Platinum‐induced peripheral neurotoxicity: From pathogenesis to treatment

Platinum‐induced peripheral neurotoxicity (PIPN) is a common side effect of platinum‐based chemotherapy that may cause dose reduction and discontinuation, with oxaliplatin being more neurotoxic. PIPN includes acute neurotoxicity restricted to oxaliplatin, and chronic non‐length‐dependent sensory neuronopathy with positive and negative sensory symptoms and neuropathic pain in both upper and lower limbs. Chronic sensory axonal neuropathy manifesting as stocking‐and‐glove distribution is also frequent. Worsening of neuropathic symptoms after completing the last chemotherapy course may occur. Motor and autonomic involvement is uncommon. Ototoxicity is frequent in children and more commonly to cisplatin. Platinum‐based compounds result in more prolonged neuropathic symptoms in comparison to other chemotherapy agents. Patient reported outcomes questionnaires, clinical evaluation and instrumental tools offer complementary information in PIPN. Electrodiagnostic features include diffusely reduced/abolished sensory action potentials, in keeping with a sensory neuronopathy. PIPN is dependent on cumulative dose but there is a large variability in its occurrence. The search for additional risk factors for PIPN has thus far yielded no consistent findings. There are currently no neuroprotective strategies to reduce the risk of PIPN, and symptomatic treatment is limited to duloxetine that was found effective in a single phase III intervention study. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of PIPN.     

Vinca alkaloids,thalidomide and eribulin‐induced peripheral neurotoxicity: From pathogenesis to treatment

Vinca alkaloids, thalidomide, and eribulin are widely used to treat patients with childhood acute lymphoblastic leukemia (ALL), adults affected by multiple myeloma and locally invasive or metastatic breast cancer, respectively. However, soon after their introduction into clinical practice, chemotherapy‐induced peripheral neurotoxicity (CIPN) emerged as their main non‐hematological and among dose‐limiting adverse events. It is generally perceived that vinca alkaloids and the antiangiogenic agent thalidomide are more neurotoxic, compared to eribulin. The exposure to these chemotherapeutic agents is associated with an axonal, length‐dependent, sensory polyneuropathy of mild to moderate severity, whereas it is considered that the peripheral nerve damage, unless severe, usually resolves soon after treatment discontinuation. Advanced age, high initial and prolonged dosing, coadministration of other neurotoxic chemotherapeutic agents and pre‐existing neuropathy are the common risk factors. Pharmacogenetic biomarkers might be used to define patients at increased susceptibility of CIPN. Currently, there is no established therapy for CIPN prevention or treatment; symptomatic treatment for neuropathic pain and dose reduction or withdrawal in severe cases is considered, at the cost of reduced cancer therapeutic efficacy. This review critically examines the pathogenesis, epidemiology, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of CIPN as a result of exposure to vinca alkaloids, thalidomide and its analogue lenalidomide as also eribulin.     

Patients' and physicians' interpretation of chemotherapy‐induced peripheral neurotoxicity

To test if and how chemotherapy‐induced peripheral neurotoxicity (CIPN) is perceived differently by patients and physicians, making assessment and interpretation challenging. We performed a secondary analysis of the CI‐PeriNomS study which included 281 patients with stable CIPN. We tested: (a) the association between patients' perception of activity limitation in performing eight common tasks and neurological impairment and (b) how the responses to questions related to these daily activities are interpreted by the treating oncologist. To achieve this, we compared patients' perception of their activity limitation with neurological assessment and the oncologists' blind interpretation. Distribution of the scores attributed by oncologists to each daily life maximum limitation (“impossible”) generated three groups: Group 1 included limitations oncologists attributed mainly to motor impairment; Group 2 ones mainly attributed to sensory impairment and Group 3 ones with uncertain motor and sensory impairment. Only a subset of questions showed a significant trend between severity in subjective limitation, reported by patients, and neurological impairment. In Group 1, neurological examination confirmed motor impairment in only 51%‐65% of patients; 76%‐78% of them also had vibration perception impairment. In Group 2, sensory impairment ranged from 84% to 100%; some degree of motor impairment occurred in 43%‐56% of them. In Group 3 strength reduction was observed in 49%‐50% and sensory perception was altered in up to 82%. Interpretation provided by the panel of experienced oncologists was inconsistent with the neurological impairment. These observations highlight the need of a core set of outcome measures for future CIPN trials.     

Bortezomib and other proteosome inhibitors—induced peripheral neurotoxicity: From pathogenesis to treatment

Proteasome inhibitors (PIs), especially bortezomib (BTZ), have come to the forefront over the last years because of their unprecedented efficacy mainly against multiple myeloma (MM). Unfortunately, peripheral neuropathy (PN) secondary to treatment of MM with PIs has emerged as a clinically relevant complication, which negatively impacts the quality of life of MM survivors. Bortezomib‐induced peripheral neuropathy (BIPN) is a dose‐limiting toxicity, which develops in 30% to 60% of patients during treatment. Typically, BIPN is a length‐dependent sensory axonopathy characterized by numbness, tingling, and severe neuropathic pain in stocking and glove distribution. BIPN mechanisms have not yet been fully elucidated. Experimental studies suggest that aggresome formation, endoplasmic reticulum stress, myotoxicity, microtubule stabilization, inflammatory response, and DNA damage could contribute to this neurotoxicity. A new generation of structurally distinct PIs has been developed, being increasingly used in clinical settings. Carfilzomib exhibits a much lower neurotoxicity profile, with a significantly lower incidence of PN compared to BTZ. Pre‐existing PN increases the risk of developing BIPN. Besides, BIPN is related to dose, schedule and mode of administration and modifications of these factors have lowered the incidence of PN. However, to date there is no cure for PIs‐induced PN (PIIPN), and a careful neurological monitoring and dose adjustment is a key strategy for preserving quality of life. This review critically looks at the pathogenesis, incidence, risk factors, both clinical and pharmacogenetics, clinical phenotype and management of PIIPN. We also make recommendations for further elucidating the whole clinical spectrum of PIIPN.     

Pain in chemotherapy‐induced peripheral neurotoxicity

Chemotherapy‐induced peripheral neurotoxicity (CIPN) is a potentially dose‐limiting side effect of the treatment of several cancers. CIPN is predominantly or exclusively sensory, and it is frequently associated with unpleasant symptoms, overall referred to as “pain.” However, given the markedly different clinical presentation and course of CIPN depending on the antineoplastic drug used, the broad term “pain” in the specific context of CIPN needs to be reconsidered and refined. In fact, a precise identification of the features of CIPN has relevant implication in the design of rational‐based clinical trials and in the selection of possible active drugs.     

Overview and critical revision of clinical assessment tools in chemotherapy‐induced peripheral neurotoxicity

Chemotherapy‐induced peripheral neurotoxicity (CIPN) is a major toxicity of cancer treatment, leading to dose reduction and premature treatment cessation, potentially affecting patient function, and quality of life. The development of accurate and sensitive assessment tools for CIPN is essential to enable clinical monitoring during treatment, follow‐up of long‐term outcomes and measurement of toxicity in clinical trials. This review examines CIPN clinical assessment scales incorporating clinician‐based, composite, and patient‐reported outcomes (PROs), providing a systematic review of their properties and an updated critical analysis of recommendations on current evidence for their use. This systematic review of CIPN assessment tools identified 50 papers containing 41 assessment tools, across 4 categories (common toxicity criteria; composite neurological scale; PROs; pain scale). The majority of these tools were PROs, underscoring the importance of patient‐based assessment of symptoms. While there has been considerable work in the field over the past 10 years, this review highlights significant gaps, including a lack of evaluation of responsiveness and problematic neuropathic pain evaluation. There remains a need for consensus on the best available tool and the need to modify existing instruments to improve utility.     

Chemotherapy‐induced peripheral neurotoxicity: A multifaceted,still unsolved issue

Chemotherapy‐induced peripheral neurotoxicity (CIPN) is a potentially dose‐limiting side effect of several commonly used cytotoxic chemotherapy agents. The main pharmacological classes that may cause CIPN include classical anticancer drugs, as well as the recently introduced immune checkpoint inhibitors and antibody drug conjugates. The absence of a complete knowledge of CIPN pathophysiology is only one of the several unsolved issues related to CIPN. Among some of the most relevant aspects of CIPN deserving further attention include the real number of patients exposed to the risk of CIPN, the long‐term impact on cancer survivors' quality of life due to incomplete recovery from CIPN, the economic burden related to acute and chronic CIPN, and the different perspective and education of the healthcare specialists in charge of managing patients with CIPN. Overall, CIPN remains a very challenging area of research as there are still several unresolved issues to be addressed in the future. In this special issue, the multifaceted profile of CIPN will be presented, with particular emphasis on bolstering the need to develop more optimized outcome measures than the existing ones to accurately evaluate the extent of CIPN, but also to ascertain the differences in the incidence, risk factors, clinical phenotype, and management of CIPN, according to the most commonly used neurotoxic chemotherapy classes. Perspectives for future research to pursue in order to cover the gaps in knowledge in the CIPN field will also be discussed.     

Genetic determinants of chronic oxaliplatin‐induced peripheral neurotoxicity: a genome‐wide study replication and meta‐analysis

We aimed at validating the role of genetic variants identified by a recent genome‐wide association study (GWAS) as determinants of chronic oxaliplatin‐induced peripheral neurotoxicity (OXAIPN). Eight polymorphisms (rs10486003, rs2338, rs843748, rs797519, rs4936453, rs12023000, rs17140129, and rs6924717) were genotyped in a total of 150 colorectal cancer patients of Caucasian origin receiving oxaliplatin‐based chemotherapy. The severity grade of chronic OXAIPN was assessed by NCI‐CTC criteria and the clinical version of the Total Neuropathy Score^© (TNSc^©). None of the polymorphisms investigated was found associated with grade ≥ 2 chronic OXAIPN (NCI‐CTC criteria), while a nominal association emerged for ACYP2 rs843748 when using the TNSc^© scale (dominant model: odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.10–0.75, P = 0.008). In the combined analysis of this results with data of the two previously published studies which assessed chronic OXAIPN by NCI‐CTC criteria, evidence suggestive of association with chronic OXAIPN (NCI‐CTC criteria) was found for ACYP2 rs843748 (dominant model: OR: 2.40, 95%CI: 1.40–5.24, P = 0.027), which, however, did not remain significant after correction for multiple testing (threshold P‐value <0.00625). These findings suggest a minor role of the single nucleotide polymorphisms (SNPs) investigated as genetic determinants of chronic OXAIPN. These results also highlight the importance of replication studies with meta‐analysis for validation of GWAS findings.     

Different effects of erythropoietin in cisplatin‐ and docetaxel‐induced neurotoxicity: An in vitro study

Chemotherapy‐induced peripheral neurotoxicity (CIPN) is a side effect limiting cisplatin (CDDP) and docetaxel (DOCE) treatment. Erythropoietin (EPO) is a hematopoietic growth factor also displaying neurotrophic properties. Evidence suggests that EPO's neuroprotective action may rely on PI3K/AKT pathway activation; however, data regarding the EPO neuroprotective mechanism are still limited. This study evaluated the effect of EPO on organotypic cultures of rat dorsal root ganglia (DRG) and in primary cultures of DRG‐dissociated sensory neurons exposed to CDDP‐ and DOCE‐induced neurotoxicity, aiming to investigate EPO's neuroprotective mechanism. Subsequently, the levels of AKT expression and activation were analyzed by Western blot in neurons exposed to CDDP or DOCE; AKT's role was further evaluated by using a chemical inhibitor of AKT activation, wortmannin. In these models EPO, was protective against both CDDP‐ and DOCE‐induced cell death and against CDDP‐induced neurite elongation reduction. A modulation of AKT activation was observed in CDDP‐treated neurons, and the presence of wortmannin prevented EPO's neuroprotective action against CDDP toxicity but did not have any effect on EPO's protection against DOCE‐induced toxicity, thus ruling out the PI3K‐AKT pathway as the mechanism of EPO's effect in neuronal death prevention after DOCE exposure. Our results confirm in vitro the effectiveness of EPO as a neuroprotectant against both CDDP‐ and DOCE‐induced neurotoxicity. In addition, a role of PI3K/AKT in EPO's protection against CDDP, but not against DOCE, neurotoxicity was shown, suggesting that alternative pathways could be involved in EPO's neuroprotective activity. © 2010 Wiley‐Liss, Inc.     

Identification of fluocinolone acetonide to prevent paclitaxel‐induced peripheral neuropathy

Paclitaxel (PTX) is among the most commonly used cancer drugs that cause chemotherapy‐induced peripheral neuropathy (CIPN), a debilitating and serious dose‐limiting side effect. Currently, no drugs exist to prevent CIPN, and symptomatic therapy is often ineffective. In order to identify therapeutic candidates to prevent axonal degeneration induced by PTX, we carried out a phenotypic drug screening using primary rodent dorsal root ganglion sensory neurons. We identified fluocinolone acetonide as a neuroprotective compound and verified it through secondary screens. Furthermore, we showed its efficacy in a mouse model of PTX‐induced peripheral neuropathy and confirmed with four different cancer cell lines that fluocinolone acetonide does not interfere with PTX's antitumor activity. Our study identifies fluocinolone acetonide as a potential therapy to prevent CIPN caused by PTX.     

Liability of the voltage‐gated potassium channel KCNN3 repeat polymorphism to acute oxaliplatin‐induced peripheral neurotoxicity

Thus far, there are conflicting results on the causal role of K+ channels in the pathogenesis of acute oxaliplatin‐induced peripheral neurotoxicity (OXAIPN). As such, we tested the hypothesis that the voltage‐gated K+ channel KCNN3 repeat polymorphism confers liability to acute OXAIPN. DNA from 151 oxaliplatin‐treated patients for colorectal cancer was extracted and genotyped. The incidence of acute OXIPN was measured by the OXA‐neuropathy questionnaire, while the severity of acute OXAIPN was scored basing on the number of symptoms reported by the patients at each clinical assessment. The increased number of acute symptoms was considered as being suggestive of an increased severity of acute OXAIPN. A total of 130/151 (86.1%) patients developed any grade of acute OXAIPN. Grade I acute neurotoxicity was revealed in 43 (28.5%) patients; grade II in 34 (22.5%); and grade III in 53 (53.1%) patients. Genotyping revealed alleles carrying 11 to 20 CAG repeats. The majority of patients were heterozygous (131; 89.4%). The most common numbers of CAG repeats were 15 (n = 46), 16 (n = 53), and 17 (n = 95). Patients carrying alleles with either 15 to 17 CAG repeats (P = .601) did not experience a higher incidence of grade III (treatment‐emergent) acute OXAIPN. Likewise, no increased incidence of acute treatment‐emergent OXAIPN was noted in heterozygous patients carrying either two short alleles (<19 CAG repeats) or one short and one long (≥19 CAG repeats) allele (P = .701). Our results do not support a causal relationship between the KCNN3CAG repeat polymorphism and acute OXΑIPN.     

Chemotherapy‐induced peripheral neurotoxicity (CIPN): what we need and what we know

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.     

Oxaliplatin rechallenge in metastatic colorectal cancer patients with clinically significant oxaliplatin‐induced peripheral neurotoxicity

We investigated whether rechallenge with oxaliplatin (OXA) can worsen the pre‐existing oxaliplatin‐induced peripheral neurotoxicity (OXAIPN) in metastatic colorectal cancer (mCRC) patients. Patients previously treated with OXA, having clinically significant grade 1 or 2 OXAIPN were assessed, after receiving rechallenge with OXA, using the clinical version of the Total Neuropathy Score (TNSc). Peripheral neuropathy was assessed at the end of first OXA exposure and at completion of OXA rechallenge. The first line OXA‐based chemotherapy was completed at least 9 months earlier (OXA‐free interval). We studied 25 mCRC patients, 14 males and 11 females, with a median age of 63 (35‐77) years. After their first exposure to OXA‐based chemotherapy, 9 (36%) patients developed grade 1 OXAIPN and 16 patients grade 2 (64%) neurotoxicity. OXA reintroduction with a median of 10 (8‐14) cycles led to grade 1 OXAIPN in two patients (8%), grade 2 in 19 patients (76%), and grade 3 neuropathy in 4 (16%) patients Worsening of pre‐existing OXAIPN was documented in seven (28%) patients and was significantly associated with higher OXA delivered cumulative dose (P < .001). Median TNSc scores following treatment (10; range 4‐18) were significantly increased (P < .001), when compared to the scores recorded at the end of first line treatment (8; range 2‐12). Rechallenging OXA appears to relatively worsen the severity of existing OXAIPN. However, the majority of rechallenged patients developed a clinically significant (grade 2) OXAIPN, rather than treatment‐emergent grade 3. As such, OXA rechallenge might be a feasible option in patients previously having OXAIPN.     

Immune checkpoint inhibitors‐induced neuromuscular toxicity: From pathogenesis to treatment

Immune checkpoint inhibitors (ICIs) are increasingly used and are becoming the standard of care in the treatment of various tumor types. Despite the favorable results in terms of oncological outcomes, these treatments have been associated with a variety of immune‐related adverse events (irAEs). Neurological irAEs are rare but potentially severe. Neuromuscular disorders represent the most common neurological irAEs following anti‐PD‐1, anti‐PD‐L1, and anti‐CTLA‐4 treatment, and include myositis, myasthenia gravis, and demyelinating polyradiculoneuropathy. Instrumental findings may differ from typical neuromuscular disorders occurring outside ICIs treatment. Despite initial severity, neurological irAEs often respond to immune‐modulating therapies. Prompt irAEs diagnosis, ICIs discontinuation, and early treatment with corticosteroids, together with patient education and a multi‐disciplinary approach, are important for optimizing clinical outcomes. Intravenous immunoglobulin, plasma exchange, and other immune‐modulating treatments should be considered in more severe cases. Consideration of re‐challenging with the same immunotherapy drug may be given in some cases, based on clinical picture and initial severity of irAEs.     

Real world,open label experience with lacosamide against acute painful oxaliplatin‐induced peripheral neurotoxicity

We report the outcome of a pilot, open‐label study that tested the potential of lacosamide (200 mg/bi.d) as an effective and safe symptomatic treatment against acute painful oxaliplatin‐induced peripheral neurotoxicity (OXAIPN). Lacosamide was introduced in 18 colorectal cancer patients with evidence of clinically significant acute, painful OXAIPN after infusion of the third course (T1) of oxaliplatin‐based chemotherapy (FOLFOX4) and was maintained until completion of all 12 courses (T4). The OXA‐Neuropathy Questionnaire (OXA‐NQ) was used to record the severity of acute OXAIPN; the PI‐NRS estimated the severity of neuropathic pain, while the chronic OXAIPN was graded with TNSc. The EuroQOL ( EQ‐5D) instrument was also applied. The Patient Global Impression of Change (PGIC) scale measured the lacosamide‐attributed perception of change. LCM‐responders were considered those with ≥50% reduction in PI‐NRS and OXA‐NQ scores at T4, compared to T1. Patients experienced on T1 a median number of acute OXAIPN symptoms of 4 and had a median neuropathic pain severity score of 6, which was strongly related to lower quality of life, according to EQ‐VAS (P < .001). At T4, 12 patients (66.7%) were classified as responders. A significant clinical improvement was documented in the severity of acute OXAIPN and neuropathic pain in relation to lacosamide (P < .001) at T4 compared to T1, which was associated with improved EQ‐VAS scores (P < .001). Twelve patients scored PGIC ≥5 (lacosamide‐attributed) at T4. There were no incidences of early drop‐outs for safety reasons. Lacosamide appears to be an effective and well‐tolerated symptomatic treatment against acute, painful OXAIPN.     

Correspondence between neurophysiological and clinical measurements of chemotherapy‐induced peripheral neuropathy: secondary analysis of data from the CI‐PeriNomS study

Chemotherapy‐induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI‐PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28–6.07), 3.49 (95%CI: 1.61–7.55), and 4.42 (95%CI: 1.35–14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81–41.42), 2.54 (95%CI: 1.19–5.41), and 7.47 (95%CI: 2.49–22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN.     

Vincristine-induced acute neurotoxicity versus Guillain–Barré syndrome: a diagnostic dilemma

We report the case of a patient with acute lymphoblastic leukaemia who, after the initiation of treatment with vincristine (VCR), developed a fulminant motor polyradiculoneuropathy resembling an axonal variant of Guillain-Barré syndrome (GBS). This report shows that differentiating between axonal GBS and VCR-induced acute neurotoxicity may be a challenge for clinicians.     

Platinum accumulation in oxaliplatin‐induced peripheral neuropathy

Oxaliplatin‐induced peripheral neuropathy (OIPN) is a common and dose‐limiting toxic effect that markedly limits the use of oxaliplatin and affects the quality of life. Although it is common, the underlying mechanisms of OIPN remain ambiguous. Recent studies have shown that the platinum accumulation in peripheral nervous system, especially in dorsal root ganglion, is a significant mechanism of OIPN. Several specific transporters, including organic cation transporters, high‐affinity copper uptake protein1 (CTR1), ATPase copper transporting alpha (ATP7A) and multidrug and toxin extrusion protein 1 (MATE1), could be associated with this mechanism. This review summarizes the current research progress about the relationship between platinum accumulation and OIPN, as well as suggests trend for the future research.