title: Hypothermia for preventing chemotherapy-induced neuropathy - a pilot study on safety and tolerability in healthy controls.
abstract: BACKGROUND
  Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of several chemotherapeutic agents, often leading to treatment discontinuation. Up to 20% of patients treated with weekly paclitaxel experience severe CIPN and no effective treatment has been established so far. The mechanisms of CIPN damage are unclear, but are directly dose-related. We had earlier demonstrated, in rats, the influence of hypothermia in reducing nerve blood flow. Here, we hypothesize that continuous flow limb hypothermia during chemotherapy reduces the incidence and severity of CIPN, by limiting deliverance of the neurotoxic drug to the peripheral nerves. In this study, prior to assessing the effect of hypothermia in preventing CIPN in cancer subjects undergoing paclitaxel chemotherapy, we assess the safety and tolerable temperatures for limb hypothermia in healthy human subjects.
  
  
  METHODS
  In 15 healthy human subjects, hypothermia was administered as continuous flow cooling, unilaterally, via a thermoregulator setup covering the digits up to the elbow/knee, along with continuous skin temperature monitoring. Thermoregulator coolant temperatures between 25 °C and 20 °C were tested for tolerability, based on a carefully designed temperature regulation protocol, and maintained for three hours mimicking the duration of chemotherapy. Tolerability was evaluated using various safety and tolerability scores to monitor the subjects.
  
  
  RESULTS
  At the end of the cooling session the healthy subjects presented without significant adverse effects, the main being brief mild skin erythema and transient numbness. Coolant temperatures as low as 22 °C were well tolerated continuously over three hours.
  
  
  CONCLUSIONS
  Our results confirm the safety and tolerability of continuous flow limb hypothermia in healthy subjects. Further studies will use 22 °C thermoregulator temperature to investigate hypothermia in preventing CIPN in breast cancer patients receiving adjuvant weekly paclitaxel. This pilot study may contribute to alleviating chemotherapy dose limitation due to CIPN and increase the likelihood of success of chemotherapy.
authors.affiliation: a Singapore Institute for Neurotechnology (SINAPSE) , National University of Singapore , Singapore .|b Department of Biomedical Engineering , National University of Singapore , Singapore .
authors.forename: Aishwarya
authors.initials: A
authors.lastname: Bandla
authors.affiliation: c Department of Haematology-Oncology , National University Cancer Institute , Singapore , National University Health System .
authors.forename: Raghav
authors.initials: R
authors.lastname: Sundar
authors.affiliation: a Singapore Institute for Neurotechnology (SINAPSE) , National University of Singapore , Singapore .|d Institute of Biomedical Engineering and Nanomedicine , National Health Research Institutes, Taiwan , R.O.C. .
authors.forename: Lun-De
authors.initials: LD
authors.lastname: Liao
authors.affiliation: a Singapore Institute for Neurotechnology (SINAPSE) , National University of Singapore , Singapore .
authors.forename: Stacey
authors.initials: S
authors.lastname: Sze Hui Tan
authors.affiliation: c Department of Haematology-Oncology , National University Cancer Institute , Singapore , National University Health System .|e Cancer Science Institute of Singapore , National University of Singapore , Singapore .
authors.forename: Soo-Chin
authors.initials: SC
authors.lastname: Lee
authors.affiliation: a Singapore Institute for Neurotechnology (SINAPSE) , National University of Singapore , Singapore .|b Department of Biomedical Engineering , National University of Singapore , Singapore .|f Department of Biomedical Engineering , Johns Hopkins University , Baltimore , MD , USA , and.
authors.forename: Nitish V
authors.initials: NV
authors.lastname: Thakor
authors.affiliation: a Singapore Institute for Neurotechnology (SINAPSE) , National University of Singapore , Singapore .|g Department of Medicine, Yong Loo Lin School of Medicine , National University of Singapore , Singapore.
authors.forename: Einar P V
authors.initials: EP
authors.lastname: Wilder-Smith
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001132:Arm; D006801:Humans; D007036:Hypothermia, Induced / Q000379:methods*; D007866:Leg; D008297:Male; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D010865:Pilot Projects; D012881:Skin Temperature; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents