Safety and tolerability of cryocompression as a method of enhanced limb hypothermia to reduce taxane-induced peripheral neuropathy

Abstract

Purpose: Severe peripheral neuropathy is a common dose-limiting toxicity of taxane chemotherapy, with no effective treatment. Frozen gloves have shown to reduce the severity of neuropathy in several studies but comes with the incidence of undesired side effects such as cold intolerance and frostbite in extreme cases. A device with thermoregulatory features which can safely deliver tolerable amounts of cooling while ensuring efficacy is required to overcome the deficiencies of frozen gloves. The role of continuous-flow cooling in prevention of neurotoxicity caused by paclitaxel has been previously described. This study hypothesized that cryocompression (addition of dynamic pressure to cooling) may allow for delivery of lower temperatures with similar tolerance and potentially improve efficacy.

Method: A proof-of-concept study was conducted in cancer patients receiving taxane chemotherapy. Each subject underwent four-limb cryocompression with each chemotherapy infusion (three hours) for a maximum of 12 cycles. Cryocompression was administered at 16 °C and cyclic pressure (5-15 mmHg). Skin surface temperature and tolerance scores were recorded. Neuropathy was assessed using clinician-graded peripheral sensory neuropathy scores, total neuropathy score (TNS) and nerve conduction studies (NCS) conducted before (NCSpre), after completion (NCSpost) and 3 months post-chemotherapy (NCS3m). Results were retrospectively compared with patients who underwent paclitaxel chemotherapy along with continuous-flow cooling and controls with no hypothermia.

Results: In total, 13 patients underwent 142 cycles of cryocompression concomitant with chemotherapy. Limb hypothermia was well tolerated, and only 1 out of 13 patients required an intra-cycle temperature increase, with no early termination of cryocompression in any subject. Mean skin temperature reduction of 3.8 ± 1.7 °C was achieved. Cryocompression demonstrated significantly greater skin temperature reductions compared to continuous-flow cooling and control (p < 0.0001). None of the patients experienced severe neuropathy (clinician-assessed neuropathy scores of grade 2 or higher). NCS analysis showed preservation of motor amplitudes at NCS3m in subjects who underwent cryocompression, compared to the controls who showed significant deterioration (NCS3m cryocompression vs. NCS3m control: ankle stimulation: 8.1 ± 21.4%, p = 0.004; below fibula head stimulation: 12.7 ± 25.6%, p = 0.0008; above fibula head stimulation: 9.4 ± 24.3%, p = 0.002). Cryocompression did not significantly affect taxane-induced changes in sensory nerve amplitudes.

Conclusion: When compared to continuous-flow cooling, cryocompression permitted delivery of lower temperatures with similar tolerability. The lower skin surface temperatures achieved potentially lead to improved efficacy in neurotoxicity amelioration. Larger studies investigating cryocompression are required to validate these findings.

Keywords: Chemotherapy-induced peripheral neuropathy; Cryocompression; Cryotherapy; Nerve conduction; Paclitaxel.

Conflict of interest statement

AB and RS received research support from Paxman Coolers Ltd. U.K.

Figures

Fig. 1

Trial flow diagram. a Schematic of a single chemo-cryocompression session indicating that limb hypothermia was administered as three parts: (i) pre-cooling (60 min) along with administration of pre-medication drugs, followed by (ii) cooling during taxane infusion (60 min) and finally a (iii) post-cooling phase (30 min). The green dots indicate the time points at which tolerability scores were assessed. b Overall schematic of the study which constituted up to 12 weeks of chemotherapy. NCS assessments were conducted before the start (NCSpre), at the end of chemotherapy (NCSpost) and after three months (NCS3m)

Fig. 2

Comparison of skin temperature changes with and without limb hypothermia via cooling and cryocompression techniques. The relative changes in skin surface temperature in the a) shin, b) calf, c) toe and d) foot plantar regions over the duration of chemotherapy indicate that cryocompression (blue) offers the best temperature drop compared to continuous-flow cooling (green). The non-cooled limb was considered as control (red) which showed a minor temperature drop as well, owing to the low room temperature. ** indicates p < 0.0001

Fig. 3

Comparison of nerve conduction changes with and without limb hypothermia via cooling and cryocompression techniques. The changes in nerve conduction amplitudes in the motor nerves (a–c) at three time points—before, end of chemotherapy and after three months indicate that cryocompression (blue) better preserves motor nerve conduction amplitudes compared to continuous-flow cooling (green). The non-cooled limb was considered as control (red), continued to deteriorate. ** indicates p < 0.01 and *** indicates p < 0.001