Photobiomodulation in the treatment of palmar–plantar erythrodysesthesia: a randomised controlled clinical study protocol

Abstract

Introduction

Hand–foot syndrome, also known as palmar–plantar erythrodysesthesia (PPE), is a complication caused by chemotherapy. Clinically, it manifests as erythema and oedema on the palms of the hands and feet, dry and scaly skin, accompanied by a sensation of tightness and pain. Extreme cases have blisters and ulcerations that may require hospitalisation and/or pause in cancer treatment. It can also be accompanied by paraesthesia. Considering the characteristics, photobiomodulation (PBM) may reduce the PPE effects. The objective of this protocol will be to evaluate the efficacy of PBM in reducing PPE induced by capecitabine and 5-fluorouracil chemotherapy.

Methods and analysis

This will be a randomised controlled, double-blind, double-centre clinical trial (Centro Asistencial del Sindicato Médico del Uruguay and Instituto Nacional del Cáncer from Uruguay). The sample population (40 individuals) will be divided into two groups: group 1 will receive moisturising cream plus PBM treatment and group 2 moisturising cream plus PBM sham treatment, at the ratio of 1:1. PBM will be performed at 630 nm two times per week in palmoplantar areas of the hands and feet (4 J/cm²), for 4 weeks. The PPE degree and the data referring to the chemotherapy treatment plan will be measured, prior to the start of treatment in the middle and at the end of it. Quality of life questionnaires will be applied at the beginning of the trial and at the end of treatment. The data will be analysed based on the intention-to-treat analysis and α<0.05 will be considered statistically significant.

Ethics and dissemination

The protocol was approved by the Research Ethics Committee of Universidad Católica del Uruguay (220316b), of Centro Asistencial del Sindicato Médico del Uruguay (221989) and of Instituto Nacional del Cáncer (2023-04). The recruitment has already started (March 2023). Protocol version: V.2, 27 October 2023.

Trial registration number

ClinicalTrials.gov Registry (NCT05337423).

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Clinical outcomes with strong relevance to patients.

• Methodological design to reduce bias (blinding of assessors, patients and statisticians, randomisation, concealed allocation, intention-to-treat analysis).

• This is the first intervention clinical trial done in Uruguay for hand–foot syndrome with photobiomodulation.

• Control group will be treated with topical cream, although evidence is still weak for this intervention.

• Poor tolerance or symptoms caused by chemotherapy may reduce patient attendance to the study sessions.

Introduction

Hand–foot syndrome, also known as acral erythema or palmar–plantar erythrodysesthesia (PPE), is one of the cytotoxic complications caused by chemotherapy.¹ Clinical symptoms encompass redness and swelling in the palms of the hands and soles of the feet, along with dry, scaly skin, accompanied by a sensation of tightness and pain. These symptoms tend to manifest upon repeated exposure to the chemotherapeutic agents and subsequently abate with treatment interruption.^{2 3}

The estimated incidence of PPE varies widely, ranging from 6% to 64% among patients undergoing chemotherapy.³ The PPE incidence hinges on various factors, including the specific chemotherapeutic agent administered, the method of drug administration, the treatment regimen and the duration of treatment. Notably, several chemotherapy agents are associated with the development of PPE, with the most frequently implicated ones being antimetabolites such as 5-fluorouracil (5-FU) and capecitabine, anthracyclines like doxorubicin, taxanes including docetaxel, and alkylating agents like cyclophosphamide and temozolomide.^2–6

In the context of a comprehensive treatment approach, four fundamental pillars have been proposed: prevention, patient education, symptom alleviation and dose management.⁷ Strategies for symptom relief encompass the oral administration of pyridoxine (vitamin B₆),^7–9 local ice application and prophylactic use of moisturising cream.^10–13 Additionally, other therapeutic modalities that have been investigated include the use of antiperspirants, topical steroids and aloe vera topical products.^{4 11 14} Given the demonstrated benefits of photobiomodulation (PBM) in the management of radiation-induced dermatitis ^{15 16} and chemotherapy-induced mucositis,^17–19 it is plausible to hypothesise that PBM may similarly mitigate PPE,²⁰ as both conditions share certain pathophysiological characteristics related to the cytotoxicity induced by oncological treatments.

PBM employs coherent and non-coherent monochromatic light within the optical range of 600–1000 nm to treat tissues in a non-destructive and non-thermal manner.^{17 21 22} Its mechanism of action is grounded in the absorption of light by cytochrome c oxidase (CCO) in the mitochondria.^23–27 Interaction of red and infrared light with the CCO chromophore enhances available energy, thereby elevating mitochondrial activity to generate ATP.²⁸ Moreover, PBM is known to modulate various substances involved in nociceptive conduction and inflammation, including prostaglandins, kinins, serotonin, histamine, cytokines, neuropeptides, reactive oxygen species and ATP.^{27 29–35} Based on a mucositis protocol, Latifyan et al ²⁰ performed a hemi-body pilot study and demonstrated beneficial effects of PBM compared with sham treatment in PPE, resulting in pain reduction in 49% of patients treated with PBM. Nonetheless, the study presented some limitations.

First, PBM has been known to elicit systemic effects, implying that local application of PBM may induce effects in various body areas, also referred to as remote PBM or indirect PBM.^36–38 Therefore, employing the hemi-body design, the side treated with sham intervention may also reflect the action of PBM. We will use different patients to sham and PBM treatment. Furthermore, the study encompassed a diverse range of neoplasms and chemotherapy drug types, resulting in a heterogeneous sample. Here, we will include only patients with gastrointestinal and breast cancer, treating with capecitabine or 5-FU.

Moreover, a majority of the patients presented with metastatic cancer. Considering the stimulatory effects of PBM and the potential presence of cancer cells in the bloodstream of patients with metastatic cancer, PBM usage could potentially stimulate cancer cell proliferation. In this context, our study’s inclusion criteria specified adjuvant chemotherapy, indicating that the tumour had been surgically removed prior to treatment.

Considering the PBM treatment regimen and dose, the authors used 2 weeks’ treatment three times a week and a radiant exposure of 2 J/cm² but suggested further exploration of higher doses, such as 4 J/cm², which supported the choice of dosimetry for this study. Here, we used 4 J/cm² and only two times per week considering patients’ health status during chemotherapy.

Regarding the significance of this topic and the PPE impact on the quality of life of individuals undergoing oncological treatment, particularly in cases involving capecitabine and 5-FU, coupled with the promising data related to PBM, we propose an interventional trial whose objective is to assess the efficacy of PBM in managing this complication evaluating the degree of PPE, the frequency of interruption of chemotherapy due to the PPE symptoms, pain and quality of life of the patient. Furthermore, the high incidence of colorectal tumours in Uruguay, both in females and males, necessitating treatment with these drugs, underscores the relevance of this study, considering the potential benefits it may offer to a substantial number of individuals if its efficacy is established.

Methods and analysis

Study design

This study will be a two-arm, double-centre, double-blind, randomised controlled clinical trial with 1:1 allocation. The study will be carried out in patients undergoing chemotherapy treatment with oral capecitabine or continuous infusion of 5-FU at the National Cancer Institute (NCI) and at Centro Asistencial del Sindicato Médico del Uruguay (CASMU), in Montevideo, Uruguay, both hospitalised or using these drugs on an outpatient basis.

Patients presenting with the symptoms of PPE will be invited to participate in the research. In addition, the institutions’ oncologists are aware of the study and have an information brochure about the clinical trial as support material. They may invite potential candidates to contact the principal investigator who will present the study to potential participants, present the informed consent form and provide the opportunity for the participant asking questions. Only patients who, after this step, agree to participate and sign the consent term will be part of the study. It will be checked whether the patients meet the inclusion and exclusion criteria prior to sign the informed consent. The study is expected to last up to 24 months starting at recruitment date (March 2023). The screening will continue until the sample size is achieved. If the desired sample is not reached, the study will continue until a significant sample is achieved and the results can be published. The protocol was written based on the Standard Protocol Items: Recommendations for Interventional Trials guidelines.

Eligibility criteria

Patients older than 18 years, carriers of oncological pathology (confirmed by anatomopathological diagnosis), undergoing treatment with adjuvant chemotherapy (oral capecitabine and 5-FU in continuous infusion), who develop PPE major or equal to 1 on the NCI Common Toxicity Criteria Version 5.0, 2017 (CTC NCI V.5.0), or on WHO Hand–Foot Syndrome Scale³⁹ or on Wasif Saif and Elfiky Scale.⁴⁰

The chemotherapy regimens for adjuvant treatment for gastrointestinal cancer include four options: Patients could receive combined treatment based on the XELOX and FOLFOX plan, as well as treatments with single-agent fluoropyrimidines, either 5-FU or capecitabine alone. In the XELOX plan, patients receive oxaliplatin at a dose of 130 mg/m² on day 1, followed by capecitabine at a dose of 2000 mg/m² administered from day 1 to day 14. This cycle is repeated every 21 days. The FOLFOX plan offers two different regimens. In the first option, known as FOLFOX6m, patients are given 5-FU at a dose of 400 mg/m² intravenously push on day 1, followed by a continuous infusion of 5-FU at a dose of 1200 mg/m² on day 1 and day 2 (totalling 2400 mg/m² in 46–48 hours). Additionally, leucovorin is administered at a dose of 400 mg/m² intravenously and oxaliplatin at a dose of 85 mg/m² intravenously, both on day 1. This regimen is repeated every 15 days. Alternatively, in the FOLFOX4 option, patients receive 5-FU at a dose of 400 mg/m² intravenously push on both day 1 and day 2. They also receive a continuous infusion of 5-FU at a dose of 600 mg/m² for 22 hours on day 1 and day 2 (totalling 1200 mg/m² over 46 hours). Leucovorin is administered at a dose of 200 mg/m² intravenously on both day 1 and day 2, and oxaliplatin at a dose of 85 mg/m² intravenously on day 1. This regimen is repeated every 15 days. The single-agent capecitabine plan consists of a dose of 1000 to 1250 mg/m2 twice a day for 14 days (day 1 to day 14), and when using single-agent 5-FU, a dose of 400 mg/m2 IV push followed by Fluorouracil: 2400 mg/m2 in 46 hours in continuous infusion. Leucovorin is administered at a dose of 400 mg/m2 intravenously (IV) over two hours. This regimen is repeated every 14 days.

For adjuvant treatment of breast cancer, patients have two options. They can receive capecitabine at a dose of 2500 mg/m² from day 1 to day 14, with the cycle repeated every 21 days. Alternatively, they can take capecitabine at a dose of 1650 mg/m² orally from day 1 to day 14, along with concomitant radiotherapy.

The clinicians administer these drugs as part of the hospital’s daily routine, prior to patients exhibiting PPE symptoms and being invited to this trial. The doctors are unaware of the specific treatment group to which each patient will be assigned in the trial.

Patients with skin comorbidities with palmar–plantar involvement, autoimmune comorbidities, amputated limbs, systemic infection, localised or regional infection of limbs, respiratory isolation, contact isolation and patients with insulin-requiring diabetes will be excluded from this trial.

Sample calculation

The calculation of the sample size was carried out with the statistical software G-Power V.3.1 (Universitat Kiel, Germany) applying the Χ² homogeneity test. Identical sample sizes were considered for the PBM group and the sham group with an efficiency of the PBM treatment equal to 57% and a placebo treatment efficiency of 25%, as estimated before.²⁰ The percentage of type 1 error was set at 5% and the statistical power at 80%, obtaining n=40 considering 10% losses.

Randomisation

Randomisation will be performed by an investigator not directly involved in the treatment of patients. The randomisation will be done using the website http://www.randomization.com, making blocks of fixed size to maintain a balance between the participants of the different groups. The block sizes will not be disclosed, to ensure concealment. The numbered opaque and sealed envelopes (each patient will be identified with a number) will contain the information on whether the treatment is real or sham following the randomisation generated. These envelopes will be kept safe and will not be seen by the outcome investigator. Before the treatment, the operator responsible for applying the therapy will receive the envelope, and open it to know which treatment is indicated to each patient.

Blinding

Patients and outcome evaluators will be blinded after assignment interventions. All patients will wear eye protection during the application of PBM. Additionally, a recorded sound signal will be used to ensure that the patient remains unaware of whether the equipment is actively delivering treatment or undergoing sham application. Only the operator responsible for administering the PBM therapy will be aware of whether the patient is receiving active or sham treatment. The assessor responsible for evaluating the outcome measures will not be present during the application of treatment.

Unblinding will be allowed only in exceptional circumstances when knowledge of the actual treatment is absolutely essential for further management of the patient. In this case, the operator responsible for applying the therapy will provide the allocation information for the medical doctor responsible for patient cancer treatment.

Intervention

The study population will be divided into two groups—group 1: cream provided by institution and PBM treatment and group 2: cream provided by institution+sham PBM treatment.

For the application of PBM, the light-emitting diode (LED) cluster containing five LEDs at 250 mW in an area of 20 cm² will be used (Antares, Ibramed, Brazil). The cluster contains both 630 and 850 nm; however, only the 630 nm will be delivered. The treatment will be performed two times per week in palmoplantar areas of the hands and feet (4 J/cm²) for 4 weeks (table 1). Taking into account that the cluster has an area of 20 cm², it is estimated that it should be applied at least twice in each zone (one that covers the area of the fingers and another that covers the palms and soles—figure 1). The sham treatment at group 2 is a simulation treatment that will be applied in the same way of the active treatment (for the same time and frequency as the interventional treatment), but the equipment will be turned off. For both groups, the patient’s eyes will be covered with goggles; therefore, they will not know if they are receiving active or sham treatment. At the sham treatment, there will only be a recorded audible signal to blind the patient.

Table 1.

Dosimetry for the study

Parameter	Amber LED
Central wavelength (nm)	630
Spectral width (nm)	20
Operation mode	Continuous
Average radiant power (one LED) (mW)	250
Power density at aperture (mW/cm2)	62.5
Total number of LEDs	5
Irradiated area per application (cm2)	20
Irradiance at the target (mW/cm2)	62.5
Exposure duration (s)	64
Radiant exposure (J/cm2)	4
Energy density at aperture (J/cm2)	4
Radiant energy per application (J)	80
Application technique	2–3 repetitions per member*, on the skin surface
Number and frequency of sessions	2×/week, 4×/month, 8 sessions

*Application on the skin of both hands and feet.

LED, light-emitting diode.

Figure 1.

Photobiomodulation application. (A) Cluster P2—Antares Ibramed (Brazil) with four 850 nm light-emitting diodes (LEDs) and five 630 nm LEDs. (B,C) Application on the participant’s hand (two to three times to cover each hand area). (D–F) Application on the participant’s foot (two to three times to cover each feet area).

As for the standard moisturising treatment application, it will be suggested that the patient apply the moisturising cream with an amount that covers the entire surface of palms and soles (an amount that is approximately 3 cm in diameter once placed on palms or soles, prior to spreading it). Cream application will be according to the patient’s needs.

Discomfort when applying PBM is rare. Regarding the application of the cream, it is not expected that there will be an interruption of treatment due to discomfort. Considering unexpected effects, they will be reported as an adverse event of the study. In these cases, the patient will not be removed from the study. The only condition to be withdrawn from the study would be if the patient wishes to abandon it.

Outcomes

The main outcome of the study will be PPE grade determined by the CTC NCI Toxicity Scale, the WHO Hand–Foot Syndrome Scale, as they may differ in symptoms assessment, and the Wasif Saif and Elfiky Scale.⁴ PPE grade will be compared within group (before and after treatment) and success of the treatment will be considered the reduction of the grade. The efficacy of the treatment will be determined by the comparison of the rate of success between groups.

The secondary variables of the study include: total dose of chemotherapy received in milligrams, need to interrupt chemotherapy treatment, need to reduce the dose of chemotherapy treatment (that will be obtained from the clinical history), score on the quality of life scale according to the Spanish translation (without validation) of the HFS-14 Questionnaire (quality of life scale developed for patients suffering from hand–foot syndrome)⁴¹ and the Dermatology Life Quality Index (DLQI) in its validated translation into Uruguayan Spanish,⁴² as well as pain, variable that will be assessed on a Visual Analogue Scale that goes from ‘no pain’ to ‘maximum pain’ in the HFS-14 Questionnaire. This scale consists of a straight line with endpoints that define extreme limits such as ‘no pain at all—0’ and ‘maximum pain—10’. The patient will be asked to mark the level of pain on the line between the two extremes. The distance between ‘no pain at all’ and ‘maximum pain’ is the mark that then defines the subject’s pain. Also, it will include assessment of peripheral neuropathy, due to the neurotoxicity caused by some chemotherapeutic drugs (such as the one included in the XELOX regimen). This assessment will be through the WHO and Eastern Cooperative Oncology Group Scales.⁴³

During the course of the investigation, a ‘diary’ for the patient’s personal use will also be included, where it will be suggested that the patient make a daily record of all the signs or symptoms that he has during the treatment. So, the appearance and intensity of symptoms will be registered, if any product was applied (either the recommended one or any other), and if before the appearance, any activity that involves the use of the palms of the hands and soles of the feet was carried out. Additionally, corticosteroids may be indicated by the medical doctor as an adjunct to pain as well as analgesics. In these cases, patients will report medication use at this diary. To ensure patient adherence to the treatment, telephone contact will be performed, to confirm the scheduled visits and/or reschedule when needed. As strategies to enrol/improve adherence and retention of patients in the study, they will be offered free care services at the University Clinic of the Universidad Católica del Uruguay.

The PPE degree variables and the data referring to the chemotherapy treatment plan will be measured and recorded by the responsible investigator, prior to starting the treatment with PBM, in the middle of the treatment and at the end of it. There will be a follow-up 1 month after the end of the treatment using a questionnaire designed by the researchers where we evaluate parameters in hands and feet such as: pain, discomfort, difficulties in carrying out activities of daily living or instrumental activities, difficulties in working or studying. We also evaluate whether in the last month, they applied any product or performed any task that could affect the skin on their hands and feet. The quality of life questionnaires (HFS-14 and DLQI) will be applied prior to starting treatment with PBM and at the end of treatment (figure 2).

Figure 2.

Standard Protocol Items: Recommendations for Interventional Trials figure. CTC NCI v5.0, National Cancer Institute Common Toxicity Criteria Version 5.0; DLQI, Dermatology Life Quality Index; HFS, hand–foot syndrome; HFS-14, Quality of Life Scale developed for patients suffering from HFS; PBM, photobiomodulation; Sham, placebo.

The patients involved in the study will be asked for authorisation to take photos of their PPE, with prior signing of informed consent. Any modification of the protocol, regarding eligibility criteria and outcomes will be performed after amendment to the Research Ethics Committee. Additionally, the trial registration will be modified and the manuscript presenting the final data will also describe all the modifications from this protocol. Auditing of the trial will be performed by the supervisor of the research, both visiting on-site or electronically, monitoring trial dataset and procedures.

Data analysis plan

The data will be manually collected and the documents will be stored safely at the institution in a place locked all the time during treatment. After finishing the data collection, documents will be stored safely at the university in a locked place with only access by the main researcher. Double-entry will be performed in an Excel sheet, electronically stored at a cloud, accessed by the main researcher and management researcher by password. Along with the main file, a document presenting the variable coding will be also stored. Standard coding will be used when available. The files will be kept for 10 years after study completion.

The analysis will follow the intention-to-treat principle. The Kolmogorov-Smirnov test will be used to assess the normality of the data. Parametric data will be presented as mean and SD. Non-parametric data will be presented as median and IQR. Categorical data will be presented as frequency (absolute and relative). The main study variable is the degree of toxicity of PPE. The PPE grade will be compared within group (before and after treatment) and success will be considered the reduction of the grade. The rate of success (absolute frequencies) will be compared between groups (sham and PBM) to evaluate the efficacy by the χ² test. A subgroup analysis regarding the baseline severity of PPE will be performed. The scores of the questionnaires will be compared using the Wilcoxon test. Categorical data will be analysed using χ². The statistical analysis will be performed using the SPSS Statistics software, V.25. The significance level of 0.05 will be adopted.

Since this study is related to a PhD thesis, interim analysis will be performed during the main student evaluation steps. The study may continue after defence in case the sample size is not reached. Only the data regarding patients who finished the treatment will be analysed and the main investigator will be the only one unblinded at this phase. The main investigator and the supervisor, along with the formal committee, will decide together in case of stopping or modifying the trial.

Patient and public involvement

None.

Ethics and dissemination

The study will be carried out following the Ethical Guidelines of the Declaration of Helsinki of the year 2000 and within the framework of Law Decree No. 158/019 for research with human beings.⁴⁴ The study will also be governed by Law 18 331 (Law on Protection of Personal Data and Action of ‘Habeas Data’). The protocol was approved by the Research Ethics Committee of Universidad Católica del Uruguay (220316b), Research Ethics Committee of CASMU (221989) and Research Ethics Committee of Instituto Nacional del Cáncer (2023-04). The study was registered at ClinicalTrials.gov (NCT05337423; first registered on 4 April 2022, updated in October 2023).

The results obtained in this trial will be presented at conferences, as well as published after finishing the trial, and the participants will receive an email, with the main findings of the study. Only the ones who performed substantive contributions to the design, conduction and reporting of this trial will be included as authors of the final manuscript.

Trial status

The recruitment started in March 2023. We are planning to finish recruiting by November 2024 and complete the study by December 2024.

Discussion

PBM has been studied as an important strategy to manage cancer therapy-related complications. The most frequent complications in oncology patients who receive treatment of radiation therapy or chemotherapy are: acute oral mucositis, xerostomia, dysphagia, radiation dermatitis, lymphoedema, dysgeusia, trismus, bone necrosis, voice and speech alterations, palmar–plantar erythrodysesthesia, graft versus host disease, peripheral neuropathy, radiation-induced fibrosis and chemotherapy-induced alopecia, among others.

There is already considerable evidence reporting the efficacy of PBM in the treatment of oral mucositis in patients receiving radiotherapy, chemotherapy or haematopoietic transplantation.^{15 18} For other complications, the World Association for Photobiomodulation Therapy (WALT)¹⁵ recommends different protocols of treatments based on recent progress in comprehending how PBM works and dosage exploration in addressing a wider array of issues linked to cancer treatment, including the management of the various complications. This therapy would improve quality of life, patient adherence to treatment and cost reduction in assistance.¹⁹

Evidence regarding beneficial effects of PBM in hand–foot syndrome is still weak. It is important to mention that PBM is a non-invasive treatment, well tolerated by patients. The study by Latifyan et al is the first randomised, split-body, double-blind clinical trial on this topic and showed significant improvement in patients treated with PBM in comparison with placebo treatment as determined by a blind assessor, and decrease of pain in more than 40% of the patients was also noticed.¹⁵ Although the protocol used the frequency of three times a week for 2 weeks, in this study, two times per week for 4 weeks was used since we believe it is hard for patients to attend high-frequency sessions per week, considering their health status during chemotherapy.

The protocol developed here was based on WALT recommendations¹⁵ and also the work published before²⁰ which used 2 J/cm² with red PBM based on usual dosimetry for the treatment of oral mucositis. At this work,²⁰ the authors mentioned 4 J/cm² was recommended for radiodermatitis; therefore, when treating skin in this study, it was decided to administer higher radiant exposure taking these references into consideration.

Usually, treatment of PPE consists of discontinuation of chemotherapy and symptomatic treatment. Symptom management includes wound care, pain medication and/or the application of topical alcohol-free (anti-inflammatory) emollients.⁴⁵ In this sense, at this protocol, both treatments (PBM and sham) were associated with the use of emollient/moisturising cream. We believe that although the evidence is weak to make this recommendation, it is a treatment that is recommended by experts in clinical practice without adding toxicity or complications.

As weaknesses of the study, we find the fact that patients must attend the hospital for treatment, which sometimes represents a strong difficulty for patients, especially considering that they often have other symptoms related to treatment such as nausea, vomiting and asthenia, which make assistance difficult for them. Additionally, severe cases may exhibit poorer response to treatment compared with moderate and mild cases and it may be considered a limitation of this study. We intend to conduct subgroup analysis to elucidate this aspect further.

Also, the deficiency of dihydropyrimidine dehydrogenase (DPD), an enzyme which catalyses chemotherapy, whose activity can be measured by the DPYD gene test, may be the cause of toxicity when receiving fluoropyrimidine chemotherapy (5-FU or oral prodrugs). Testing the deficiency of this gene prior to the administration of chemotherapy allows dose adjustments to be made to prevent severe toxicity.⁴⁶ We do not have data on the incidence of DPD deficiency in Uruguay (which has an ethnicity mainly of European descent), but a low incidence is estimated in the Caucasian population of no more than 5% with partial deficiency of the gene and only 0.02% have total deficiency.^{47 48} In Uruguay, this study is not done routinely, so we consider it a limitation in our clinical trial.

Another weakness that should be considered is the absence of validation of the Spanish version of the HFS-14 Questionnaire. An exhaustive search has been done; however, there was no Spanish version of the HFS-14 Questionnaire or others focused on patients with PPE. Therefore, it was decided to translate it into Spanish with a public translator. Furthermore, for greater security and veracity of the data, we have included the DLQI (in its Spanish-validated version) to assess quality of life in patients with dermatological conditions. Although it is not specific for hand–foot syndrome, we can apply it to have a record and evaluation of quality of life in skin injury. The DLQI evaluates the quality of life in dermatology, in the last 7 days, where the patient rates their symptoms in each of the 10 questions presented.

Among the advantages that we found in the study is its clinical relevance. As we mentioned previously, PPE is a common adverse effect of chemotherapy and to date, there is not enough evidence to recommend a standard therapy for this complication that affects the quality of life of patients, leading in many cases to discontinue treatment. Hand–foot syndrome is a very common adverse effect of 5-FU and capecitabine, which are chemotherapy drugs active in several tumours, mainly colon cancer, which is the third most common cancer in the world. Chemotherapy discontinuation may affect cancer treatment evolution. Therefore, the impact of this work is very important if we take into account the number of patients who can benefit from this therapy.

This clinical trial for the treatment of hand–foot syndrome using low-level laser therapy (630 nm) is expected to contribute to improving the quality of life of patients with cancer, in addition to improving adherence to the indicated treatment and being a non-invasive treatment. This is work within the supportive care field, with PPE being a toxicity of oncological treatment that has not yet been investigated. We believe that this study will contribute to the scientific community as well as the advantages already mentioned in relation to the treatment and prognosis of the patient by potentially contributing to avoiding the interruption of the indicated plan. At the end of the study, after the data have been analysed, if PBM shows to be effective, patients who receive sham treatment during the study will be informed and will be able to receive PBM treatment on their hands and feet if their symptoms persist.

Ethics statements

Patient consent for publication

Not applicable.