The CONTRoL Trial: Cryotherapy vs. cOmpression Neuropathy TRiaL (CONTRoL)

Randomized Controlled Selection Trial of Cryotherapy vs. Compression Therapy for the Prevention of Taxane-induced Peripheral Neuropathy in Breast Cancer Patients

The primary objective of this study is to select the best intervention from cold therapy, compression therapy and placebo at reducing neuropathic pain as measured by the change in the Neurotoxicity (NTX) component of the Functional Assessment of Cancer Therapy (FACT) - Taxane questionnaire, following 12 weeks of neoadjuvant/adjuvant chemotherapy with paclitaxel or docetaxel among breast cancer patients.

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent side effect resulting from the administration of cytotoxic chemotherapeutic agents. The incidence of CIPN can vary on the type of agent used, the frequency with which it is given, and the cumulative dose. Unfortunately, for some patients, symptoms may persist even after discontinuation of the drug due to irreversible nerve damage. As of now, there are no established agents for CIPN prevention. This is a randomized, placebo-controlled clinical selection trial of interventions for CIPN in patients treated with docetaxel every 3 weeks or paclitaxel on a weekly schedule. Patients will be randomly assigned to receive either frozen gloves and socks, compression gloves and socks, or "loose" gloves and socks (placebo arm) during chemotherapy infusion to study the best intervention at reducing neuropathic pain.

The preferred intervention can be selected during the ongoing enrollment as soon as the pre-specified selection criteria are met, and further enrollment will cease.

Men or women over the age of 18 with a history of stage I-III breast cancer and is scheduled to receive adjuvant or neoadjuvant paclitaxel or docetaxel for at least 12 weeks.

Men or women over the age of 18 with a history of stage I-III breast cancer and is scheduled to receive adjuvant or neoadjuvant paclitaxel or docetaxel for at least 12 weeks.

Men or women over the age of 18 with a history of stage I-III breast cancer and is scheduled to receive adjuvant or neoadjuvant paclitaxel or docetaxel for at least 12 weeks.

Study subjects will wear NatraCure flexible socks on bilateral hands and feet. The sock will act as a mitten and covers the entire hand until past the wrist. There are 2 gel packs inserted into the sock, to provide cooling to the dorsal and frontal aspect of the hand. For the feet, the sock will cover the entire foot until above the ankle. Garments will be refrigerated for at least 3 hours at -25 to -30 Celsius prior to use. With each infusion, patients will wear the frozen garments on their hands and feet for a total of 90-120 minutes, beginning 15 minutes before the start of the infusion and until 15 minutes after the end of the infusion. Two sets of socks will be used during each session for 45-60 minutes each to maintain a consistently low temperatures of the extremities.

Study participants will wear Sigvaris Secure Arm Sleeves and Gloves on bilateral upper extremities. The sleeves and gloves provide 20-30mmHg of compression. Subjects will wear Sigvaris CompreFlex Lite compression garments on the lower extremities which includes a transition liner with a compressive foot, providing 20-30mmHg of compression on the lower leg and 15mmHg on the toes and feet. AccuTabs will be placed along the CompreFlex Lite to easily and accurately set the compression level at 20-30mmHg. With each chemotherapy infusion, patients will wear the sleeves/gloves and socks for a total of 90-120 minutes, beginning 15 minutes before the start of the infusion and until 15 minutes after the end of the infusion.

Study participants will wear a non-compressive sleeve and loosely fitting glove on bilateral arms and hands. They will also wear a non-compressive Sigvaris Basic Liner with the CompreFlex Lite loosely applied over it. The investigators will verify that no compression is applied via using an interface pressure sensor (PicoPress). The maximum level of allowed pressure for garments will be 3mmHg. If the pressure reading is greater than 3mmHg, then a larger garment size will be used. Measurements with the pressure sensor will be repeated as needed to ensure a low pressure level of less than 3mmHg. With each chemotherapy infusion, patients will wear the gloves and socks for a total of 90-120 minutes, beginning 15 minutes before the start of the infusion and until 15 minutes after the end of the infusion.

The primary endpoint is the change in FACT NTX at 12 weeks from the start of chemotherapy. The change in FACT NTX will be dichotomized into a good outcome (change in FACT NTX less than 5 from baseline to week 12) versus a poor outcome (change in FACT NTX greater than or equal to 5 from baseline to week 12). The FACT-NTX subscale includes 11 items, each of which is divided into 5 scoring levels: 0, 1, 2, 3, 4, and a total score of 44. The scale is graded 0-4. A low score indicates a good effect. This change in FACT-NTX scale score indicates the proportion of patients with successful outcomes.

National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) is a subjective method to evaluate CIPN which is performed by a healthcare professional. The patient's peripheral sensory neuropathy, peripheral motor neuropathy, dysesthesia, paresthesia and neuralgia will be graded on a scale of 1 to 5 depending on severity with 1 indicating a better outcome.

Cutaneous toxicity and onycholysis will be assessed by a healthcare professional using the National Cancer Institute Common Toxicity Criteria (Version 2), specifically nail changes. Grade 1 includes discoloration, ridging (koilonychia), or pitting of the nails and Grade 2 is partial or complete loss of nail(s) or pain in the nail beds.

Comfort with the study intervention will be assessed on a 4-point scale, (0=dissatisfied; 1=not satisfied; 2=satisfied; 3=very satisfied) with 3 indicating a better outcome.

Study participants will be assessed for development of sensory neurological dysfunction. Vibration perception will be assessed using a tuning fork. Vibration threshold will be tested on the bilateral dorsum of the distal interphalangeal joint of the index finger and dorsum of the interphalangeal joint of the hallux. Subjects will be asked to indicate when the vibration stimulus is initially felt (perception threshold) and when the stimulus disappears (disappearance threshold.) The vibration perception threshold is the average of three paired measurements.

Evaluation of other sensory endpoints including touch, pressure and pain will be evaluated using a Neuropen. Touch and pressure sensation will be assessed using a 10-g monofilament on the subject's dominant foot. Pain and subjective sharpness sensation will be assessed using the Neuropen on the dominant foot. The spring mechanism is calibrated to exert a force of 40 grams to help identify subjects with loss of pain sensation.

The 'timed get up and go' test is a rapid and widely used clinical performance-based measure of lower extremity function, mobility, and fall risk. Subjects are asked to stand up from a standard chair (seat height between 44 and 47 cm), walk a distance of 3 m (marked on the floor) at a comfortable pace, turn, walk back and sit down. Time will be measured in seconds. Shorter times indicate better performance.

Balance will be assessed using the tandem and unipedal stance test. In this assessment, the subject stands with one foot in front of the other (heel to toe) (30 seconds), then on one leg with: eyes open (60 seconds), eyes closed (30 seconds), and eyes open with head rotation (30 seconds) with arms held comfortably at the side. The test was accepted failure when the stance foot shifted in any way or the nonstance foot touched the ground. Tests are recorded as achieved or not. Time will be measured in seconds. If the subject did not reach the maximum time, the best time was recorded.

Inclusion Criteria: Age greater or equal to 18 years. History of stage I-III breast cancer Patient scheduled to be receiving adjuvant or neoadjuvant paclitaxel or docetaxel for at least 12 weeks Signed informed consent Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Karnofsky ≥60%,) Exclusion Criteria: Prior treatment with taxane or platinum based chemotherapy Known history of neuropathy Raynaud's phenomenon Peripheral arterial ischemia Cold intolerance Current use of duloxetine which may mitigate chemotherapy-induced peripheral neuropathy (CIPN)