Limb Hypothermia for Preventing Paclitaxel-Induced Peripheral Neuropathy in Breast Cancer Patients: A Pilot Study

Abstract

Background: Peripheral neuropathy (PN) due to paclitaxel is a common dose-limiting toxicity with no effective prevention or treatment. We hypothesize that continuous-flow limb hypothermia can reduce paclitaxel-induced PN.

Patients and methods: An internally controlled pilot trial was conducted to investigate the neuroprotective effect of continuous-flow limb hypothermia in breast cancer patients receiving weekly paclitaxel. Patients underwent limb hypothermia of one limb for a duration of 3 h with every paclitaxel infusion, with the contralateral limb used as control. PN was primarily assessed using nerve conduction studies (NCSs) before the start of chemotherapy, and after 1, 3, and 6 months. Skin temperature and tolerability to hypothermia were monitored using validated scores.

Results: Twenty patients underwent a total of 218 cycles of continuous-flow limb hypothermia at a coolant temperature of 22°C. Continuous-flow limb hypothermia achieved mean skin temperature reduction of 1.5 ± 0.7°C and was well tolerated, with no premature termination of cooling due to intolerance. Grade 3 PN occurred in 2 patients (10%), grade 2 in 2 (10%), and grade 1 in 12 (60%). Significant correlation was observed between amount of skin cooling and motor nerve amplitude preservation at 6 months (p < 0.0005). Sensory velocity and amplitude in the cooled limbs were less preserved than in the control limbs, but the difference did not attain statistical significance. One patient with a history of diabetes mellitus had significant preservation of compound muscle action potential in the cooled limb on NCS analysis.

Conclusion: This study suggests that continuous limb hypothermia accompanying paclitaxel infusion may reduce paclitaxel-induced PN and have therapeutic potential in select patients and warrants further investigation. The method is safe and well tolerated.

Keywords: chemotherapy-induced peripheral neuropathy; limb hypothermia; nerve conduction; neuroprotection; paclitaxel.

Figure 1

(A) Limb hypothermia protocol for one chemotherapy cycle. Premedication drugs: dexamethasone, diphenhydramine, and ranitidine. (B) Study schema.

Figure 2

(A) Continuous-flow limb hypothermia setup by means of a thermoregulator device supplying coolant (water) at a set desired temperature (22°C) to limb wraps that cool the limb. Continuous skin temperature data are acquired via a temperature monitoring system consisting of wireless sensors placed at seven different sensor locations on the cooled and control legs as indicated in (B), which transmit data wirelessly to a receiver and recorded for analysis.

Figure 3

Trend of skin temperature of the cooled (blue) vs. control (red) leg over the duration of limb hypothermia in breast cancer patients. Skin temperature was acquired continuously at various sensor locations: (A) below knee, (B) at the shin, (C) calf, (D) dorsum of the foot, (E) toe (hallux), (F) first metatarsal head, and (G) foot arch (foot plantar). Skin temperatures of the cooled leg showed significantly lower temperatures than the control leg at each time point (p < 0.05). Limb hypothermia was administered at a coolant temperature of 22°C throughout the duration of chemotherapy.

Figure 4

Percentage change of sensory nerve action potential (SNAP) amplitudes (A–C) and velocities (D–F), and compound motor action potential (cMAP) amplitudes (G–I) and velocities (J–L) over four nerve conduction study visits from baseline.

Figure 4

Percentage change of sensory nerve action potential (SNAP) amplitudes (A–C) and velocities (D–F), and compound motor action potential (cMAP) amplitudes (G–I) and velocities (J–L) over four nerve conduction study visits from baseline.

Figure 5

Comparison of changes in compound motor action potential (cMAP) amplitudes in the cooled and non-cooled limb of a subject with well-preserved cMAP amplitudes in the extensor digitorum brevis (EDB) muscle on the common peroneal nerve. Over the time, the cooled leg showed consistently more preserved compound motor action potential amplitudes than the control leg at all the three stimulation points [(A) ankle, (B) below fibula head, and (C) above fibula head] on the EDB muscle.

Figure 6

Relation of changes of skin temperature at the calf and compound motor action potential (cMAP) amplitude percentage changes of extensor digitorum brevis (distal stimulation) cMAP at NCS_3m, with data grouped into “high” cooling, “moderate” cooling, and “low” cooling. Statistical significance (*p < 0.05).