Hypothermia for Preventing Chemotherapy-Induced Peripheral Neuropathy Hypothermia for Preventing Chemotherapy-Induced Peripheral Neuropathy. Part 1: A Study Protocol Raghav Sundar1, Venkatesh H R2, Aishwarya Bandla2,3, Soo-Chin Lee1,4, Nitish Thakor2,3,5, and Einar Wilder-Smith2,6* 1Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Health System.  2Singapore Institute of Neurotechnology, National University of Singapore. 3Department of Biomedical Engineering, National University of Singapore. 4Cancer Science Institute of Singapore, National University of Singapore. 5Department of Biomedical Engineering, Johns Hopkins University, USA. 6Department of Medicine, National University of Singapore. * Corresponsing author : einar_wilder-smith@nuhs.edu.sg Introduction Introduction Safety and tolerability scores Paclitaxel is a key drug in the treatment of breast cancer. Peripheral neuropathy is a common dose-dependent toxicity in patients treated with Paclitaxel, occurring in more than 50%. We have demonstrated in animal studies that hypothermia reduces nerve blood flow and may therefore have neuro-protective effects. We present a study designed to investigate the safety and tolerability of limb hypothermia and its effect on the development of paclitaxel induced neuropathy. Visual analogue pain scale (VAS) Shivering assessment scale (SAS) 0 – none 1 – mild 2 – moderate 3 – severe Composite Tolerability Score (CTS) Subjective tolerance scale (STS) Methods 0= tolerated 1 = no problem maintaining 2 = tolerating cooling, but not without discomfort 3 = only barely tolerated 4 = intolerable Intolerable >7 on VAS OR > 2 on SAS OR > 3 on STS OR >6 on VAS AND >1 on SAS AND >1 on STS  Phase 1: Temperature tolerability in 15 healthy subjects determined by cooling the digits to the elbow/knee via a cooling device attached to one randomly selected arm and leg. Initial device temperature is set at 25°C for 3 hours–duration of paclitaxel infusion. Temperature is decreased by 1°C every 3 subjects, until the lowest tolerable temperature is achieved. Skin temperature is monitored continuously and tolerability scores of the subject are recorded every 15 minutes. Temperature manipulation protocol Tolerability scores Action STS=2 Increase temperature of cooling device by 1°C (upto max 28°C) every 15 minutes till STS = 1 STS=3 Increase temperature of cooling device by 2°C (upto max 28°C) every 15 minutes till STS = 1 CTC=Intolerable Stop Hypothermia for the cycle Conclusions This study aims to establish safety, tolerability and effect of limb hypothermia for use in preventing paclitaxel-induced neuropathy in early stage breast cancer patients. Since neuropathy is one of the most important dose-limiting factors leading to dose reduction and treatment discontinuation, this research may contribute to alleviating dose-limitation and increase the likelihood of success of chemotherapy. Thermoregulator and cooling wraps for hypothermia administration Graphic representation of setup for delivering hypothermia for limb cooling Phase 2: Tolerability and clinical effect of limb hypothermia is tested in 15 breast cancer patients receiving weekly adjuvant paclitaxel. Subjects will have a randomly selected leg for cooling, to the temperature derived from the first phase of the study, for the duration of each cycle of paclitaxel administration for 12 weeks, for 3 hours each time. The contralateral limb will serve as reference. Primary outcome measure is the aggregate difference in the nerve sensory action potential before and 6 months after chemotherapy. References L. D. Liao, J. Orellana, Y. H. Liu, Y. R. Lin, A. Vipin, N. V. Thakor, K. Shen, and E. Wilder-Smith, "Imaging of temperature dependent hemodynamics in the rat sciatic nerve by functional photoacoustic microscopy," Biomedical Engineering Online, vol. 12, p. 120, Nov 2013.