Abstract
Background:
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating adverse effect of taxane therapy. Small non-randomized studies in patients with early-stage breast cancer (ESBC) suggest both cryotherapy and compression therapy may prevent CIPN. It is unknown which is more effective.
Methods:
We conducted a randomized phase IIB adaptive sequential selection trial of cryotherapy vs. compression therapy vs. placebo (“loose” gloves/socks) during taxane chemotherapy. Participants were randomized in triplets. Garments were worn for 90-120 minutes, beginning 15 minutes prior and continuing for 15 minutes following the infusion. The primary goal was to select the best intervention based on a Levin-Robbins-Leu sequential selection procedure. The primary endpoint was a <5-point decrease in the Functional Assessment of Cancer Therapy Neurotoxicity (FACT-NTX) at 12-weeks. An arm was eliminated if it had four or more fewer successes than the currently leading arm. Secondary endpoints included intervention adherence and patient-reported comfort/satisfaction.
Results:
Between 4/2019-4/2021 63 patients were randomized (cryotherapy (20); compression (22); placebo (21)). Most patients (60.3%) were treated with docetaxel. The stopping criterion was met after the 17th triplet (n=51) was evaluated; success at 12-weeks occurred in 11 (64.7%) on compression therapy, 7 (41.1%) on cryotherapy, and 7 (41.1%) on placebo. Adherence to the intervention was lowest with cryotherapy (35.0%) compared to compression (72.7%) and placebo (76.2%).
Conclusion:
Compression therapy was the most effective intervention in this phase IIB selection trial to prevent CIPN and was well tolerated. Compression therapy for the prevention of CIPN should be evaluated in a phase III study.
ClinicaTrials.gov Identifier:
Keywords: chemotherapy-induced peripheral neuropathy, taxane chemotherapy, cryotherapy, compression therapy
Introduction
Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting toxicity of neurotoxic chemotherapy such as paclitaxel and docetaxel, which are used to treat many cancers.[1] Up to 81% of patients treated with paclitaxel have reported CIPN symptoms [2-5], that can persist for years after treatment, and can impact quality of life (QOL) and limit daily functioning. [6, 7]
At present, dose modification remains the most successful method for prevention of worsening CIPN. The tradeoff with this approach, is the potential for lower efficacy of chemotherapy, which could impact outcomes. There are no effective therapies for CIPN prevention,[8, 9] however, both cryotherapy and compression therapy have shown some benefit in small trials.[8-13] Both techniques result in vasoconstriction which limits blood flow to the extremities and are hypothesized to reduce exposure of peripheral nerves to chemotherapeutic agents. This approach is effective in the reduction of chemotherapy-related alopecia.[14] In self-controlled small studies of cryotherapy where participants used a frozen glove on one hand but not the other, rates of patient reported and objectively assessed CIPN and taxane-induced nail changes were significantly reduced in the extremity that received cryotherapy.[10, 11] In a similarly designed study of compression, rates of sensory and motor neuropathy were significantly lower in the hand that received compression.[15] Limitations of these studies include lack of randomization, utilization of unblinded self-control (i.e., opposite limbs) which could lead to bias, and limited evaluation of the efficacy in the feet.
We conducted a randomized phase IIB adaptive sequential clinical selection trial comparing frozen gloves/socks, compression gloves/socks, or “loose” gloves/socks (placebo arm) in patients with early-stage breast cancer (BC)starting taxane chemotherapy treatment. The primary goal was to select the best intervention.
METHODS
Study Design and Participants
This was a single-center randomized phase IIB 3-arm adaptive sequential selection trial based on one of the Levin-Robbins-Leu family of sequential selection procedures.[16-21] Patients were enrolled at Columbia University Irving Medical Center (CUIMC) in New York, New York between April 2019 and April 2021. Eligible patients were ≥18 years old with stage I-III BC who were scheduled to receive adjuvant/neoadjuvant nab-paclitaxel, paclitaxel, or docetaxel for at least 12-weeks. Patients were not eligible if they previously received taxane or platinum-based chemotherapy; had a known history of neuropathy, Raynaud’s phenomenon, peripheral arterial ischemia, or cold intolerance; or if they currently used duloxetine. This study was conducted with approval from the Institutional Review Board at CUIMC and is registered under NCT03873272 at ClinicalTrials.gov.[22]
Intervention
Participants wore study garments (Supplement) applied by trained study staff, on their upper and lower extremities beginning 15-minutes prior to the start of taxane infusions, during their taxane infusion, and for 15-minutes post taxane infusion. If a participant received chemotherapy through a peripheral IV, or had any limitation to the use of one extremity (i.e. amputation), the study garments were applied to the remaining available extremities.
Cryotherapy with Frozen Gloves/Socks:
Patients wore NatraCure flexible socks on bilateral hands and feet. The sock acted as a mitten and covered the entire hand past the wrist, and two gel packs were inserted into the sock, to provide cooling to the dorsal and frontal aspect of the hand. For the feet, the sock covered the entire foot above the ankle. Garments were refrigerated for at least 3 hours at −25 to −30°C prior to use. Two sets of socks were used during each session for 45-60 minutes each to maintain a consistently low temperatures of the extremities.
Compression with Compression Gloves/Socks:
Patients wore Sigvaris Secure Armsleeves Gloves, and Gauntlet under a Sigvaris CompreFlex Standard Arm wrap on bilateral upper extremities. The sleeves and gloves provided 20-30mmHg of compression. Patients wore Sigvaris CompreFlex Transition compression garments on the lower extremities which includes a transition liner with a compressive foot, which provided 20-30mmHg of compression on the lower leg and 15mmHg on the toes and feet. An interface pressure sensor (PicoPress[23]) was used to ensure accurate compression levels.
Placebo with “Loose” Gloves/Socks:
Patients wore a non-compressive Sigvaris Basic Cotton Liner with Sigvaris CompreFlex garments loosely applied over the liner on the upper and lower extremities. We verified that ≤3 mmHg of pressure was applied using the PicoPress[23]. If pressure was >3mmHg, larger garment size was used. Measurements with the pressure sensor were repeated until pressure was ≤3mmHg.
Outcome Measures
Primary Endpoint was success defined as a change in the Functional Assessment of Cancer Therapy Neurotoxicity (FACT-NTX) at 12-weeks from baseline. Success was defined as a change of <5 points based on the literature.[24] All patients randomized were considered evaluable for the primary endpoint. Patients who discontinued prior to the 12-week assessment were considered failures for the primary endpoint. The FACT NTX is an 11-item questionnaire with questions that pertain to sensory, motor, and auditory neuropathy, as well as dysfunction associated with neuropathy; each item is measured on a 0-4 scale (0, not at all; 4, very much).[25-27] Secondary endpoints included comfort/satisfaction and adherence with study garments, QOL, vibration and pressure sensation, taxane toxicity, and safety of garments. All endpoints were assessed at baseline, 12- and 24-weeks.
Comfort/Satisfaction and Adherence
Comfort/Satisfaction with Study Garments was assessed on a 4-point scale, (1=dissatisfied; 4=very satisfied). This scale was previously used to assess comfort with cryotherapy.[28] Adherence to Study Garments (yes/no) was assessed by research staff and defined as the proportion of taxane infusions patients attended during their time on study, up to death or withdrawal of consent, in which participants were documented to have worn the assigned garments on all available extremities ≥80% of the required infusion time. Patients who withdrew from the intervention, but not from the study were considered non-adherent
Patient Reported QOL
QOL was assessed by PROMIS-29 v2.1 a validated assessment tool that evaluates seven domains (physical function, anxiety, depression, fatigue, sleep disturbance, social functioning, and pain interference) using a 5-point Likert scale, as well as a single item to assess pain severity on a 0-10 scale.[29-31] The scores were normalized using the HealthMeasures Scoring Service online tool[32], and t-scores were generated for all domains (except for pain intensity) based on a large sample of the general US population, as established by the HealthMeasures Scoring Service. Differences in normalized t-scores were used to calculate change from baseline to week 12 and week 24.
Sensory Perception
Sensory perception testing was conducted by trained research staff. Pressure sensation was assessed by 10-g monofilament Neuropen on the dominant foot at 10 sites, diminished sensation defined as <8/10 touch points.[33]. Vibration perception was assessed with a 128 Hertz tuning fork on the bilateral dorsum of the distal interphalangeal joint of the index finger and dorsum of the interphalangeal joint of the hallux in a distal to proximal fashion; participants were asked to indicate when the vibration was initially felt and when the stimulus disappeared.[34-36].
Taxane Toxicity and Safety
Taxane toxicity, defined as onycholysis, peripheral and motor sensory neuropathy, dysesthesia, paresthesia, and neuralgia were assessed by the study team using the National Cancer Institute–Common Terminology Criteria for Adverse Events (CTCAE) (Version 4).[37] Safety was assessed using the CTCAE. All AEs are graded on a scale of 1-5 depending on severity.[37] Nail toxicities were patient-reported.
Statistical Analysis
The methods for this three-arm adaptive trial were based on the Levin-Robbins-Leu family of sequential selection procedures.[16-21] Patients were randomized in triplets within chemotherapy strata to one of the three intervention arms. Elimination Criteria: after completion of the 12-week assessment for each patient in a triplet, the triplet was available for sequential monitoring by adding their data to a running tally of the success outcomes (change in FACT NTX <5), for each intervention. These tallies were used for the elimination criterion, defined as a difference of ≥4 between the current greatest and smallest success tallies, if this occurred that/those intervention(s) were eliminated (no further patients randomized to that arm). If one arm was eliminated, the trial would continue randomizing patients in pairs to the remaining interventions until the difference in success tallies was ≥4, and the intervention with the smaller success tally was eliminated. If two arms tied with ≥4 fewer successes than the lead intervention, both trailing interventions would be eliminated. Stopping Rule: If two intervention arms were eliminated at our before 100 patients’ outcomes were observed, the trial would be stopped. If the stopping rule was not reached at or before 100 observed outcomes, the trial would stop by truncation and the intervention with the largest success tally among the remaining arms would be selected. To ensure adequate sample size for estimating success probability for each intervention, no intervention was eliminated before the outcomes of 15 triplets were observed.
The specified procedure guarantees a probability of at least 80% correct selection (of the truly best intervention), if that one is truly superior to the others by a pre-specified amount,[16-21] namely, by an odds ratio (OR) greater than or equal to 2.0 comparing the odds on a successful outcome with the truly best treatment to the next best. The details of the design in terms of the sampling rule, the elimination rule, the stopping rule, and the terminal decision rule are provided in the study protocol (supplemental). Of note, if at the time of first elimination there were partially filled/observed triplets randomized to start their intervention, each patient in a triplet would complete their follow-up even if their randomization arm was eliminated and these outcomes would contribute to the secondary goal of obtaining unbiased estimates of success probabilities and study interpretation as explained below. However, data from patients in incomplete triplets randomized to eliminated arms would not be considered in applying the criterion to eliminate a subsequent intervention, to preserve the validity of the sequential stopping procedure. Similarly, if there were partially observed triplets or pairs at the stopping time with a selection decision prior to truncation, they were allowed to complete follow-up to observe their outcomes. Data from such overrun triplets or pairs would be used to weigh the evidence concerning success probabilities, but not used to alter the stopping time and terminal decision to preserve the validity of the stopping procedure. We report the success proportion for each arm and their ORs at the time of final selection. We anticipated at the time of final selection, there would be a few open randomized triplets with not-yet-observed endpoints. The protocol pre-specified allowing patients in such triplets to complete their follow-up period and the resulting “overrun” data would be included in the terminal analysis. We report the success proportion and ORs including the overrun data as well. To assess the strength of evidence that the selected therapy arm is truly best as opposed to the observed second best (respectively, the observed third best), we report the likelihood ratio both excluding and including the overrun data.
Continuous variables are summarized mean and standard deviation. Categorical variables are summarized as counts and frequencies. Baseline characteristics are reported overall and by arm. For patient-reported secondary endpoints, the analysis only included patients who completed the assessments and are reported as changed from baseline at 12- or 24-weeks or as reported at 12- and 24-weeks.
Sample Size Justification:
The operating characteristics of the design were evaluated under various scenarios with success probabilities between 65%-79% for the intervention arms and 40%-65% for the control arm using simulation studies. Previous studies of cryotherapy and compression gloves the observed success rates were 72% and 79%, respectively, and experience suggests a 40% success rate in the control arm is plausible.[15, 38] Under the design alternative, the average sample size is 66 (median 59), ranging between 45 and 100 patients. To ensure that there were some unbiased estimates of the proportion of patients with success outcomes available for each intervention arm, the elimination and selection criteria were not applied until 15 participants-per-arm were observed (45 in total). Fifteen participants-per-arm provided a 95% confidence interval no wider than 0.52 (+/− 0.26) percentage points for the estimate of the proportion of patients with a success outcome based on the Clopper-Pearson method.[39] The details of the operating characteristics of the study design are provided in the study protocol (supplemental).
Results
There were 63 patients randomized (n=20 cryotherapy, n=22 compression therapy, and n=21 placebo) from 4/2019 through 4/2021 (Figure 1). All patients were female, and the median age at consent was 54.4 years (Table 1). The patient population was racially and ethnically diverse, 28.6% White/Caucasian, 23.8% Black/African American, 31.7% Asian/Other, and 15.9% Unknown, and 46.0% self-identified as Hispanic. The majority of patients (60.3%) received every-3-week docetaxel-based chemotherapy. There were no relevant differences in sociodemographic or clinical characteristics between intervention groups (Table 1).
Figure 1: Flowchart of Patients in the CONTRoL Trial.
CONSORT diagram, 72 patients were screened and 63 patients were included in the analysis. During the study period three patients died (unrelated to study-treatment), two patients died prior to the week-12 assessment and one patient died prior to the week-24 assessment.,
Table 1.
Demographic and Clinical Characteristics of the Study Population n=63
| Characteristic n(%) |
Overall n=63 |
Cryotherapy n=20 |
Compression n=22 |
Placebo n=21 |
|---|---|---|---|---|
| Sex | ||||
| Female | 63 (100.0) | 20 (100.0) | 22 (100.0) | 21 (100.0) |
| Age at Consent Mean (SD) | 54.4 (14.2) | 57.5 (15.3) | 53.5 (14.7) | 52.4 (12.6) |
| Race | ||||
| Asian/Other | 20 (31.7) | 8 (40.0) | 5 (22.7) | 7 (33.3) |
| Black | 15 (23.8) | 4 (20.0) | 6 (27.3) | 5 (23.8) |
| Unknown | 10 (15.9) | 3 (15.0) | 5 (22.7) | 2 (9.5) |
| White | 18 (28.6) | 5 (25.0) | 6 (27.3) | 7 (33.3) |
| Ethnicity | ||||
| Hispanic or Latino | 29 (46.0) | 11 (55.0) | 10 (45.5) | 8 (38.1) |
| Not Hispanic or Latino | 28 (44.4) | 6 (30.0) | 11 (50.0) | 11 (52.4) |
| Unknown | 6 (9.5) | 3 (15.0) | 1 (4.5) | 2 (9.5) |
| BMI Kg/m2 | ||||
| <25 | 17 (27.0) | 5 (25.0) | 8 (36.4) | 4 (19.0) |
| >=25 | 46 (73.0) | 15 (75.0) | 14 (63.6) | 17 (81.0) |
| Clinical Stage | ||||
| I | 19 (30.2) | 7 (35.0) | 6 (27.3) | 6 (28.6) |
| II | 32 (50.8) | 9 (45.0) | 12 (54.5) | 11 (52.4) |
| III | 12 (19.0) | 4 (20.0) | 4 (18.2) | 4 (19.0) |
| Receptor Status | ||||
| HR Negative/HER2 Negative | 17 (27.0) | 6 (30.0) | 5 (22.7) | 6 (28.6) |
| HR Negative/HER2 Positive | 10 (15.9) | 2 (10.0) | 5 (22.7) | 3 (14.3) |
| HR Positive/HER2 Negative | 22 (34.9) | 7 (35.0) | 7 (31.8) | 8 (38.1) |
| HR Positive/HER2 Positive | 14 (22.2) | 5 (25.0) | 5 (22.7) | 4 (19.0) |
| Comorbidities | ||||
| Diabetes | 8 (12.7) | 3 (15.0) | 2 (9.1) | 3 (14.3) |
| Vitamin D deficiency | 8 (12.7) | 1 (5.0) | 5 (22.7) | 2 (9.5) |
| Autoimmune disorder | 4 (6.3) | 1 (5.0) | 1 (4.5) | 2 (9.5) |
| Type of Chemotherapy | ||||
| Docetaxel every 3 weeks | 38 (60.3) | 12 (60.0) | 13 (59.1) | 13 (61.9) |
| Number docetaxel of treatments (Mean (SD)) | 5.1 (1.3) | 5.1 (1.3) | 5.5 (0.9) | 4.8 (1.7) |
| Weekly paclitaxel | 25 (39.7) | 8 (40.0) | 9 (40.9) | 8 (38.1) |
| Number of paclitaxel treatments (Mean (SD)) | 11.7 (1.2) | 11.9 (0.4) | 11.3 (2.0) | 12.0 (0.0) |
| Carboplatin Received | ||||
| No | 42 (66.7) | 14 (70.0) | 12 (54.5) | 16 (76.2) |
| Yes | 21 (33.3) | 6 (30.0) | 10 (45.5) | 5 (23.8) |
Primary Endpoint:
The stopping criterion was met after the patients in the 17th triplet (n=51 patients) were evaluated for the primary endpoint. At the time, success occurred in 11 (64.7%) patients in the compression arm, 7 (41.1%) patients in the cryotherapy arm, and 7 (41.1%) patients in the placebo arm. The OR comparing compression therapy to either of the other two groups was 2.62. The likelihood ratio at the time of stopping was 47.05 which indicated strong evidence that the selected arm (i.e., the compression arm) is truly the best as opposed to the apparently second best (i.e., the cryotherapy or placebo arm) being the truly best. At completion of the study there were 63 patients evaluable for the primary endpoint, of whom 13 out of 22 (59.1%) in the compression arm had a successful outcome, 9 out of 20 (45.0%) had a successful outcome in the cryotherapy arm, and 11 out of 21 (52.4%) had a successful outcome in the placebo arm (Table 2). Including the overrun data, the observed ORs decreased to 1.77 and 1.59 for compression therapy versus cryotherapy and placebo, respectively. The weight of evidence that the compression arm is truly best as opposed to the cryotherapy arm (respectively, the placebo arm) is weak (with likelihood ratio 5.37 and 3.13, respectively).
Table 2A:
Proportion of Patients with Successful Outcomes (<5-point decrease in FACT-NTX from baseline) by Arm Once Stopping Criterion Met (n=51)
| Proportion who Achieved Success at Week-12 | ||
|---|---|---|
| Study Arm | Success Rate | Proportion (Clopper- Pearson 95% CI) |
| Compression | 11/17 | 0.65 (0.38 – 0.86) |
| Cryotherapy | 7/17 | 0.41 (0.18 – 0.67) |
| Placebo | 7/17 | 0.41 (0.18 – 0.67) |
Tolerability of the Study Garments
Participants reported satisfaction with study garments on a 4-Point Likert scale. At 12-weeks, 90.5% reported being satisfied/very satisfied with the study garments in the compression arm, compared to 75.0% treated with cryotherapy, and 93.8% treated with placebo (Figure 2). Adherence to the study garments (wore garments for ≥80% of all infusions) was lowest for cryotherapy (35.0%) compared to compression (72.7%) and placebo (76.2%). There were no episodes of frostbite or cutaneous toxicity in any patient. Only two patients experienced grade 1 intervention related toxicity. Both were in the cryotherapy arm.
Figure 2: Percentage of Patients who Endorse Satisfaction with Study Interventions (1-4 Likert) Scale at week-12 (n=53) and week-24 (n=45).
The percentage of patients who endorse each category of patient reported satisfaction (x-axis) with assigned study garments, the right side (blue) indicates satisfaction and the left side (red) indicates dissatisfaction. At 12-weeks, 90.5% reported being satisfied/very satisfied with the study garments in the compression arm, compared to 75.0% treated with cryotherapy, and 93.8% treated with placebo.
QOL
At 12-weeks, pain interference increased from baseline in all arms (mean change from baseline of 2.1 cryotherapy, 8.1 compression, 2.1 placebo), at 24-weeks mean pain interference change from baseline was lowest in the compression arm (+0.2), compared to cryotherapy (+8.0), and placebo (+1.9). This trend was similar for pain intensity as well. The summaries for the other PROMIS measures are provided in Supplemental Table 1.
Sensory Perception
At 12-weeks 21.4%, and at 24-weeks 23.1% of participants reported diminished pressure sensation in the cryotherapy arm. No participants reported diminished sensation in the compression or placebo arms at these time points (Supplemental Table 2).
At baseline, diminished sensation at the interphalangeal index finger joint occurred in 50.0%, 66.7%, and 57.9% in the cryotherapy, compression, and placebo arms, respectively. At 12-weeks diminished sensation was noted in 64.3%, 81.3%, and 50.0% in the cryotherapy, compression, and placebo arms, respectively (Supplemental Table 2).
Nail Toxicity/Onycholysis
At 12-weeks, 71.4% of participants in the cryotherapy arm had worsened nail toxicity, compared to 46.7% of participants in the compression arm, and 62.5% of participants in the placebo arm. At 24-weeks, 87.5% of participants in the cryotherapy arm had worsened nail toxicity from baseline, compared to 53.8% of participants in the compression arm, and 73.3% of participants in the placebo arm. Data for taxane tolerability are displayed in Figure 3.
Figure 3.
A: Worsening CTCAE Toxicities Related to Taxane-Chemotherapy From Baseline to 12-Weeks (n=63)
Figure 3B: Worsening CTCAE Toxicities Related to Taxane-Chemotherapy From Baseline to 24-Weeks (n=63)
The percentage of patients in each study arm with worsening from baseline CTCAE toxicities related to taxane-chemotherapy including: peripheral sensory neuropathy, paresthesia, dysesthesia, neuralgia, and peripheral motor neuropathy, at (A) 12-week and (B) 24-weeks.
Discussion
In this randomized trial, compression therapy was selected over cryotherapy and placebo by a procedure designed to correctly identify the best treatment with 80% probability if it has a pre-specified superiority of an OR of 2. At the pre-specified selection time, a successful outcome (FACT-NTX change of <5 points from baseline) occurred in approximately two thirds of patients treated with compression therapy, and 41.1% of patients in the cryotherapy and placebo group. Adherence and patient reported satisfaction with the study garments was also higher in the compression arm compared to patients treated with cryotherapy. Compression therapy was selected as the most promising intervention for a future phase III trial, but the evidence of true superiority is weak.
Our finding that compression is effective for CIPN prevention is consistent with the conclusions of other recent studies. In a self-controlled clinical trial in which 42 patients with BC wore two surgical gloves (one size too small) on their dominant hand during nab-paclitaxel administration.[15] The rates of CTCAE grade 2 or higher sensory and motor neuropathy were significantly lower in the hand treated with compression compared to the control hand (sensory neuropathy 21.4 vs. 76.1%; motor neuropathy 26.2 vs. 57.1%).[15]. Kanbayashi and colleagues[40] conducted a randomized trial of cryotherapy vs. compression therapy among 38 patients with BC who were receiving albumin-bound paclitaxel. Patients served as their own control with randomization of treatment to either the dominant or non-dominant hand. Cryotherapy was administered with frozen gloves. Compression was administered by surgical gloves (two surgical gloves, both one size too small). There was no difference in grade 2 or higher CIPN or patient reported CIPN between groups, however the number of events in both arms was low. Of note, two patients withdrew from the trial because they could not tolerate cryotherapy.
Several prior studies reported efficacy and tolerability with cryotherapy. In a randomized phase II study of cryotherapy vs. control among 44 patients with BC who received weekly paclitaxel, 41% in the cryotherapy group had a marked decrease in FACT-NTX scores (>10% or 6-point change) compared to 73% in the control arm (p-0.03).[41] In a similarly designed study of 40 participants who received weekly paclitaxel, frozen gloves and socks were worn only on the dominant side, and patients reported less CIPN (patient neurotoxicity questionnaire grade D/E 2.8% vs. 41.7% p<0.001), and experienced less tactile deterioration (27.8% vs. 80.6%, p<0.001) on the side treated with cryotherapy. In this study no patient discontinued cryotherapy due to cold intolerance.[10] The lack of detail on controlling temperature in prior cryotherapy trials may explain the variability in tolerability.
Continuous-flow cooling devices and cryocompression may overcome limitations of cryotherapy by improving tolerability and allow for lower temperatures to be achieved comfortably and safely. In a pilot study, patients with BC treated with weekly paclitaxel received cryotherapy via continuous-flow cooling at 22°C on one side, while the non-cooled side served as the control. At 6-months, nerve conduction was mildly improved in the cooled limb compared to the untreated contralateral limb; and there was correlation between the degree of skin cooling and motor amplitude preservation (p<0.0005).[42] To reach lower cooling temperatures, Bandla et al added cyclic pressure to cooling per the gate control theory of pain which suggests non-painful sensory inputs can inhibit pain sensation. They found that cryocompression, allowed participants to tolerate cooler temperatures, down to 11°C. They conducted a randomized study of frozen gloves, continuous-flow cooling, and cryocompression among 58 healthy volunteers, and found that frozen gloves were minimally tolerated, but continuous-flow cooling an cryocompression were safe and tolerable.[43] Cryocompression achieved lower skin temperatures than continuous-flow cooling (mean 20°C for cryocompression vs. 27°C for continuous-flow cooling), with similar safety profiles.[43] Since a greater degree of cooling may lead to improved efficacy in preventing CIPN, cryocompression may be a promising modality to study in future trials.
This study overcomes some of the reporting-bias of previous non-randomized studies, where participants served as their own controls.[10, 15, 28] There are several notable limitations of this study. It was an unblinded study performed at a single institution, and it was not designed to find significant differences in efficacy among interventions, but rather to identify the best intervention for a larger trial. Participants randomized to the placebo arm were aware this was the control arm, which may have affected their response to patient reported outcomes. This trial was conducted in part during the COVID-19 pandemic, which affected adherence with the garments in all three study-arms. Another limitation is that follow-up data was only collected until 24-weeks, and therefore we are unable to determine if clinical benefit of any intervention is sustained over time. Additionally, the small sample size and missing data for the secondary outcomes limits the ability to draw meaningful conclusions from the QOL and sensory perception analyses, further the vibration perception data is difficult to interpret as many patients had reduced vibration perception at baseline. Finally, the cooling device lacked the ability to tightly control the temperature administered over time.
In this pilot study, compression therapy was found to be the most effective intervention and was well tolerated. It is possible that cryocompression therapy or continuous-flow coolant devices with temperature control could overcome the tolerability limitations of cryotherapy. Compression therapy for prevention of CIPN should be a component of future large, rigorous randomized phase III trials.
Supplementary Material
Table 2B:
Proportion of Patients with Successful Outcomes (<5-point decrease in FACT-NTX from baseline) by Arm of All Participants (n=63)
| Proportion who Achieved Success at Week-12 | ||
|---|---|---|
| Study Arm | Success Rate | Proportion (Clopper- Pearson 95% CI) |
| Compression | 13/22 | 0.59 (0.36 – 0.79) |
| Cryotherapy | 9/20 | 0.45 (0.23 – 0.68) |
| Placebo | 11/21 | 0.52 (0.30 – 0.74) |
Funding:
This research was funded by the National Cancer Institute NIH/NCI 1R03CA238982-01A1 (MA) and the Thompson Family Foundation Initiative at Columbia University. Study garments were donated by Sigvaris and NatraCure
Footnotes
Conflicts of Interest: Kevin Kalinksy: Advisory/Consulting: Genentech/Roche, Immunomedics, Seattle Genetics, Oncosec, 4D pharma, Daiichi Sankyo, Puma Biotechnology, Mersna, Menarini Silicon Biosystems, Myovant Sciences, Takeda. Spouse: Stock: EQRX; Grail, Array BioPharma and Pfizer (Prior Employee)
Data Availability:
Data are available from the authors upon reasonable request and permission from the Columbia University Medical Center.
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Data Availability Statement
Data are available from the authors upon reasonable request and permission from the Columbia University Medical Center.