by compression or invasion of the CNS
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Fig. 1 Diagram for diagnosis, measurement and management of CiPN signs or symptoms of peripheral neuropathy
asymmetrical, mulfocal, proximal distribuon, predominantly motor
CIPN unlikely
distal, symmetrical distribuon; neuropathy typical for chemotherapy
-qualificaon of neuropathy: motor/sensory/neuropathic pain -quanficaon of neuropathy: NCI-CTC criteria
dose adjustment: -based on recommendaons: bortezomib, thalidomide -based on physician/local protocols: vincrisne decrease dose; cisplanum hold, start carboplan when recovered
-treatment of neuropathic pain -praccal recommendaons
by non-Hodgkin lymphomas or the leukemias and finally, radiation or (intrathecal) chemotherapy-induced polyradiculopathy/myelopathy may resemble CiPN. However, these CNS syndromes can usually be distinguished from peripheral neuropathy by a thorough neurological examination and additional MRI and/or cerebrospinal fluid examination.
After a diagnosis of CiPN has been established, the severity of neuropathy should be quantified, since this is essential for an appropriate intervention. One of the most widely used grading systems for assessing CiPN is the National Cancer Institute’s Common Toxicity Criteria (NCICTC) version 4.0, on which severity of motor and sensory symptoms and neuropathic pain can be scored on a 0–5 scale
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(http://evs.nci.nih.gov/ftp1/CTCAE/). Other grading systems include the 11-item functional assessment of cancer therapy neurotoxicity (Ntx-FACT/GOG) subscale [43]. More complex clinical scales such as the total neuropathy score (TNSr) [18, 44], combining assessment of clinical symptoms with electrophysiological measurements, may result in higher sensitivity for detection of peripheral neuropathy. Although the degree of peripheral neuropathy in NCI-CTC terms is subjective and dependent on patients’ reporting, a recent study reported good intra- en interobserver scores for both the NCI-CTC and TNSr [44]. The additional value of NCS/electromyography (EMG) in CiPN is still a matter of debate. NCS/EMG may appear normal in small fiber neuropathies, such as those induced by bortezomib and thalidomide [45]. Secondly, most current treatment algorithms are based on clinical criteria, i.e. NCI-CTC, rather than on NCS/EMG [18, 46]. Therefore, our personal view is that NCS/EMG should not be part of the standard work-up of CiPN, but may certainly provide valuable additional information in cases where CiPN must be differentiated from pre-existing neuropathy or from concomitant M-protein related peripheral neuropathy. In these cases, a comprehensive or even serial NCS/ EMG(s) may be very helpful and exceptionally skin biopsy or sural nerve biopsy may be considered. Early recognition and timely dose modification or even discontinuation according to guidelines (see below) is essential to prevent more serious and potentially irreversible neurologic damage. Especially, patients with preexisting or concomitant peripheral neuropathy should be watched closely during initial treatment for deterioration of neuropathy. On the other hand, the decision to take a patient off chemotherapy is complicated and should not be made lightly, since the chemotherapy may be the best or even the only treatment for the underlying malignancy. Dose-modification guidelines for the management of bortezomib-induced peripheral neuropathy have been based on experience in early clinical trials and were subsequently validated [18]. This resulted in improvement or resolution of bortezomib-induced peripheral neuropathy in up to 64 % of patients with peripheral neuropathy grade C 2 within a median time of 110 days, while survival outcome did not appear adversely affected in patients who had dose modification [18]. More recently, multi-agent studies have shown that, in addition to dose reduction, weekly dosing may prevent the progression of peripheral neuropathy and reduce severe peripheral neuropathy [47]. Weekly bortezomib dosing is therefore considered an effective strategy to prevent further worsening of peripheral neuropathy once patients have developed bortezomib-induced peripheral neuropathy grade 1. Furthermore, for patients age C 75 years, with comorbidities, frailty or disability who may be more prone to bortezomib-induced peripheral neuropathy, a
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reduced intensity strategy is recommended [48]. Finally, it was published and recently updated that subcutaneous administration of bortezomib versus intravenous administration of bortezomib resulted in non-inferiority in terms of response, but significantly lower rates of bortezomibinduced peripheral neuropathy (53 versus 38 %) as a result of lower peak-dose toxicity [30]. Subcutaneous administration therefore is now the recommended choice of administration. Guidelines for reduction of thalidomide are merely based on expert opinion [49]. Limiting the initial dose of thalidomide to a maximum of 200 mg daily is recommended to prevent rapid development of thalidomideinduced peripheral neuropathy. Because this peripheral neuropathy is correlated with the total cumulative dose, thalidomide should not be given for longer than 6–12 months [46].
Neuroprotective strategies and treatment of neuropathic pain Neuroprotective interventions mostly involve pharmacological treatment administered just before or concomitantly with chemotherapy. Molecules that have been investigated as neuroprotective in CiPN include amifostine, glutathione, calcium and magnesium infusion, glutamine, vitamins, erythropoietine, acetyl-L-carnitine, an ACTH analogue and human leukemia inhibitory factor. However, a recent review on neuroprotective strategies in CiPN concluded that clinical evidence for the efficacy of these drugs is sparse and that therefore no recommendations can be given on the use of neuroprotective agents in CiPN [50]. Our personal view is that given the lack of convincing clinical evidence these agents should not be routinely prescribed, especially when they may be associated with serious side effects, like hypotension in amifostine, or may potentially interfere with anti-neoplastic activity, like vitamin C that blocks the inhibitory effect of bortezomib on proteasome 20S activity in vitro and blocks the inhibitory effect of bortezomib on multiple myeloma growth in vivo [51]. First-line treatment of chemotherapy-induced neuropathic pain includes drugs like gabapentin and pregabalin, together called gabapentinoids; tricyclic antidepressants like amitriptyline, nortriptyline and imipramine; serotonin and norepinephrine reuptake inhibitors like duloxetine and venlafaxine and anti-epileptics like carbamazepine and oxcarbazepine [52]. A suggested order of preference and a summary of dosing-schedules is presented in Table 2. However, we would not recommend prescribing these drugs by someone who is not familiar with treating neuropathic pain, because of potential side-effects, interactions and contra-indications. Opioid analgesics are generally considered second-line treatment for neuropathic pain [53].
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Table 2 Treatment of neuropathic pain Group
Specific drug
Dose of drug
1. Gabapentinoids
Gabapentin
300–1200 mg tid
Pregabalin
75–300 mg bid
Amitriptyline
10–100 mg qd
2. Tricyclic antidepressants
3. SNRI 4. Anti-epileptics
Nortriptyline
10–100 mg qd
Imipramine
25–100 mg qd
Duloxetine
60–90 mg qd
Venlafaxine
75–150 mg qd
Carbamazepine
100–600 mg bid
Oxcarbazepine
150–900 mg bid
SNRI serotonin and norepinephrine reuptake inhibitors
The use of the aforementioned drugs in neuropathic cancer pain is mostly extrapolated from their (proven) efficacy in other neuropathic pain syndromes, such as painful diabetic neuropathy, postherpetic neuralgia and trigeminal neuralgia. Clinical evidence for the use of these compounds in neuropathic cancer pain is sparse, with only three class I (according to the classification of clinical evidence of the American Academy of Neurology) articles specifically on neuropathic cancer pain [54, 55]. Local application of lidocaine or menthol cream may temporarily alleviate chemotherapy-induced neuropathic pain. Simple emollients such as cocoa butter or transcutaneous electrical nerve stimulation (TENS) are safe and may be helpful for symptom relief. Patients may be advised to wear loose-fitting clothes and shoes and to keep feet uncovered in bed, to prevent mechanical allodynia. Patients with autonomic dysfunction should rise cautiously and avoid strenuous physical activity. Patients suffering from severe peripheral neuropathy that are disabled in the exertion of daily tasks may benefit from exercise and physical therapy.
Conclusions and recommendations for clinical practice CiPN has become a frequent dose and treatment limiting adverse event in hematological malignancies, with a major impact on quality of life. In addition, the clinical picture may be obscured by (a concomitant) M-protein related peripheral neuropathy or disease-related peripheral neuropathy mimic. CiPN may occur during and after treatment with cis-platinum, vincristine, thalidomide and bortezomib. For the latter two, dose adjustment guidelines have been developed, thus early recognition of peripheral neuropathy by adhering to these schedules is essential. Fortunately, subcutaneous bortezomib and recently developed second-generation proteasome inhibitors like carfilzomib and immunomodulatory drugs like lenalidomide and pomalidomide confer a much
lower risk on development of peripheral neuropathy. When peripheral neuropathy develops in spite of dose adjustments or treatment discontinuation, gabapentinoids, anti-depressants, SNRIs or anticonvulsants may be considered to treat neuropathic pain and/or practical supportive measures may be considered for all forms of CiPN. No compelling clinical evidence is currently available to recommend the routine use of neuroprotective drugs. Therefore, the key issue to prevent (exacerbation) of CiPN remains early recognition and timely dose modification. Acknowledgments Supported by a clinical research grant from the European Hematology Association, EMCR Translational Research Grant, Janssen Orthobiotech, and Multiple Myeloma Stem cell Network of the European Myeloma Network. Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Cata JP, Weng HR, Burton AW, Villareal H, Giralt S, Dougherty PM (2007) Quantitative sensory findings in patients with bortezomib-induced pain. J Pain 8:296–306 2. Thompson SW, Davis LE, Kornfeld M, Hilgers RD, Standefer JC (1984) Cisplatin neuropathy. Clinical, electrophysiologic, morphologic, and toxicologic studies. Cancer 54:1269–1275 3. Hilkens PH, van der Burg ME, Moll JW, Planting AS, van Putten WL, Vecht CJ, van den Bent MJ (1995) Neurotoxicity is not enhanced by increased dose intensities of cisplatin administration. Eur J Cancer 31A:678–681 4. McDonald ES, Randon KR, Knight A, Windebank AJ (2005) Cisplatin preferentially binds to DNA in dorsal root ganglion neurons in vitro and in vivo: a potential mechanism for neurotoxicity. Neurobiol Dis 18:305–313 5. Gill JS, Windebank AJ (1998) Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle. J Clin Invest 101:2842–2850 6. Podratz JL, Knight AM, Ta LE, Staff NP, Gass JM, Genelin K, Schlattau A, Lathroum L, Windebank AJ (2011) Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons. Neurobiol Dis 41:661–668 7. Mollman JE, Hogan WM, Glover DJ, McCluskey LF (1988) Unusual presentation of cis-platinum neuropathy. Neurology 38:488–490 8. Boogerd W, ten Bokkel Huinink WW, Dalesio O, Hoppenbrouwers WJ, van der Sande JJ (1990) Cisplatin induced neuropathy: central, peripheral and autonomic nerve involvement. J Neurooncol 9:255–263 9. Patchell RA, Posner JB (1985) Neurologic complications of systemic cancer. Neurol Clin 3:729–750 10. Sandler SG, Tobin W, Henderson ES (1969) Vincristine-induced neuropathy. A clinical study of fifty leukemic patients. Neurology 19:367–374 11. Dougherty PM, Cata JP, Burton AW, Vu K, Weng HR (2007) Dysfunction in multiple primary afferent fiber subtypes revealed by quantitative sensory testing in patients with chronic vincristine-induced pain. J Pain Symptom Manage 33:166–179 12. Pal PK (1999) Clinical and electrophysiological studies in vincristine induced neuropathy. Electromyogr Clin Neurophysiol 39:323–330
123
236 13. Korsching S (1993) The neurotrophic factor concept: a reexamination. J Neurosci 13:2739–2748 14. Tanner KD, Levine JD, Topp KS (1998) Microtubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat. J Comp Neurol 395:481–492 15. Siau C, Xiao W, Bennett GJ (2006) Paclitaxel- and vincristineevoked painful peripheral neuropathies: loss of epidermal innervation and activation of Langerhans cells. Exp Neurol 201:507–514 16. Argyriou AA, Bruna J, Marmiroli P, Cavaletti G (2012) Chemotherapy-induced peripheral neurotoxicity (CIPN): an update. Crit Rev Oncol Hematol 82:51–77 17. Verstappen CC, Koeppen S, Heimans JJ, Huijgens PC, Scheulen ME, Strumberg D, Kiburg B, Postma TJ (2005) Dose-related vincristine-induced peripheral neuropathy with unexpected offtherapy worsening. Neurology 64:1076–1077 18. Richardson PG, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Blade J, Boccadoro M, Cavenagh JD, Boral AL, Esseltine DL, Wen PY, Amato AA, Anderson KC, San Miguel J (2009) Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. Br J Haematol 144:895–903 19. Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM (2012) Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol 30:2946–2955 20. Dimopoulos MA, Kastritis E, Christoulas D, Migkou M, Gavriatopoulou M, Gkotzamanidou M, Iakovaki M, Matsouka C, Mparmparoussi D, Roussou M, Efstathiou E, Terpos E (2010) Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities and of previous therapies. Leukemia 24:1769–1778 21. Dimopoulos MA, Mateos MV, Richardson PG, Schlag R, Khuageva NK, Shpilberg O, Kropff M, Spicka I, Palumbo A, Wu KL, Esseltine DL, Liu K, Deraedt W, Cakana A, Van De Velde H, San Miguel JF (2011) Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalanprednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study. Eur J Haematol 86:23–31 22. Broyl A, Corthals SL, Jongen JL, van der Holt B, Kuiper R, de Knegt Y, van Duin M, el Jarari L, Bertsch U, Lokhorst HM, Durie BG, Goldschmidt H, Sonneveld P (2010) Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol 11:1057–1065 23. Corthals SL, Kuiper R, Johnson DC, Sonneveld P, Hajek R, van der Holt B, Magrangeas F, Goldschmidt H, Morgan GJ, AvetLoiseau H (2011) Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients. Haematologica 96:1728–1732 24. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Treon SP, Munshi NC, Richardson PG, Hideshima T, Anderson KC (2002) Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 99:14374–14379
123
J Neurooncol (2015) 121:229–237 25. Cavaletti G, Gilardini A, Canta A, Rigamonti L, RodriguezMenendez V, Ceresa C, Marmiroli P, Bossi M, Oggioni N, D’Incalci M, De Coster R (2007) Bortezomib-induced peripheral neurotoxicity: a neurophysiological and pathological study in the rat. Exp Neurol 204:317–325 26. Arastu-Kapur S, Anderl JL, Kraus M, Parlati F, Shenk KD, Lee SJ, Muchamuel T, Bennett MK, Driessen C, Ball AJ, Kirk CJ (2011) Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res 17:2734–2743 27. Zheng H, Xiao WH, Bennett GJ (2012) Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy. Exp Neurol 238:225–234 28. Trevisan G, Materazzi S, Fusi C, Altomare A, Aldini G, Lodovici M, Patacchini R, Geppetti P, Nassini R (2013) Novel therapeutic strategy to prevent chemotherapy-induced persistent sensory neuropathy by TRPA1 blockade. Cancer Res 73:3120–3131 29. Rampen AJ, Jongen JL, van Heuvel I, Scheltens-de Boer M, Sonneveld P, van den Bent MJ (2013) Bortezomib-induced polyneuropathy. Neth J Med 71:128–133 30. Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL (2011) Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 12:431–440 31. Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, Kukreti V, Jagannath S, McDonagh KT, Alsina M, Bahlis NJ, Reu FJ, Gabrail NY, Belch A, Matous JV, Lee P, Rosen P, Sebag M, Vesole DH, Kunkel LA, Wear SM, Wong AF, Orlowski RZ, Siegel DS (2012) An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomibnaive patients with relapsed and/or refractory multiple myeloma. Blood 119:5661–5670 32. Glasmacher A, Hahn C, Hoffmann F, Naumann R, Goldschmidt H, von Lilienfeld-Toal M, Orlopp K, Schmidt-Wolf I, Gorschluter M (2006) A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma. Br J Haematol 132:584–593 33. Richardson P, Schlossman R, Jagannath S, Alsina M, Desikan R, Blood E, Weller E, Mitsiades C, Hideshima T, Davies F, Doss D, Freeman A, Bosch J, Patin J, Knight R, Zeldis J, Dalton W, Anderson K (2004) Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity. Mayo Clin Proc 79:875–882 34. Chaudhry V, Cornblath DR, Corse A, Freimer M, SimmonsO’Brien E, Vogelsang G (2002) Thalidomide-induced neuropathy. Neurology 59:1872–1875 35. Giannini F, Volpi N, Rossi S, Passero S, Fimiani M, Cerase A (2003) Thalidomide-induced neuropathy: a ganglionopathy? Neurology 60:877–878 36. Li S, Xue F, Cheng Z, Yang X, Wang S, Geng F, Pan L (2009) Effect of artesunate on inhibiting proliferation and inducing apoptosis of SP2/0 myeloma cells through affecting NFkappaB p65. Int J Hematol 90:513–521 37. Ibanez CF, Simi A (2012) p75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity. Trends Neurosci 35:431–440 38. Badros A, Goloubeva O, Dalal JS, Can I, Thompson J, Rapoport AP, Heyman M, Akpek G, Fenton RG (2007) Neurotoxicity of bortezomib therapy in multiple myeloma: a single-center experience and review of the literature. Cancer 110:1042–1049 39. Johnson DC, Corthals SL, Walker BA, Ross FM, Gregory WM, Dickens NJ, Lokhorst HM, Goldschmidt H, Davies FE, Durie
J Neurooncol (2015) 121:229–237
40.
41.
42. 43.
44.
45.
46.
BG, Van Ness B, Child JA, Sonneveld P, Morgan GJ (2011) Genetic factors underlying the risk of thalidomide-related neuropathy in patients with multiple myeloma. J Clin Oncol 29:797–804 Cavaletti G, Beronio A, Reni L, Ghiglione E, Schenone A, Briani C, Zara G, Cocito D, Isoardo G, Ciaramitaro P, Plasmati R, Pastorelli F, Frigo M, Piatti M, Carpo M (2004) Thalidomide sensory neurotoxicity: a clinical and neurophysiologic study. Neurology 62:2291–2293 Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foa R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD (2007) Multiple myeloma study I (2007) lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. New Engl J Med 357:2123–2132 Schey S, Ramasamy K (2011) Pomalidomide therapy for myeloma. Expert Opin Investig Drugs 20:691–700 Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M, Yellen SB, Winicour P, Brannon J et al (1993) The functional assessment of cancer therapy scale: development and validation of the general measure. J Clin Oncol Off J Am Soc Clin Oncol 11:570–579 Cavaletti G, Cornblath DR, Merkies IS, Postma TJ, Rossi E, Frigeni B, Alberti P, Bruna J, Velasco R, Argyriou AA, Kalofonos HP, Psimaras D, Ricard D, Pace A, Galie E, Briani C, Dalla Torre C, Faber CG, Lalisang RI, Boogerd W, Brandsma D, Koeppen S, Hense J, Storey D, Kerrigan S, Schenone A, Fabbri S, Valsecchi MG (2013) The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings. Ann Oncol 24:454–462 Richardson PG, Xie W, Mitsiades C, Chanan-Khan AA, Lonial S, Hassoun H, Avigan DE, Oaklander AL, Kuter DJ, Wen PY, Kesari S, Briemberg HR, Schlossman RL, Munshi NC, Heffner LT, Doss D, Esseltine DL, Weller E, Anderson KC, Amato AA (2009) Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. J Clin Oncol 27:3518–3525 Richardson PG, Delforge M, Beksac M, Wen P, Jongen JL, Sezer O, Terpos E, Munshi N, Palumbo A, Rajkumar SV, Harousseau JL, Moreau P, Avet-Loiseau H, Lee JH, Cavo M, Merlini G, Voorhees P, Chng WJ, Mazumder A, Usmani S, Einsele H, Comenzo R, Orlowski R, Vesole D, Lahuerta JJ, Niesvizky R,
237
47.
48. 49.
50.
51.
52.
53.
54.
55.
Siegel D, Mateos MV, Dimopoulos M, Lonial S, Jagannath S, Blade J, Miguel JS, Morgan G, Anderson KC, Durie BG, Sonneveld P (2012) Management of treatment-emergent peripheral neuropathy in multiple myeloma. Leukemia 26:595–608 Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A (2010) Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 116:4745–4753 Palumbo A, Mina R (2013) Management of older adults with multiple myeloma. Blood Rev 27:133–142 Delforge M, Blade J, Dimopoulos MA, Facon T, Kropff M, Ludwig H, Palumbo A, Van Damme P, San-Miguel JF, Sonneveld P (2010) Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol 11:1086–1095 Beijers AJ, Jongen JL, Vreugdenhil G (2012) Chemotherapyinduced neurotoxicity: the value of neuroprotective strategies. Neth J Med 70:18–25 Perrone G, Hideshima T, Ikeda H, Okawa Y, Calabrese E, Gorgun G, Santo L, Cirstea D, Raje N, Chauhan D, Baccarani M, Cavo M, Anderson KC (2009) Ascorbic acid inhibits antitumor activity of bortezomib in vivo. Leukemia 23:1679–1686 Finnerup NB, Sindrup SH, Jensen TS (2010) The evidence for pharmacological treatment of neuropathic pain. Pain 150:573–581 Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy RK, Rice AS, Stacey BR, Treede RD, Turk DC, Wallace MS (2007) Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132:237–251 Jongen JL, Huijsman ML, Jessurun J, Ogenio K, Schipper D, Verkouteren DR, Moorman PW, van der Rijt CC, Vissers KC (2013) The Evidence for Pharmacologic Treatment of Neuropathic Cancer Pain: Beneficial and Adverse Effects. J Pain Symptom Manage 46:581–590 Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, Bressler LR, Fadul CE, Knox C, Le-Lindqwister N, Gilman PB, Shapiro CL, Alliance for Clinical Trials in O (2013) Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA 309:1359–1367
123
