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Reduction in severity of radiation-induced dermatitis in head and neck cancer patients treated with topical aloe vera gel: A randomized multicenter double-blind placebo-controlled trial

Open AccessPublished:June 16, 2022DOI:https://doi.org/10.1016/j.ejon.2022.102164

      Highlights

      • Acute dermatitis is a common side effect in the head and neck cancer patients receiving concurrent chemoradiation.
      • Standard skin care is recommend from the beginning of the radiotherapy course until the skin has completely recovery.
      • Aloe vera gel reduced the severity of radiation dermatitis in head and neck cancer patients treated with chemoradiation.

      Abstract

      Purpose

      To assess the efficacy of topical aloe vera gel on radiation induced dermatitis (RID) in head and neck cancer (HNC) patients.

      Method

      In this multicenter randomized double-blind controlled study, HNC patients treated with concurrent chemoradiation (CCRT) received either aloe vera gel or placebo gel. Adverse skin toxicity levels were evaluated with the radiation-induced skin reaction assessment scale (RISRAS).

      Results

      One hundred-twenty patients were enrolled in this study. Analysis of the baseline characteristics did not reveal any differences between the groups. The median RISRAS values from the 1st to the 8th week of the CCRT course were not statistically different between the two groups. In the 5th and 6th weeks of treatment, moderate to severe grades of skin erythematous were observed at values of 13.6% and 24.1% versus 27.8 and 42.6% for members of the aloe vera gel group and the placebo group, respectively (p = 0.05 for the 5th week and p = 0.038 for the 6th week). In the 7th week, moderate to severe instances of moist desquamation were observed in eight patients (19.0%) in the placebo group (p = 0.001). Subjects experienced a burning sensation with RISRAS scores of 3–4 in the 7th week representing only 11.9% of patients in the placebo group (p = 0.016).

      Conclusion

      Topical applications of aloe vera gel significantly reduced moderate to severe grades of skin erythematous and instances of moist desquamation in HNC patients receiving CCRT. In this study, there was no prophylactic efficacy for RID in the aloe vera gel group when compared to the placebo group.

      Keywords

      1. Introduction

      Head and neck cancer (HNC) is a commonly diagnosed form of cancer in Thailand. In 2018, the National Tumor Registration reported 5123 new cases of HNC in the country (
      • Imsamran W.
      • Pattatang A.
      • Supaattagorn P.
      • Chiawiriyabunya I.
      • Namthaisong K.
      • Wongsena M.
      • Puttawibul P.
      • Chitapanarux I.
      • Suwanrungruang K.
      • Sangrajrang S.
      • Buasom R.
      National Cancer Institute Thailand
      ). In terms of treatment modalities for locally advanced stages of HNC, concurrent chemoradiation (CCRT) has exhibited advantages that have led to improved treatment results and survival rates (
      • Pignon J.P.
      • le Maître A.
      • Maillard E.
      • Bourhis J.
      MACH-NC Collaborative Group
      Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients.
      ,
      • Lacas B.
      • Carmel A.
      • Landais C.
      • Wong S.J.
      • Licitra L.
      • Tobias J.S.
      • Burtness B.
      • Ghi M.G.
      • Cohen E.
      • Grau C.
      • Wolf G.
      • Hitt R.
      • Corvò R.
      • Budach V.
      • Kumar S.
      • Laskar S.G.
      • Mazeron J.J.
      • Zhong L.P.
      • Dobrowsky W.
      • Ghadjar P.
      • Fallai C.
      • Zakotnik B.
      • Sharma A.
      • Bensadoun R.J.
      • Ruo Redda M.G.
      • Racadot S.
      • Fountzilas G.
      • Brizel D.
      • Rovea P.
      • Argiris A.
      • Nagy Z.T.
      • Lee J.W.
      • Fortpied C.
      • Harris J.
      • Bourhis J.
      • Aupérin A.
      • Blanchard P.
      • Pignon J.P.
      MACH-NC Collaborative Group
      Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group. Radiotherapy and oncology.
      ). Radiation induced dermatitis (RID) is a common cause of radiation related toxicity. Almost 95 percent of patients who had received radiotherapy experienced RID (
      • Archambeau J.O.
      • Pezner R.
      • Wasserman T.
      Pathophysiology of irradiated skin and breast.
      ;
      • Hickok J.T.
      • Morrow G.R.
      • Roscoe J.A.
      • Mustian K.
      • Okunieff P.
      Occurrence, severity, and longitudinal course of twelve common symptoms in 1129 consecutive patients during radiotherapy for cancer.
      ;
      • Salvo N.
      • Barnes E.
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      • Stacey E.
      • Mitera G.
      • Breen D.
      • Giotis A.
      • Czarnota G.
      • Pang J.
      • De Angelis C.
      Prophylaxis and management of acute radiation-induced skin reactions: a systematic review of the literature.
      ). Patients who suffered from radiation dermatitis were known to develop an erythematous skin reaction that caused sensations of itching and burning. The skin of these patients would be severely damaged to the stage of desquamation and/or necrosis (
      • Cox J.D.
      • Stetz J.
      • Pajak T.F.
      Toxicity criteria of the radiation therapy oncology group (RTOG) and the European organization for research and treatment of cancer (EORTC).
      ;
      • Denham J.W.
      • Hauer-Jensen M.
      The radiotherapeutic injury--a complex ’wound.
      ;
      • Hegedus F.
      • Mathew L.M.
      • Schwartz R.A.
      Radiation dermatitis: an overview.
      ). Due to the existence of a wide variety of radiation treatment protocols, the volume of radiation fields and chemotherapy regimens may yield different results with regard to the severity of RID. Furthermore, as a radiosensitizer, chemotherapy would likely deliver greater radiation doses to normal organs (
      • Kasibhatla M.
      • Kirkpatrick J.P.
      • Brizel D.M.
      How much radiation is the chemotherapy worth in advanced head and neck cancer?.
      ;
      • Hartley A.
      • Sanghera P.
      • Glaholm J.
      • Mehanna H.
      • McConkey C.
      • Fowler J.
      Radiobiological modelling of the therapeutic ratio for the addition of synchronous chemotherapy to radiotherapy in locally advanced squamous cell carcinoma of the head and neck.
      ). These increased doses have resulted in a greater degree of frequency for both non-hematologic and hematologic toxicity levels in HNC patients who had received CCRT when compared to those who had received radiotherapy alone. Although CCRT has been associated with higher severe grades of acute oral mucositis, esophagitis, and certain hematologic side effects when compared to radiotherapy alone, no significant increases were observed in severe grades of RID (
      • Bernier J.
      • Domenge C.
      • Ozsahin M.
      • Matuszewska K.
      • Lefèbvre J.L.
      • Greiner R.H.
      • Giralt J.
      • Maingon P.
      • Rolland F.
      • Bolla M.
      • Cognetti F.
      • Bourhis J.
      • Kirkpatrick A.
      • van Glabbeke M.
      European Organization for Research and Treatment of Cancer Trial 22931
      Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer.
      ;
      • Cooper J.S.
      • Pajak T.F.
      • Forastiere A.A.
      • Jacobs J.
      • Campbell B.H.
      • Saxman S.B.
      • Kish J.A.
      • Kim H.E.
      • Cmelak A.J.
      • Rotman M.
      • Machtay M.
      • Ensley J.F.
      • Chao K.S.
      • Schultz C.J.
      • Lee N.
      • Fu K.K.
      Radiation Therapy Oncology Group 9501/Intergroup
      Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.
      ;
      • Fountzilas G.
      • Ciuleanu E.
      • Dafni U.
      • Plataniotis G.
      • Kalogera-Fountzila A.
      • Samantas E.
      • Athanassiou E.
      • Tzitzikas J.
      • Ciuleanu T.
      • Nikolaou A.
      • Pantelakos P.
      • Zaraboukas T.
      • Zamboglou N.
      • Daniilidis J.
      • Ghilezan N.
      Concomitant radiochemotherapy vs radiotherapy alone in patients with head and neck cancer: a Hellenic Cooperative Oncology Group Phase III Study.
      ;
      • Salama J.K.
      • Seiwert T.Y.
      • Vokes E.E.
      Chemoradiotherapy for locally advanced head and neck cancer.
      ;
      • Pignon J.P.
      • le Maître A.
      • Maillard E.
      • Bourhis J.
      MACH-NC Collaborative Group
      Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients.
      ;
      • Ghosh-Laskar S.
      • Kalyani N.
      • Gupta T.
      • Budrukkar A.
      • Murthy V.
      • Sengar M.
      • Chaukar D.
      • Pai P.
      • Chaturvedi P.
      • D'Cruz A.
      • Agarwal J.
      Conventional radiotherapy versus concurrent chemoradiotherapy versus accelerated radiotherapy in locoregionally advanced carcinoma of head and neck: results of a prospective randomized trial.
      ).
      The Supportive Care Guideline Group (SCGG) (
      • Bolderston A.
      • Lloyd N.S.
      • Wong R.K.
      • Holden L.
      • Robb-Blenderman L.
      Supportive Care Guidelines Group of Cancer Care Ontario Program in Evidence-Based Care
      The prevention and management of acute skin reactions related to radiation therapy: a systematic review and practice guideline.
      ) has suggested clinical guidelines for RID management during the administration of CCRT. These guidelines include washing the skin with water or mild soap, along with the use of mild lotions or bland emollient moisturizers that do not contain perfumes or essential oils. Accordingly, patients have been encouraged to follow the SCGG guidelines for skin care from the beginning of the radiation treatment until the skin has completely recovered. Although the SCCG guidelines suggest routine skin care with gentle skin washing and moisturizing during radiotherapy in HNC patients, the occurrence of RID had been alleviable (
      • Zenda S.
      • Ishi S.
      • Kawashima M.
      • Arahira S.
      • Tahara M.
      • Hayashi R.
      • Kishimoto S.
      • Ichihashi T.
      A Dermatitis Control Program (DeCoP) for head and neck cancer patients receiving radiotherapy: a prospective phase II study.
      ,
      • Zenda S.
      • Ishi S.
      • Akimoto T.
      • Arahira S.
      • Motegi A.
      • Tahara M.
      • Hayashi R.
      • Asanuma C.
      DeCoP, a Dermatitis Control Program using a moderately absorbent surgical pad for head and neck cancer patients receiving radiotherapy: a retrospective analysis.
      ). The Multinational Association of Supportive Care in Cancer (MASCC) has suggested gentle washing with or without mild soap or the application of a topical steroidal agent during radiotherapy to reduce any itching or burning sensations; however, the evidence in support of this recommendation has been categorized as level II, Grade B (
      • Wong R.K.
      • Bensadoun R.J.
      • Boers-Doets C.B.
      • Bryce J.
      • Chan A.
      • Epstein J.B.
      • Eaby-Sandy B.
      • Lacouture M.E.
      Clinical practice guidelines for the prevention and treatment of acute and late radiation reactions from the MASCC Skin Toxicity Study Group.
      ). Systematic reviews of the prevention and treatment of RID in HNC patients treated with either radiotherapy alone or concomitant chemoradiation concluded that there was no strong evidence supporting the use of any topical products over those described in the recommended routine skin care SCGG and MASCC guidelines (
      • Ferreira E.B.
      • Vasques C.I.
      • Gadia R.
      • Chan R.J.
      • Guerra E.N.
      • Mezzomo L.A.
      • De Luca Canto G.
      • Dos Reis P.E.
      Topical interventions to prevent acute radiation dermatitis in head and neck cancer patients: a systematic review.
      ;
      • Iacovelli N.A.
      • Galaverni M.
      • Cavallo A.
      • Naimo S.
      • Facchinetti N.
      • Iotti C.
      • Fallai C.
      • Orlandi E.
      Prevention and treatment of radiation-induced acute dermatitis in head and neck cancer patients: a systematic review.
      ). Furthermore , there has been no conclusive evidence to support the superiority of any specific preventive and treatment agents in the management of RID.
      Aloe vera (Aloe vera (L.) Burm.f.) is an herbal plant that has long been used in the treatment of patients suffering from burns and scalds (
      • Moriyama M.
      • Moriyama H.
      • Uda J.
      • Kubo H.
      • Nakajima Y.
      • Goto A.
      • Akaki J.
      • Yoshida I.
      • Matsuoka N.
      • Hayakawa T.
      Beneficial effects of the genus aloe on wound healing, cell proliferation, and differentiation of epidermal keratinocytes.
      ;
      • Irani P.S.
      • Varaie S.
      Comparison of the effect of aloe vera gel and nitrofurazone 2% on epithelialization and granulation tissue formation regarding superficial second-degree burns.
      ;
      • Komatsu D.
      • Mistura D.V.
      • Motta A.
      • Domingues J.A.
      • Hausen M.A.
      • Duek E.
      Development of a membrane of poly (L-co-D,L lactic acid-co-trimethylene carbonate) with aloe vera: an alternative biomaterial designed to improve skin healing.
      ;
      • Varaei S.
      • Ardabili F.M.
      • Irani P.S.
      • Ranjbar H.
      The effect of aloe vera gel and nitrofurazone on dressing related pain of superficial burn wounds.
      ;
      • Akgun S.G.
      • Aydemir S.
      • Ozkan N.
      • Yuksel M.
      • Sardas S.
      Evaluation of the wound healing potential of Aloe vera-based extract of Nerium oleander.
      ;
      • Teplicki E.
      • Ma Q.
      • Castillo D.E.
      • Zarei M.
      • Hustad A.P.
      • Chen J.
      • Li J.
      The effects of aloe vera on wound healing in cell proliferation, migration, and viability.
      ). Importantly, some studies have reported on the substantial benefits of aloe vera gel treatment for RID patients (
      • Haddad P.
      • Amouzgar-Hashemi F.
      • Samsami S.
      • Chinichian S.
      • Oghabian M.A.
      Aloe vera for prevention of radiation-induced dermatitis: a self-controlled clinical trial.
      ;
      • Rao S.
      • Hegde S.K.
      • Baliga-Rao M.P.
      • Palatty P.L.
      • George T.
      • Baliga M.S.
      An aloe vera-based cosmeceutical cream delays and mitigates ionizing radiation-induced dermatitis in head and neck cancer patients undergoing curative radiotherapy: a clinical study.
      ). Aloe vera gel treatment can not only relieve the symptoms of RID but can also activate macrophages and exhibit some aspects of tumor control (
      • Harlev E.
      • Nevo E.
      • Lansky E.P.
      • Ofir R.
      • Bishayee A.
      Anticancer potential of aloes: antioxidant, antiproliferative, and immunostimulatory attributes.
      ). Recent systematic reviews and meta-analysis by Ginex et al., which were used to evaluate the role of aloe vera applications in the management of RID among cancer patients, have reported equivalent effective results for aloe vera products in reducing the severity grade or symptoms associated RID when compared with soap, the placebo, or phospholipid cream (
      • Ginex P.K.
      • Backler C.
      • Croson E.
      • Horrell L.N.
      • Moriarty K.A.
      • Maloney C.
      • Vrabel M.
      • Morgan R.L.
      Radiodermatitis in patients with cancer: systematic review and meta-analysis.
      ). Importantly, the objective results that included quality of life were not reported due to an absence of previously published data.
      Currently, the preventive benefits of using topical aloe vera gel by HNC patients who have received curative CCRT remain unclear, while the objective outcomes should be further evaluated. This study aimed to assess the efficacy of aloe vera gel applications in preventing and reducing the severity of RID in HNC patients who had received high dose radiotherapy concurrently with chemotherapy when compared with a placebo gel.

      2. Method

      2.1 Design

      This multicenter randomized double-blind placebo-controlled study was conducted in three hospitals in Thailand, namely Udon Thani Cancer Hospital (UCH), Lampang Cancer Hospital (LCH), and Chiang Mai University Hospital (CMUH). This study aimed to evaluate the degree of severity reduction by using aloe vera in RID prevention in HNC patients undergoing treatment with CCRT.

      2.2 Samples and setting

      All patients (N = 120) participating in this study had been enrolled at the out-patient department of each cancer center. The eligibility criteria for all recruited subjects stated that they must be at least 18 years of age and have been diagnosed with histological squamous cell carcinoma of the head and neck. The performance status was confirmed by the Eastern Cooperative Oncology Group (ECOG) with scores in the range of 0–2. Treatment plans involving radiation doses of at least 50 Gy (Gy) to the neck region were concurrently approved in conjunction with platinum-based chemotherapy. The exclusion criteria omitted patients who had evidence of a metastatic disease, had received palliative radiotherapy, reported a history of an aloe vera allergy, or who had concomitantly been treated with targeted or immunotherapeutic agents. Patients that reported a history of an autoimmune disease or skin disease that resulted in severe skin toxicity as a reaction to radiation were also excluded.

      2.3 Procedure

      2.3.1 Skin care counselling

      All included patients were asked to follow a basic skin care counselling program that included gentle skin cleansing with mild soap or tap water, drying the skin gently with a soft cotton towel, and preventing any bolus effect from radiation (that might have resulted from increased radiation doses delivered to the epidermis). This was achieved by avoiding the use of essential oils and the application of occlusive moisturizers or lotions to the radiation zone for at least 1 h before initiating the radiotherapy session. Accordingly, subjects were asked to wear ample, soft cotton clothing, avoid sun exposure, protect themselves from exposure to the sun, avoid applying products to the skin that contain alcohol (perfumes, ether, or talcum powder), and to keep the radiation zone dry to prevent skin desquamation.

      2.4 Randomization and blinding

      After simulated radiotherapy planning, patients underwent block randomization via the interactive-web response to receive treatments with either 87.4% of aloe vera in hydrophilic gel (Radiara Gel™, Bangkok Drug CO., LTD) or the placebo (plain, odorless, and colorless hydrophilic gel). Each opaque tube of either aloe vera gel or the placebo gel was packed into a plastic bag and labeled either “AB” or “YZ”, respectively in order to blind both the patients and the investigators. The letters indicating the gel code were revealed to the central investigator only after completion of the study.

      2.5 Intervention

      After a patient was assigned to the group, the protocol nurse distributed the gel packages to the patient and gave instructions on how to apply the gel to the area of irradiated skin. Relevant substances were applied to the radiation treatment zones on the face and neck of all patients. Treatments were administered two times a day every morning and evening from the first day of initiating radiation treatments until two weeks after completion of the treatment. Each group received 10 g of gel packed into an opaque tube, which was sufficient to cover the skin of the head and neck area by about 180–200 square inches at a time. All patients were advised to begin applying the gel throughout the irradiated area from the cheekbones, nose, chin, ears, front of the neck, side of the neck, back of the neck, under the chin, and all the way down to cover the area of the collarbone without being wiped off. Patients were then instructed to wait for at least 5 min to let the gel dry before wearing soft clothes and to allow at least 30 min for absorption before each radiation session. All of the empty gel tubes used by both groups were returned each week. Any remaining amount of gel in the tubes was checked by the protocol nurse to assess the patient's compliance with the instructions and for purposes of quality control.

      2.6 Assessment

      The severity of radiation dermatitis was recorded using RISRAS (
      • Noble-Adams R.
      Radiation-induced skin reactions. 3: evaluating the RISRAS.
      ) every week during the course of CCRT and four weeks after completion of the treatment by the same radiation oncologist. RISRAS is a dermatitis assessment tool specifically developed for acute RID. The scale consists of both subjective and objective parameters. For subjective symptoms, patients were asked to self-evaluate their own symptoms related to itchiness, burning sensations, pain, and any limitations to their daily lives. They were asked to rate their symptoms accordingly: 1 as no symptom, 2 as mild symptom, 3 as moderate symptom, and 4 as severe symptom. The objective results from RISRAS were assessed by a qualified radiation oncologist. These included erythematous skin, dry desquamation, moist desquamation, and necrosis. Each objective result was scored by the radiation oncologist as follows: 0 score was equivalent to no area of involvement, 1 as 0–25% area of involvement, 2 as 25–50% area of involvement, 3 as 50–75% area of involvement, and 4 as more than 75% area of involvement for skin dermatitis. Objective RISRAS values of 1–2, 3, and 4 were reported as mild, moderate, and severe, respectively.
      For patients with a severe grade of RID, the physicians recommended a break from radiation treatment for at least a week. If there was a severe grade of wound inflammation or infection of the skin, the radiation oncologist might consider giving the patient certain drugs or other topical drugs according to a qualified doctor's determination. A general health assessment was given, and other radiation side effects were evaluated throughout the course of treatment.

      2.7 Standard care

      2.7.1 Radiation therapy

      All patients were capable of receiving radical treatment by radiation therapy with concomitant chemotherapy. Various techniques of radiation were employed including 2-dimensional technique (2D), three-dimensional conformal technique (3D-CRT), intensity modulated radiotherapy technique (IMRT), and image-guided radiotherapy technique (IGRT) depending upon the suitability of each institution, the individual primary subsite, and any reimbursement issues. The primary site of the tumor received a radiation dose of 60–70 Gy. The neck area received a radiation dose of at least 50 Gy with a maximum dose of not more than 110% of the total treatment dose. The total treatment duration was 30–35 days over 6–8 weeks.

      2.7.2 Chemotherapy

      All patients were required to receive platinum-based chemotherapy concurrently with radiotherapy. The regimens were dependent upon each center protocol and involved weekly cisplatin, weekly carboplatin, tri-weekly cisplatin, and tri-weekly carboplatin administrations. Dose adjustment and chemotherapy discontinuation were dependent upon the oncologist's decision according to patient performance status, laboratory results, or the patient's degree of toxicity toleration.

      2.8 Ethical considerations

      This study was approved of by the Institutional Ethics Review Board of individually institute. This study has been registered at the Thai Clinical Trial Registry under number TCTR20200727002. The study consent form was signed by all patients included in this study. All patients were free to discontinue their participation in this study, at which point they were free to receive standard radiation treatments or to pursue any other treatment options available.

      2.9 Statistical analysis

      Sample size was calculated by applying the following formula: n = 2 (Zα/2 + Zβ)2 σ2/(X1-X2). The reference data was obtained from a study conducted by
      • Haddad P.
      • Amouzgar-Hashemi F.
      • Samsami S.
      • Chinichian S.
      • Oghabian M.A.
      Aloe vera for prevention of radiation-induced dermatitis: a self-controlled clinical trial.
      . On the 6th week, the mean grade of RID in aloe vera arm and control arm was 1.00 and 1.57 (p = 0.006), respectively. With the power of 0.90 and beta of 0.1, the sample size was calculated to be 39.73, or 40 per arm. An assumption of the objects lost to a follow-up rate of 10% was determined. Accordingly, this study required there to be 44 patients in each group.
      The data will be presented in descriptive basis. The RISRAS scores for each week were recorded as median values and were compared using the Chi-square test or Fisher's exact test. The alpha-level of a p-value of 0.05 was considered statistically significant.
      Statistical data analyses were performed using IBM SPSS statistics for Windows, version 20.0. (Armonk, NY: IBM Corp).

      3. Results

      3.1 Patient characteristics and compliance with CCRT

      Between January 2019 and April 2020, HNC patients from three radiation therapy centers were enrolled in this study. A total of 120 patients; 52 patients from UCH, 38 patients from CMUH, and 30 patients from LCH, were randomly assigned (1:1) to receive either aloe vera gel or a placebo gel at the initial point of treatment of CCRT and two weeks after completion of the treatment. A total of 60 patients of each study group were deemed eligible. Eight of the 120 randomized patients did not complete the treatment protocol, along with two patients and six patients who had received treatment in the aloe vera and placebo arms, respectively. Only one patient who received treatment in the aloe vera arm was lost to the follow-up assessment after treatment. As treated analysis was made during each week. A study flow diagram of the clinical trial is shown in Fig. 1. An analysis of the baseline data of the patient's characteristics did not reveal any differences between the groups (Table 1). The most common HNC subsite was nasopharynx followed by oropharynx and the oral cavity. Mean radiation doses to the planning target volume (PTV) of both the primary site and the neck region were not different when members of the aloe vera and placebo groups were compared. Ninety-three percent of patients completed the CCRT treatment; 58 patients received treatment in the aloe vera arm, and 54 patients received treatment in the placebo arm. Median total treatment time was 53.5 days for patients who received treatment in the aloe vera gel arm and 51.5 days in the placebo arm. The radiation treatment break and chemotherapy treatment break were recorded at 13.3% and 41.6% for the aloe vera group, and 15% and 28.3% for the placebo group, respectively. The common reasons for issuing radiation treatment breaks and delaying chemotherapy were severe mucositis and the presence of hematologic toxicity. Treatment breaks during CCRT due to acute dermatitis were not observed in this study.
      Fig. 1
      Fig. 1Study flow diagram
      Abbreviations: HNC= Head and neck cancer, CCRT = concurrent chemoradiation, ECOG = Eastern Cooperative Oncology Group.
      Table 1Patient characteristics.
      CharacteristicsStudy group (n = 60)Control group (n = 60)p-value
      N%N%
      GenderMale4778.34880.00.822
      Female1321.71220.0
      HospitalCMUH1830.02033.30.699
      LCH1728.31321.7
      UCH2541.72745.0
      Age group30–409Median2Median0.249
      41–501753.51657
      51–6017(33–71)20(33–83)
      61–701215
      >7057
      T stage00011.60.346
      1813.3813.3
      22135.01220.0
      31016.61423.3
      42135.02541.6
      N stage0915.058.30.566
      1711.6711.6
      23761.63761.6
      3711.61118.3
      M stage05795.05896.61.000
      135.023.3
      Primary siteOral cavity1118.3915.00.996
      Oropharyx1118.31016.6
      Nasopharynx2643.32846.6
      Supraglottis23.335.0
      Glottis23.323.3
      Hypopharynx58.358.3
      Nasal cavity35.023.3
      Unknown primary0011.6
      Technique2D1830.01931.60.377
      3D-CRT11.635.0
      IMRT1626.62135.0
      IGRT2541.61728.3
      ChemotherapyCisplatin weekly2948.32948.30.697
      Cisplatin Q3W2033.31728.3
      Carboplatin weekly1016.61423.3
      Carboplatin Q3W11.600
      AimRadical CCRT5185.05388.30.494
      Post-operative CCRT915.0711.7
      Primary dose (Gy)mean 69.3mean 69.30.666
      (60–70)(66–70)
      Neck dose (Gy)mean 59.3mean 59.20.976
      (50–70)(50–70)
      Total treatment time (day)median 53.5median 51.50.289
      (23–68)(7–67)
      Treatment break for RT813.3915.00.793
      Treatment break for chemotherapy2541.61728.30.126
      Abbreviations: CMU=Chiang Mai University, LCH = Lampang Cancer Hospital, UCH=Udon Thani Cancer Hospital, 2D = 2-dimensional technique, 3D-CRT = three-dimensional conformal technique, IMRT = intensity modulated radiotherapy technique, IGRT = image-guided radiotherapy technique, CCRT = concurrent chemoradiation.

      3.2 RISRAS assessment

      As the treated analysis for use of RID has been reported, all of the patients in this study experienced RID during CCRT treatment. Median RISRAS values for those treated with CCRT in each group are shown in Fig. 2 without any statistically significant differences.
      Fig. 2
      Fig. 2Median RISRAS score
      Abbreviation: RISRAS = radiation induced skin reaction assessment scale.

      3.2.1 RISIAS subjective symptom scale

      The results of the subjective symptom scale are presented in Table 2. There were no statistically significant differences between members of both groups in terms of the subjective scales of pain and whether pain disturbed the daily lives of the patients. On the 4th week, six of 60 patients (10%) who received treatment in the aloe vera arm developed RISRAS grade 3–4 itching, which was not observed in the placebo arms (p = 0.028) of these patients. There was a significant difference in the RISRAS grade 3–4 for a burning sensation between patients who received treatment in the arms on the 7th week of CCRT, while none was observed in the aloe vera arms and this grade was observed in 11.9% of the placebo arms (p = 0.016).
      Table 2Subjective assessment.
      SubjectiveItchingBurning sensationPainLimit daily activity
      Aloe arm (%)Control arm (%)Aloe arm (%)Aloe arm (%)Aloe arm (%)Control arm (%)Aloe arm (%)Control arm (%)
      Week 1N = 60N = 60N = 60N = 60N = 60N = 60N = 60N = 60
      - RISRAS 1-260 (100)59 (98.3)60 (100)60 (100)60 (100)60 (100)60 (100)60 (100)
      - RISRAS 3-401(1.8)000000
      p-value1.000
      Week 2N = 60N = 59N = 60N = 59N = 60N = 59N = 60N = 59
      - RISRAS 1-260 (100)59 (100)60 (100)59 (100)60 (100)59 (100)60 (100)59 (100)
      - RISRAS 3-400000000
      p-value
      Week 3N = 60N = 57N = 60N = 57N = 60N = 57N = 60N = 57
      - RISRAS 1-258 (96.7)57 (100)60 (100)57 (100)60 (100)57 (100)60 (100)57 (100)
      - RISRAS 3-42 (3.3)0000000
      p-value0.496
      Week 4N = 60N = 55N = 60N = 60N = 60N = 55N = 60N = 55
      - RISRAS 1-254 (90.0)55 (100)59 (98.3)54 (98.2)59 (98.3)55 (100)59 (98.3)54 (98.2)
      - RISRAS 3-46 (10.0)01 (1.7)1 (1.8)1 (1.7)01 (1.7)1 (1.8)
      p-value0.0281.0001.0001.000
      Week 5N = 59N = 54N = 59N = 54N = 59N = 54N = 59N = 54
      - RISRAS 1-255 (93.2)50 (92.6)54 (91.5)51 (94.4)59 (100)52 (96.3)59 (100)54 (100)
      - RISRAS 3-44 (6.8)4 (7.4)5 (8.5)3 (5.56)02 (3.7)00
      p-value1.0000.7190.226
      Week 6N = 58N = 54N = 58N = 54N = 58N = 54N = 58N = 54
      - RISRAS 1-246 (79.3)48 (88.8)53 (91.4)47 (87.0)52 (89.7)49 (90.7)58 (100)53 (98.1)
      - RISRAS 3-412 (20.6)6 (11.2)5 (8.6)7 (13.0)6 (10.3)5 (9.3)01 (1.9)
      p-value0.1680.4580.8470.482
      Week 7N = 51N = 42N = 51N = 42N = 51N = 42N = 51N = 42
      - RISRAS 1-242 (82.4)34 (81.0)51 (100)37 (88.1)51 (100)41 (97.6)50 (98.0)41 (97.6)
      - RISRAS 3-49 (17.6)8 (19.0)05 (11.9)01 (2.4)1 (2.0)1 (2.4)
      p-value0.8620.0160.4521.000
      Week 8N = 18N = 11N = 18N = 11N = 18N = 11N = 18N = 11
      - RISRAS 1-215 (83.3)10 (90.9)18 (100)9 (81.8)18 (100)11 (100)18 (100)11 (100)
      - RISRAS 3-43 (16.7)1 (9.1)02 (18.2)0000
      p-value1.0000.135
      Follow upN = 57N = 54N = 57N = 54N = 57N = 54N = 57N = 54
      - RISRAS 1-257 (100)54 (100)57 (100)54 (100)57 (100)54 (100)57 (100)54 (100)
      - RISRAS 3-400000000
      p-value
      Abbreviation: RISRAS = radiation induced skin reaction assessment scale.

      3.2.2 RISRAS objective symptom scale

      An objective assessment was made by the radiation oncologist and is presented in Table 3. There were no statistically significant differences in terms of dry desquamation among members of all groups. The number of patients that experienced a moderate to severe grade of skin erythematous on their placebo arm was higher than for that on the aloe vera arm with statistically significant differences recorded on the 4th, 5th, and 6th weeks. On the 6th week of CCRT, a moderate to severe degree of moist desquamation was observed in both arms of three out of 58 patients (5.2%) in the aloe vera arm and seven out of 54 patients (13.0%) in the placebo arm (p = 0.149). A moderate to severe grade of moist desquamation that occurred on the 7th week of CCRT was significantly reduced among members of the aloe vera group when compared to members of the placebo group with a p value of 0.001. Importantly, no skin necrosis occurred in this study.
      Table 3The objective assessment.
      Skin erythemaDry desquamationMoist desquamation
      ObjectivesAloe arm (%)Control arm (%)Aloe arm (%)Control arm (%)Aloe arm (%)Control arm (%)
      Week 1N = 60N = 60N = 60N = 60N = 60N = 60
      - asymptomatic/mild grade60 (100)60 (100)60 (100)60 (100)60 (100)60 (100)
      - moderate/severe grade000000
      p-value
      Week 2N = 60N = 59N = 60N = 59N = 60N = 59
      - asymptomatic/mild grade60 (100)59 (100)60 (100)59 (100)60 (100)59 (100)
      - moderate/severe grade000000
      p-value
      Week 3N = 60N = 57N = 60N = 57N = 60N = 57
      - asymptomatic/mild grade59 (98.3)57 (100)60 (100)57 (100)60 (100)57 (100)
      - moderate/severe grade1 (1.7)00000
      p-value0.5130.513
      Week 4N = 60N = 55N = 60N = 55N = 60N = 55
      - asymptomatic/mild grade58 (96.3)46 (83.6)54 (90.0)46 (85.2)60 (100)55 (100)
      - moderate/severe grade2 (3.3)9 (16.4)6 (10.0)9 (14.8)00
      p-value0.0180.311
      Week 5N = 59N = 54N = 59N = 54N = 59N = 54
      - asymptomatic/mild grade51 (86.4)39 (72.2)40 (67.8)40 (74.1)59 (100)54 (100)
      - moderate/severe grade8 (13.6)15 (27.8)19 (32.2)14 (25.9)00
      p-value0.0500.464
      Week 6N = 58N = 54N = 58N = 54N = 58N = 54
      - asymptomatic/mild grade44 (75.9)31 (57.4)31 (53.4)24 (44.4)55 (94.8)47 (87.0)
      - moderate/severe grade14 (24.1)23 (42.6)27 (46.6)30 (55.6)3 (5.2)7 (13.0)
      p-value0.0380.3410.149
      Week 7N = 51N = 42N = 51N = 42N = 51N = 42
      - asymptomatic/mild grade33 (64.7)27 (64.3)16 (31.4)14 (33.3)51 (100)34 (81.0)
      - moderate/severe grade18 (35.3)15 (35.7)35 (68.6)28 (66.7)08 (19.0)
      p-value0.9660.8400.001
      Week 8N = 18N = 11N = 18N = 11N = 18N = 11
      - asymptomatic/mild grade11 (61.1)7 (63.6)5 (27.8)2 (18.2)17 (94.4)10 (90.9)
      - moderate/severe grade7 (38.9)4 (36.4)13 (72.2)9 (81.8)1 (5.6)1 (9.1)
      p-value0.6040.4530.623
      Follow upN = 57N = 54N = 57N = 54N = 57N = 54
      - asymptomatic/mild grade57 (100)52 (96.3)56 (98.2)52 (96.3)57 (100)54 (100)
      - moderate/severe grade02 (3.7)1 (1.8)2 (3.7)00
      p-value0.2390.486
      Abbreviation: RISRAS = radiation induced skin reaction assessment scale.

      4. Discussion

      RID is an unavoidable condition of the head and neck region even though there have been numerous advances in radiotherapy technology. About 85%–95% of patients treated with radiotherapy have suffered from moderate to severe grades of acute RID (Sulvo et al., 2010;
      • Rosenthal A.
      • Israilevich R.
      • Moy R.
      Management of acute radiation dermatitis: a review of the literature and proposal for treatment algorithm.
      ). Severe skin reactions have been associated with negative impacts in terms of treatment compliance, which would then have resulted in poor clinical outcomes (
      • Hansen O.
      • Overgaard J.
      • Hansen H.S.
      • Overgaard M.
      • Höyer M.
      • Jörgensen K.E.
      • Bastholt L.
      • Berthelsen A.
      Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: dependency on tumor differentiation.
      ;
      • Mazzola R.
      • Fiorentino A.
      • Ricchetti F.
      • Gregucci F.
      • Corradini S.
      • Alongi F.
      An update on radiation therapy in head and neck cancers.
      ). This present multicenter randomized double-blind controlled study was designed to evaluate the efficacy of topical aloe vera gel on RID specific for HNC patients receiving curative CCRT.
      With regard to RID prevention, this study demonstrated that the addition of topical aloe vera gel to standard skin care regimens was not found to be effective for RID prevention in HNC patients receiving CCRT. Acute skin reactions occurred in the arms of both groups of patients without statistically significant differences in terms of the median RISRAS scores. Several studies (
      • Heggie S.
      • Bryant G.P.
      • Tripcony L.
      • Keller J.
      • Rose P.
      • Glendenning M.
      • Heath J.
      A Phase III study on the efficacy of topical aloe vera gel on irradiated breast tissue.
      ;
      • Richardson J.
      • Smith J.E.
      • McIntyre M.
      • Thomas R.
      • Pilkington K.
      Aloe vera for preventing radiation-induced skin reactions: a systematic literature review.
      ;
      • Bolderston A.
      • Lloyd N.S.
      • Wong R.K.
      • Holden L.
      • Robb-Blenderman L.
      Supportive Care Guidelines Group of Cancer Care Ontario Program in Evidence-Based Care
      The prevention and management of acute skin reactions related to radiation therapy: a systematic review and practice guideline.
      ;
      • Ahmadloo N.
      • Kadkhodaei B.
      • Omidvari S.h.
      • Mosalaei A.
      • Ansari M.
      • Nasrollahi H.
      • Hamedi S.H.
      • Mohammadianpanah M.
      Lack of prophylactic effects of aloe vera gel on radiation induced dermatitis in breast cancer patients.
      ;
      • Williams M.S.
      • Burk M.
      • Loprinzi C.L.
      • Hill M.
      • Schomberg P.J.
      • Nearhood K.
      • O'Fallon J.R.
      • Laurie J.A.
      • Shanahan T.G.
      • Moore R.L.
      • Urias R.E.
      • Kuske R.R.
      • Engel R.E.
      • Eggleston W.D.
      Phase III double-blind evaluation of an aloe vera gel as a prophylactic agent for radiation-induced skin toxicity.
      ) have reported that topical aloe vera was ineffective in the prevention of RID. However, topical aloe vera was found to be able to reduce the severity or delayed onset of acute dermatitis in other previous studies (
      • Olsen D.L.
      • Raub Jr., W.
      • Bradley C.
      • Johnson M.
      • Macias J.L.
      • Love V.
      • Markoe A.
      The effect of aloe vera gel/mild soap versus mild soap alone in preventing skin reactions in patients undergoing radiation therapy.
      ;
      • Weheida S.M.
      • Riad N.A.
      • Masry S.E.
      The effect of skin preparation by using aloe vera gel on incidence of skin reactions among breast cancer patients undergoing radiation therapy.
      ;
      • George J.T.
      • Sharma K.K.
      A randomized study to assess the effectiveness of aloe vera gel on acute radiation dermatitis.
      ). Remarkably, this present randomized study reported similar results for reduced degrees of severity of acute RID in terms of both patient symptoms and objective assessments. A self-controlled study that involved various sites of cancer has determined that aloe vera lotion could significantly reduce the severity of dermatitis but could not confirm a preventive effect of aloe vera lotion on acute RID (
      • Haddad P.
      • Amouzgar-Hashemi F.
      • Samsami S.
      • Chinichian S.
      • Oghabian M.A.
      Aloe vera for prevention of radiation-induced dermatitis: a self-controlled clinical trial.
      ). A previous randomized controlled study focusing on HNC radiation that included 43.8% of patients treated with CCRT, reported on the benefits of aloe vera gel in terms of delaying or reducing the severity of RID (
      • George J.T.
      • Sharma K.K.
      A randomized study to assess the effectiveness of aloe vera gel on acute radiation dermatitis.
      ). Despite differences in the skin reaction grading system employed in our study, the application of aloe vera gel on the start date of the CCRT treatment provided a significantly favorable difference in skin reactions during the course of HNC-CCRT.
      Prophylactic use of topical aloe vera among HNC patients receiving high dose radiotherapy also revealed a delayed onset of RID (
      • Rao S.
      • Hegde S.K.
      • Baliga-Rao M.P.
      • Palatty P.L.
      • George T.
      • Baliga M.S.
      An aloe vera-based cosmeceutical cream delays and mitigates ionizing radiation-induced dermatitis in head and neck cancer patients undergoing curative radiotherapy: a clinical study.
      ); however, these same endpoints were not observed in our study. The pattern of skin reaction in our study was similar for both groups of patients. Only 10 patients in our study developed high grade moist desquamation on the 6th week of the treatment course, along with 3 patients in the study group and 7 patients in the control group. Notably, this group of patients received a radiation dose higher than 60 Gy or were put on a delayed treatment schedule. On a follow-up date, 4 weeks after CCRT, subjective and objective RID values were improved and no statistically significant differences were observed between the two groups of subjects.
      This study reported incidences of RID using the RISRAS grading system which was used to assess both the subjective and objective parameters. Moreover, specific dermatitis symptoms and the four types of skin reactions were separately scored and analyzed. The application of topical aloe vera gel showed a significant reduction in burning sensation symptoms in the later weeks of treatment when compared to the placebo. We found that patients in the aloe vera group developed RISRAS 3–4 itching to a greater degree than those in the placebo group with a statistically significant difference on the 4th week of receiving the CCRT course. Importantly, these outcomes did not clearly demonstrate the benefits of aloe vera gel to treat subjective in-field itching symptoms. In our study, we determined that incidences of moderate to severe skin erythematous and moist desquamation in the later weeks of CCRT were significantly lower in the aloe vera gel group when compared with the placebo group. According to the Radiation Oncology Group (RTOG) grading system, erythematous of skin and moist desquamation were assessed together, while the subjective symptoms were not included. Thus, the RTOG criteria did not indicate a specific endpoint for a clear determination of the efficacy of topical products for RID management.
      At present, both topical steroidal and non-steroidal agents have been studied in clinical trials to assess their potential prophylactic activity or capability of treating RID symptoms. Topical aloe vera plant extracts are known to have an anti-inflammatory effect and have been widely used to treat skin burns and dermatitis. However, there have been a limited number of studies that have provided irrefutable evidence to support this determination (
      • Farrugia C.E.
      • Burke E.S.
      • Haley M.E.
      • Bedi K.T.
      • Gandhi M.A.
      The use of aloe vera in cancer radiation: an updated comprehensive review.
      ). Remarkably, topical olive oil has been reported as the most effective agent for RID prevention in treating HNC in one of the Meta-analyses (
      • Kao Y.S.
      • Ma K.S.
      • Wu M.Y.
      • Wu Y.C.
      • Tu Y.K.
      • Hung C.H.
      Topical prevention of radiation dermatitis in head and neck cancer patients: a network meta-analysis.
      ). Recently, the clinical practice guidelines obtained from the Oncology Nursing Society ( ONS ) have recommended that topical aloe vera be used only in clinical studies due to a low level of evidence to support the clinical benefits of aloe vera agents in RID prevention or treatment (
      • Gosselin T.
      • Ginex P.K.
      • Backler C.
      • Bruce S.D.
      • Hutton A.
      • Marquez C.M.
      • McGee L.A.
      • Shaftic A.M.
      • Suarez L.V.
      • Moriarty K.A.
      • Maloney C.
      • Vrabel M.
      • Morgan R.L.
      ONS Guidelines™ for cancer treatment-related radiodermatitis.
      ). To improvement of our knowledge, this is the first randomized placebo-controlled study of its kind to evaluate the efficacy of topical aloe vera gel for RID by RISRAS in HNC patients who had received CCRT. In this study, we have employed specific tools to assess the patients’ subjective experience, while objectively measuring the results from the perspective of a radiation oncologist.
      The limitations of this study would include the variations associated with radiotherapy techniques. Notably, IMRT in HNC could demonstrate a significant reduction in radiation related complications such as acute mucositis, xerostomia, or dysphagia. As compared to conventional radiotherapy, incidences of acute dermatitis were not reported with any significant differences among patients receiving radiation therapy (
      • Nutting C.M.
      • Morden J.P.
      • Harrington K.J.
      • Urbano T.G.
      • Bhide S.A.
      • Clark C.
      • Miles E.A.
      • Miah A.B.
      • Newbold K.
      • Tanay M.
      • Adab F.
      • Jefferies S.J.
      • Scrase C.
      • Yap B.K.
      • A'Hern R.P.
      • Sydenham M.A.
      • Emson M.
      • Hall E.
      PARSPORT trial management group
      Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial.
      ;
      • Gupta T.
      • Agarwal J.
      • Jain S.
      • Phurailatpam R.
      • Kannan S.
      • Ghosh-Laskar S.
      • Murthy V.
      • Budrukkar A.
      • Dinshaw K.
      • Prabhash K.
      • Chaturvedi P.
      • D’Cruz A.
      Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: a randomized controlled trial.
      ;
      • Peng G.
      • Wang T.
      • Yang K.Y.
      • Zhang S.
      • Zhang T.
      • Li Q.
      • Han J.
      • Wu G.
      A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma.
      ). However, several patient factors may have affected the severity of RID in the way of significant weight loss, responses of the neck node to CCRT, and incidences of diabetes mellitus. In our study, mixed HNC patients received definitive CCRT and postoperative CCRT, thus the range of radiation doses was determined to be 50 Gy–70 Gy. Additionally, this study used only two codes on the packages of gel plastic tubes (“AB” or “YZ”), which would have to unfortunately be unblinded to address any serious adverse events. Accordingly, all patients taking part in the clinical study would also have to be unblinded.
      The results of this study encourage the topical use of aloe vera gel, particularly for HNC patients who had received a planned treatment with radiation doses of at least 50 Gy. Importantly, patient education with regard to standard routine skin care played an essential role in RID management during the course of radiation treatment for cancer patients.

      5. Conclusion

      The preventive effects of topical aloe vera gel on RID was not demonstrated in this randomized controlled study. However, the application of aloe vera gel in conjunction with a routine program of skin care from the start date of receiving radiation could reduce the severity of any burning sensations, along with incidences of skin erythematous and moist desquamation for HNC patients who had been treated with CCRT.

      CRediT authorship contribution statement

      Tharatorn Tungkasamit: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing. Somvilai Chakrabandhu: Conceptualization, Methodology, Investigation, Writing – original draft, Writing – review & editing. Vatanyu Samakkarn: Conceptualization, Methodology, Investigation. Natthanan Kunawongkrit: Conceptualization, Methodology, Investigation. Naruemon Jirawatwarakul: Conceptualization, Methodology, Investigation. Ausareeya Chumachote: Methodology, Investigation. Imjai Chitapanarux: Conceptualization, Methodology, Writing – review & editing, Supervision.

      Declaration of competing interest

      No conflicts of interest to disclose.

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