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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 . To date, none of the potential neuroprotective agents tested in clinical trials have proven effective .
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 . It has also been observed that paclitaxel administration produces abnormalities in axonal mitochondria . Additional targets of neurotoxicity include direct axonal toxicity at the distal nerve terminals . Patients with pre-existing conditions that are capable of inducing PN (such as diabetes, Charcot–Marie–Tooth, or kidney disease) are particularly predisposed to developing CIPN .
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 in vivo study showed that a drop in rat sciatic nerve temperature from 30 to 20°C produced a fivefold reduction of nerve blood flow . Furthermore, in studies of chemotherapy-induced alopecia (CIA), which is a result of toxic accumulation of chemotherapeutics in the hair follicle, there is compelling evidence that cooling of the scalp protects against the development of CIA . The rationale behind using hypothermia in the prevention of CIA is that scalp cooling decreases the blood supply to the hair follicles, and hence, hair follicle protection is a result of reduced delivery of toxic chemotherapeutics . However, scalp cooling employing traditional cooling methods such as ice packs is poorly tolerated, which limits efficacy of the treatment itself . Hence, we employed a better-tolerated and efficient cooling technique of continuous-flow hypothermia. In a previous study in healthy subjects, we also established that continuous-flow limb hypothermia at a coolant temperature of 22°C was the lowest tolerable temperature for a duration of 3 h, matching the duration of paclitaxel infusion in cancer patients .
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.
Patients and Methods
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 supplementary material.) During every cycle of chemotherapy, premedication drugs (dexamethasone, diphenhydramine, and ranitidine) were administered 30 min prior to paclitaxel infusion. 80 mg/m2 of paclitaxel was administered as a 1-h infusion (indicated in orange in Figure 1A). The chemotherapy unit ambient temperature was adjusted to 21°C via air-conditioning. Randomization for limb cooling was carried out and the non-cooled limb served as internal control prior to the first cycle of therapy, and the same limb underwent cooling for all subsequent cycles, while the non-cooled limb remained as control (Figure 2A).
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.
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 1A). Overall, hypothermia was administered for no longer than 4 h. A detailed safety protocol was followed for coolant thermoregulation, if the patient found the hypothermia intolerable (Tables S1 and S2 in Supplementary Material).
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) . Skin surface temperature was continuously recorded throughout limb hypothermia via temperature sensors (accurate to ±0.1°C) placed at seven locations on both the legs (Figure 2B) . Body core temperature was measured over the frontal non-glabrous scalp (Figure 1A).
Assessment of Neuropathy
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 . Primary endpoint was differences in NCSs carried out at baseline (NCSbaseline), 1 month into treatment (NCSmid), the end of treatment (NCSend), and 3 months post-treatment (NCS3m) (Figure 1B). Sensory nerve action potential (SNAP) amplitudes and conduction velocities were measured in the bilateral sural, superficial peroneal, saphenous, and medial and lateral plantar nerves . Compound motor action potential (cMAP) amplitudes and motor nerve conduction velocities were evaluated in the bilateral common peroneal and tibial nerves .
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 t-test was used to compare the changes in temperature and NCS values of the cooled and control limbs in each patient. A two-tailed p-value <0.05 was considered statistically significant. The Pearson’s correlation coefficient was calculated to determine the correlation between amount of limb cooling and NCS preservation. All statistical analyses were performed in Microsoft Excel (V.12.0 for Windows, Microsoft Corp., Washington, DC, USA).
Twenty female breast cancer patients were enrolled in the study (Table 1). Of these 20 patients, 17 (85%) completed 12 cycles of continuous-flow limb hypothermia and one patient developed an infected seroma after her ninth cycle and deemed not fit for further paclitaxel by the treating oncologist. The abovementioned 18 patients completed all TNS and nerve conduction assessments before and after chemotherapy and were included in the analysis of nerve conduction changes and assessment of clinical neuropathy. The remaining two patients who were enrolled in the study did not complete all assessments and hence were not included for analysis of nerve conduction changes and assessment of clinical neuropathy [one patient completed two cycles before discontinuing due to development of grade 3 PN. Another withdrew from the study after three cycles due to ineligible inclusion criteria (not adjuvant therapy, Stage IV disease)]. However, all the 20 enrolled patients were included for safety and tolerability analysis.
Table 1. Baseline patient characteristics.
Safety and Tolerability
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 with Limb Hypothermia
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 (p = 0.0003) (Figures 3A–G). A mean temperature drop of 1.5 ± 0.7°C was achieved across all sensor points on the cooled limb and averaged across all the patients. The largest temperature drops in the cooled limb was achieved in the shin (2.2 ± 1.1°C) (Figure 3B) and foot arch (2.2 ± 1.3°C) (Figure 3G).