Edited by: R. Thomas Jagoe, McGill University, Canada
Reviewed by: Raquel Abalo, King Juan Carlos University, Spain; Maria Caffo, University of Messina, Italy
†These authors have contributed equally to this work.
Specialty section: This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology
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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.
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.
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 (
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.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity of paclitaxel. At present, dose modification remains the most successful approach for the management of CIPN, and pharmacological treatment is limited to alleviating symptoms such as paresthesias, dysesthesia, and pain (
The mechanisms of neurotoxicity in paclitaxel-induced peripheral neuropathy (PN) have not been fully elucidated; however, disruption of microtubule dynamics has been identified. Taxanes binding to β-tubulin components of microtubule assemblies lead to microtubule stabilization, thereby causing a disruption of microtubule dynamics (
Given the dose-dependent pathophysiology of paclitaxel-induced PN, we proposed a novel strategy for prevention of paclitaxel-induced PN by employing continuous-flow limb hypothermia to reduce delivery of the toxic chemotherapeutic agents to the peripheral nerves. Our previous
The goal of the current study was to determine if continuous-flow limb hypothermia may be neuroprotective in patients receiving paclitaxel chemotherapy, as well as assessing safety and tolerability.
This prospective study was carried out in accordance with the recommendations of the Institutional Review Board of the National Health Group, Singapore, with written informed consent from all subjects. All the subjects gave written informed consent in accordance with the Declaration of Helsinki. The study population comprised breast cancer patients scheduled to receive adjuvant weekly paclitaxel chemotherapy for 12 cycles following standard anthracycline-based chemotherapy (doxorubicin and cyclophosphamide). (For detailed inclusion/exclusion criteria, see
Limb hypothermia sessions comprised of a pre-cooling period (1 h), continued with paclitaxel infusion and a post-cooling period (on average 30 min after the end of paclitaxel infusion) (Figure
Safety and tolerance of limb hypothermia were measured using three validated scales: visual analog pain scale (VAS), subjective tolerance scale, and the Shivering Assessment Scale (Figure S1 and Tables S3 and S4 in Supplementary Material) (
Assessment for neuropathy was performed using nerve conduction studies (NCSs) and clinical examination. NCSs are the most sensitive and specific detection method for neuropathies and superior to clinical examination or scores (
At the same time points, clinical evaluation using the validated Total Neuropathy Score (TNS) was performed (
Temporal trend of skin temperature variation over the duration of hypothermia was summarized as an average of the recorded temperatures for all cycles of cooling for all the patients. Similarly, tolerability was analyzed as an average of all patients’ tolerance scores across all cycles of cooling. Sensory and motor nerve parameters of amplitude and velocity at every NCS visit were analyzed as relative percentage changes with respect to the first NCS visit (NCSbase) and averaged across patients.
We assessed the effect of varying amounts of cooling on nerve conduction parameters through correlation analysis (Pearson). Limb cooling was quantified by calculating each patient’s average reduction in baseline skin temperature over 12 cooling cycles. Limb cooling was correlated with mean SNAP amplitude/velocity percentage changes at the sural, superficial peroneal, and saphenous nerves. Similarly, limb cooling was correlated with mean cMAP amplitude/velocity percentage changes from all peroneal nerve stimulation points (ankle, below fibula head, and above fibula head) at the recording site of the extensor digitorum brevis (EDB) and from the tibial nerve ankle stimulation point on the abductor hallucis. This was done for values obtained at NCSend and NCS3m. A negative correlation shows that more cooling results in better preservation of nerve conduction parameters. Comparison of three different degrees of cooling achieved and the relation to the degree of preservation on nerve conduction parameters were also assessed.
Continuous variables are shown as mean ± SD. A parametric paired
Twenty female breast cancer patients were enrolled in the study (Table
Variables | Mean (range) | |
---|---|---|
Age (years) | 53 (32–67) | |
Weight (kg) | 60 (38–81) | |
Height (cm) | 154 (135–167) | |
BSA (m2) baseline | 1.6 (1.2–1.9) | |
Cumulative dose of paclitaxel (mg/m2) | 868.0 (160.0–960.0) | |
Cancer stage | – | |
Stage 1 | 3 (15) | |
Stage 2 | 11 (55) | |
Stage 3 | 5 (25) | |
Stage 4 | 1 (5) | |
Type of surgery | – | |
Breast conservation | 5 (25) | |
Mastectomy | 15 (75) | |
Lymph node assessment | – | |
Sentinel lymph node biopsy | 9 (45) | |
Axillary clearance | 8 (40) | |
Both | 3 (15) | |
ER-positive | 18 (90) | – |
Her-2-positive | 3 (15) | – |
Concurrent herceptin | 3 (15) | – |
TNS baseline | – | |
0 | 15 (75) | |
1 | 4 (20) | |
2 | 1 (5) |
Continuous-flow limb hypothermia was well tolerated by all patients. Premature termination of cooling was never necessary and only one patient (for 2 out of a total 218 cycles) required one intra-cycle thermoregulator temperature increase of 1°C toward the end of a hypothermia session (Figure S2 in Supplementary Material). Overall, minimal discomfort was reported at the end of each limb hypothermia session. No serious or lasting adverse events as a result of hypothermia were encountered. Only temporary erythema lasting a few minutes was observed upon removal of the cooling wrap. All recorded adverse events were due to chemotherapy (Table S5 in Supplementary Material). Patients’ core body temperature showed negligible changes (0.03 ± 0.18°C) across chemotherapy cycles.
Skin temperature changes at all the seven sensor locations on the cooled and control limbs were calculated and averaged across all patients over all 218 cycles. Following the onset of hypothermia, skin temperatures of the cooled leg showed significantly lower temperatures than the control leg (
Assessment of neuropathy using clinical and nerve conduction parameters of 18 patients was done. The TNS grade of PN reported during all the four visits were documented (Figure S3 in Supplementary Material). Baseline TNS ranged between 0 and 2 for all patients, thereby indicating absence of any baseline neuropathy. As per the National Cancer Institute-Common Toxicity Criteria grading of neuropathy (
The SNAP amplitudes showed decreasing trend over time, in both cooled and control limbs (Figures
The cMAP amplitudes of all recorded motor nerves were more preserved in the cooled limb than the control limb (Figures
We identified one subject who experienced significant preservation of cMAP amplitudes (EDB) in the cooled leg, compared to the control leg (Figure
While her cMAP (EDB) amplitudes in the cooled and control legs were below baseline for NCSmid, NCSend, and NCS3m, separation between cMAP in the cooled and control legs was shown at NCSend where cMAP amplitude (EDB, ankle stimulation) was 41.8% higher in the cooled leg than the control leg. At NCS3m, cMAP amplitude (EDB, ankle stimulation) was 53.2% higher in the cooled leg.
The greatest negative correlation was between cooling and cMAP recordings over the EDB with distal stimulation at NCS3m (
To ascertain whether different degrees of cooling achieved different preservation of cMAP amplitude, three different degrees of cooling were plotted against the achieved preservation in cMAP. All groups showed highly significant differences: high (Δ
Our study shows that continuous-flow limb hypothermia using coolant temperatures of 22°C lasting the duration of paclitaxel chemotherapy is well tolerated and safe. Limb hypothermia with higher degrees of cooling significantly preserves selected nerve motor amplitudes at 3 months after start of chemotherapy.
Our results show good tolerability (Figure S2 in Supplementary Material) and, importantly, no early termination of cooling.
Various limb cooling modalities are used for different therapeutic interventions, most of which involve the direct application of ice or frozen gloves and cause steep cooling gradients with varied and often poor tolerability (
Limb hypothermia caused significant decrease in skin temperature in the cooled limb across all sensor locations (Figure
In studies of scalp cooling to prevent CIA, subcutaneous scalp temperature (depth 1–2 mm) had to be less than 22°C to prevent doxorubicin-induced alopecia (
Although thermoregulator temperature was constant (22°C), different patients achieved different amounts of limb cooling due to varying body surface area and factors beyond experimental control, such as intermittent toilet breaks. On average, each patient took one toilet break per chemotherapy cycle typically lasting 5–7 min, during which limb wraps were removed. Toilet breaks for trial subjects were similar in nature to chemotherapy patients not undergoing limb hypothermia with respect to frequency and duration and were not likely increased due to hypothermia. These breaks were mostly immediately before or after the end of paclitaxel infusion itself (Figure
Both SNAP and cMAP amplitudes represent the number of functioning axons within each nerve. Lower amplitude reflects chemotherapeutic axonal damage, whereas reduction in velocity signifies nerve myelin sheath dysfunction (
Our study is the first to systematically record motor function over the course of chemotherapy using sensitive parameters (cMAP) and reveals frequent motor involvement. Clinical examination used in clinical scoring (TNS) was not able to detect motor involvement. Likely, this is because of poor sensitivity which explains the low rates of involvement in the literature (
It is important to consider why motor nerve parameters (cMAP) showed more effect to hypothermia than sensory parameters. cMAP amplitude, in contrast to sensory parameters, is dependent not only on nerve axonal function but additionally on muscle fiber function. Considering that paclitaxel motor neuropathy is rare (
Our hypothesis for the prevention of CIPN suggests that hypothermia reduces paclitaxel delivery to the nerve. Since hypothermia induces reduced blood flow to all exposed tissues, both motor axonal and myopathic components could underlie cMAP preservation (
Overall, our primary endpoint of differences in nerve conduction parameters between cooled and non-cooled limbs did not reach significance (Figure
Our study is adversely affected by the relatively small sample size and clinical methods that are not sensitive for assessment of mild or moderate degrees of motor dysfunction. Furthermore, only relatively modest degrees of limb cooling were achieved. While the lack of formal quality-of-life analysis in our study is a limitation, it was partially replaced by our safety scoring systems which did not reflect any concern. Future studies will also need to include more specific tests to determine the thresholds for mechanical and temperature sensitivity, or muscle strength, and to reveal alterations in sensory and motor functions related to neuropathy and myopathy (including plasma markers), as well as quality-of-life measures. A larger study using cryocompression of all four limbs is currently underway to prove efficacy. Studies to detect predictive biomarkers for paclitaxel-induced PN and to potentially identify patients from these protective therapies are also being conducted (
In summary, our results suggest that limb hypothermia, given for the duration of paclitaxel chemotherapy, preserves certain nerve conduction parameters. Preservation is directly related to the degree of limb cooling.
Our findings open up a new opportunity for more research to be conducted toward the goal of achieving neuroprotection and preventing CIPN
RS, AB, NT, S-CL, and EW-S developed the study concept and design. RS, NK, AJ, SO, JH, DT, and JL treated patients in this trial. AB, ST, JV, AT, ZH, EA, SA, and EW-S were involved in data acquisition. RS, AB, ST, and EW-S analyzed the data. RS, AB, ST, L-DL, and EW-S drafted the manuscript. NT, S-CL, and EW-S supervised the study. RS and AB contributed equally to this work. This manuscript has been seen, read, and agreed upon in its content by all the designated authors.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors would like to thank all the patients who participated in this study and also the support and assistance of the physicians and nurses from the National University Hospital, Singapore. They would also like to thank the support of the Neurophotonics group under Singapore Institute for Neurotechnology.
The work was supported by the National Research Foundation, Singapore (NRF2013NRF-POC002-027) and the National Health Innovation Centre, Singapore (NHIC-I2D-1409031).
The Supplementary Material for this article can be found online at
AH, abductor hallucis; CIPN, chemotherapy-induced peripheral neuropathy; cMAP, compound muscle action potentials; CTS, composite tolerability score; EDB, extensor digitorum brevis; NCI-CTC, National Cancer Institute-Common Toxicity Criteria grading of neuropathy; NCSs, nerve conduction studies; PN, peripheral neuropathy; PPMC, Pearson’s Product Moment Coefficient; SAS, Shivering Assessment Scale; SNAP, sensory nerve action potential; STS, subjective tolerance scale; TNS, Total Neuropathy Score; VAS, visual analog pain scale.