The effect of hilotherapy on chemotherapy-induced peripheral neuropathy in the treatment of breast cancer with Paclitaxel.

In 2021, in the Netherlands123,672 people were diagnosed with cancer (NKR,
2022). The amount of people who are diagnosed with cancer and treated with
chemotherapy has increased from 7.000 to more than 30.000 over the past 25
years (Vonk et al., 2016). Because of the increasingly effective cancer
treatments and the rising indications for the use of chemotherapy, the life
expectancy of patients is rising and because of that the side effects of
chemotherapy are more and more important (Beijers et al., 2020; Vonk et al.,
2016). One of the side effects of chemotherapy is chemotherapy-induced
peripheral neuropathy (CIPN), which the NVKNF (2005) defines as follows;

Peripheral neuropathy (polyneuropathy) is a symmetrical disorder of the
peripheral nerves, characterized by sensory and/or motor abnormalities, usually
present more distally than proximal and more in the legs than in the arms. By
definition, a polyneuropathy involves several nerves.*

CIPN can have a negative effect on the quality of life and safety of the
patient, but also on the treatment plan (Al-Atiyyat et al., 2018). Molassiotis
et al. (2019) indicate that CIPN is associated with fatigue, psychological
problems and a decrease in physical independence. Patients may experience
significant difficulties with essential daily functions, including difficulty
with fine motoric skills. Patients may also experience difficulties in walking
(Flatters et al., 2017), which increases the risk of falling (Selvy et al.,
2021).

CIPN is a common side effect in patients receiving neurotoxic chemotherapy for
the treatment of, among others, breast, gastrointestinal, gynecological and
haematological malignancies. Among these patients, the incidence of CIPN is
estimated to be approximately 48-52% (Selvey et al., 2021). CIPN depend on the
type of chemotherapy in combination with the amount, duration and speed with
which the drug is administered. The complaints can be sensory, motor and/or
autonomous in nature. These complaints can be temporary or permanent. One of
the agents that causes CIPN are the taxoid cytostatics, of which Paclitaxel is
one of the agents (Gutiérrez-Gutiérrez et al., 2010).

Taal and Jongen (2021) state that if CIPN complaints are present, drug
treatment options only have an effect on pain relief. According to Scheel et
al. (2014), Beijers et al. (2020) and Taal en Jongen (2021), the only
intervention to reduce CIPN complaints in time is dose reduction or early
discontinuation of the cytostatic treatment. According to Beijers et al.
(2020), treatment adjustments may have a negative effect on the life expactency
of these patients.

The Guideline Diagnosis and Treatment of Pain in Patients with Cancer (NVA,
2019) states that applying cold therapy to hands and feet may have a beneficial
effect on reducing CIPN. Cold causes blood vessels to constrict, so that
cytostatics cannot reach capillaries and thus reach nerves, which could prevent
nerve damage (NVA, 2019). Cold therapy can be applied in various ways,
according to Beijers et al. (2020) the most commonly used form is ice gloves
that patients wear during treatment with taxoid cytostatics. Since 2018, the
medical device Hilotherm (hilotherapy) can also be used, which, as manufacturer
BeMedico (2022) describes, delivers regulated cold through gloves, which
greatly reduces CIPN.

Studies by Coolbrandt et al. (2022) and Oneda et al. (2020) indicated that
hilotherapy is effective in reducing CIPN symptoms in patients treated with
taxoid cytostatics. In the study by Oneda et al. (2020), five patients
developed grade 2 complaints, while in the other 29 patients the CIPN
complaints were limited to grade 1. Coolbrandt et al. (2022) saw 43.6% of the
patients with hilotherapy do develop grade 2 complaints, but that hilotherapy
leads to significantly fewer CIPN grade 2 complaints than when using ice gloves
and slippers.

According to Oneda et al. (2020) and Coolbrandt et al. (2020), continuous
cooling makes hilotherapy more comfortable for the patient than ice gloves and
slippers, resulting in fewer interruptions to the cooling, which increases the
effectiveness of cold therapy through hilotherapy. CIPN is not prevented in
both studies (Oneda et al., 2020; Coolbrandt et al., 2020) with the use of
hilotherapy by paclitaxel or docetaxel treatment, but the symptoms are
significantly reduced.

Coolbrandt et al. (2022) and Oneda et al. (2020) did not have a control group
due to the study design, so the comparison only takes place in the study
population that used hilotherapy. Coolbrandt et al. (2022) concluded a
significant difference in CIPN grade 2, but do not describe whether patients
developed more than CIPN grade 2. This creates uncertainty as to whether
hilotherapy limits CIPN to grade 2, or whether more than grade 2 can develop.
Oneda et al. (2020) concluded limitation to grade 1 CIPN. These results cannot
be fully generalized because patients with three different cancer types and
therefore different doses and number of treatments were included. Oneda et al.
(2020) did also not include patients who prematurely stopped receiving
cytostatics due to CIPN which makes it seem as if no patient developed CIPN
grade 2 complaints after 12 courses.

De Jong et al. (2023) concluded that the GG genotype (rs879207, A>G) of TRPV1
(minor allele frequency G allele = 0.32) was associated with an almost 5-fold
increased risk of developing malignant neuropathy after treatment with
neurotoxic chemotherapy. CIPN grading was measured based on the CTCAE v4.03 for
peripheral sensory neuropathy. De Jong et al. (2023) investigated this
association among 320 patients with lung cancer (NSCLC) treated with
platinum-based therapy whether or not combined with Paclitaxel. De Jong et al.
(2023) recommend further research into the association between the GG genotype
(rs879207) and the development of CIPN in an independent cohort of patients
with different malignancies. In addition to investigating this association, it
may be valuable to gain insight into the effect of hilotherapy on the
development of CIPN in patients with this genotyping with possible consequences
for treatment with hilotherapy in these patients. This study offers a good
opportunity to obtain a first indication of the influence of GG genotype
(rs879207) on the development of CIPN complaints.

Investigate the effect of hilotherapy on the severity of CIPN and nail
toxicity, and its influence on treatment management and quality of life in
patients with breast cancer during, and three and six months after treatment
with Paclitaxel.

Randomized controlled trial with two arms: hilotherapy with the device Hilocare
during all treatments and no hilotherapy or other form of cooling. Follow-up
during therapy and three and six months after the end of therapy consisting of
physical examination and questionnaires.

Hilotherapy is given by using the Hilotherm Chemocare device from BeMedico
(2022). By applying Hilotherapy at 10°C, the hands and feet are continuously
cooled, which locally slows down the metabolism and blood circulation
(BeMedico, 2022).

The Hilotherapy is compared with current standard care; patients with the same
treatment in the control group receive no intervention that could reduce CIPN
or nail toxicity.

There is not much different in this study from normal care. The checks that are
part of this examination take place during the regular visits to the doctor or
nurse practitioner. Only the check-up 6 months after the treatment is an extra
visit to the hospital. This check takes a maximum of 30 minutes. Travel and/or
parking costs for this extra visit will be reimbursed.

The hilotherapy can give a cold feeling in the hands and / or feet when used.
This disappears after each treatment. No damage can occur from the use of
hilotherapy.

Blood collection is not an additional burden or risk since this collection
takes place during a regular collection. Risks of blood collection are minimal;
pain at the puncture site and possible bruising at the puncture site.