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    -  Sunku R
    -  Kalita AK
    -  Bhattacharyya M
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    -  Bansal S
    -  Borah L
    -  Nayan N
    -  Bora G
    -  Paul M
    -  Saikia S
    -  Kataki AC

 
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ORIGINAL ARTICLE
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Effect of corticosteroid ointment on radiation induced dermatitis in head and neck cancer patients: A prospective study


 Department of Radiation Oncology, Dr. B Borooah Cancer Institute, Gopinath Nagar, Guwahati, Assam, India

Date of Submission06-Dec-2018
Date of Decision03-Apr-2019
Date of Acceptance09-Apr-2019

Correspondence Address:
Shashank Bansal,
Department of Radiation Oncology, Dr. B Borooah Cancer Institute, Gopinath Nagar, Guwahati, Assam
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_790_18

  Abstract 


Background: Almost all the patients receiving curative radiotherapy for head and neck cancer develop radiation dermatitis, which many a times leads to treatment interruption and reduce patient compliance. In this study, we evaluated the effect of potent topical steroid (Betamethasone Valerate 0.1%) cream on acute radiation dermatitis in head and neck cancer patients receiving curative radiotherapy.
Methods: A total 106 patients of head and neck cancers were randomly divided into arm A (52 patients) and arm B (54 patients). The patient in study arm A were treated with topical betamethasone 0.1% twice daily during radiotherapy/chemo-radiotherapy and arm B was kept as control. The radiation reaction in both the groups was monitored weekly according to Radiation Therapy Oncology Group (RTOG) acute radiation dermatitis grading.
Results: Out of 106 patients, 85 (80.2%) patients completed treatment. Patient in control arm had earlier onset of grade 1 reaction (5.7% in arm A vs 16.7 % in arm B at 2nd week, P value 0.157 and 28.8% in arm A vs 50% in arm B at 3rd week, P value 0.028) and progression of radiation dermatitis. In 7th week patient in arm A had higher grade 1 reaction (17.3% in arm A vs 0% in arm B), while arm B had higher grade 2 reaction (66.7% arm B vs 55.8% in arm A). There was no difference in incidence of grade 3 and 4 reaction. No difference was observed in time taken for reaction to heal.
Conclusion: Topical Betamethasone can delay the onset and progression of radiation dermatitis in head and neck cancer, without significant delay in wound healing.


Keywords: Betamethasone, head and neck cancer, radiation dermatitis
Key Message: Radiation dermatitis can be effectively delayed with the use of betamethasone, without having adverse effects on wound healing in long term follow-up.



How to cite this URL:
Sunku R, Kalita AK, Bhattacharyya M, Medhi PP, Bansal S, Borah L, Nayan N, Bora G, Paul M, Saikia S, Kataki AC. Effect of corticosteroid ointment on radiation induced dermatitis in head and neck cancer patients: A prospective study. Indian J Cancer [Epub ahead of print] [cited 2020 Oct 20]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=297035





  Introduction Top


Since the inception of external beam radiotherapy in management of cancer, radiation dermatitis has been a matter of serious concern. The radiation dermatitis often leads to treatment interruption during long duration of radiotherapy, such as in head and neck cancer.[1] Definite radiotherapy with or without chemotherapy is the treatment of choice for locally advanced or inoperable cancer in head and neck region.[2] Many of the patients develop grade 3 skin reactions which require interruption of treatment and also hamper patient compliance, therefore compromising the efficacy of radiotherapy. But still, there is no guideline or even uniform consensus among radiation oncologist regarding management of radiation dermatitis.

The radiation dermatitis is the result of underlying inflammatory process, due to release of cytokines like TNFα, IL-6, IL-1[3],[4],[5] after radiation exposure. Beetz et al. reported an up-regulation of IL-6 expression in an irradiated human epithelial cell line, which could be inhibited by corticosteroids.[5] Corticosteroids produce an anti-inflammatory effect by downregulation of cytokine gene expression, inhibition of adhesion, and migration of inflammatory cells, which can be postulated as ideal for management of radiation dermatitis.[6],[7] But exact mechanism of this anti-inflammatory effect of corticosteroid on radiation dermatitis is not yet completely understood.[8]

Although many studies have been done on the effect of topical steroids during radiation on breast cancer, no study in head and neck cancer is available as per our knowledge. In this study, we evaluated the effect of potent topical steroid (Betamethasone Valerate 0.1%) cream in preventing the onset of acute radiation dermatitis and progression of severity in head and neck cancer patients.


  Materials and Methods Top


This study was conducted after taking ethical clearance from our institutional ethical committee and according to declaration of Helsinki. Consent was taken from all the patients before conducting the study.

Patient's selection

From 1st February 2018 to 15th May 2018 a total of 150 patients attended our clinic, of which 106 were included in the study. All patients who presented with histopathologically proven primary squamous cell carcinoma of head and neck, with or without lymph node metastasis, who were planned for definitive radiotherapy or chemo-radiotherapy with curative intent, were included. The patients were scheduled for fractionated radiotherapy of head and neck region with the telecobalt machine. Exclusion criteria were postoperative cases, cutaneous diseases, allergy to any topical steroid, uncontrolled co-morbidities, previous radiation in head and neck region, cancer of nasopharynx, paranasal sinus and salivary gland tumour. The number of patients to be enrolled was not predetermined, but as per the trend in our hospital record, we estimated the registration of average 160 patients of head and neck cancer within the said duration, in our institute.

We systematically randomized patients in 1:1 ratio in two arms, as per se quence of their enrolment in the trial. Neither the patient nor the reviewer was blinded. The 52 patients in study arm A received topical steroid (betamethasone valerate) over the radiation area from day one, while 54 patients in arm B (control group) were instructed not to use anything over the radiation area. All patients were advised to wash face and neck with clean normal temperature water, but no soap, oil, lotion or cream, except for topical steroid over irradiated skin in study arm A.

Radiotherapy methods

All patients were treated with bi-lateral parallel opposed head and neck portals using a Bhabhatron II or Theratron Cobalt-60 Teletherapy machine. Radiation was delivered in 2 Gy per fractions at five days per week to a total dose of 66-70 Gy. Most of the patients received weekly cisplatin or carboplatin as concurrent chemotherapy according to stage of the disease.

Topical steroid application

Betamethasone Valerate 0.1% w/w cream is a moderately potent or highly potent steroid according to World Health Organization and British National Formulary Classification.[9],[10] Betamethasone cream of one particular brand was advised to all the patients in arm A that is betnovate by GlaxoSmithKline (GSK), which is cheap and very easily available, to avoid any discrepancy due to preparation. These patients were instructed regarding the proper application of cream over the radiation area before starting radiation. Betnovate cream has to be started preferably from first day and not later than third day of radiation. Before every application, patients were instructed to wash face and neck with normal plain water and let it dry, after which a thin layer of cream in one fingertip unit had to be applied on each side of face and neck up to the clavicle. The application was done twice daily, first in the morning before taking radiotherapy and then in the evening after taking radiotherapy. Emphasis was given regarding the maintenance of proper hygiene and not to wear closed tight collar dress to avoid skin infection and mechanical irritation. Patients were evaluated after every five fractions of radiation and compliance to steroid use was noted in arm A and skin care was noted in both the arms.

Assessment and grading

All the patients were assessed to note and compare: (1) the onset of radiation dermatitis, (2) time taken in progression of severity, (3) interruption in treatment, and (4) time taken for healing of dermatitis. The area to be irradiated was thoroughly examined and documented before the starting of radiotherapy. Once treatment was started, patients were seen after completion of 6 Gy in 3 fractions to note study compliance, followed by weekly evaluation, by single reviewer and monitoring of skin reaction at 16, 26, 36, 46, 56, 66 and 70 Gy. Radiation field was shrunk after 46 Gy in 23 fractions to spare the spinal cord in all patients. The adverse reaction in the skin was visually described and recorded according to RTOG acute radiation morbidity scoring criteria.[11] Radiotherapy was interrupted in patients who developed grade 3 skin reactions characterized by confluent moist desquamation. The wound dressing with normal saline was done daily under sterile conditions and antibiotics given when necessary. Meanwhile, the patients in study arm A had to continue applying betnovate in surrounding region of skin where moist desquamation has not started. Once healed, remaining radiation dose was completed as planned and patients were not excluded from study. Other causes of treatment interruptions were severe weakness, bleeding and technical problems, which were noted accordingly.

Follow-up

The patients were advised to come for first follow-up at 7-14 days, when healing of skin reactions and any change in skin texture was assessed. Second follow-up was done at 6 weeks for evaluation of treatment response as well as re-evaluation of skin condition. Thereafter patients were kept on regular follow-up of 3 months as recommended.

Statistical analysis

In this intent-to-treat analysis, data of all the patients were analysed irrespective of treatment compliance or drop out. This will decrease the risk of bias and chance of false positive result. Analysis of the data was done using IBM SPSS statistic data editor version 20 software. A descriptive study was used to analyse the data regarding patients' details. To compare the characteristics and results between the two arms, Pearson Chi-Square test was used. Results are considered to be of significant difference if P- Value is ≤0.05.


  Results Top


Out of 106 patients enrolled in this study, 14 patients did not start treatment after radiotherapy planning, 5 in arm A and 9 in arm B. One patient in arm A stopped treatment after 8 fractions and another patient in arm B stopped after 4 fractions. One patient each in arm A and arm B discontinued radiation after 50 Gy in 25 fractions due to financial and family problems. One patient in arm B refused to take further treatment after 60 Gy in 30 fractions due to weakness. Two patients in arm B died during treatment, one was 50 years old man who died after 38 Gy due to severe bleeding and another one was 72 years old man who died suddenly at home after taking 44 Gy. Total of 85 patients, 44 patients in arm A and 41 patients in arm B, completed treatment of 66 Gy to 70 Gy in 33 to 35 fractions respectively [Figure 1]: Study Flowchart].
Figure 1: Study flow chart

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Patients in both the arms were comparable in terms of age, sex, religion, marital status, education and occupation, therefore ruling out any difference in social conditions of the groups. No difference in patient factors such as body mass index (BMI), presence of any co-morbidity, tobacco use or alcohol intake was seen [Table 1]. Most of the patients in both the groups had locally advanced disease that is 94.2% of group A and 90.7% in group B. There was no difference in stage-wise distribution of patients in either group (P- value 0.68) [Table 2]. Thirty-three (63.5%) patients in arm A and 36 (66.7%) patients in arm B received chemotherapy, which was comparable. About 90 patients received more than 20 Gy in 10 fractions of radiation, 46 patients in arm A and 44 patients in arm B, but treatment status of only 89 patients could be traced at the end.
Table 1: Comparison of patient's characteristics between arm A and arm B

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Table 2: Comparison of treatment characteristics between arm A and arm B

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No skin reaction was seen in any of the 92 patients who were evaluated at first week, which is after 6 Gy/3 fractions and 16 Gy/8 fractions. This could be due to darker skin in our patient where mild erythema is difficult to appreciate and only visual grading was done, while a device like a reflectance spectrophotometer was used in other studies.[12] In second week [Table 3], after completion of 26Gy/13 fractions, grade 1 dermatitis was seen in 9 patients (16.7%) in arm B and 3 patients (5.7%) in arm A, which shows a trend towards higher reaction in arm B. By 3rd week grade 1 skin reaction was significantly more in arm B (50%) than arm A (28.8%) (P-value 0.028) [Table 3]. At 4th, 5th and 6th weeks, grade 1 reaction became higher in arm A [Graph 1]. But grade 2 reaction remained slightly higher in arm B as compared to arm A [Graph 2]. Grade 3 skin reaction occurred in 1 patient in arm A at 5th week, 3 patients each in arm A and B at 6th week [Graph 3]. At 7th week, arm A patient had higher grade 1 reaction (17.3% arm A vs 0% in arm B) and grade 3 reaction (11.5% in arm A vs 7.4% in arm B) but arm B had higher grade 2 (66.7% in arm B vs 55.8% in arm A) and grade 4 reaction (1.9% in arm A vs 0% in arm B). A statistically significant difference was seen between the two groups (P-value 0.015) because of difference in grade 1 and 2 reactions. Difference in moist grade 3 and 4 reactions is negligible. The secondary outcome, that is, subjective symptoms of itching, burning or pain, as described by the patients was adequately noted in only 50 out of 90 treated patients (26 in arm A and 24 in arm B). There was no significant difference seen in subjective symptoms among these patients.
Table 3: Comparison of radiation dermatitis between arm A and arm B at 1st week to 7th week

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Overall treatment gap was seen in 20 patients, 12 in arm A and 8 in arm B due to various reason, but treatment interruptions due to grade 3 skin reaction was seen in 3 patients each in arm A and arm B at 6th week. There was no significant difference in overall treatment gap between the two groups (P-value 0.325). Out of 88 patients who took radiation and were alive, 56 patients (63.6%) came for follow-up. There were 28 patients in each arm, who were evaluated for healing of skin reaction and changes in skin texture. In 46.4% (13/28) of arm A and 33% (9/28) of arm B patients, skin reaction was healed within seven days, while 25% (7/28) arm A and 30% (8/28) of arm B patients healing of reaction took more than ten days. There is no difference in time taken for skin reaction to heal in both the arms (P value 0.531).


  Discussion Top


The topical steroid has delayed the onset and progression of radiation dermatitis as well as improved quality of life in breast cancer patients receiving radiation.[13] Various topical corticosteroids have been tried, but steroid of moderate to high potency give better result than mild steroids.[6],[14] Some studies did not show any benefit over placebo or moisturizing cream, but in these studies either steroid of mild potency was used or application was started after onset of dermatitis.[8],[15],[16] When potent steroid like Betamethasone or momentasone furoate was compared with moisturizing cream or emollient, benefit of steroid was significantly evident.[12],[17] In spite of encouraging result shown in breast cancer, there is paucity of trial in head and neck radiation. Ferreira et al. reviewed the effect of topical intervention on radiation dermatitis of head and neck, where 13 articles from 1980 to 2015 were sorted out. There was no benefit of topical pharmacological ointments such as aloe-vera, trolamine, allantoin, hyaluronic acid, dexpanthenol etc., over the usual skin care or non-pharmacological creams/gel for prevention of acute radiation. But in this review, none of the study used topical steroid, which may be reason for negative result.[18] The reason behind paucity of study evaluating use steroid during radiation in head and neck cancer can be due to fear of possible side effects in long term steroid use that is for duration of seven weeks as compare to five weeks in breast cancer.[19] The incidence of acute radiation dermatitis in breast cancer has decreased due to increasing adaptation of hypofractionation. But on the other hand, the role of hyperfractionation has increased as compared to hypofractionation in head and neck cancer, which further emphasizes the necessity to find methods to decrease radiation dermatitis.

In this study, we found that betamethasone cream delayed the onset of grade 1 radiation dermatitis, therefore steroid should be started prophylactically along with radiation. This finding was similar to the study done by Farhan et al.[13] Grade 2 reaction remains persistently higher in arm B as compared to arm A from 4th week to 7th week, although difference was not statistically significant. The incidence in wet desquamation was not significantly different in both the arms, which was in contrast to study by Shukla et al. where steroid seems to delay wet desquamation.[20] The effect of subjective response in terms of decrease in itching, burning and pain as seen in some studies, was not seen in our study.[8],[20] Time taken for skin reaction to heal in steroid group was same as in control group. No atropic dermatitis, telengectatic changes or eczema was seen in any of the patients in steroid group who came for follow-up in our study.

Limitation of study

The evaluation of skin reaction was done only by visual inspection, which can vary slightly between observers. Evaluation of subjective benefit in terms of itching, burning and pain could not be adequately evaluated. Not all the patient came for follow-up, and longer duration of follow-up is required.


  Conclusion Top


The topical betamethasone cream can delay the onset and progression of radiation dermatitis in head and neck cancer, but no decrease in moist grade 3 or 4 reaction were seen. In our study long term potent corticosteroid was used for the duration of 7 weeks, but no delay in wound healing or adverse effect were seen in the patients who came on follow-up. Therefore, our study allays the fear of long term topical steroid use. We conclude that benefit of topical steroid outweighs the possible risk of side-effect in head and neck cancer patient receiving radiotherapy. But further study with long term follow-up with documentation of systemic side-effects as well as long-term effect is required.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Hansen O, Overgaard J, Hansen HS, Overgaard M, Höyer M, Jörgensen KE, et al. Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: Dependency on tumor differentiation. Radiother Oncol 1997;43:47-51.  Back to cited text no. 1
    
2.
Pignon JP, 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. Radiother Oncol 2009;92:4-14.  Back to cited text no. 2
    
3.
Kupper TS. The activated keratinocyte: A model for inducible cytokine production by non-bone marrow-derived cells in cutaneous inflammatory and immune responses. J Invest Dermatol 1990;94:146-50.  Back to cited text no. 3
    
4.
Brach MA, Hass R, Sherman ML, Gunji H, Weichselbaum R, Kufe D. Ionizing radiation induces expression and binding activity of the nuclear factor kappa B. J Clin Invest 1991;88:691-5.  Back to cited text no. 4
    
5.
Beetz A, Messer G, Oppel T, Beuningen DV, Peter RU, Kind P. Induction of interleukin 6 by ionizing radiation in a human epithelial cell line: Control by corticosteroids. Int J Radiat Biol 1997;72:33-43.  Back to cited text no. 5
    
6.
Haruna F, Lipsett A, Marignol L. Topical Management of acute radiation dermatitis in breast cancer patients: A systematic review and meta-analysis. Anticancer Res 2017;37:5343-53.  Back to cited text no. 6
    
7.
Pitzalis C, Pipitone N, Bajocchi G, Hall M, Goulding N, Lee A, et al. Corticosteroids inhibit lymphocyte binding to endothelium and intercellular adhesion: An additional mechanism for their anti-inflammatory and immunosuppressive effect. J Immunol 1997;158:5007-16.  Back to cited text no. 7
    
8.
Bolderston A, Lloyd NS, Wong RK, 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. Support Care Cancer 2006;14:802-17.  Back to cited text no. 8
    
9.
apps.who.int [internet]. WHO model prescribing information: Drugs used in skin diseases; Annex: Classification of topical corticosteroids. Available from: http://apps.who.int/medicinedocs/en/d/Jh2918e/32.html#Jh2918e. 32.1. [Last updated on 2018 Oct 29; Last cited on 2019 Apr 03].  Back to cited text no. 9
    
10.
British National Formulary (BNF). 69th ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2015.  Back to cited text no. 10
    
11.
Cox JD, Stetz J, Pajak TF. Toxicity criteria of the radiation therapy oncology group (RTOG) and the European organization for research and treatment of cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341-6.  Back to cited text no. 11
    
12.
Boström A, Lindman H, Swartling C, Berne B, Bergh J. Potent corticosteroid cream (mometasone furoate) significantly reduces acute radiation dermatitis: results from a double-blind, randomized study. Radiother Oncol 2001;59:257-65.  Back to cited text no. 12
    
13.
Farhan F, Kazemian A, Alagheband H. Topical betamethasone for the prevention of acute radiation dermatitis in breast cancer patients. Iran J Radiat Res 2003;1:105-11.  Back to cited text no. 13
    
14.
Ahmed I, Marrium H, Wahid Z. Efficacy of potent topical corticosteroid (betamethasone valerate 0.1%) compared with mild topical corticosteroid (hydrocortisone 1%) in the management of acute radiodermatitis. J Pak Ass Dermatol 2006;16:151-6.   Back to cited text no. 14
    
15.
Potera ME, Lookingbill DP, Stryker JA. Prophylaxis of radiation dermatitis with a topical cortisone cream. Radiology 1982;143:775-7.  Back to cited text no. 15
    
16.
Schmuth M, Wimmer MA, Hofer S, Sztankay A, Weinlich G, Linder DM, et al. Topical corticosteroid therapy for acute radiation dermatitis: a prospective, randomized, double-blind study. British Journal of Dermatology 2002;146:983-91.   Back to cited text no. 16
    
17.
Ulff E, Maroti M, Serup J, Falkmer U. A potent steroid cream is superior to emollients in reducing acute radiation dermatitis in breast cancer patients treated with adjuvant radiotherapy: A randomised study of betamethasone versus two moisturizing cream. Radiother Oncol 2013;108:287-92.  Back to cited text no. 17
    
18.
Ferreira EB, Vasques CI, Gadia R, Chan RJ, Guerra EN, Mezzomo LA, et al. Topical interventions to prevent acute radiation dermatitis in head and neck cancer patients: A systematic review. Support Care Cancer 2017;25:1001-11.  Back to cited text no. 18
    
19.
Fisher DA. Adverse effects of topical corticosteroid use. West J Med 1995;162:123-6.  Back to cited text no. 19
    
20.
Shukla PN, Gairola M, Mohanti BK, Rath GK. Prophylactic beclomethasone spray to the skin during postoperative radiotherapy of carcinoma breast: A prospective randomized study. Indian J Cancer 2006;43:180-4.  Back to cited text no. 20
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