Paola Alberti
@unimib.it
Assistant Professor (Human Anatomy)
University of Milano-Bicocca
Her main expertise is related to peripheral nervous system diseases, especially Chemotherapy-Induced Peripheral Neurotoxicity (CIPN). She is an active member of the Toxic Neuropathy Consortium (TNC), part of the Peripheral Nervous System (PNS) society. During the Residency in Neurology, she was a visiting fellow at Johns Hopkins University (Prof. D.R. Cornblath, MD) to refine her knowledge of neurophysiological techniques. Since 2015 she has been pursuing an interest for preclinical research and joined the Experimental Neurology Unit (ENU, University of Milano-Bicocca) team, where she completed the PhD program in Neuroscience (2019). Her PhD project was focused on Oxaliplatin Induced Peripheral Neurotoxicity in preclinical models: she introduced advanced neurophysiological techniques, nerve excitability testing, to ENU after having learnt them from Prof H. Bostock, (UCL, London). She was a visiting fellow at University of Baltimore (Prof. S.G. Dorsey and Prof C. Renn) where learned DRG
EDUCATION
EDUCATION AND TRAINING
July 2010: Degree: MD – 110/110 cum laude – University of Milano-Bicocca (Monza, Italy)
June 2016 – Degree: Board in Neurology – 70/70 cum laude – University of Milano-Bicocca (Monza, Italy)
February 2019 – Degree: PhD in Neuroscience – University of Milano-Bicocca (Monza, Italy)
RESEARCH, TEACHING, or OTHER INTERESTS
Medicine, Anatomy, Neurology (clinical)
FUTURE PROJECTS
Sodium-calcium exchanger (NCX) and ion channels: pivotal elements leading to axonal damage in peripheral nerves?
The project investigates mechanisms leading to peripheral neuropathies (PN), with a specific interest for axonal damage. PN have many different causes: genetic, metabolic, toxic, dysimmune(Scuteri and Cavaletti, 2016). Patients affected by PN can experience impaired strength, sensation and involuntary functions (e.g. control of the gastrointestinal tract). Unfortunately, in the majority of cases there are only symptomatic treatments; this is partly due to the incomplete knowledge of axonal damage mechanisms. The project investigates a possible pathogenetic cascade, shared by different PN, with the aim of shedding light on the chronological and causative sequence of events leading to peripheral nerve axon damage. Goals Verifying the role of a particular molecular family, the sodium/calcium exchangers (NCX) family, as downstream pivotal elements leading to axonal damage.
Applications Invited
PhD students, postdoc. technicians
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Paola Alberti, Andreas A. Argyriou, Jordi Bruna, M. Imad Damaj, Sara Faithfull, Alice Harding, Ahmet Hoke, Robert Knoerl, Noah Kolb, Tiffany Li,et al.
Springer Science and Business Media LLC
Roberta Bonomo, Annalisa Canta, Alessia Chiorazzi, Valentina Alda Carozzi, Cristina Meregalli, Eleonora Pozzi, Paola Alberti, Cecile F. Frampas, Daan R. Van der Veen, Paola Marmiroli,et al.
Wiley
AbstractBackground and AimsChemotherapy‐induced peripheral neurotoxicity (CIPN) is one of the most common dose‐limiting side effects of paclitaxel (PTX) treatment. Many age‐related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated.MethodsTwenty‐four young (2 months) and 24 adult (9 months) Wistar male rats were randomized to either PTX treatment (10 mg/kg i.v. once/week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed at baseline, after 4 weeks of treatment and 2‐week follow‐up. Skin biopsies and nerve specimens collected from sacrificed animals were examined for intraepidermal nerve fiber (IENF) density assessment and nerve morphology/morphometry. Blood and liver samples were collected for targeted metabolomics analysis.ResultsAt the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (p < .05) in the caudal nerve of young PTX‐animals, and in both the digital and caudal nerve of adult PTX‐animals (p < .05). A significant decrease in the mechanical threshold was observed only in young PTX‐animals (p < .001), but not in adult PTX‐ones. Nevertheless, both young and adult PTX‐rats had reduced IENF density (p < .0001), which persisted at the end of follow‐up period. Targeted metabolomics analysis showed significant differences in the plasma metabolite profiles between PTX‐animals developing peripheral neuropathy and age‐matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, sphingolipids, and bile acids playing a major role in the response to PTX administration.InterpretationOur study identifies for the first time multiple related metabolic axes involved in PTX‐induced peripheral neurotoxicity, and suggests age‐related differences in CIPN manifestations and in the metabolic profile.
Alessia Chiorazzi, Annalisa Canta, Valentina Alda Carozzi, Cristina Meregalli, Eleonora Pozzi, Elisa Ballarini, Virginia Rodriguez‐Menendez, Paola Marmiroli, Guido Cavaletti, and Paola Alberti
Wiley
AbstractBackground and AimsChemotherapy‐induced peripheral neurotoxicity (CIPN) is a common and long‐lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test in vivo axonal properties and can be used to monitor early changes leading to axonal damage.MethodsWe tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density.ResultsNET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement.InterpretationNET after the first administration demonstrated the ongoing OHP‐related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage.
Paola Alberti, Andreas A. Argyriou, Jordi Bruna, M. Imad Damaj, Sara Faithfull, Alice Harding, Ahmet Hoke, Robert Knoerl, Noah Kolb, Tiffany Li,et al.
Springer Science and Business Media LLC
Abstract Purpose This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research. Methods An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science. Results Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship. Conclusion Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide. Relevance to inform research policy Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship.
Daniel L Hertz, Cindy Tofthagen, Emanuela Rossi, Davide Paolo Bernasconi, Jiyoon Lim, Martha Carlson, Katharine E. Sheffield, Larissa Nekhlyudov, Lisa Grech, Diane Von Ah,et al.
Springer Science and Business Media LLC
Marianna Dionisi, Beatrice Riva, Marta Delconti, Cristina Meregalli, Alessia Chiorazzi, Annalisa Canta, Paola Alberti, Valentina Carozzi, Eleonora Pozzi, Dmtry Lim,et al.
Springer Science and Business Media LLC
AbstractOxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN), one of the major dose-limiting side effects of colorectal cancer treatment, is characterized by both acute and chronic syndromes. Acute exposure to low dose OHP on dorsal root ganglion (DRG) neurons is able to induce an increase in intracellular calcium and proton concentration, thus influencing ion channels activity and neuronal excitability. The Na+/H+ exchanger isoform-1 (NHE1) is a plasma membrane protein that plays a pivotal role in intracellular pH (pHi) homeostasis in many cell types, including nociceptors. Here we show that OHP has early effects on NHE1 activity in cultured mouse DRG neurons: the mean rate of pHi recovery was strongly reduced compared to vehicle-treated controls, reaching levels similar to those obtained in the presence of cariporide (Car), a specific NHE1 antagonist. The effect of OHP on NHE1 activity was sensitive to FK506, a specific calcineurin (CaN) inhibitor. Lastly, molecular analyses revealed transcriptional downregulation of NHE1 both in vitro, in mouse primary DRG neurons, and in vivo, in an OIPN rat model. Altogether, these data suggest that OHP-induced intracellular acidification of DRG neurons largely depends on CaN-mediated NHE1 inhibition, revealing new mechanisms that OHP could exert to alter neuronal excitability, and providing novel druggable targets.
Susanna B Park, Aysel Cetinkaya-Fisgin, Andreas A Argyriou, Ahmet Höke, Guido Cavaletti, and Paola Alberti
BMJ
Multiple pathological mechanisms are involved in the development of chemotherapy-induced peripheral neurotoxicity (CIPN). Recent work has provided insights into the molecular mechanisms underlying chemotherapy-induced axonal degeneration. This review integrates evidence from preclinical and clinical work on the onset, progression and outcome of axonal degeneration in CIPN. We review likely triggers of axonal degeneration in CIPN and highlight evidence of molecular pathways involved in axonal degeneration and their relevance to CIPN, including SARM1-mediated axon degeneration pathway. We identify potential clinical markers of axonal dysfunction to provide early identification of toxicity as well as present potential treatment strategies to intervene in axonal degeneration pathways. A greater understanding of axonal degeneration processes in CIPN will provide important information regarding the development and progression of axonal dysfunction more broadly and will hopefully assist in the development of successful interventions for CIPN and other neurodegenerative disorders.
Maria Lopez-Garzon, Annalisa Canta, Alessia Chiorazzi, and Paola Alberti
Elsevier BV
Guido Cavaletti, Katherine Forsey, and Paola Alberti
Wiley
AbstractBackground and AimsSeveral widely used medications, with a relevant efficacy profile, are toxic to the peripheral nervous system and an even larger number of agents are suspected to be neurotoxic. There are concerns about the use of these drugs in patients with Charcot–Marie–Tooth disease (CMT), a hereditary motor and sensory neuropathy. This review provides evidence‐based updated recommendations on this clinically relevant topic.MethodsA systematic review of the available studies/reports written in English was performed from July to September 2022 including in the search string all reported putative neurotoxic drugs.ResultsThe results of our systematic review provide evidence‐based support for the statement that use of vincristine, and possibly paclitaxel, can occasionally induce an atypical, and more severe, course of drug‐related peripheral neurotoxicity in CMT patients. It is therefore reasonable to recommend caution in the use of these compounds in CMT patients. However, no convincing evidence for a similar recommendation could be found for all other drugs.InterpretationIt is important that patients with CMT are not denied effective treatments that may prolong life expectancy for cancer or improve their health status if affected by non‐oncological diseases. Accurate monitoring of peripheral nerve function in CMT patients treated with any neurotoxic agent remains mandatory to detect the earliest signs of neuropathy worsening and atypical clinical courses. Neurologists monitoring CMT patients as part of their normal care package or for natural history studies should keep detailed records of exposures to neurotoxic medications and support reporting of accelerated neuropathy progression if observed.
Stefanie Stoller, Scott Capozza, Paola Alberti, Maryam Lustberg, and Ian R. Kleckner
Springer Science and Business Media LLC
Eleonora Pozzi, Elisa Ballarini, Virginia Rodriguez-Menendez, Annalisa Canta, Alessia Chiorazzi, Laura Monza, Mario Bossi, Paola Alberti, Alessio Malacrida, Cristina Meregalli,et al.
MDPI AG
Chemotherapy-induced peripheral neurotoxicity is one of the most common dose-limiting toxicities of several widely used anticancer drugs such as platinum derivatives (cisplatin) and taxanes (paclitaxel). Several molecular mechanisms related to the onset of neurotoxicity have already been proposed, most of them having the sensory neurons of the dorsal root ganglia (DRG) and the peripheral nerve fibers as principal targets. In this study we explore chemotherapy-induced peripheral neurotoxicity beyond the neuronocentric view, investigating the changes induced by paclitaxel (PTX) and cisplatin (CDDP) on satellite glial cells (SGC) in the DRG and their crosstalk. Rats were chronically treated with PTX (10 mg/Kg, 1qwx4) or CDDP (2 mg/Kg 2qwx4) or respective vehicles. Morpho-functional analyses were performed to verify the features of drug-induced peripheral neurotoxicity. Qualitative and quantitative immunohistochemistry, 3D immunofluorescence, immunoblotting, and transmission electron microscopy analyses were also performed to detect alterations in SGCs and their interconnections. We demonstrated that PTX, but not CDDP, produces a strong activation of SGCs in the DRG, by altering their interconnections and their physical contact with sensory neurons. SGCs may act as principal actors in PTX-induced peripheral neurotoxicity, paving the way for the identification of new druggable targets for the treatment and prevention of chemotherapy-induced peripheral neurotoxicity.
Eleonora Pozzi, Laura Monza, Elisa Ballarini, Mario Bossi, Virginia Rodriguez-Menendez, Annalisa Canta, Alessia Chiorazzi, Valentina Alda Carozzi, Luca Crippa, Paola Marmiroli,et al.
MDPI AG
Peripheral Neuropathies (PN) are common conditions whose treatment is still lacking in most cases. Animal models are crucial, but experimental procedures should be refined in some cases. We performed a detailed characterization of the ventral caudal nerve to contribute to a more effective assessment of axonal damage in future PN studies. PN was induced via weekly systemic injection of a neurotoxic drug (paclitaxel); we compared the control and PN-affected rats, performing serial neurophysiological evaluations of the caudal nerve for its entire length. On the same nerve portions, we performed light microscopy and ultrastructural pathological observations to assess the severity of damage and verify the integrity of the surrounding structures. Neurophysiological and morphological analyses confirmed that a severe axonopathy had ensued in the PN group, with a length-dependent modality, matching morphological observations. The site of neurophysiological recording (e.g., distance from the base of the tail) was critical for achieving useful data. A flexible experimental paradigm should be considered in animal studies investigating axonal PN, particularly if the expected severity is relevant; the mid-portion of the tail might be the most appropriate site: there damage might be remarkable but neither as extreme as at the tip of the tail nor as mild as at the base of the tail.
Paola Alberti, Alessandro Salvalaggio, Andreas A. Argyriou, Jordi Bruna, Andrea Visentin, Guido Cavaletti, and Chiara Briani
MDPI AG
Various neurological complications, affecting both the central and peripheral nervous system, can frequently be experienced by cancer survivors after exposure to conventional chemotherapy, but also to modern immunotherapy. In this review, we provide an overview of the most well-known adverse events related to chemotherapy, with a focus on chemotherapy induced peripheral neurotoxicity, but we also address some emerging novel clinical entities related to cancer treatment, including chemotherapy-related cognitive impairment and immune-mediated adverse events. Unfortunately, efficacious curative or preventive treatment for all these neurological complications is still lacking. We provide a description of the possible mechanisms involved to drive future drug discovery in this field, both for symptomatic treatment and neuroprotection.
Elisa Ballarini, Alessio Malacrida, Virginia Rodriguez-Menendez, Eleonora Pozzi, Annalisa Canta, Alessia Chiorazzi, Laura Monza, Sara Semperboni, Cristina Meregalli, Valentina Alda Carozzi,et al.
MDPI AG
Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a frequent adverse event of colorectal cancer treatment. OIPN encompasses a chronic and an acute syndrome. The latter consists of transient axonal hyperexcitability, due to unbalance in Na+ voltage-operated channels (Na+VOC). This leads to sustained depolarisation which can activate the reverse mode of the Na+/Ca2+ exchanger 2 (NCX2), resulting in toxic Ca2+ accumulation and axonal damage (ADa). We explored the role of NCX2 in in vitro and in vivo settings. Embryonic rat Dorsal Root Ganglia (DRG) organotypic cultures treated with SEA0400 (SEA), a NCX inhibitor, were used to assess neuroprotection in a proof-of-concept and pilot study to exploit NCX modulation to prevent ADa. In vivo, OHP treated mice (7 mg/Kg, i.v., once a week for 8 weeks) were compared with a vehicle-treated group (n = 12 each). Neurophysiological and behavioural testing were performed to characterise acute and chronic OIPN, and morphological analyses were performed to detect ADa. Immunohistochemistry, immunofluorescence, and western blotting (WB) analyses were also performed to demonstrate changes in NCX2 immunoreactivity and protein expression. In vitro, NCX inhibition was matched by ADa mitigation. In the in vivo part, after verifyingboth acute and chronic OIPN had ensued, we confirmed via immunohistochemistry, immunofluorescence, and WB that a significant NCX2 alteration had ensued in the OHP group. Our data suggest NCX2 involvement in ADa development, paving the way to a new line of research to prevent OIPN.
Paola Alberti, Sara Semperboni, Guido Cavaletti, and Arianna Scuteri
MDPI AG
Neurons are permanent cells whose key feature is information transmission via chemical and electrical signals. Therefore, a finely tuned homeostasis is necessary to maintain function and preserve neuronal lifelong survival. The cytoskeleton, and in particular microtubules, are far from being inert actors in the maintenance of this complex cellular equilibrium, and they participate in the mobilization of molecular cargos and organelles, thus influencing neuronal migration, neuritis growth and synaptic transmission. Notably, alterations of cytoskeletal dynamics have been linked to alterations of neuronal excitability. In this review, we discuss the characteristics of the neuronal cytoskeleton and provide insights into alterations of this component leading to human diseases, addressing how these might affect excitability/synaptic activity, as well as neuronal functioning. We also provide an overview of the microscopic approaches to visualize and assess the cytoskeleton, with a specific focus on mitochondrial trafficking.
Sofia Karteri, Jordi Bruna, Andreas A. Argyriou, Sara Mariotto, Roser Velasco, Montse Alemany, Foteini Kalofonou, Paola Alberti, Alessandro Dinoto, Dimitrios Velissaris,et al.
Wiley
AbstractOur aim was to assess the significance of measuring serum neurofilament light chain (sNfL) levels as a biomarker of paclitaxel‐induced peripheral neurotoxicity (PIPN). We longitudinally measured sNfL in breast cancer patients, scheduled to receive the 12‐weekly paclitaxel‐based regimen. Patients were clinically examined by means of the Total Neuropathy Score‐clinical version (TNSc), while sNfL were quantified, using the highly sensitive Simoa technique, before starting chemotherapy (baseline), after 2 (week 2) and 3 (week 3) weekly courses, and at the end of chemotherapy (week 12). Among 59 included patients (mean age: 53.1 ± 11.5 years), 33 (56%) developed grade 0‐1 and 26 (44%) grade 2‐3 PIPN at week 12. A significant longitudinal increase of sNfL levels from baseline to week‐12 was determined, whereas patients with TNSc grade 2‐3 PIPN had significantly increased sNfL levels at week 12, compared to those with grade 0‐1. receiver‐operated characteristics (ROC) analysis defined a value of NfL of >85 pg/mL at week 3 as the best discriminative determination to predict the development of grade 2‐3 PIPN at week 12 (sensitivity 46.2%, specificity 84.8%). The logistic binary regression analysis revealed that age > 50 years and the cutoff of >85 pg/mL of sNfL levels at week 3 independently predicted the development of grade 2‐3 PIPN at week 12 with a sensitivity of 46%, a specificity of 91%, and a positive and negative predictive values of 75% and 67%, respectively. sNfL levels seem to be a valuable biomarker of neuro‐axonal injury in PIPN. An early increase of this biomarker after a 3‐weekly chemotherapy course can be a predictive marker of final PIPN severity.
Stefano Tamburin, Susanna B. Park, Angelo Schenone, Elisa Mantovani, Mehrnaz Hamedani, Paola Alberti, Vesile Yildiz-Kabak, Ian R. Kleckner, Noah Kolb, Miryam Mazzucchelli,et al.
Elsevier BV
Peter Bloomingdale, Cristina Meregalli, Kevin Pollard, Annalisa Canta, Alessia Chiorazzi, Giulia Fumagalli, Laura Monza, Eleonora Pozzi, Paola Alberti, Elisa Ballarini,et al.
Frontiers Media SA
Chemotherapy-induced peripheral neurotoxicity is a common dose-limiting side effect of several cancer chemotherapeutic agents, and no effective therapies exist. Here we constructed a systems pharmacology model of intracellular signaling in peripheral neurons to identify novel drug targets for preventing peripheral neuropathy associated with proteasome inhibitors. Model predictions suggested the combinatorial inhibition of TNFα, NMDA receptors, and reactive oxygen species should prevent proteasome inhibitor-induced neuronal apoptosis. Dexanabinol, an inhibitor of all three targets, partially restored bortezomib-induced reduction of proximal action potential amplitude and distal nerve conduction velocity in vitro and prevented bortezomib-induced mechanical allodynia and thermal hyperalgesia in rats, including a partial recovery of intraepidermal nerve fiber density. Dexanabinol failed to restore bortezomib-induced decreases in electrophysiological endpoints in rats, and it did not compromise bortezomib anti-cancer effects in U266 multiple myeloma cells and a murine xenograft model. Owing to its favorable safety profile in humans and preclinical efficacy, dexanabinol might represent a treatment option for bortezomib-induced neuropathic pain.
Eleonora Pozzi and Paola Alberti
Springer US
Susanna B. Park, Stefano Tamburin, Angelo Schenone, Ian R. Kleckner, Roser Velasco, Paola Alberti, Grace Kanzawa-Lee, Maryam Lustberg, Susan G. Dorsey, Elisa Mantovani,et al.
Informa UK Limited
ABSTRACT Introduction Chemotherapy-induced peripheral neurotoxicity (CIPN) remains a significant toxicity in cancer survivors without preventative strategies or rehabilitation. Exercise and physical activity-based interventions have demonstrated promise in reducing existing CIPN symptoms and potentially preventing toxicity, however there is a significant gap in evidence due to the lack of quality clinical trials and appropriate outcome measures. Areas Covered We systematically reviewed outcome measures in CIPN exercise and physical rehabilitation studies with expert panel consensus via the Peripheral Nerve Society Toxic Neuropathy Consortium to provide recommendations for future trials. Across 26 studies, 75 outcome measures were identified and grouped into 16 domains within three core areas – measures of manifestations of CIPN (e.g. symptoms/signs), measures of the impact of CIPN and other outcome measures. Expert Opinion This article provides a conceptual framework for CIPN outcome measures and highlights the need for definition of a core outcome measures set. The authors provide recommendations for CIPN exercise and physical rehabilitation trial design and outcome measure selection. The development of a core outcome measure set will be critical in the search for neuroprotective and treatment approaches to support cancer survivors and to address the gap in the identification of effective rehabilitation and treatment options for CIPN.
Laura Monza, Giulia Fumagalli, Alessia Chiorazzi, and Paola Alberti
Elsevier BV
Paola Alberti and Christopher B. Steer
Springer International Publishing
Paola Alberti, Davide P. Bernasconi, David R. Cornblath, Ingemar S.J. Merkies, Susanna B. Park, Roser Velasco, Jordi Bruna, Dimitri Psimaras, Susanne Koeppen, Andrea Pace,et al.
Ovid Technologies (Wolters Kluwer Health)
Background and Objective There is no agreement on the gold standard for detection and grading of chemotherapy-induced peripheral neurotoxicity (CIPN) in clinical trials. The objective is to perform an observational prospective study to assess and compare patient-based and physician-based methods for detection and grading of CIPN. Methods Consecutive patients, aged 18 years or older, candidates for neurotoxic chemotherapy, were enrolled in the United States, European Union, or Australia. A trained investigator performed physician-based scales (Total Neuropathy Score–clinical [TNSc], used to calculate Total Neuropathy Score–nurse [TNSn]) and supervised the patient-completed questionnaire (Functional Assessment of Cancer Treatment/Gynecologic Oncology Group–Neurotoxicity [FACT/GOG-NTX]). Evaluations were performed before and at the end of chemotherapy. On participants without neuropathy at baseline, we assessed the association between TNSc, TNSn, and FACT/GOG-NTX. Considering a previously established minimal clinically important difference (MCID) for FACT/GOG-NTX, we identified participants with and without a clinically important deterioration according to this scale. Then, we calculated the MCID for TNSc and TNSn as the difference in the mean change score of these scales between the 2 groups. Results Data from 254 participants were available: 180 (71%) had normal neurologic status at baseline. At the end of the study, 88% of participants developed any grade of neuropathy. TNSc, TNSn, and FACT/GOG-NTX showed good responsiveness (standardized mean change from baseline to end of chemotherapy >1 for all scales). On the 153 participants without neuropathy at baseline and treated with a known neurotoxic chemotherapy regimen, we verified a moderate correlation in both TNSc and TNSn scores with FACT/GOG-NTX (Spearman correlation index r = 0.6). On the same sample, considering as clinically important a change in the FACT/GOG-NTX score of at least 3.3 points, the MCID was 3.7 for TNSc and 2.8 for the TNSn. Conclusions MCID for TNSc and TNSn were calculated and the TNSn can be considered a reliable alternative objective clinical assessment if a more extended neurologic examination is not possible. The FACT/GOG-NTX score can be reduced to 7 items and these items correlate well with the TNSc and TNSn. Classification of Evidence This study provides Class III evidence that a patient-completed questionnaire and nurse-assessed scale correlate with a physician-assessed scale.
Paola Alberti and Helmar C. Lehmann
Elsevier BV