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

JNCI: Journal of the National Cancer Institute, Feb 2018

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.

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

Received: February Effects of Cryotherapy on Objective and Subjective Symptoms of Paclitaxel-Induced Neuropathy: Prospective Self-Controlled Trial Akiko Hanai 0 Hiroshi Ishiguro 0 Takashi Sozu 0 Moe Tsuda 0 Ikuko Yano 0 Takayuki Nakagawa 0 Satoshi Imai 0 Yoko Hamabe 0 Masakazu Toi 0 Hidenori Arai 0 Tadao Tsuboyama 0 0 Affiliations of authors: Graduate School of Medicine, Kyoto University , Kyoto, Japan (AH, HI, MTs, MTo , TT); Department of Medical Oncology, International University of Health and Welfare Hospital (HI); Japan Society for the Promotion of Science , Tokyo , Japan ( AH); Department of Information and Computer Technology, Tokyo University of Science , Tokyo , Japan ( TS); Kyoto University Hospital , Kyoto, Japan (IY, TN, SI , YH); National Center for Geriatrics and Gerontology , Aichi, Japan (HA). Nasushiobara, Tochigi, 329-2763 , Japan 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 ¼ 27.8% vs 80.6%, odds ratio [OR] ¼ 20.00, 95% confidence interval [CI] ¼ 3.20 to 828.96, P < .001; foot: tacile sensitivity ¼ 25.0% vs 63.9%, OR ¼ infinite, 95% CI ¼ 3.32 to infinite, P < .001; hand: warm sense ¼ 8.8% vs 32.4%, OR ¼ 9.00, 95% CI ¼ 1.25 to 394.48, P ¼ .02; foot: warm sense: 33.4% vs 57.6%, OR ¼ 5.00, 95% CI ¼ 1.07 to 46.93, P ¼ .04; hand: PNQ ¼ 2.8% vs 41.7%, OR ¼ infinite, 95% CI ¼ 3.32 to infinite, P < .001; foot: PNQ ¼ 2.8% vs 36.1%, OR ¼ infinite, 95% CI ¼ 2.78 to infinite, P < .001; hand: hazard ratio [HR] ¼ 0.13, 95% CI ¼ 0.05 to 0.34; foot: HR ¼ 0.13, 95% CI ¼ 0.04 to 0.38, dexterity mean delay ¼ 2.5 seconds, SD ¼ 12.0 seconds, vs þ 8.6 seconds, SD ¼ 25.8 seconds, P ¼ .005). Conclusions: Cryotherapy is useful for preventing both the objective and subjective symptoms of CIPN and resultant dysfunction. - Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and disabling side effect of cancer treatment, primarily taxanes and platinum agents ( 1 ). CIPN reduces health-related quality of life ( 2 ) and often results in dose delay, dose reduction, or treatment discontinuation ( 3 ). A patient-reported outcome study found that CIPN numbness persisted in 67%–80% of patients for one year following the completion of paclitaxel therapy ( 4 ). Duloxetine was recommended for CIPN; however, it has limited efficacy for the amelioration of chemotherapyinduced pain, and none for numbness or functional disability ( 4,5 ). Furthermore, no established strategy exists for CIPN prevention (4). Therapeutic regional hypothermia (cryotherapy) can reduce chemotherapy-induced complications by decreasing regional perfusion with acceptable tolerability ( 6 ). Frozen gloves and socks prevented docetaxel-induced nail and skin toxicity in prospective, self-controlled trials that compared the protected side with the nonprotected side ( 7,8 ). A retrospective study indicated that the occurrences of docetaxel-induced peripheral neuropathy was lower in the patients who used frozen gloves and socks compared to the patients who did not wear them (35% vs. 57%) (9). Because CIPN symptoms are largely subjective and many clinicians underestimate their severity using the Common Terminology Criteria for Adverse Events v. 4.0 (CTCAE) ( 10,11 ), prospective trials with patient-reported outcomes may be superior for evaluating preventative efficacy; however, additional end points, including objective and functional assessments, are also needed to control for the placebo response bias of patientreported outcomes. A self-controlled design can mitigate the effects of other confounders, including individual differences in sensory detection. Therefore, we investigated the effectiveness of cryotherapy against paclitaxel-induced peripheral neuropathy in a prospective self-controlled trial with multiple end points (e.g., objective, subjective, and functional assessments). Methods Study Design This self-controlled clinical trial evaluated the preventive effects of cryotherapy for CIPN. As in previous cryotherapy studies ( 7,8 ), each patient wore frozen flexible gloves and socks (Elasto-Gel, 84400 APT Cedex, Akromed, France) on the dominant hand and foot from 15 minutes before paclitaxel administration to 15 minutes after the infusion was complete (90 minutes in total). Frozen gloves were replaced after the first 45 minutes. The nondominant side acted as the untreated control. Symptoms of CIPN were assessed before chemotherapy (baseline) and before every cycle of paclitaxel administration during outpatient care. We analyzed the time to events (the cumulative doses to subjective CIPN events [PNQ D]) and CIPN symptoms at the cumulative dose of 960 mg/m2, which is the recommended dose for neo-adjuvant and adjuvant weekly paclitaxel therapy (12). To explore the risk factors for CIPN, we assessed the pharmacokinetics during the first administration of paclitaxel. Breast cancer patients were recruited from the Kyoto University Hospital (Kyoto, Japan) between May 2014 and August 2015 according to the following inclusion criteria: planned administration of weekly paclitaxel (80 mg/m2 for one hour) for at least 12 cycles (cumulative dose of 960 mg/m2), an Eastern Cooperative Oncology Group Performance Status of 0 or 1, and a provision of signed informed consent. The exclusion criteria were as follows: peripheral sensory/motor neuropathy (CTCAE grade 2); neuralgia or edema (CTCAE grade 2); tumor metastasis in bone, soft tissue, or skin of the hands or feet; the absence of one or more fingers or toes; Raynaud’s symptoms; peripheral arterial ischemia; hand-foot syndrome; and any other reasons based on the primary physician’s judgment. This trial was approved by the Ethics Committee of Kyoto University Graduate School and Faculty of Medicine (G638) in accordance with Helsinki guidelines and was registered with the University Hospital Medical Information Network in February 2014 (UMIN000013398). Outcome Measures Primary End Point Assessment: Tactile Disturbance The primary end point was the incidence of CIPN (any grade), defined as a decline in tactile sensation from the pretreatment baseline as assessed by the Semmes-Weinstein monofilament test (NIHON MEDIX, Chiba, Japan), which is a validated measure of peripheral neuropathy ( 13 ). Patients were blinded and stimulated by 20 grades of nylon filaments. We set the SemmesWeinstein monofilament test as the primary end point for two reasons: 1) it is a robust and patient-blinded assessment, which will decrease the effects of patient expectancy in this nonblinded intervention trial; and 2) patients suffer who undergo paclitaxel therapy from tactile problems more than other types of sensory or motor problems. ( 14 ). Patients experiencing at least a diminished sensation in response to light touch after a cumulative dose of 960 mg/m2 were counted as events in the primary end point assessment. Thermosensory Disturbance (Objective Symptoms) Thermosensory disturbance was assessed using a thermal stimulator (Yufu Itonaga, Tokyo, Japan) with 3 C and 48 C outputs. We stimulated the patients’ (with their eyes closed) hands or feet with hot or cold stimulation and assessed the sensation following the thermal stimulation (normal, delayed, or diminished compared with baseline). The delayed and diminished sensations at 12 cycles (cumulative dose, 960 mg/m2) compared with the pretreatment baseline were classified as events. Vibration Perception (Objective Symptoms) Vibration perception at the wrist and ankle was assessed by a C 128-Hz tuning fork (NITI-ON CO, LTD, Chiba, Japan). Patients no longer feeling vibrations within 10 seconds of application after 12 paclitaxel cycles were considered events. Patients who exhibited abnormal scores at baseline were excluded from the analysis. Performance Speed (Objective Symptoms) Manipulative dexterity was assessed using the grooved pegboard test (Lafayette Instrument Company, Lafayette IN), a validated sensory motor speed test ( 15 ). The pegboard has 25 holes, with randomly positioned slots for pegs and keys along one side. Each peg must be properly rotated to match the hole before it can be inserted. We measured the time (seconds) required for the insertion of 25 pegs by each hand (dominant vs nondominant) and calculated the mean difference from the baseline score. Patient-Reported Assessment (Subjective Symptoms) Subjective symptoms were assessed using the Japanese version of the PNQ, a validated patient-reported questionnaire on neuropathy and activities of daily living (ADL) that correlates with quality of life ( 11 ). The patient subjectively responded to each item, grading each as A (no neuropathy), B (mild neuropathy), C (moderate neuropathy that does not interfere with ADL), D (moderate neuropathy that interferes with ADL), or E (severe Received allocated intervention (n = 40) No pa ent dropped out because of cold intolerance Assessed for eligibility (n = 44) Analyzed Cumulative dose to event (n = 40) Analyzed Cumulative dose of 960 mg/m2 outcome (n = 36) Excluded (n = 4) Paclitaxel canceled (n = 2) Refused to participate (n = 2) Did not complete cumulative dose of 960 mg/m2 of paclitaxel pneumonia (n = 1) hepatopathy (n = 1) severe fatigue (n = 1) macular edema (n = 1) chemotherapy at a cumulative dose higher than 960 mg/m2 (maximum ¼ 4080 mg/m2). Cryotherapy Tolerability No patients dropped out due to cold intolerance. The most frequently reported adverse events (events / (person*cycle)) were pain (8.2%), sensory abnormalities (0.4%), and feeling cold (4.2%). The adverse events diminished immediately during or after cryotherapy intervention. Primary End Point The proportion of hands and feet exhibiting tactile deterioration were clinically and statistically significantly lower for the intervention side than the control side (hand: 27.8% vs 80.6%, OR ¼ 20.00, 95% CI ¼ 3.20 to 828.96, P < .001; foot: 25.0% vs 63.9%, OR ¼ infinite, 95% CI ¼ 3.32 to infinite, P < .001). The proportions include the patients who experienced CIPN from both the intervention and control sides of the hand and foot (Figure 2A). P = .005 Secondary End Points Baseline Cumula ve dose of 960 mg/m paclitaxel dose of 960 mg/m2, leaving 36 patients for the analysis (Figure 1; Table 1). A total of 25 patients completed paclitaxel therapy at a cumulative dose of 960 mg/m2, and 11 underwent Objective End Points Figure 2B presents the incidence of thermosensory deficits. Patients who exhibited an abnormal thermal sense at baseline (hands warmth, n ¼ 2; feet warmth, n ¼ 3; and feet cold, n ¼ 4) were excluded from the analysis. The incidence of a reduced perception of warmth was clinically and statistically significantly lower on the intervention side (hand: 8.8% vs 32.4%, OR ¼ 9.00, 95% CI ¼ 1.25 to 394.48, P ¼ .02; foot: 33.4% vs 57.6%, OR ¼ 5.00, 95% CI ¼ 1.07 to 46.93, P ¼ .04). The proportions include the patients who experienced CIPN from both the intervention and control sides of the hands and feet). In contrast, cold-sense deficits also tended to be numerically lower on the intervention side but showed no statistical significance (hand: 2.8% vs 13.9%, OR ¼ inifinite, 95% CI ¼ 0.66 to infinite, P ¼ .13; foot: 12.6% vs 18.8%, OR ¼ 2.00, 95% CI ¼ 0.29 to 22.11, P ¼ .69). The proportions include the patients who experienced CIPN from both the intervention and control sides of the hands and feet). For the incidence of vibration perception deficits, patients exhibiting an intervention control + censored 100 80 t 60 n e c r e P40 20 0 intervention control + censored 960 1600 2400 Hand (P < .001) 3200 4000 Cumulative dose, mg/m2 0 800 1600 2400 3200 4000 Cumulative dose, mg/m2 Foot (P = .007) abnormal sense at the pretreatment baseline (hand, n ¼ 5; foot, n ¼ 7) were excluded from the analysis; however, the incidences tended to be numerically lower on the intervention side but showed no statistically significant differences between the intervention and control sides (hand: 9.7% vs 12.9%, OR ¼ inifinite, 95% CI ¼ 0.03 to infinite, P ¼ 1.00; foot: 13.8% vs 24.1%, OR ¼ inifinite, 95% CI ¼ 0.41 to infinite, P ¼ .25). The proportions include the patients who experienced CIPN from both the intervention and control sides of the hands and feet). The performance speed compared with the baseline level exhibited a greater delay on the control side ( 2.5-second delay, SD ¼ 12.0 seconds, on the intervention side vs þ8.6-second delay, SD ¼ 25.8 seconds, on the control side, P ¼ .005) (Figure 2C). Some patients showed abnormal scores, and there were no statistically significant differences in nerve degeneration in the electrophysiological signs. Supplementary Figure 1 (available online) shows the incidence overlaps of CIPN in the hands and feet. Subjective End Point For sensory dysfunction, Figure 3 shows the subjective severity grades of CIPN at a cumulative dose of 960 mg/m2 (PNQ grades A–E). The occurrences of CIPN (PNQ grades C–E) were prevented by cryotherapy (severe CIPN with grades D or E; hand: 2.8% vs 41.7%, OR ¼ infinite, 95% CI ¼ 3.32 to infinite, P < .001; foot: 2.8% vs 36.1%, OR ¼ infinite, 95% CI ¼ 2.78 to infinite, P < .001). A log-rank analysis of Kaplan-Meier curves (Figure 4) revealed that CIPN also occurred faster on the control side than on the intervention side (hand: HR ¼ 0.13, 95% CI ¼ 0.05 to 0.34, P < .001; foot: HR ¼ 0.13, 95% CI ¼ 0.04 to 0.38, P ¼ .007). Only two patients reported motor dysfunction, which lasted less than one week. Risk Factors of CIPN We analyzed the effect of clinical factors on the time to subjective CIPN events (PNQ D) on the control side. No statistically significant differences were found for the time to events between the low AUC0 24 group, with the low AUC means below the median value (group mean ¼ 6.6 mg h/mL, SD ¼ 0.5 mg h/mL; total cohort median ¼ 7.2 mg h/mL) and the high AUC0 24 group (mean ¼ 8.3 mg h/mL, SD ¼ 1.4 mg h/mL) (hand: P ¼ .54, foot: P ¼ .56) (Figure 5A). The dose intensity varied because of the results of temporary delays due to chemotherapy-induced neutropenia. Symptoms occurred statistically earlier in the high–dose intensity group (mean ¼ 75.0 mg/m2/wk, SD ¼ 4.8 mg/m2/wk) above the median (68.6 mg/m2/wk) than in the low–dose intensity group (mean ¼ 56.6 mg/m2/wk, SD ¼ 7.0 mg/m2/wk; hand: P ¼ .001, foot: P ¼ .003) (Figure 5B). We also examined the effects of other factors; however, none were statistically significant risk factors for CIPN (Supplementary Table 1, availale online). Electrophysiological Signs For the incidence of electrophysiological signs, patients exhibiting a normal sense at the pretreatment baseline were included in the analysis (median nerve conduction velocity, n ¼ 18; median nerve action potential amplitude, n ¼ 14; current perception thresholds, hands, n ¼ 11, feet, n ¼ 8); they showed no statistically significant differences between intervention and control sides (nerve conduction velocity: 5.5% vs 5.5%, OR ¼ 1.00, 95% CI ¼ 0.01 to 78.50, P ¼ 1.00; action potential: 28.5% vs 28.5%, OR ¼ 1.00, 95% CI ¼ 0.01 to 78.50, P ¼ 1.00; current perception threshold; hand: 18.1% vs 27.2%, OR ¼ inifinite, 95% CI ¼ 0.03 to inifinite, P ¼ 1.00, foot: 25.0% vs 25.0%, OR ¼ 1.00, 95% CI ¼ 0.01 to 78.50, P ¼ 1.00) . All P values were analyzed using McNemar’s test. E L C I T R A A R T I C L E A 100 80 60 40 20 0 high low + censored + high low censored 100 80 60 t n e c r e P 40 20 0 100 80 t 60 n e c r e P 40 20 0 high low + censored + high low censored 0 800 1600 2400 3200 4000 Cumulative dose, mg/m2 0 800 1600 2400 3200 4000 Cumulative dose, mg/m2 Hand (P = .54) Foot (P = .56) 0 800 1600 Hand (P 2400 3200 4000 Cumulative dose, mg/m2 .001) 0 800 1600 2400 3200 4000 Cumulative dose, mg/m2 Foot (P = .003) Discussion Our findings support the efficacy of cryotherapy for CIPN prevention, as evidenced by a clinically and statistically significant reduction in patient-reported subjective symptoms, diminished objective signs (tactile and thermosensory), and prevention of manipulative dexterity. The development of subjective CIPN symptoms was clinically and statistically significantly delayed during the course of the paclitaxel treatment, the occurrence of subjective CIPN at a cumulative dose of 960 mg/m2 was almost completely prevented, and the CIPN incidence as assessed by other objective modalities tended to be lower on the intervention side. Because the self-controlled design can reduce the effects of unknown potential confounders to levels lower than expected in randomized clinical trials, data consistency among the multiple assessments and large effect size, as exampled by a small hazard ratio, support the robustness of our conclusions despite the limited sample size ( 19 ). Furthermore, no patients dropped out due to cold intolerance in response to cryotherapy. Our study had several limitations. First, placebo effects are inevitable. To minimize differences in expectancy between the intervention and control sides, we supported a subjective symptom evaluation with objective measures. One potential confounder is that the control side may exhibit higher skin temperatures concomitant with a homeostatic whole-body temperature increase due to cooling on the intervention side; however, this influence was likely minimal because the incidence of CIPN symptoms on the control sides did not deviate substantially from that reported in previous studies ( 1,2 ). A comparison between patients with and without intervention would control for this physiological response. Second, the nondominant hand and foot always acted as the control, as in previous studies of cryotherapy ( 7,8 ). To the best of our knowledge, there have been no reports on bilateral differences in CIPN symptoms (either subjective or objective). Impairments in ADL are likely less severe when CIPN occurs in the nondominant hand due to easier compensation using the dominant hand. Third, we did not plan to follow the patients after the completion of paclitaxel treatment because postpaclitaxel therapy could impact the sensory status. In this study, patients underwent surgery (n ¼ 10), radiotherapy (n ¼ 8), hormonal therapy, and/or additional chemotherapy (n ¼ 18) following paclitaxel therapy. The 30 patients who returned to our clinic within a median of 6.1 weeks (2 to 126 weeks) stated that there was no worsening of CIPN symptoms after the cessation of paclitaxel treatment. While previous studies have suggested that the development of additional CIPN signs or coasting is relatively rare after cessation of chemotherapy ( 20,21 ), long-term follow-up would reveal the effects of cryotherapy on the natural course of CIPN signs and symptoms. Compression therapy using surgical gloves modestly prevents CTCAE grade 2 or higher sensory and motor peripheral neuropathy with four cycles of triweekly nanoparticle albuminbound paclitaxel ( 22 ). Compression therapy and cryotherapy share an analogous mechanism of reduced drug exposure due to vasoconstriction during paclitaxel infusion. The low temperature associated with cryotherapy may also decrease the uptake of paclitaxel and damage of neurons or mechanotransductions, which might be related to decreased CIPN ( 20,23 ). Total drug exposure may also enhance the risk of CIPN. In a previous study, the CIPN incidence increased with AUC and time above the paclitaxel concentration threshold ( 24 ). Although we found clinically and statistically significant differences in the cumulative dose to events between the high- and low-dose intensity groups, no differences were found between high- and low-AUC groups with a uniform dosage and relatively small variability in pharmacokinetics. Any other risk factor analyses have low power, and we could not identify any correlation between CIPN occurrence and the baseline assessments. We conclude that cyrotherapy is a simple, safe, and effective strategy for the prevention of CIPN in patients with cancer undergoing paclitaxel treatment. Cyrotherapy could support the delivery of optimal chemotherapy by preventing a dose delay or reduction, as well as inhibiting the deterioration of quality of life in cancer patients during and after treatment. Funding This work was supported by the Japan Society for the Promotion of Science (grant No. DC1-6751 to AH) and the Promotion Plan for the Platform of Human Resource Development for Cancer administered by the Ministry of Education, Culture, Sports, Science and Technology in Japan (grant No. 12 to TT). Notes We gratefully acknowledge support for the data collection provided by H. Ishikawa, A. Mizushima, A. Yamaguchi, K. Maekawa, Y. Fukui, M. Nio, T. Nakakimura, Y. Nakayama, T. Kotake, S. Yanai, T. Hitomi, Y, Nakayama, M.Torii, K. Tsuji, M. Miyayama, and the medical staff (physicians, nurses, and pharmacists) of Kyoto University Hospital. This material is based on work supported by the Japan Society for the Promotion of Science and the Promotion Plan for the Platform of Human Resource Development for Cancer administered by the Ministry of Education, Culture, Sports, Science and Technology in Japan. Neither funder had a role in the study design; collection, analysis, or interpretation of the data; the writing of the report; or the decision to submit the article for publication. Parts of this manuscript have previously been presented at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting, June 3–7, 2016, Chicago, Illinois. The authors have declared no conflicts of interest. E L C I T R A 1. Cavaletti G , Marmiroli P . Chemotherapy-induced peripheral neurotoxicity . Nat Rev Neurol . 2010 ; 6 ( 12 ): 657 - 666 . 2. 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Hanai, Akiko, Ishiguro, Hiroshi, Sozu, Takashi, Tsuda, Moe, Yano, Ikuko, Nakagawa, Takayuki, Imai, Satoshi, Hamabe, Yoko, Toi, Masakazu, Arai, Hidenori, Tsuboyama, Tadao. Effects of Cryotherapy on Objective and Subjective Symptoms of Paclitaxel-Induced Neuropathy: Prospective Self-Controlled Trial, JNCI: Journal of the National Cancer Institute, 2018, 141-148, DOI: 10.1093/jnci/djx178