Study design
Three-arm prospective randomized controlled trial, as illustrating in Figure 1.
The study followed guidelines for reporting parallel group randomized trials [10], the CONSORT checklist as CONSORT guidelines was checked out (Supplementary File 1).
Participants and setting
We enrolled patients with NPC who were transferred to the radiotherapy Center of Tianjin Medical University Cancer Institute and Hospital of China for initial radiotherapy from September 2020 to September 2021. All patients were inpatients and received IMRT.
Effective rate of moist desquamation incidence is the main outcome measure that we used to calculate the sample size. In a pilot study, 22% patients had moist desquamation in group 1, and 10% patients had it group 3. Therefore, the highest effective rate was 12%. The study was able to detect a 12% reduction in the incidence of moist desquamation. The power was 80% and the degree of significance alpha was 0.05 (one-sided test). To achieve this power, we needed 51 patients in each group. Considering a 10% loss to follow-up, we recruited 56 patients for each group. Before the start of the study, we set 168 as the sample size.
Before the beginning of radiotherapy, 168 patients were randomly divided into three groups: patients did not wash their skin during radiotherapy (group 1), patients washed with water (group 2), and patients washed with water and soap (group 3). The inclusion criteria were as follows: (a) NPC diagnosed with a definitive pathological report; (b) initially received radiotherapy on the head and neck, plans to receive head and neck IMRT treatment with a total prescription dose of more than 60 Gy and a dose fraction of more than 28; (c) age >18 years; and (d) provision of written informed consent. The exclusion criteria were as follows: (a) diabetes or severe illnesses of the heart, liver, kidney, or hematopoietic system; (b) with skin ulceration or other skin diseases in the radiotherapy field; (c) communication disorder or mental illness; and (d) inability to be followed up.
The primary nurse in the ward is responsible for completing and supervising the cleaning methods of patients. There was no chance for patients in 3 different floors to communicate either in wards or in the radiotherapy rooms because their treatment time is assigned into different time intervals.
Intervention
Potentially eligible patients were interviewed during the simulation or before the first treatment by two researchers for enrollment. Eligible patients were randomly allocated before starting radiotherapy by special nurse who only charged for assigning them to interventions. Before recruiting patients, the random allocation sequence was generated by specialist researchers in clinical trail center, who didn't participate the clinical work. The assignment numbers were placed into an opaque envelope only known by him. When a patient consented to participate in the study, the next patient number in chronological order was assigned to her and the corresponding envelope was unsealed, revealing assignment to one of the three groups. Patients were asked not to tell healthcare professionals or other patients which group they belonged to. For technical reasons, cleaning methods could not be blinded to the patients and the interveners. Therefore, only outcome measures were blind.
Patients used various cleaning methods for irradiated skin during radiotherapy: group 1 non-washing irradiated skin, group 2 gentle washing of irradiated skin with warm water (35–40℃) and group 3 gentle washing of irradiated skin with warm water (35–40℃) and mild soap (Dove®), followed by rinsing with water to remove residual soap. Patients in groups 2 and 3 were instructed to wash correctly but were not permitted to shower or bathe. Frequencies of cleaning in groups 2 and 3 were 2 or 3 times a day. The cleaning time should be at least half an hour removed from the radiotherapy time. Towels and Dove® Soap were provided by the researchers. Trained nurses from three different floors completed the intervention for the patients in that floor separately. Supportive Care Guidelines Group (2005) defines “mild” soap as a pH balanced product that does not contain lanolin. The Dove® Soap used in group 3 was low irritant, which was lanolin free and non-alkaline with the mild pH. What’s more, Dove® is the popular brand which is considered mild by the general public and may be used more frequently [6].
General recommendations for all three groups were as follows: (a) remove dentures, earrings, necklaces, and other metal products before radiotherapy to avoid increased radiation absorption; (b) consume a high-protein diet, with daily consumption of more than 2000ml water to reduce a systemic radiation response during radiotherapy; (c) wear loose soft cotton or silk clothing, and do not scratch the radiation field skin; and (d) avoid using deodorant, lotion, cream, perfume, cosmetics; avoid direct sunlight on the radiation field skin; avoid pasting medical dressings and using iodine, alcohol, or other irritating disinfectants; avoid hot or cold stimulation, such as hot compresses and ice pack. The three groups were consistent in the use of skin protectants during radiotherapy.
All patients received IMRT with positioning under the simulator, resting on the head and neck, with a fixed mask and personalized lead blocks. IMRT was utilized to treat primary tumors to the dose of 2.12 Gy/fraction of 70 Gy and all regional lymph nodes were treated with the dose of 1.8 Gy/fraction to 60 Gy simultaneously. The following treatment measures may or may not be provided: (1) Induction chemotherapy: intravenous chemotherapy with TPF regimen before radiotherapy, docetaxel 80 mg/m2 on day 1, cisplatin 80 mg/m2 from days 1 to 3, and tegafur 1000 mg from days 2 to 6. There were two or three cycles before radiotherapy; (2) Concurrent chemotherapy with cisplatin: intravenous chemotherapy was performed on the first day of radiotherapy, and cisplatin was used as a single-drug chemotherapy at 80 mg/m2, on days 1, 22, and 43; or (3) Synchronous targeting therapy: intravenous targeting therapy with nituzumab 200 mg once per week during radiotherapy.
Measures
The main outcomes were the incidence of acute RD and moist desquamation, the secondary outcomes were the severity of subjective symptoms (pain, burning, itching) and QOL. RD and moist desquamation was scored by two principal authors according to the Chinese version [11] of the RTOG acute toxicity scale in the radiotherapy oncology group [12]. Two lead authors accountable for results evaluation were trained by the enterostomy therapist (ET) who had been certified internationally. When physicians did not agree on RD grade or whether moist desquamation occured, ruling by ET. RD and moist desquamation were assessed every day from the beginning of radiotherapy to 1 month after the completion of radiotherapy.
Because moist desquamation worsens quality of life (QOL), this was recorded separately. Before starting treatment, we used a questionnaire to record socio-demographic data. We recorded scores of pain, itching and burning using patient-reported outcome software every day, and we measured symptoms using a visual analogue scale (VAS). VAS is the international commonly used scale in pain or other subjective feelings, which reliability has been confirmed in China [13]. We used the maximal score of the symptoms to compare among three groups.
QOL was assessed at three time points for the Chinese version of EORTC QOL-C30 (V3.0) as an instrument at the beginning, the end and 1 month after the completion of radiotherapy. EORTC QOL-C30 is a cross-cultural quality of life measurement tool for cancer patients, which the Chinese version has been verified to have good reliability (Cronbach’s alpha≥0.70) and validity (r>0.81) [14].
Socio-demographic data was computed with the use of a questionnaire before the beginning of treatment. Other data from this study included the type of cleaning, the frequency of cleaning, characteristics related to tumors and previous treatments, radiation techniques, treatment interruptions and adjuvant treatments. If we did not see a patient during the follow-up, they would receive a questionnaire by email or written form by express delivery, and were required to replay photos of the irradiated skin through e-mail transmission.
Statistical analysis
The chi-squared test was used to compare the frequency of RTOG acute toxicity severity in each group, as well as other categorical variables. We calculated differences in measured data (age, BMI, and patient-reported outcome symptom score) using analysis of variance. We set the significance level of P<0.05. All P values were two-tailed.