Effects of Cryotherapy on Objective and Subjective Symptoms of Paclitaxel-Induced Neuropathy: Prospective Self-Controlled Trial

Abstract

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting and disabling side effect of taxane anticancer agents. We prospectively evaluated the efficacy of cryotherapy for CIPN prevention.

Methods: Breast cancer patients treated weekly with paclitaxel (80 mg/m2 for one hour) wore frozen gloves and socks on the dominant side for 90 minutes, including the entire duration of drug infusion. Symptoms on the treated sides were compared with those on the untreated (nondominant) sides. The primary end point was CIPN incidence assessed by changes in tactile sensitivity from pretreatment baseline in a monofilament test at a cumulative dose of 960 mg/m2. We also assessed thermosensory deficits, subjective symptoms (Patient Neuropathy Questionnaire [PNQ]), manipulative dexterity, and the time to events and hazard ratio by PNQ. All statistical tests were two-sided.

Results: Among the 40 patients, four did not reach the cumulative dose (due to the occurrence of pneumonia, severe fatigue, severe liver dysfunction, and macular edema), leaving 36 patients for analysis. None dropped out due to cold intolerance. The incidence of objective and subjective CIPN signs was clinically and statistically significantly lower on the intervention side than on the control (hand: tactile sensitivity = 27.8% vs 80.6%, odds ratio [OR] = 20.00, 95% confidence interval [CI] = 3.20 to 828.96, P < .001; foot: tacile sensitivity = 25.0% vs 63.9%, OR = infinite, 95% CI = 3.32 to infinite, P < .001; hand: warm sense = 8.8% vs 32.4%, OR = 9.00, 95% CI = 1.25 to 394.48, P = .02; foot: warm sense: 33.4% vs 57.6%, OR = 5.00, 95% CI = 1.07 to 46.93, P = .04; hand: PNQ = 2.8% vs 41.7%, OR = infinite, 95% CI = 3.32 to infinite, P < .001; foot: PNQ = 2.8% vs 36.1%, OR = infinite, 95% CI = 2.78 to infinite, P < .001; hand: hazard ratio [HR] = 0.13, 95% CI = 0.05 to 0.34; foot: HR = 0.13, 95% CI = 0.04 to 0.38, dexterity mean delay = -2.5 seconds, SD = 12.0 seconds, vs + 8.6 seconds, SD = 25.8 seconds, P = .005).

Conclusions: Cryotherapy is useful for preventing both the objective and subjective symptoms of CIPN and resultant dysfunction.

Figure 1.

Study flow diagram. We included 40 patients who received the allocated intervention and analyzed the cumulative dose for subjective chemotherapy-induced peripheral neuropathy (CIPN) events. All CIPN signs were analyzed in the 36 patients who reached a cumulative dose of 960 mg/m². We compared the hands and feet of the intervention side to those of the control side.

Figure 2.

Objective chemotherapy-induced peripheral neuropathy (CIPN) events at a cumulative dose of 960 mg/m². A) The efficacy of cryotherapy for reducing the primary end point, incidence of CIPN, was assessed by tactile-sensory deficits on the monofilament test. Any tactile deterioration from the pretreatment baseline in an intervention or control side hand or foot at a cumulative dose of 960 mg/m² was considered a CIPN event. The differential incidence between the intervention and control sides was evaluated using a two-sided McNemar’s test (n = 36). B) Treatment with cryotherapy reduced thermosensory dysfunction. Only patients who exhibited a normal sensory threshold at baseline were included (hand: warm, n = 34, cold, n = 36; foot: warm, n = 33, cold, n = 32). Any response delay, response reduction, or thermal analgesia at a cumulative dose of 960 mg/ m² was considered a CIPN. C) This figure shows manipulative dexterity deficits. P values were determined by a two-sided paired t test between the intervention and control side. The solid line denotes the intervention side, and the dotted line indicates the control side (N = 36).

Figure 3.

Severity of subjective symptoms (at a cumulative dose of 960 mg/m²). The administration of cryotherapy also reduced the subjective symptoms based on the Patient Neuropathy Questionnaire responses (the secondary end point, subjective) at a cumulative dose of 960 mg/m² (P values determined by the McNemar’s test, n = 36). The subjective responses to each item were graded from A (no neuropathy) to E (severe neuropathy) by the patient. A rank of D or E indicates impaired activities of daily living. *Activities of daily living were interfered with.

Figure 4.

The appearance of severe subjective neuropathy symptoms with cumulative dose. Severe subjective neuropathy symptoms (Patient Neuropathy Questionnaire ≥ D; moderate to severe tingling, pain, or numbness that interferes with activities of daily living) with cumulative dose were compared between the intervention and control sides using a log-rank test (n = 40). The solid line denotes the intervention side, and the dotted line indicates the control side. The dotted vertical line represents a cumulative dose of 960 mg/m². We included four censored patients who did not complete cumulative dose of 960 mg/m² paclitaxel due to pneumonia (n = 1), severe fatigue (n = 1), severe liver dysfunction (n = 1), and macular edema (n = 1). A two-sided log-rank test was used to calculate the P values.

Figure 5.

Cumulative dose to subjective symptoms (Patient Neuropathy Questionnaire rank ≥ D; moderate to severe tingling, pain, or numbness that interferes with activities of daily living [ADL]) on the control side to identify chemotherapy-induced peripheral neuropathy (CIPN) risk factors (n = 40). A) This figure presents the high/low area under the curve (AUC; µg·h/mL). The low-AUC group (mean = 6.6 µg·h/mL, SD = 0.5µg·h/mL) and high-AUC group (mean = 8.3 µg·h/mL, SD = 1.4 µg·h/mL) were divided by the median AUC (7.2 µg·h/mL). The solid line denotes the high-AUC group, and the dotted line indicates the low-AUC group. B) This figure presents high/low dose intensity (mg/m²/wk). The low–dose intensity group (mean = 56.6 mg/m²/wk, SD = 6.7 mg/m²/wk) and high–dose intensity group (mean = 75.0 mg/m²/wk, SD = 4.8 mg/m²/wk) were divided by the median dose intensity (68.6 mg/ m²/wk). The solid line represents the high–dose intensity group, and the dotted line denotes the low–dose intensity group. A two-sided log-rank test was used to calculate the P values.