Grading of chemotherapy-induced peripheral neurotoxicity using the Total Neuropathy Scale G. Cavaletti, MD; G. Bogliun, MD; L. Marzorati, MD; A. Zincone, MD; M. Piatti, MD; N. Colombo, MD; G. Parma, MD; A. Lissoni, MD; F. Fei, MD; S. Cundari; and C. Zanna, MD Abstract—The authors compared clinically based neurotoxicity scales with the Total Neuropathy Scale, with the aim of improving the grading of the severity of chemotherapy-induced peripheral neuropathy (CIPN). The severity of CIPN was evaluated in a series of 60 women treated with cisplatin- and paclitaxel-based chemotherapy. A reduced version of TNS (TNSr) was also compared. The authors concluded that the TNS and TNSr can be used to assess the severity of CIPN effectively, and the results of this evaluation can be reliably correlated with the oncologic grading of sensory peripheral neurotoxicity. NEUROLOGY 2003;61:1297–1300 Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and potentially disabling side effect of some widely used anticancer agents. 1 CIPN has important clinical relevance because it might represent the dose-limiting side effect of the treat- ment, thus impairing patients’ quality of life and the effectiveness of treatment. Although different clinically based scales for onco- logic use are currently available, the accurate grading of CIPN represents an unsolved issue (particularly in clinical trials). 2 This is largely due to the lack of sensi- tivity of the proposed scales. Moreover, grading may differ between different examiners. 3 We compared oncologic grading scales for peripheral neurotoxicity (National Cancer Institute–Common Toxicity Criteria [NCI-CTC] 2.0, Eastern Cooperative Oncology Group [ECOG], Ajani score) 4-6 with a compos- ite score already formally validated for patients with diabetes and used in small series of patients with can- cer (Total Neuropathy Score [TNS]). 7-9 Patients and methods. Following Institutional Review Board approval and patients’ written informed consent, 60 women with squamous cervical carcinoma were examined during treatment with TP (paclitaxel 175 mg/m 2 + cisplatin 75 mg/m 2 ) or TIP (TP + iphosphamide 5 mg/m 2 ) chemotherapy. According to TNS (table 1), sensory, motor, or autonomic symp- toms were assessed by interviewing the patients. The neurologic examination was based on the standard evaluation of strength, deep tendon reflexes (DTR), and pin and vibration sensibility. For the latter, the patient was asked to report the subjective percep- tion of cessation of vibration while the 128 Hz tuning fork was gradually changing from the maximal vibration (score 0 if per- ceived) to nearly null (score 8). Nerve conduction studies were performed with a Medelec Premiere Plus electromyograph (Vick- ers Medicals, Woking, UK) using standard methods. 10 Vibration detection threshold (VDT) was assessed by a trained examiner using a Vibrameter type IV device (Somedic AB, Stockholm, Swe- den) at the first metatarsal bone using the method of limits (i.e., stimuli increased or decreased in a continuous manner until sen- sation occurred or disappeared and, finally, until the same value was obtained with the two different modalities). The neurophysio- logic and VDT normal reference values were previously deter- mined in the Department of Neurology in age-matched subjects (see table 1). CIPN was also assessed by a single examiner (G.C.) using the NCI-CTC 2.0, ECOG, and Ajani scores (see table 1). Finally, a reduced version of TNS (TNSr) was calculated (see table 1), and correlations with the common toxicity scale results were recalcu- lated (Spearman test for nonparametric data, significant level p  0.05); the 95% CL were also calculated using PRISM software (GraphPad Software Inc., San Diego, CA). Results. A total of 110 examinations were available for the correlation study. No patient was graded more than 0 in the motor NCI-CTC 2.0 scale and, accordingly, no motor symptoms were reported by any of the patients. However, in some patients, mild distal weakness was observed at the neurologic examination. No autonomic symptoms were re- ferred by the patients. The results of the correlation study between TNS and sensory common toxicity scores are reported in table 2. The overall TNS score correlated very closely with NCI- CTC 2.0, Ajani, and ECOG scores. The correlation between TNS and the selected neurotoxicity scales was calculated also after stratification of the entire population into two subgroups according to TNS severity (i.e., score  5 vs  5; see table 2); a positive result was obtained in the patients with a milder neurotoxicity, but not in the most severe cases. The statistical results were unchanged when, be- sides the examination level, a patient level comparison was also performed (i.e., using only one visit in those pa- tients examined more than once, data not shown). From the Dipartimento di Neuroscienze e Tecnologie Biomediche (Drs. Cavaletti and Piatti) and Dipartimento di Scienze Chirurgiche (Drs. Lissoni and Fei), Università di Milano “Bicocca,” Monza; Clinica Neurologica (Drs. Bogliun, Marzorati, Zincone, and Piatti) and Clinica Ginecologica (Drs. Lissoni and Fei), A.O. S. Gerardo, Monza; Dipartimento di Ginecologia Oncologica (Drs. Colombo and Parma), Istituto Europeo di Oncologia, Milan; and Sigma-Tau ifr (Drs. Cundari and Zanna), Pomezia, Italy. Received April 16, 2003. Accepted in final form July 10, 2003. Address correspondence and reprint requests to Prof. Guido Cavaletti, Clinica Neurologica–Ospedale S. Gerardo, v. Donizetti 106, 20052 Monza (MI), Italy; e-mail: guido.cavaletti@unimib.it Copyright © 2003 by AAN Enterprises, Inc. 1297