Journal of the Peripheral Nervous System 19:66–76 (2014)

2013 PERIPHERAL NERVE SOCIETY MEETING PLENARY LECTURE

Chemotherapy-induced peripheral neurotoxicity (CIPN): what we need and what we know Guido Cavaletti Experimental Neurology Unit and Milan Center for Neuroscience, Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy

Abstract Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most frequent and severe long-term side effects of cancer chemotherapy. Preclinical and clinical studies have extensively investigated CIPN searching for effective strategies to limit its severity or to treat CIPN-related impairment, but the results have been disappointing. Among the reasons for this failure are methodological flaws in both preclinical and clinical investigations. Their successful resolution might provide a brighter perspective for future studies. Among the several neurotoxic chemotherapy drugs, oxaliplatin may offer a clear example of a methodological approach eventually leading to successful clinical trials. However, the same considerations apply to the other neurotoxic agents and, although frequently neglected, also to the new “targeted” agents. Key words: chemotherapy, neuropathy, pathogenesis, toxicity, treatment

Introduction

the reasons for this improved survival is the use of effective antineoplastic drugs, oxaliplatin in the specific case of CRC. Cancer survivors are used to dealing with serious acute/subacute side effects of treatment and, given the life-threatening disease they faced and defeated, are in some way prone also to cope with unavoidable long-term treatment-related side effects. Nonetheless, they are now strongly requesting a more careful management of long-term toxicities induced by chemotherapy, particularly if these toxicities have an impact on daily life activities (Binkley et al., 2012; Fitzpatrick et al., 2012; Shimozuma et al., 2012; Au et al., 2013; Smith et al., 2013) and have no effective symptomatic treatments. Unfortunately, increased life expectancy and improved survival rates are often associated with long-term treatment-related neurological complications that severely compromise the quality of life (better “quality of survival”) and the functional status of patients. One of the most challenging and debilitating of these side effects due to the toxicity of anticancer drugs is on the peripheral nervous system. For instance, in CRC patients, oxaliplatin-induced peripheral neurotoxicity occurs in

Over the last decades medical surveillance and the use of effective therapies have improved the outcome of cancer patients, and in several settings a definitive cure or long-term survival can be achieved. As an example, the 5-year survival rates for stages II and III colorectal cancer (CRC), the third leading cause of tumor-related death among both men and women in the western countries, are now generally over 60%, which translates into hundreds of thousands of patients living with a history of cancer. In Italy, this improvement led to a 5-year prevalence of over 150,000 persons (http://eu-cancer.iarc.fr) and this trend is confirmed by the US 5-year relative survival rates in the period 1975–2009 (changing from 49% to 68% for all cancers, from 51%–48% to 65%–68% for colon and rectum cancers, http://www.cancer.org/research/ cancerfactsstatistics/cancerfactsfigures2014/). Among

Address correspondence to: Prof. Guido Cavaletti, Department of Surgery and Translational Medicine, University of Milano-Bicocca, Via Cadore 48, 20900 Monza (MB), Italy. Tel: +(39)02-6448-8039; Fax: +(39)02-6448-8250; E-mail: [email protected] © 2014 Peripheral Nerve Society

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up to 80% of patients who receive the drug alone or in combination with other chemotherapeutics (Argyriou et al., 2012a; 2012c; 2012d; 2013), and impairment may be permanent. A number of studies and qualified reviews are now available describing the clinical features of the peripheral neurotoxicity of the most commonly used drugs (Chamberlain, 2010; Argyriou et al., 2012b; Grisold et al., 2012), and awareness of its importance is increasing. However, in several settings, the complexity of the problem is still underestimated and most aspects are not properly considered by the treating physicians. An illuminating example of a superficial approach to the toxicity of chemotherapy on the peripheral nervous system is the interpretation of the widely used acronym “CIPN” that frequently is defined as “chemotherapy-induced peripheral neuropathy”, while in several cases “neuronopathy” would be more appropriate, and therefore the preferred description is “chemotherapy-induced peripheral neurotoxicity”: the difference is not simply semantic, but rather implies a careful consideration of the pathogenesis of the signs and symptoms experienced by patients and acknowledges our still incomplete understanding of the mechanisms at the basis of the different toxic effects of anticancer drugs (Cavaletti et al., 2008; Cavaletti and Marmiroli, 2010; Hoke, 2012; Marmiroli et al., 2012). This review is not aimed at being a comprehensive, systematic review of the literature, but rather a critical revision of the difficulties we still have in the understanding and management of CIPN based on real-life clinical and preclinical personal experience, using as a fil rouge oxaliplatin, but also exploring unexpected drug targets and rare toxicities.

et al., 2001). That study had several methodological limitations, but the results were in substantial agreement with a more recent study which demonstrated that patients with a neuropathy have healthcare costs triple those of controls (Berger et al., 2004). Unfortunately, this second study did not examine the costs associated with CIPN. In 2011, the results of the first study specifically designed to assess health outcomes as well as the healthcare and work loss cost burden of CIPN in different tumor types were published. The most impressive conclusion of the study was that CIPN patients have an average healthcare extra-costs of USD 17,344 with outpatient costs being the highest component (Pike et al., 2012). This fairly remarkable value multiplied for the number of patients exposed to the risk of developing CIPN leads to a possible cost of billions USD. In fact, based on the data available at http://www.wcrf.org/, there were an estimated 12.7 million cancer cases around the world in 2008, 56% of all cancers excluding non-melanoma skin cancer occurring in less developed countries and 44% in more developed countries. This number is expected to increase to 21 million by 2030 and at the moment more than 50% of these patients are potential candidates to treatment with one or more drugs toxic on the peripheral nervous system. While it is likely patients living in more developed countries will be treated in the (near?) future with new, more expensive and presumably less toxic drugs, the present drugs will probably become the way to access relatively low-cost anticancer treatment in less developed parts of the world and CIPN will remain a relevant medical and socio-economic issue.

The Socio-Economic Burden of CIPN

The Clinical Relevance of CIPN

Similar to most long-term or chronic diseases, CIPN has a remarkable effect at the socio-economic level. However, while this socio-economic impact is well-recognized by patients and their families, only recently has this important aspect been formally investigated. This fact is not completely surprising, because CIPN is still frequently perceived as a “niche” problem in oncology and in neurology, and this is fundamentally true on an epidemiological basis if compared with diabetic neuropathy or stroke. However, a small pilot study on patient recall of medical services was performed in 2001 in a cohort of 42 CIPN women with ovarian cancer, and the results showed that the medical costs directly attributable to CIPN were nearly USD 700 per episode, but that overall indirect costs (e.g., patient and caregiver work-loss and paid caregiver costs) were over USD 4,000 per episode (Calhoun

Besides the economic cost, the measurable impact of CIPN on patients’ daily quality of survival is now emerging (Bennett et al., 2012). In fact, until a few years ago, CIPN (as well as other side effects of treatment) has been considered as an unavoidable “toll” to be paid to life-saving anticancer chemotherapy. However, the development of effective supportive treatments (e.g., growth factors to prevent hematological side effects, effective anti-emetic drugs, etc.) has allowed a reduction on the impact on patients’ daily life of previously dose-limiting side effects, and CIPN is now perceived by patients as one of the most severe side effects of treatment. Moreover, patients often believe that the real impact of CIPN on their quality of life, as well as the long-term effects of the persistence of symptoms/signs, are underestimated by healthcare providers (Hershman et al., 2011). A change in this 67

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Table 1. Summary of the most frequent symptoms and signs associated with the administration of commonly used antineoplastic drugs. Drug Platinum drugs Cisplatin (carboplatin)

Oxalipatin

Antitubulins Taxanes (paclitaxel, docetaxel)

Epothilones (ixabepilone, sagopilone) Vinca alkaloids (particularly vincristine)

Thalidomide

Bortezomib

Symptoms/signs

• Distal, symmetric, upper and lower limb impairment/loss of all sensory modalities • Large myelinated fibers are more severely involved so that sensory ataxia and gait imbalance are frequent • Early reduction/loss of DTR • Neuropathic pain is rare • Coasting phenomenon is frequent* • Carboplatin is generally much less neurotoxic than cisplatin • Acute • Cold-induced transient paresthesias in mouth, throat, and limb extremities • Cramps/muscle spasm in throat muscle • Jaw spasm • Chronic • Similar to cisplatin • Distal, symmetric, upper and lower limb impairment/loss of all sensory modalities • Gait unsteadiness is possible due to proprioceptive loss • Reduction/loss of DTR • Neuropathic pain/paresthesia at limb extremities is relatively frequent. • “Myalgia syndrome” is frequent, possible expression of atypical neuropathic pain • Distal, symmetric weakness in lower limbs is generally mild • Similar to taxanes, but neuropathic pain is less frequent and recovery is reported to be faster • Distal, symmetric, upper and lower limb impairment/loss of all sensory modalities • Reduction/loss of DTR • Neuropathic pain/paresthesia at limb extremities is relatively frequent. • Distal, symmetric weakness in lower limbs progressing to foot drop • Autonomic symptoms may be severe (e.g., orthostatic hypotension, constipation, paralytic ileus) • Mild to moderate, distal symmetric loss of all sensory modalities • Reduction/loss of DTR • Relatively frequent neuropathic pain at limb extremities • Weakness is rare • Mild to moderate, distal symmetric loss of all sensory modalities. Small myelinated and unmyelinated fibers are markedly affected leading to severe neuropathic pain • Reduction/loss of DTR • Mild distal weakness in lower limbs is possible

DTR, deep tendon reflexes. *Coasting, worsening of neuropathy signs/symptoms over months after drug withdrawal.

situation requires physicians and nurses involved in cancer patient care to have a more solid knowledge of CIPN in order to properly assess and manage the problem (Table 1). It is now generally recognized by oncologists, neurologists, and healthcare providers that CIPN is frequent and that it might be a severe medical problem, because it can cause treatment delays or withdrawal, induce symptoms which are difficult to be treated and interfere with daily life over a (very) long period of time (Grisold et al., 2012). However, awareness of the problem and homogeneity in the assessment among examiners should be further improved (Postma et al., 1998; Postma and Heimans, 2000; Cavaletti et al., 2012). For instance, if “frequent” and “severe” should be translated into numerical and scientifically-based figures, it becomes clear that marked differences among different evaluators exist, even if they are

experienced (Postma et al., 1998). These differences do not impact only on daily clinical practice, but are also reflected by the inconsistent results of clinical trials, and in this latter case they are magnified by concurrent methodological flaws, such as improper outcome measures, lack of baseline assessments, retrospective analysis, insufficiently powered therapeutic trials or confounding effects of concomitant diseases. The occurrence of neuropathic pain, a clear distinction between acute and chronic symptoms of CIPN, and the need for a real multidisciplinary collaboration are among the main unsettled issues. Pain relevance in CIPN has not yet been reliably assessed (Lavoie Smith et al., 2011; Wolf et al., 2012), although in a cross-sectional analysis in patients with stable symptoms its incidence was remarkably high (Cavaletti et al., 2013). Among the reasons for this uncertainty is the presence of pain of different origin 68

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in cancer patients, but also methodological aspects are not irrelevant. In fact, on the one hand, still too frequently the interpretation of the symptoms reported by patients is confused and misleading, so that disturbing, but not really painful, symptoms (e.g., paresthesias) are included in the assessment, thus inflating the estimate. On the other hand, in most clinical trials tools which are not designed to capture this important aspect (particularly relevant with some drugs such as bortezomib and taxanes) are used (Cavaletti et al., 2010; 2011a). The incomplete acknowledgement of the presence during the course of the same treatment course of acute symptoms and signs (e.g., cold induced paresthesias, cramps and muscular spasm in oxaliplatin- or myalgias in taxane-treated patients) (Argyriou et al., 2012c; Lucchetta et al., 2012; Reeves et al., 2012) overlapping with or followed by chronic impairment (e.g., distal hypoesthesia, ataxia) which can even worsen for months after treatment withdrawal, as typically occur in the case of oxaliplatin treated patients (Argyriou et al., 2008), may lead to inconsistent results in apparently similar studies. This is particularly relevant in neuroprotective clinical trials, because acute and chronic symptoms/signs have a different pathogenesis and clinical relevance, improper definition, and assessment may impair the detection of the effect of the drug under investigation. Moreover, CIPN is typically a multidisciplinary medical issue, with different perspectives and degrees of involvement during patient treatment and follow-up. There is now consensus on the need for a neurological baseline assessment followed by personalized follow-up examinations in clinical trials, but this is not yet the standard of care in daily practice for several logistic, economic and cultural reasons, and a real collaboration among specialists is still rare. Frequently the standard neurological assessment is based on the rapid, but relatively uninformative, “common toxicity scales” or on questionnaires, while more precise outcome measures are already used in clinical trials, but should be implemented in simpler, but valid, versions also in daily practice (Cavaletti et al., 2013). Improvement in multidisciplinary CIPN assessment is a major aim, achievable through education (also profiting from e-learning platforms such the EU-funded http://www.ecco-org.eu/oncovideos/) and selection of suitable clinical tools. Using this approach the identification of the optimal outcome measures can be based on a solid scientific basis, also profiting from new clinimetric methodologies such as the Rasch analysis (Merkies and Hughes, 2010; Merkies et al., 2012; Binda et al., 2013), able to create valid and reliable assessment methods, with the final aim to reduce results variability to the minimum and perform a useful

objective assessment of CIPN (Merkies and Hughes, 2010). Finally, the very different perception of CIPN existing between healthcare providers and patients is now clear and should be carefully considered (Hershman et al., 2011). The results of a recent study comparing treating physician and patient perception of CIPN formally confirmed the differences already suggested in previous studies, but also demonstrated that the combination of objective and subjective assessments are mandatory, but can really add useful information only if they are properly selected in order to eliminate duplication of results and to capture all the facets of this complex medical disorder (Alberti et al., 2014).

The Pathogenesis of CIPN The pathogenesis of CIPN induced by the several conventional anticancer agents such as platinum-drugs, antitubulins, thalidomide, and bortezomib has been investigated in a huge number of studies. The majority of the hypotheses generated so far are based on the results of preclinical in vitro and in vivo experiments, translated into the clinical setting with variable, but generally clinically irrelevant success. The first in vivo model of chronic CIPN was established in 1992 using cisplatin (Cavaletti et al., 1992), and since then several different laboratories contributed to the design and evaluation of animal models reproducing the neurotoxic effect of virtually all the conventional anticancer drugs, with the only exception of thalidomide (Hoke, 2012). These studies provided evidence for subsequent in vitro mechanistic studies aimed at discovering “druggable” targets for existing or new drugs to be tested in clinical trials. On the basis of similarity in the mechanism of antineoplastic action with cisplatin, it was not a surprise when oxaliplatin was reported to be neurotoxic in CRC patients in the early 90s (Levi et al., 1992; 1993). Since then oxaliplatin has been extensively investigated, and its history is a typical example of the back and forth between preclinical and clinical studies as well as a valuable instrument to highlight the need for a very careful and critical assessment and refinement of the applied methodologies to achieve a truly translation approach to CIPN. On the background of the existing cisplatin CIPN model, the first animal model of chronic oxaliplatin peripheral neurotoxicity was established in rats in 2001 (Cavaletti et al., 2001), and simple translation of the experience gained in the cisplatin model seemed adequate. Actually, this assumption resulted to be simplistic: in fact, while cisplatin was well tolerated after 69

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intraperitoneal administration, oxaliplatin repeated administration was invariably associated with local reaction and abdominal bloating. This observation suggested a major change in the model moving to the intravenous drug delivery in order to guarantee a predictable absorption and bioavailability of oxaliplatin in long-term experiments (Cavaletti et al., 2002), although even recent studies failed to recognize this important methodological aspect (Liu et al., 2013b). Another possible bias in the set up and evaluation of animal models of oxaliplatin-induced CIPN emerged very clearly looking at the clinical picture of its peripheral neurotoxicity, which typically is characterized by early, acute symptoms occurring within days after drug treatment and chronic neurotoxicity requiring weeks/months to be fully evident (Peltier and Russell, 2006; Joseph and Levine, 2009). This course, that is not unique for oxaliplatin, imposes specifically designed short- or long-term experiments depending on the type of toxicity aimed at being reproduced, but also this fundamental difference has not always been properly considered, with possible misleading results. The results obtained in the rat model were subsequently confirmed in mice and dorsal root ganglia (DRG) neuron damage was confirmed in chronically treated animals (Renn et al., 2011), while short-term experiments allowed to reproduce acute cold hypersensitivity and allodynia (Kanat et al., 2013; Aoki et al., 2014). On the basis of results obtained in the animal models, in vitro cellular systems, mostly based on cultured DRG neurons, but also on neuronally differentiated SH-SY5Y neuroblastoma or PC12 pheochromocytoma cells, have been used to investigate on the mechanisms of oxaliplatin neurotoxicity searching for a possible intracellular mechanism of its toxicity (Adelsberger et al., 2000; Ta et al., 2006; Scuteri et al., 2009; 2010; Ceresa et al., 2014) (Fig. 1). Despite considerable efforts focused on rather “obvious” mechanistic targets in CIPN, no useful results have been translated to the clinical field so far, suggesting that probably these targets are not the most relevant. With this respect, the search for “unexpected” targets of neurotoxic anticancer drugs should be pursued, because most of the “obvious” ones are based on the assumption that the mechanisms of anticancer and neurotoxic activity are similar. This unproven assumption does not consider the several and pivotal differences existing between cancer cells and neurons which should be overcome by future studies. Looking for more CIPN-relevant mechanisms, evidence has been provided suggesting mitochondrial damage and possible subsequent oxidative stress affecting DRG neurons exposed to neurotoxic anticancer drugs (Zheng et al., 2011;

Figure 1. Summary of the mechanisms and intracellular targets proposed for oxaliplatin-induced peripheral neurotoxicity on dorsal root ganglia neurons. CTR1, copper transporter 1; ERK 1/2, extracellular-signal-regulated kinases 1/2; mtDNA, mitochondrial DNA; OCT2, organic cation transporter 2; p38 MAPK, p38 mitogen-activated protein kinases; SAP/JNK, stress-activated kinase/c-Jun N-terminal kinase; TRPV1, transient receptor potential cation channel, subfamily V, member 1; TRPA1, transient receptor potential cation channel, subfamily A, member 1; TRPM8, transient receptor potential cation channel, subfamily M, member 8.

Toyama et al., 2014). However, the importance of a clinically relevant oxidative stress in the peripheral nervous system structures or at the systemic level is still equivocal: for example when we measured the levels of potential anti-oxidant (PAO), malondialdehyde (MDA), and reactive oxygen species (ROS) as biomarkers for oxidative stress in the plasma of cisplatin-, paclitaxel-, or bortezomib-treated rats exposed to the drugs for 4 weeks at a neurotoxic dose, no difference vs. untreated control animals was observed (personal observation). Besides mitochondria, tubulin is another intracellular structure recently identified as a possible target not only for drugs typically acting at that level such as taxanes, vinca alkaloids, or epothilones (Fumoleau et al., 2007; Canta et al., 2009; Schiff et al., 2009). In fact, remarkable increases in tubulin polymeration have been demonstrated in vitro and in DRG and peripheral nerves of rats after bortezomib treatment, with a different dynamic from that demonstrated for proteasome inhibition (i.e., the “obvious” target of the drug) (Meregalli et al., 2013; Staff et al., 2013). A new frontier in the investigation of the pathogenesis of CIPN is represented by the study of the 70

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Can New “Targeted” Drugs Cause CIPN?

role of cellular transporters able to drive the influx and efflux of neurotoxic drugs in the peripheral nervous system (Ceresa and Cavaletti, 2011). In this case, oxaliplatin has been a preferred target of these studies, and a role for selective accumulation of the drug within DRG neurons has been reported for a specific membrane molecule belonging to the copper and organic cation transporters families (Liu et al., 2009; Ip et al., 2010; Jong et al., 2011; Liu et al., 2012; 2013a; Sprowl et al., 2013). Pharmacological modulation of the activity of these drug transporters or the use of adequate knock-out mice models have allowed prevention of neurotoxicity (Sprowl et al., 2013). All these recent mechanistic observations not only represent examples of the advance in the knowledge in CIPN, but they should be used to design rationale-based therapeutic attempts in order to limit anticancer drug neurotoxicity, and the first step to test neuroprotective strategies is represented by a return toward reliable in vivo animal models. However, existing animal models should undergo continuous refinement, for instance considering the possible “paraneoplastic” effect of cancer which might be important, at least in some settings. In order to address this challenging issue, immunodeficient mice represent an optimal animal model, because they allow examination of the growth of cancers of human origin and simultaneous testing of the role of the tumor, the activity of anticancer drugs, the severity of CIPN and, possibly, the effectiveness and non-interference of putative neuroprotectant strategies. Preliminary evidence of the importance of this more complex approach is already available as we observed in multiple myeloma-bearing mice treated with bortezomib that the diseased, untreated animals already had mild peripheral nerve damage which worsened after treatment (Meregalli C., personal communication). Finally, differences among strains (and not only among species) should be carefully considered, because the use of different strains might lead to very different results. In fact, similar to the clinical situation where patients treated with the same drug schedules can experience much variable severity of CIPN unrelated to the presence of common risk factors or remain asymptomatic, the susceptibility to anticancer drug neurotoxicity can be remarkably different among strains belonging to the same animal species. If these different phenotypes are carefully genotyped, this diversity might represent a powerful tool to drive rationale cross-validation of the results in pharmacogenomics studies in humans, thus overcoming one of the major limitations of most pharmacogenetic studies reported so far, based on the examination of existing cohorts and not designed to test a rationale hypothesis (Cavaletti et al., 2011b).

The most recent development of anticancer pharmacological treatment pointed toward drugs able to target specific molecules such as receptors or enzymes expressed preferentially or exclusively by cancer cells. The first rationally designed, molecularly targeted drugs appeared in the 90s, and since then an increasing number of new drugs have been made available for clinical use. These “targeted” drugs, which are planned to be used also for prolonged periods and can be combined with neurotoxic drugs, are supposed to be more effective and less toxic than the conventional agents: because they generally have high bioavailability, slow metabolism rate, and extremely high affinity for their target, these assumptions are substantially true in most cases. However, with an increasing number of patients exposed to treatment, drug interaction and off-target toxicities emerged and CIPN is sometimes severe. As shown in Table 2, peripheral nervous system damage has been reported with most of the “targeted” drugs currently in use. However, systematic investigations are still missing and assessments are questionable. Although most of the reports are anecdotal and known neurotoxic drugs are frequently combined to targeted agents, it is apparent that the spectrum of clinical involvement is wide, ranging from acute polyradiculoneuropathies resembling classical Guillain-Barré syndrome to sensory and/or motor polyneuropathies with a subacute/chronic course. The pathogenesis of “targeted” drug peripheral neurotoxicity is unknown, although it has been suggested that a major role might be attributed to their capacity to interact with the immune system. This hypothesis might introduce a relevant difficulty in the attempt to implement reliable animal models, because of possible species-specific differences. The inclusion of careful neurological monitoring during the administration of “targeted” drugs based on a formal neurological assessment is advisable to ascertain in prospective clinical trials their real toxicity profile, alone, or in combination treatments.

Treatment for CIPN: An Unmet Clinical Need No treatment is currently available to prevent CIPN, as extensively reviewed by different groups of experts (Hershman et al., 2014) and formally assessed for platinum drugs by a Cochrane review (Albers et al., 2014). The incomplete knowledge of the pathogenesis of CIPN is the major factor responsible for this highly unsatisfactory situation, but several methodological 71

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Table 2. Selection of studies reporting CIPN in patients treated with “targeted” drugs. Drug

Study type

Description of peripheral neurotoxicity

Alemtuzumab (Avivi et al., 2004)

Related/unrelated donor stem cell transplantation following therapy with alemtuzumab, fludarabine, and melphalan (N = 85) Case report Phase III: Bevacizumab with 5FU/LV vs. Bevacizumab with CT (oxaliplatin or irinotecan based) versus CT alone (N = 820) Phase II: Brentuximab vedotin (N = 102)

Progressive peripheral sensori-motor radiculo-neuropathy and/or myelitis in five patients

(Abbi et al., 2010) Bevacizumab (Bennouna et al., 2013) Brentuximab vedotin (Younes et al., 2012) (Fanale et al., 2012)

Phase I: Brentuximab vedotin (N = 44)

(Pastorelli et al., 2013) (Zinzani et al., 2013)

Case report Observational multicenter retrospective study

Carfilzomib (O’Connor et al., 2009) (Jagannath et al., 2012)

Phase I (N = 29)

(Vij et al., 2012)

Phase II (N = 35)

(Badros et al., 2013)

Phase II (N = 50)

Ibritumomab (Wiseman et al., 2002) Imatinib (Demetri et al., 2013)

Phase II (N = 30)

(Chakupurakal et al., 2011)

Pertuzumab (Baselga et al., 2010) Regorafenib (Grothey et al., 2013) Vemurafenib (Sosman et al., 2012)

Phase II: PX-171-003-A0 (N = 46)

Phase II: 400 mg arm versus 600 mg arm (N = 147) Case report

Phase II (N = 66) Phase III: Regorafenib vs. placebo (N = 760) Phase II: (N = 132)

GBS Peripheral neuropathy: 12% bevacizumab/CT arm, 6% in CT alone arm (NCI-CTC v. 3.0) Sensory neuropathy: 42% any grade 42%, 8% grade 3 Motor neuropathy: 11% any grade, 1% grade 3 (NCI-CTC v. 3.0) Sensory neuropathy: 66% any grade, 14% grade 3, 14% grade 4 Motor neuropathy: 7% grade 3, 5% grade 4 (NCI-CTC v. 3.0) Severe motor neuropathy Sensory neuropathy: 22% any grade, 14% grade 1–2, 8% grade 3–4 (one of these patients also had grade 4 motor neuropathy) (NCI-CTC v. 3.0) Hypoesthesia in eight patients (28%): grade 1 (n = 5; 17%) and grade 2 (n = 3; 10%) (NCI-CTC v. 3.0) 15.2% treatment-emergent peripheral neuropathy, all grades 1–2, with one grade 3 (grade 2 before treatment) (NCI-CTC v. 3.0) 17.1% treatment-emergent peripheral neuropathy; four were grade 1, one was grade 2, and one grade 3 (NCI-CTC v. 3.0) 12% treatment-emergent or worsening neuropathy of any grade (NCI-CTC v. 3.0) Grade 1 paresthesia in 13% of patients (NCI-CTC v. 2.0) Grades 1–2 paresthesia in 1.4% of patients in 400 mg arm, 6.8% in 600 mg arm (NCI-CTC v. 2.0) After 5.5 years of imatinib therapy, onset of bilateral lower limb paresthesia to ankle weakness and tripping. NCS: mixed sensory motor peripheral neuropathy After imatinib discontinuation resolution was observed after a period of 6 months. Grades 1–2 paresthesia in 11% of patients (NCI-CTC v. 3.0) Sensory neuropathy in Regorafenib arm 7% grades 1–2 neuropathy, 1% grade 3 (NCI-CTC v. 3.0) 10% treatment-emergent peripheral neuropathy, 1% grade 3 (NCI-CTC v. 4.0)

CT, chemotherapy; 5FU/LV, 5 fluorouracil/leucovorin; GBS, Guillain-Barré syndrome; NCI-CTC v. 2.0, 3.0, 4.0, National Cancer Institute-Common Toxicity Criteria versions 2.0, 3.0, 4.0.

to prevent its toxicity (Gamelin et al., 2004; Hochster et al., 2007; Gamelin et al., 2008; Ishibashi et al., 2010; Kurniali et al., 2010; Cavaletti, 2011; Grothey et al., 2011; Xu et al., 2013) or by several trials using antioxidants, such as reduced glutathione, vitamin E, and lipoic acid (Cascinu et al., 2002; Kottschade et al., 2010; Guo et al., 2013). Besides sound pathogenetic hypotheses to be tested, the future therapeutic trials need to be adequately powered, include precise, and validated outcomes (CI-PeriNoms, 2009) and appropriate time points of evaluation including capturing the long-term

aspects of the clinical trials performed so far are importantly relevant. In fact, when carefully and objectively examined, several of the reported neuroprotective trials were rather poorly designed or performed, particularly regarding the neurological assessment methods, and, even when the assessment was fairly precise, the sample size of the trial was inadequate. These limitations resulted in a number of partially positive results, never unequivocally confirmed by subsequent studies, as paradigmatically demonstrated in the case of our leading example, oxaliplatin, by the inconsistencies in the use of calcium and magnesium (CaMg) infusion 72

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course of CIPN. Moreover, the actual, and not simply the scheduled, dose of chemotherapy drugs received should be recorded in order to ensure a balanced and reliable comparison during the analysis and rule out any possible predictable bias.

Conclusions Despite considerable efforts in preclinical and clinical research, CIPN remains a rather elusive entity for oncologists and neurologists. The unique opportunity to investigate a disease with a precise onset and a definite cause has not yet been fully exploited. It is now evident that CIPN is a severe, and sometimes persistent, impairment in the quality of survival of cancer patients, who are strongly asking researchers to join their efforts and provide solutions. This goal can successfully be achieved only through an intensive collaboration between basic researchers and clinicians creating networks able to share knowledge and recruit a large number of patients in order to provide regulatory agencies and pharmaceutical companies rationale-based information allowing to design less neurotoxic drugs and test effective neuroprotectant agents.

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