The Effect of Cold Therapy on Peripheral Neuropathy

This study examines the feasibility, acceptability, and efficacy of cold therapy on vincristine-induced peripheral neuropathy (VIPN) in pediatric patients with cancer.

Vincristine (VCR) is one of the most used vinca alkaloid chemotherapy in pediatric oncology patients. It leads to symptoms of peripheral neuropathy, numbness in the hands and feet, tingling, muscle/joint pain, burning sensation, decreased peripheral reflexes, and constipation. These symptoms negatively affect the daily life and quality of life of children. Therefore, it is essential to managing peripheral neuropathy. We aim to decrease the level of VIPN and pain and improve patients' quality of life.

Unfortunately, the neurotoxicity mechanisms of vinca alkaloids are not well known, which is one of the significant limitations in developing effective treatments to prevent VIPN among pediatric oncology patients. We were unable to locate a randomized controlled trial that has evaluated the effectiveness, tolerability, and acceptability of cold therapy on VIPN for pediatric oncology patients. Our study findings will be the first in Turkish national and international literature, and we believe that our results will provide evidence for clinical nursing practice.

An estimated 400 000 children and adolescents ages 0-19 years old are diagnosed with cancer each year (WHO, 2021a). More than 80% of children with cancer are cured in high-income countries, where comprehensive care is generally available; whereas in some low- and middle-income countries less than 30% of patients survive (WHO, 2021b; Lam et al., 2019). Considering the global increase in childhood cancer incidence (Bhakta et al., 2019; Ward et al., 2019), it is critical to characterize the long-lasting side effects of treatment for childhood cancer and accurately assess, monitor, and ultimately develop management strategies to prevent treatment-related side effects (Kandula et al., 2016). Many chemotherapy agents used in cancer treatment can cause acute and chronic peripheral nervous system injury and dysfunction, termed chemotherapy-induced peripheral neuropathy (CIPN) (Rodwin et al., 2021; Kandula et al., 2016). CIPN is a significant problem becoming more prevalent as oncological therapies that use potentially neurotoxic chemotherapy enhance cancer cure and survival (Cavaletti et al., 2019). Peripheral neuropathy is a severe side effect of chemotherapeutic agents, and it can damage the sensory-motor-autonomic regions of the peripheral nervous system (Park et al., 2013; Kandula et al., 2016). Peripheral nerve toxicity has been described with vinca alkaloids, platinum compounds, taxanes, epothilones, bortezomib, and thalidomide (Kandula et al., 2016; Kandula et al., 2018; Cavaletti et al., 2019). Acute CIPN can develop during chemotherapy, necessitating dosage reduction or discontinuation and reducing survival (Colvin, 2019). In a recent systematic review of 42 publications (2009-2020) the reported CIPN incidence ranges from 2.8% to 100%, depending on risk variables. Sensory, motor, autonomic CIPN, and pain had incidence rates of 2-28%, 50-72%, 0.8-83%, and 5.7-44%, respectively (Smith et al., 2021). According to another review, although not life-threatening, CIPN threatens function in children and adolescents treated for cancer both during and following treatment (Bjornard et al., 2018). Smith et al. (2021) noted, "...sensory and motor neuropathy, pain, and functional impairments..." are not uncommon and appear to continue into adulthood. The most common CIPN symptoms in children and adolescents are numbness, tingling, neuropathic pain in the upper and lower limbs, weakness, loss of ankle dorsiflexion range of motion (foot drop), and impaired balance (van de Velde et al., 2017; Kandula et al., 2016; Schouten et al., 2020; van de Velde et al., 2021) VCR is one of the most commonly used vinca alkaloids in pediatric cancer patients and is included in a variety of multiple chemotherapy treatments for acute lymphoblastic leukemia, lymphomas, neuroblastoma, sarcomas, and central nervous system tumors (Mora et al., 2016; Schouten et al., 2020). Neurotoxicity as a prominent side effect of VCR, defined by autonomic and peripheral sensory-motor neuropathy, has been documented in three studies to be as low as 12% and as high as 87% of VCR-exposed children (Gilchrist et al., 2014; van de Velde et al., 2017; van de Velde et al., 2021). The fact that the prevalence of VIPN is so wide is due to the difference in the measurement tools used (van de Velde et al., 2017). VIPN symptoms generally arise after only a few VCR injections, and symptoms often fade a few months after VCR medication is stopped. Paresthesia, constipation, muscular weakness, areflexia, neuropathic pain, and lack of sensation symptoms commonly relate to VIPN (van de Velde et al., 2021).

VIPN treatment addresses symptoms and involves analgesics like gabapentin and amitriptyline (van de Velde et al., 2021). However, the only successful therapy option for VIPN is VCR dosage reduction, even though this limits optimal treatment (Mora et al., 2016). The limited treatment options for VIPN and the symptoms it causes in children have been linked to reducing the quality of life (QoL) both during and after treatment (Mora et al., 2016). Furthermore, it is known that peripheral neuropathy pain affects QoL during cancer therapy. However, it is uncertain how much VIPN affects the QoL in children with cancer during therapy (Bjornard et al., 2018; van de Velde et al., 2021).

Many pharmacological and non-pharmacological methods are used in the management of peripheral neuropathy. However, the neurotoxicity mechanisms of peripheral neuropathy are not well known, which a significant limitation in discovering effective treatments to prevent VIPN among pediatric oncology patients. A systematic review focusing on the efficacy and safety of cryotherapy for preventing VIPN in adults, reported that cryotherapy is a reasonable option to prevent VIPN (Bailey et al., 2021). The primary mechanism of benefit from cryotherapy has been hypothesized to be via vasoconstriction that decreases blood flow (and therefore, chemotherapy delivery) to treated areas (Loprinzi et al., 2020). Unfortunately, the following factors prevent the use of cryotherapy to prevent CIPN: (i) rare reports of frostbite, (ii) patient irritation, (iii) administrative difficulties (for patients, parents, and care professionals alike), and (iv) the lack of conclusive evidence that this approach reduces CIPN (Loprinzi et al., 2020). Nevertheless, many cryotherapy studies have shown the effectiveness of cryotherapy on peripheral neuropathy in adults (Beijers et al., 2020; Ng et al., 2020), we were unable to identify any studies in children and adolescents with cancer. There is a need for studies to evaluate the effectiveness of cryotherapy in reducing peripheral neuropathy in pediatric oncology patients. This study aims to evaluate the effectiveness, tolerability, and acceptability of cold therapy on VIPN among pediatric oncology patients in Turkey.

Eligibility Criteria:
Inclusion Criteria:

* aged 7-18 years,
* receiving VCR therapy,
* diagnosed with leukemia, medulloblastoma, rhabdomyosarcoma, or Wilms tumor,
* able to speak and understand Turkish
* receiving initial treatment
* consent to participate in the research project.

Exclusion Criteria: Risk factors for peripheral neuropathy were considered exclusion criteria. Risk factor criteria were:

* receiving a dose of VCR \<2.5 mg/m2,
* receiving VCR and azole antifungal treatment simultaneously,
* a hematological malignancy with neurological disease,
* a history of peripheral neuropathy,
* diabetes,
* self-reported cold sensitivity.
* Additionally, children who receive chemotherapy or other treatment using the peripheral veins of their hands or feet will not be included since the cold application is contraindicated.