Review
Topical corticosteroid therapy for the prevention of acute radiation dermatitis: a systematic review of randomized controlled trials Expert Rev. Clin. Pharmacol. 6(6), 641–649 (2013)
Chandra F Meghrajani*1, Henri Cartier S Co2, Charlene Marie U Ang-Tiu3 and Francisca C Roa4 1 Department of Medicine, Section of Dermatology, University of the Philippines-Philippine General Hospital Taft Avenue, Manila, Philippines 2 Department of Radiology, Section of Radiation Oncology, University of the Philippines-Philippine General Hospital Taft Avenue, Manila, Philippines 3 Department of Medicine, Section of Dermatology, University of the Philippines-Philippine General Hospital Taft Avenue, Manila, Philippines 4 Department of Medicine, Section of Dermatology, University of the Philippines-Philippine General Hospital Taft Avenue, Manila, Philippines * Author for correspondence: Tel.: +632 554 8400 e 5105 Fax: +632 526 2397 [email protected]
www.expert-reviews.com
Acute radiation dermatitis (ARD) is a common side effect of radiation therapy and is characterized by erythema, dry desquamation or moist desquamation. This wet desquamation is a very painful condition for the patient and often leads to interruption of radiotherapy. The objective of this article is to assess the efficacy of topical corticosteroids in the prevention of ARD compared with placebo, other topical medication or no treatment. The prophylactic application of topical corticosteroid among patients undergoing radiotherapy appears to significantly reduce the incidence of ARD, specifically moist desquamation, compared with other treatments. Future trials with a more standardized measure of radiation dermatitis grading are recommended. Further research may also be conducted to determine if a mildly potent, midpotent or super potent topical steroid will be more effective in preventing ARD. KEYWORDS: acute radiation dermatitis • moist desquamation • prophylaxis • randomized controlled trials • systematic review • topical corticosteroid
Description of the condition
Acute radiation dermatitis (ARD) is a frequent side effect encountered by cancer patients undergoing radiotherapy, occurring in about 87% of irradiated patients [1]. The acute effects of radiotherapy to the skin normally occur within 90 days from the first day of treatment [2,3]. A transient early erythema can be seen within a few hours after radiation and subsides after 24–48 h. This is believed to be due to the release of histamine-like substances which cause dermal edema and skin erythema from the permeability and dilation of capillaries [4]. The main erythematous reaction of ARD appears 2 weeks after radiation begins and reflects a varying severity of loss of epidermal basal cells. It has been shown that fields treated with 2 Gray (Gy) daily fractionation do not show changes in the basal cell density until a total dose of 20–25 Gy are delivered [5]. During the third to sixth week of therapy, populations of basal-layer stem cells become 10.1586/17512433.2013.841079
depleted in the treated area, and dry desquamation can develop. Dry desquamation is clinically characterized by scaling and pruritus. Moist desquamation results if all stem cells are eradicated from the basal layer, and is characterized by serous oozing and exposure of the dermis. Moist desquamation may occur following 4–5 weeks of therapy [3]. ARD occurs because skin cells are relatively radiosensitive since they originate from rapidly reproducing differentiated stem cells. These cells which undergo cell division are found in the basal cell layer, and are the primary target for radiation injury. This causes acute skin reactions which are a reflection of the inflammatory response, and the inability of epidermal and dermal cells to keep up with the accelerated loss caused by radiation. Skin response to radiation depends on numerous patient-related and treatment-related factors. Treatment-related factors include beam type and energy, use of tangent fields, use of tissue equivalent material, weekly dose rate,
2013 Informa UK Ltd
ISSN 1751-2433
641
Review
Meghrajani, Co, Ang-Tiu & Roa
accelerated fractionation and field size. On the other hand, patient-related factors include skin folds in the treatment area, nutritional status, smoking, co-morbidities and the use of irritants to irradiated skin [6]. The use of chemotherapy concurrently with radiotherapy is also known to increase skin reactions [5]. The National Cancer Institute has released a guideline called the Common Terminology Criteria for Adverse Events version 3.0 (TABLE 1) in order to help assess the effects of radiation on the skin [6]. It includes skin reactions such as erythema, dry desquamation, hyperpigmentation, hypopigmentation and moist desquamation. If radiation continues at a time when moist desquamation is evident then further injury may cause varying degrees of pain, increase the risk for skin infection and lead to treatment interruptions [5]. Description of the intervention
Topical corticosteroids (TCS) refer to any solution, cream, ointment or lotion containing corticosteroids. The basic steroid structure consists of 17 carbon atoms, arranged in 4 rings, 3 hexane rings and 1 pentane ring. Hydrocortisone is the prototype topical corticosteroid; chemical substitution at certain key positions of this molecule allows for better therapeutic effect and reduced side effects [7]. Corticosteroid strength has been classified according to the vasoconstrictor assay, which depends on the extent to which a compound induces cutaneous vasoconstriction. This roughly estimates the efficacy of TCS, however this vasoconstrictive ability does not always correlate to clinical efficacy [8,9]. Topical corticosteroids are therapeutic because of their anti-inflammatory, immunosuppressive, antiproliferative and vasoconstrictive effects. Immunosuppression is achieved by mitigating the production of humoral factors, inhibiting leukocyte migration and depleting lymphocytes and macrophages. Several cytokines and proteins are also targeted by TCS in order to block inflammation, such as reducing the production of IL-1, IL-2, IFN-g, TNF and GM-CSF, and inducing lipocortins which inhibit the release of phospholipase A2. Suppressing keratinocyte mitosis and inhibiting fibroblast migration and proliferation explain its antiproliferative effects. Cutaneous vasoconstriction is induced by potentiating vascular response to
cathecholamines and reducing their sensitivity to histamine and bradykinin [10]. These same properties of TCS are also responsible for its adverse effects, especially with prolonged use. Common side effects with chronic use are atrophy, telangiectasia, striae, purpura and skin infection [8]. Owing to its anti-inflammatory and antiproliferative properties, TCS have been used extensively for various inflammatory and hyperproliferative dermatoses. Skin conditions that are known to respond well to TCS are atopic dermatitis, seborrheic dermatitis, diaper dermatitis and intertriginous psoriasis [10]. How the intervention might work?
Topical corticosteroids are one of the many interventions recommended for the treatment and prophylaxis of radiation dermatitis because these agents have documented antiinflammatory effects. The beneficial effect of topical steroids in preventing radiation dermatitis has been linked to the suppression of cytokines released during radiotherapy. After irradiating murine skin with 15 Gy, researchers detected an increase in pro-inflammatory mediators such as IL-1B, TNF-a, TGF-b1 and IL-6. These cytokines have been shown to contribute to cutaneous inflammation after irradiation. Some of the irradiated skin samples were then treated with topical mometasone and were noted to have a significant decrease of the abovementioned proinflammatory mediators [11]. In an in vitro study involving the human epithelial HeLa cell line, they were able to detect an elevation of the pluripotent cytokine IL-6 after irradiation. They similarly demonstrated that application of topical steroids, such as mometasone and hydrocortisone, were able to downregulate the expression of IL-6 [12]. Indicating that the application of topical corticosteroids can mitigate skin toxicity caused by irradiation. In both studies, it was also noted that the proinflammatory mediators involved in radiation dermatitis were elevated within the first 24 h of radiation exposure [11,12]. This underscores the need for application of topical steroids starting on the first day of radiotherapy, even if there are no signs of radiation dermatitis yet. Another substance possibly targeted by topical corticosteroids in radiation dermatitis is histamine. Moriyasu et al. were able to demonstrate that histamine was involved in the development of radiation-induced erythema and edema. They observed that
Table 1. Acute radiation dermatitis scoring criteria (CTCAE v3.0). Grade 0
1
2
Radiation dermatitis
None
Faint erythema or dry desquamation
Moderate to brisk erythema; patchy moist desquamation, mostly confined to skin folds and creases; moderate edema
Hyperpigmentation
None
Slight or localized
Marked or generalized
Hypopigmentation
None
Slight or localized
Marked or generalized
642
3 Confluent moist desquamation, other than skin folds and creases; bleeding induced by minor trauma or abrasion
4 Skin necrosis or ulceration of full thickness dermis; spontaneous bleeding from involved site
Expert Rev. Clin. Pharmacol. 6(6), (2013)
Topical corticosteroid therapy for the prevention of acute radiation dermatitis
the irradiation of skin of mast cell deficient mice never led to erythema and edema, and that blockage of H1 receptors with antihistamine inhibited erythema and edema induced by gamma irradiation [13]. The long-term application of topical steroids (>6 weeks) has been shown to decrease histamine and deplete mast cells on skin [14,15]. Why it is important to do this review?
At present, there are many skin care regimens that have been recommended for the prevention and management of ARD, such as the use of aloe vera gel, hydrocolloid dressing and zinc. However, there is a lack of support for most practice interventions [6]. Topical corticosteroids are also one of the many interventions recommended for the treatment and prophylaxis of radiation dermatitis. However, its use in radiation dermatitis is deemed controversial since most randomized controlled trials done on this mode of therapy show conflicting results [1,16–20]. Another limitation is that most trials had small sample sizes and used topical corticosteroids of varying potency. In performing a systematic review, we can pool together the data from randomized trials and determine if the prophylactic use of topical corticosteroids for ARD will be beneficial. Methodology
An electronic literature search was conducted in PubMed, Cochrane Library, Ovid, Clinicaltrials.gov and Google Scholar. Search terms used were: radiation dermatitis, treatment, prophylaxis and topical corticosteroid. All randomized controlled trials with parallel study design on topical corticosteroids for the prevention of ARD, regardless of year of publication, were considered eligible. A limit for this review is that only articles published in English were included. The list of references of all included studies and other related articles were also reviewed. Two authors independently screened all potential articles and reviewed the eligible studies. In the studies selected, participants should be cancer patients undergoing external radiotherapy for any form of malignancy, whether male or female, with no exclusion on the basis of age or other demographic characteristics. Intervention included any topical corticosteroid applied as a single agent from the first to the last day of radiotherapy with the intent of preventing ARD. Corticosteroids may be in the form of cream, ointment, lotion or spray. Any dosing regimen was considered acceptable. Comparators could be placebo, other topical medication or no treatment. For the purpose of calculating clinical efficacy, the prevention of moist desquamation or grade 3 radiation dermatitis was agreed upon as the primary outcome measure. Outcome assessment was set at the 5th week, since moist desquamation usually occurs by the 5th week of radiotherapy. Secondary outcomes included were mean ARD scores, patient-reported symptoms of pruritus, burning and pain, quality of life scores and adverse events due to the medication. Data that were extracted from the eligible studies were assembled in Review Manager (version 5.0). Each study was www.expert-reviews.com
Review
also reviewed for risk of bias. In the five articles where incidence of moist desquamation was reported (Omidvari et al. [1], Bostrom et al. [16], Farhan et al. [18], Shukla et al. [19], Miller et al. [20]), a meta-analysis was performed. Quantitative synthesis of mean ARD scores was also done on five studies (Omidvari et al. [1], Bostrom et al. [16], Schmuth et al. [17], Farhan et al. [18] and Miller et al. [20]). Statistical analysis was carried out using the Review Manager software. Data on quality of life and adverse effects from study medication were also summarized. Results
A total of 11 clinical trials utilizing topical steroids for the prevention of ARD were identified. Of these, five studies were excluded. One was a left-right comparison study [21], two were not randomized controlled trials [22,23] and two did not meet the inclusion criteria [24,25]. The study by Glees did not apply topical steroids at the beginning of radiotherapy [24] while the study by Bjo¨rnberg et al. had normal subjects as study participants instead of cancer patients [25]. In the end, six trials met the inclusion criteria and were included in the systematic review (FIGURE 1). All six studies were randomized controlled trials with parallel study design; five were double-blinded while one study did not indicate if blinding was done [19]. All randomized controlled studies utilizing a topical corticosteroid compared with vehicle or other emollients as prophylaxis for ARD were included in the review. The studies were published in 2001, 2002, 2003, 2006, 2007 and 2011. A total of 413 participants were enrolled in the six studies. All the subjects had histopathologic evidence of breast cancer who underwent modified radical mastectomy or breast conservation surgery with an indication for post-operative radiotherapy. Participants were all female with age ranging from 27 to 89 years. Radiotherapy was administered for an average of 25–39 days at a dose of 50–60 Gy. There was no statistically significant difference in the patients’ baseline data and demographics among the studies. Participants were randomly assigned to receive a topical corticosteroid, vehicle, another emollient or no treatment. Topical corticosteroids used in the studies ranged from mild to potent (TABLE 2) and the vehicles used were cream, ointment or liquid solution. Topical agents were applied either once or twice a day from the first to the last day of radiotherapy, and some up to 2 weeks post-radiotherapy. In all of the studies, patients were not allowed to apply any other medication to the treatment area during the study period. The study by Bostrom et al. in 2001 was a randomized double-blind trial comparing the efficacy of mometasone furoate cream to an emollient cream. Adverse reaction on the skin was graded on a 7-point scale, with 0 = no reaction and 6 = moist desquamation or ulceration. Erythema, as detected by spectrophotometry, and maximal skin reactions were significantly lower in the steroid group (p = 0.0033 and 0.011) [16]. In 2002, Schmuth et al. conducted a double-blind randomized study comparing 0.1% methylprednisolone cream with dexpanthenol cream (they also compared the two groups with an 643
Review
Meghrajani, Co, Ang-Tiu & Roa
Records identified from database (n = 115)
Duplicates (n = 9)
Articles screened on basis of title and abstract (n = 106)
Excluded (n = 95) • Not relevant to radiodermatitis = 41 • Intervention not topical steroid = 37 • Laboratory work = 4 • Case reports = 4 • Guidelines/review = 4 • Article not in English = 3 • Combination therapy = 1 • Animal studies = 1
petrolatum, the difference did not reach significance but approached it (p = 0.055) [1]. Both studies observed that ARD occurred much later in the study period among the steroid group. In 2011, Miller et al. conducted a randomized, double-blind study comparing 0.1% mometasone furoate cream with placebo cream. They found no difference in mean maximum grade of radiation dermatitis between the two groups (p = 0.18); however, CTCAE scores for pruritus were lower in the steroid group (p = 0.04) [20]. Primary outcome
Among the six studies included in the systematic review, only five articles stated the incidence of moist desquamation Excluded (n = 5) or grade 3 radiation dermatitis in its • Left-right comparison study = 1 • Not a randomised controlled trial = 2 results [1,16,18–20], together those five stud• Did not meet inclusion criteria = 2 ies had a total of 383 subjects. Four Articles included in out of the five studies showed a lower qualitative synthesis incidence of moist desquamation in the (n = 6) steroid group as compared with control [1,16–18]. In the pooled analysis, use of Articles included in topical corticosteroid was associated with quantitative synthesis a significantly lower incidence of moist (n = 5) desquamation (risk ratio = 0.39; 95% confidence interval: 0.19–0.80; p = 0.01). Figure 1. Study selection process. There was no evidence of heterogeneity (I2 = 0%). Simply stated, the risk of initial cohort of untreated patients). Patients were assessed for developing moist desquamation is 2.5-times less likely with the transepidermal water loss and signs of erythema, desquamation, use of topical steroids (FIGURE 2). erosion, induration and hyperpigmentation. With topical corticosteroids, it was noted that clinical symptoms and transepider- Secondary outcomes mal water loss were less pronounced than with dexpanthenol [17]. ARD scores were reported in five of the six studies in this In 2006, Shukla et al. compared the prophylactic application of review [1,16–18,20]. As mentioned above, the clinical scale used by beclomethasone spray to no treatment. Patients in the steroid each study differed. Omidvari et al. [1] and Farhan et al. [18] used group had a lower incidence of moist desquamation compared the RTOG scale which is similar to the CTCAE scale used by with control (13.33 vs 36.66% for the beclomethasone and con- Miller et al. [20]. Schmuth et al. [17] and Bostrom et al. [16], on the trol groups, respectively; p = 0.0369) [19]. Both Farhan et al. and other hand, used their own clinical scales. Mean ARD scores and Omidvari et al. performed a randomized, double-blind trial com- their standard deviation were imputed from the graphs presented paring 0.1% betamethasone ointment with petrolatum [1,18]. by Omidvari et al. [1] and Schmuth et al. [17], while values for However, Omidvari et al. had a third group of patients receiving Bostrom et al. [16] and Farhan et al. [18] were derived from their no topical treatment. The subjects’ dermatitis grade was measured maximum erythema score table and maximal intensity of dermausing the Radiation Therapy Oncology Group acute radiation titis table, respectively. Mean ARD scores at the end of treatment morbidity scoring criteria for skin, which is similar to the for each study are shown in TABLE 3. Since the clinical scales used CTCAE (Common Terminology Criteria for Adverse Events) to measure ARD scores between trials varied, we used the standscale. Farhan et al. demonstrated that the weekly mean dermatitis ardized mean difference to do a quantitative synthesis of these grade was lower for the steroid group during the whole trial and results. Results showed that there was reduction of mean radiapatients receiving topical steroid recovered sooner (patients tion dermatitis scores across the trials; however, data were not with radiation dermatitis 3 weeks post-treatment: 26.3% in the homogenous (I2 = 71%) (FIGURE 3). betamethasone group vs 73.5% in the petrolatum group, Patient-reported symptoms of pruritus, burning and pain p = 0.001) [18]. In the study by Omidvari et al., patients receiving were noted in three trials [16,18,20]. All three studies reported less betamethasone had lower mean ARD scores compared with itching and burning in the steroid arm as compared with the Full-text articles assessed for eligibility (n = 11)
644
Expert Rev. Clin. Pharmacol. 6(6), (2013)
www.expert-reviews.com
47–76
All female
BCS
Linear accelerator
54–56
39
Age range (years)
Gender
Surgery
RT machine
RT dose (Gy)
Duration of RT (days)
2/week 2 weeks, then once daily
8 weeks
Frequency of application
Duration of treatment
8 weeks
0
Study duration
Dropout rate (%)
8.7 (methyl)
8 weeks
Clinical scale
3.9 (placebo)
8 weeks
RTOG
7–8 weeks
Twice daily
Placebo ointment
Betamethasone 0.1% ointment
25–30
50–60
Cobalt machine
MRM & BCS
All female
27–70
76 (38 beta/38 placebo)
Farhan et al. (2003) [18]
0
9 weeks
Clinical scale
5 weeks
2 puffs Twice daily
No treatment
Beclomethasone aerosol 100 mg/puff
25
50
Cobalt machine
MRM & BCS
All female
28–60
60 (30 beclo/30 no tx)
Shukla et al. (2006) [19]
0
7 weeks
RTOG
7 weeks
Twice daily
Petrolatum
Betamethasone 0.1% ointment
25
50
Cobalt machine
MRM
All female
35–66
36 (19 beta/17 pet)
Omidvari et al. (2007) [1]
1.76 (1.17 MMF/ 2.38 placebo)
7 weeks
CTCAE
7–8 weeks
Once daily
Placebo cream
Mometasone 0.1% cream
25–30
50–60
Linear accelerator
MRM & BCS
All female
27–89
169 (85 MMF/ 84 placebo)
Miller et al. (2011) [20]
BCS: Breast conservation surgery; beclo: Beclomethasone; beta: Betamethsone; CTCAE: Common terminology criteria for adverse events; dex: Dexpanthenol; Gy: Gray; methyl: Methylprednisolone; MMF: Mometasone furoate; MRM: Modified radical mastectomy; no tx: No treatment; pet: Petrolatum; RT: Radiotherapy; RTOG: Radiation therapy oncology group.
Clinical scale
Scale used
Outcome assessment
Twice daily
Placebo cream
Comparator
8 weeks
Dexpanthenol
Mometasone 0.1% cream
Metyhlprednisolone 0.1% cream
30
50–60
Linear accelerator
BCS
All female
29–75
23 (12 methyl/11 dex)
Schmuth et al. (2002) [17]
Topical steroid
Intervention
49 (24 MMF/25 placebo)
Subjects (n)
Population characteristics
Bostrom e t al. (2001) [16]
Table 2. Study characteristics of included trials.
Topical corticosteroid therapy for the prevention of acute radiation dermatitis
Review
645
Review
Meghrajani, Co, Ang-Tiu & Roa
Steroid Control Odds ratio Events Total Events Total Weight M–H, fixed, 95% CI Year
Study (year) Bostrom et al. (2001) [16] Farhan et al. (2003) [18] Shukla et al. (2006) [19] Omidvari et al. (2007) [1] Miller et al. (2011) [20]
4 0 4 0 4
24 38 30 19 84
10 1 11 1 4
25 34 30 17 82
33.1% 6.3% 38.7% 6.2% 15.6%
Total (95% CI) 195 188 100.0% Total events 12 27 Heterogeneity: Chi2 = 2.16, df = 4 (p = 0.71); I2 = 0% Test for overall effect: Z = 2.56 (p = 0.01)
0.30 [0.08, 1.14] 0.29 [0.01, 7.36] 0.27 [0.07, 0.96] 0.28 [0.01, 7.40] 0.97 [0.24, 1.04]
Odds ratio M–H, fixed,95% CI
2001 2003 2006 2007 2011
0.39 [0.19, 0.80]
0.01 0.1 1 Favors [experimental]
10 100 Favors [control]
Figure 2. Forest plot of comparison: steroid versus control, incidence of moist desquamation at week 5. df: degrees of freedom, Fixed: Fixed Effect, M–H: Mantel–Haenszel.
control arm, however, only the study by Farhan et al. and Miller et al. showed significant results (TABLE 3) [18,20]. There was no difference in pain between treatment groups in all three studies. The study by Schmuth et al. and by Miller et al. assessed quality of life in their patients. They both utilized Skindex to assess skin-related mental issues [17,20]. Schmuth et al. noted that the control group had deterioration in all dimensions while only four of seven dimensions worsened in the steroid
group [17]. The study by Miller et al. reported a mean Skindex score of 1.4 for the steroid arm and 1.7 for the placebo arm [20]. Although both studies did not demonstrate a significant difference between treatment groups with regards to quality of life, they both suggested a trend toward a more favorable outcome in patients treated with topical steroids. Adverse events due to the medication were reported only by Schmuth et al. They noted itching in three patients (dexpanthenol n = 1; methylprednisolone n = 2), burning in one
Table 3. Primary and secondary outcomes. Outcome
Bostrom et al. (2001) [16] MMF versus placebo
Schmuth et al. (2002) [17] methyl versus dex
Farhan et al. (2003) [18] beta versus placebo
Shukla et al. (2006) [19] beclo versus no tx
Omidvari et al. (2007) [1] Beta vers us pet
Miller et al. (2011) [20] MMF versus placebo
Beta 0% Placebo 2.9%
Beclo 13.3% No tx 36.6%
Beta 0% Pet 6%
MMF 4.8% Placebo 4.9%
1.3 ± 0.3 versus 1.5 ± 0.3
1.2 ± 0.85 versus 1.3 ± 0.80
Primary outcomes Incidence of moist desquamation
MMF 16% Placebo 40%
Secondary outcomes ARD scores (mean + SD)
1.8 ± 0.7 versus 2.3 ± 0.63
Quality of life
1.6 ± 0.25 versus 2.2 ± 0.4
1.0 ± 0.37 versus 1.4 ± 0.56
1.4 versus 1.7 (p = 0.07)
methyl: 4 out of 7 worsened dex: 7 out of 7 worsened
Patient-reported symptoms Pruritus
Less in MMF, p = 0.087
Less in beta, p < 0.05
1.5 versus 2.2 (p = 0.002)
Burning
Less in MMF, p = 0.069
Less in beta, p < 0.05
1.5 versus 2.1 (p = 0.02)
Pain
No difference
No difference
2.1 versus 2.5 (p = 0.11)
Beclo: Beclomethasone; Beta: Betamethsone; Dex: Dexpanthenol; Methyl: Methylprednisolone; MMF: Mometasone furoate; No tx: No treatment; Pet: Petrolatum; SD: Standard deviation.
646
Expert Rev. Clin. Pharmacol. 6(6), (2013)
Topical corticosteroid therapy for the prevention of acute radiation dermatitis
Study (year)
Steroid Control Standard mean difference Mean SD Total Mean SD Total Weight IV, fixed, 95% CI Year
Bostrom et al. (2001) [16] Schmuth et al. (2002) [17] Farhan et al. (2003) [18] Omidvari et al. (2007) [1] Miller et al. (2011) [20]
1.8 1.6 1 1.3 1.2
0.7 0.25 0.37 0.3 0.85
24 10 38 19 84
2.3 2.2 1.4 1.5 1.3
0.63 0.4 0.56 0.3 0.8
Total (95% CI) 175 Heterogeneity: Chi2 = 13.99, df = 4 (p = 0.007); I2 = 71% Test for overall effect: Z = 4.33 (p
Topical corticosteroid therapy for the prevention of acute radiation dermatitis: a systematic review of randomized controlled trials Expert Rev. Clin. Pharmacol. 6(6), 641–649 (2013)
Chandra F Meghrajani*1, Henri Cartier S Co2, Charlene Marie U Ang-Tiu3 and Francisca C Roa4 1 Department of Medicine, Section of Dermatology, University of the Philippines-Philippine General Hospital Taft Avenue, Manila, Philippines 2 Department of Radiology, Section of Radiation Oncology, University of the Philippines-Philippine General Hospital Taft Avenue, Manila, Philippines 3 Department of Medicine, Section of Dermatology, University of the Philippines-Philippine General Hospital Taft Avenue, Manila, Philippines 4 Department of Medicine, Section of Dermatology, University of the Philippines-Philippine General Hospital Taft Avenue, Manila, Philippines * Author for correspondence: Tel.: +632 554 8400 e 5105 Fax: +632 526 2397 [email protected]
www.expert-reviews.com
Acute radiation dermatitis (ARD) is a common side effect of radiation therapy and is characterized by erythema, dry desquamation or moist desquamation. This wet desquamation is a very painful condition for the patient and often leads to interruption of radiotherapy. The objective of this article is to assess the efficacy of topical corticosteroids in the prevention of ARD compared with placebo, other topical medication or no treatment. The prophylactic application of topical corticosteroid among patients undergoing radiotherapy appears to significantly reduce the incidence of ARD, specifically moist desquamation, compared with other treatments. Future trials with a more standardized measure of radiation dermatitis grading are recommended. Further research may also be conducted to determine if a mildly potent, midpotent or super potent topical steroid will be more effective in preventing ARD. KEYWORDS: acute radiation dermatitis • moist desquamation • prophylaxis • randomized controlled trials • systematic review • topical corticosteroid
Description of the condition
Acute radiation dermatitis (ARD) is a frequent side effect encountered by cancer patients undergoing radiotherapy, occurring in about 87% of irradiated patients [1]. The acute effects of radiotherapy to the skin normally occur within 90 days from the first day of treatment [2,3]. A transient early erythema can be seen within a few hours after radiation and subsides after 24–48 h. This is believed to be due to the release of histamine-like substances which cause dermal edema and skin erythema from the permeability and dilation of capillaries [4]. The main erythematous reaction of ARD appears 2 weeks after radiation begins and reflects a varying severity of loss of epidermal basal cells. It has been shown that fields treated with 2 Gray (Gy) daily fractionation do not show changes in the basal cell density until a total dose of 20–25 Gy are delivered [5]. During the third to sixth week of therapy, populations of basal-layer stem cells become 10.1586/17512433.2013.841079
depleted in the treated area, and dry desquamation can develop. Dry desquamation is clinically characterized by scaling and pruritus. Moist desquamation results if all stem cells are eradicated from the basal layer, and is characterized by serous oozing and exposure of the dermis. Moist desquamation may occur following 4–5 weeks of therapy [3]. ARD occurs because skin cells are relatively radiosensitive since they originate from rapidly reproducing differentiated stem cells. These cells which undergo cell division are found in the basal cell layer, and are the primary target for radiation injury. This causes acute skin reactions which are a reflection of the inflammatory response, and the inability of epidermal and dermal cells to keep up with the accelerated loss caused by radiation. Skin response to radiation depends on numerous patient-related and treatment-related factors. Treatment-related factors include beam type and energy, use of tangent fields, use of tissue equivalent material, weekly dose rate,
2013 Informa UK Ltd
ISSN 1751-2433
641
Review
Meghrajani, Co, Ang-Tiu & Roa
accelerated fractionation and field size. On the other hand, patient-related factors include skin folds in the treatment area, nutritional status, smoking, co-morbidities and the use of irritants to irradiated skin [6]. The use of chemotherapy concurrently with radiotherapy is also known to increase skin reactions [5]. The National Cancer Institute has released a guideline called the Common Terminology Criteria for Adverse Events version 3.0 (TABLE 1) in order to help assess the effects of radiation on the skin [6]. It includes skin reactions such as erythema, dry desquamation, hyperpigmentation, hypopigmentation and moist desquamation. If radiation continues at a time when moist desquamation is evident then further injury may cause varying degrees of pain, increase the risk for skin infection and lead to treatment interruptions [5]. Description of the intervention
Topical corticosteroids (TCS) refer to any solution, cream, ointment or lotion containing corticosteroids. The basic steroid structure consists of 17 carbon atoms, arranged in 4 rings, 3 hexane rings and 1 pentane ring. Hydrocortisone is the prototype topical corticosteroid; chemical substitution at certain key positions of this molecule allows for better therapeutic effect and reduced side effects [7]. Corticosteroid strength has been classified according to the vasoconstrictor assay, which depends on the extent to which a compound induces cutaneous vasoconstriction. This roughly estimates the efficacy of TCS, however this vasoconstrictive ability does not always correlate to clinical efficacy [8,9]. Topical corticosteroids are therapeutic because of their anti-inflammatory, immunosuppressive, antiproliferative and vasoconstrictive effects. Immunosuppression is achieved by mitigating the production of humoral factors, inhibiting leukocyte migration and depleting lymphocytes and macrophages. Several cytokines and proteins are also targeted by TCS in order to block inflammation, such as reducing the production of IL-1, IL-2, IFN-g, TNF and GM-CSF, and inducing lipocortins which inhibit the release of phospholipase A2. Suppressing keratinocyte mitosis and inhibiting fibroblast migration and proliferation explain its antiproliferative effects. Cutaneous vasoconstriction is induced by potentiating vascular response to
cathecholamines and reducing their sensitivity to histamine and bradykinin [10]. These same properties of TCS are also responsible for its adverse effects, especially with prolonged use. Common side effects with chronic use are atrophy, telangiectasia, striae, purpura and skin infection [8]. Owing to its anti-inflammatory and antiproliferative properties, TCS have been used extensively for various inflammatory and hyperproliferative dermatoses. Skin conditions that are known to respond well to TCS are atopic dermatitis, seborrheic dermatitis, diaper dermatitis and intertriginous psoriasis [10]. How the intervention might work?
Topical corticosteroids are one of the many interventions recommended for the treatment and prophylaxis of radiation dermatitis because these agents have documented antiinflammatory effects. The beneficial effect of topical steroids in preventing radiation dermatitis has been linked to the suppression of cytokines released during radiotherapy. After irradiating murine skin with 15 Gy, researchers detected an increase in pro-inflammatory mediators such as IL-1B, TNF-a, TGF-b1 and IL-6. These cytokines have been shown to contribute to cutaneous inflammation after irradiation. Some of the irradiated skin samples were then treated with topical mometasone and were noted to have a significant decrease of the abovementioned proinflammatory mediators [11]. In an in vitro study involving the human epithelial HeLa cell line, they were able to detect an elevation of the pluripotent cytokine IL-6 after irradiation. They similarly demonstrated that application of topical steroids, such as mometasone and hydrocortisone, were able to downregulate the expression of IL-6 [12]. Indicating that the application of topical corticosteroids can mitigate skin toxicity caused by irradiation. In both studies, it was also noted that the proinflammatory mediators involved in radiation dermatitis were elevated within the first 24 h of radiation exposure [11,12]. This underscores the need for application of topical steroids starting on the first day of radiotherapy, even if there are no signs of radiation dermatitis yet. Another substance possibly targeted by topical corticosteroids in radiation dermatitis is histamine. Moriyasu et al. were able to demonstrate that histamine was involved in the development of radiation-induced erythema and edema. They observed that
Table 1. Acute radiation dermatitis scoring criteria (CTCAE v3.0). Grade 0
1
2
Radiation dermatitis
None
Faint erythema or dry desquamation
Moderate to brisk erythema; patchy moist desquamation, mostly confined to skin folds and creases; moderate edema
Hyperpigmentation
None
Slight or localized
Marked or generalized
Hypopigmentation
None
Slight or localized
Marked or generalized
642
3 Confluent moist desquamation, other than skin folds and creases; bleeding induced by minor trauma or abrasion
4 Skin necrosis or ulceration of full thickness dermis; spontaneous bleeding from involved site
Expert Rev. Clin. Pharmacol. 6(6), (2013)
Topical corticosteroid therapy for the prevention of acute radiation dermatitis
the irradiation of skin of mast cell deficient mice never led to erythema and edema, and that blockage of H1 receptors with antihistamine inhibited erythema and edema induced by gamma irradiation [13]. The long-term application of topical steroids (>6 weeks) has been shown to decrease histamine and deplete mast cells on skin [14,15]. Why it is important to do this review?
At present, there are many skin care regimens that have been recommended for the prevention and management of ARD, such as the use of aloe vera gel, hydrocolloid dressing and zinc. However, there is a lack of support for most practice interventions [6]. Topical corticosteroids are also one of the many interventions recommended for the treatment and prophylaxis of radiation dermatitis. However, its use in radiation dermatitis is deemed controversial since most randomized controlled trials done on this mode of therapy show conflicting results [1,16–20]. Another limitation is that most trials had small sample sizes and used topical corticosteroids of varying potency. In performing a systematic review, we can pool together the data from randomized trials and determine if the prophylactic use of topical corticosteroids for ARD will be beneficial. Methodology
An electronic literature search was conducted in PubMed, Cochrane Library, Ovid, Clinicaltrials.gov and Google Scholar. Search terms used were: radiation dermatitis, treatment, prophylaxis and topical corticosteroid. All randomized controlled trials with parallel study design on topical corticosteroids for the prevention of ARD, regardless of year of publication, were considered eligible. A limit for this review is that only articles published in English were included. The list of references of all included studies and other related articles were also reviewed. Two authors independently screened all potential articles and reviewed the eligible studies. In the studies selected, participants should be cancer patients undergoing external radiotherapy for any form of malignancy, whether male or female, with no exclusion on the basis of age or other demographic characteristics. Intervention included any topical corticosteroid applied as a single agent from the first to the last day of radiotherapy with the intent of preventing ARD. Corticosteroids may be in the form of cream, ointment, lotion or spray. Any dosing regimen was considered acceptable. Comparators could be placebo, other topical medication or no treatment. For the purpose of calculating clinical efficacy, the prevention of moist desquamation or grade 3 radiation dermatitis was agreed upon as the primary outcome measure. Outcome assessment was set at the 5th week, since moist desquamation usually occurs by the 5th week of radiotherapy. Secondary outcomes included were mean ARD scores, patient-reported symptoms of pruritus, burning and pain, quality of life scores and adverse events due to the medication. Data that were extracted from the eligible studies were assembled in Review Manager (version 5.0). Each study was www.expert-reviews.com
Review
also reviewed for risk of bias. In the five articles where incidence of moist desquamation was reported (Omidvari et al. [1], Bostrom et al. [16], Farhan et al. [18], Shukla et al. [19], Miller et al. [20]), a meta-analysis was performed. Quantitative synthesis of mean ARD scores was also done on five studies (Omidvari et al. [1], Bostrom et al. [16], Schmuth et al. [17], Farhan et al. [18] and Miller et al. [20]). Statistical analysis was carried out using the Review Manager software. Data on quality of life and adverse effects from study medication were also summarized. Results
A total of 11 clinical trials utilizing topical steroids for the prevention of ARD were identified. Of these, five studies were excluded. One was a left-right comparison study [21], two were not randomized controlled trials [22,23] and two did not meet the inclusion criteria [24,25]. The study by Glees did not apply topical steroids at the beginning of radiotherapy [24] while the study by Bjo¨rnberg et al. had normal subjects as study participants instead of cancer patients [25]. In the end, six trials met the inclusion criteria and were included in the systematic review (FIGURE 1). All six studies were randomized controlled trials with parallel study design; five were double-blinded while one study did not indicate if blinding was done [19]. All randomized controlled studies utilizing a topical corticosteroid compared with vehicle or other emollients as prophylaxis for ARD were included in the review. The studies were published in 2001, 2002, 2003, 2006, 2007 and 2011. A total of 413 participants were enrolled in the six studies. All the subjects had histopathologic evidence of breast cancer who underwent modified radical mastectomy or breast conservation surgery with an indication for post-operative radiotherapy. Participants were all female with age ranging from 27 to 89 years. Radiotherapy was administered for an average of 25–39 days at a dose of 50–60 Gy. There was no statistically significant difference in the patients’ baseline data and demographics among the studies. Participants were randomly assigned to receive a topical corticosteroid, vehicle, another emollient or no treatment. Topical corticosteroids used in the studies ranged from mild to potent (TABLE 2) and the vehicles used were cream, ointment or liquid solution. Topical agents were applied either once or twice a day from the first to the last day of radiotherapy, and some up to 2 weeks post-radiotherapy. In all of the studies, patients were not allowed to apply any other medication to the treatment area during the study period. The study by Bostrom et al. in 2001 was a randomized double-blind trial comparing the efficacy of mometasone furoate cream to an emollient cream. Adverse reaction on the skin was graded on a 7-point scale, with 0 = no reaction and 6 = moist desquamation or ulceration. Erythema, as detected by spectrophotometry, and maximal skin reactions were significantly lower in the steroid group (p = 0.0033 and 0.011) [16]. In 2002, Schmuth et al. conducted a double-blind randomized study comparing 0.1% methylprednisolone cream with dexpanthenol cream (they also compared the two groups with an 643
Review
Meghrajani, Co, Ang-Tiu & Roa
Records identified from database (n = 115)
Duplicates (n = 9)
Articles screened on basis of title and abstract (n = 106)
Excluded (n = 95) • Not relevant to radiodermatitis = 41 • Intervention not topical steroid = 37 • Laboratory work = 4 • Case reports = 4 • Guidelines/review = 4 • Article not in English = 3 • Combination therapy = 1 • Animal studies = 1
petrolatum, the difference did not reach significance but approached it (p = 0.055) [1]. Both studies observed that ARD occurred much later in the study period among the steroid group. In 2011, Miller et al. conducted a randomized, double-blind study comparing 0.1% mometasone furoate cream with placebo cream. They found no difference in mean maximum grade of radiation dermatitis between the two groups (p = 0.18); however, CTCAE scores for pruritus were lower in the steroid group (p = 0.04) [20]. Primary outcome
Among the six studies included in the systematic review, only five articles stated the incidence of moist desquamation Excluded (n = 5) or grade 3 radiation dermatitis in its • Left-right comparison study = 1 • Not a randomised controlled trial = 2 results [1,16,18–20], together those five stud• Did not meet inclusion criteria = 2 ies had a total of 383 subjects. Four Articles included in out of the five studies showed a lower qualitative synthesis incidence of moist desquamation in the (n = 6) steroid group as compared with control [1,16–18]. In the pooled analysis, use of Articles included in topical corticosteroid was associated with quantitative synthesis a significantly lower incidence of moist (n = 5) desquamation (risk ratio = 0.39; 95% confidence interval: 0.19–0.80; p = 0.01). Figure 1. Study selection process. There was no evidence of heterogeneity (I2 = 0%). Simply stated, the risk of initial cohort of untreated patients). Patients were assessed for developing moist desquamation is 2.5-times less likely with the transepidermal water loss and signs of erythema, desquamation, use of topical steroids (FIGURE 2). erosion, induration and hyperpigmentation. With topical corticosteroids, it was noted that clinical symptoms and transepider- Secondary outcomes mal water loss were less pronounced than with dexpanthenol [17]. ARD scores were reported in five of the six studies in this In 2006, Shukla et al. compared the prophylactic application of review [1,16–18,20]. As mentioned above, the clinical scale used by beclomethasone spray to no treatment. Patients in the steroid each study differed. Omidvari et al. [1] and Farhan et al. [18] used group had a lower incidence of moist desquamation compared the RTOG scale which is similar to the CTCAE scale used by with control (13.33 vs 36.66% for the beclomethasone and con- Miller et al. [20]. Schmuth et al. [17] and Bostrom et al. [16], on the trol groups, respectively; p = 0.0369) [19]. Both Farhan et al. and other hand, used their own clinical scales. Mean ARD scores and Omidvari et al. performed a randomized, double-blind trial com- their standard deviation were imputed from the graphs presented paring 0.1% betamethasone ointment with petrolatum [1,18]. by Omidvari et al. [1] and Schmuth et al. [17], while values for However, Omidvari et al. had a third group of patients receiving Bostrom et al. [16] and Farhan et al. [18] were derived from their no topical treatment. The subjects’ dermatitis grade was measured maximum erythema score table and maximal intensity of dermausing the Radiation Therapy Oncology Group acute radiation titis table, respectively. Mean ARD scores at the end of treatment morbidity scoring criteria for skin, which is similar to the for each study are shown in TABLE 3. Since the clinical scales used CTCAE (Common Terminology Criteria for Adverse Events) to measure ARD scores between trials varied, we used the standscale. Farhan et al. demonstrated that the weekly mean dermatitis ardized mean difference to do a quantitative synthesis of these grade was lower for the steroid group during the whole trial and results. Results showed that there was reduction of mean radiapatients receiving topical steroid recovered sooner (patients tion dermatitis scores across the trials; however, data were not with radiation dermatitis 3 weeks post-treatment: 26.3% in the homogenous (I2 = 71%) (FIGURE 3). betamethasone group vs 73.5% in the petrolatum group, Patient-reported symptoms of pruritus, burning and pain p = 0.001) [18]. In the study by Omidvari et al., patients receiving were noted in three trials [16,18,20]. All three studies reported less betamethasone had lower mean ARD scores compared with itching and burning in the steroid arm as compared with the Full-text articles assessed for eligibility (n = 11)
644
Expert Rev. Clin. Pharmacol. 6(6), (2013)
www.expert-reviews.com
47–76
All female
BCS
Linear accelerator
54–56
39
Age range (years)
Gender
Surgery
RT machine
RT dose (Gy)
Duration of RT (days)
2/week 2 weeks, then once daily
8 weeks
Frequency of application
Duration of treatment
8 weeks
0
Study duration
Dropout rate (%)
8.7 (methyl)
8 weeks
Clinical scale
3.9 (placebo)
8 weeks
RTOG
7–8 weeks
Twice daily
Placebo ointment
Betamethasone 0.1% ointment
25–30
50–60
Cobalt machine
MRM & BCS
All female
27–70
76 (38 beta/38 placebo)
Farhan et al. (2003) [18]
0
9 weeks
Clinical scale
5 weeks
2 puffs Twice daily
No treatment
Beclomethasone aerosol 100 mg/puff
25
50
Cobalt machine
MRM & BCS
All female
28–60
60 (30 beclo/30 no tx)
Shukla et al. (2006) [19]
0
7 weeks
RTOG
7 weeks
Twice daily
Petrolatum
Betamethasone 0.1% ointment
25
50
Cobalt machine
MRM
All female
35–66
36 (19 beta/17 pet)
Omidvari et al. (2007) [1]
1.76 (1.17 MMF/ 2.38 placebo)
7 weeks
CTCAE
7–8 weeks
Once daily
Placebo cream
Mometasone 0.1% cream
25–30
50–60
Linear accelerator
MRM & BCS
All female
27–89
169 (85 MMF/ 84 placebo)
Miller et al. (2011) [20]
BCS: Breast conservation surgery; beclo: Beclomethasone; beta: Betamethsone; CTCAE: Common terminology criteria for adverse events; dex: Dexpanthenol; Gy: Gray; methyl: Methylprednisolone; MMF: Mometasone furoate; MRM: Modified radical mastectomy; no tx: No treatment; pet: Petrolatum; RT: Radiotherapy; RTOG: Radiation therapy oncology group.
Clinical scale
Scale used
Outcome assessment
Twice daily
Placebo cream
Comparator
8 weeks
Dexpanthenol
Mometasone 0.1% cream
Metyhlprednisolone 0.1% cream
30
50–60
Linear accelerator
BCS
All female
29–75
23 (12 methyl/11 dex)
Schmuth et al. (2002) [17]
Topical steroid
Intervention
49 (24 MMF/25 placebo)
Subjects (n)
Population characteristics
Bostrom e t al. (2001) [16]
Table 2. Study characteristics of included trials.
Topical corticosteroid therapy for the prevention of acute radiation dermatitis
Review
645
Review
Meghrajani, Co, Ang-Tiu & Roa
Steroid Control Odds ratio Events Total Events Total Weight M–H, fixed, 95% CI Year
Study (year) Bostrom et al. (2001) [16] Farhan et al. (2003) [18] Shukla et al. (2006) [19] Omidvari et al. (2007) [1] Miller et al. (2011) [20]
4 0 4 0 4
24 38 30 19 84
10 1 11 1 4
25 34 30 17 82
33.1% 6.3% 38.7% 6.2% 15.6%
Total (95% CI) 195 188 100.0% Total events 12 27 Heterogeneity: Chi2 = 2.16, df = 4 (p = 0.71); I2 = 0% Test for overall effect: Z = 2.56 (p = 0.01)
0.30 [0.08, 1.14] 0.29 [0.01, 7.36] 0.27 [0.07, 0.96] 0.28 [0.01, 7.40] 0.97 [0.24, 1.04]
Odds ratio M–H, fixed,95% CI
2001 2003 2006 2007 2011
0.39 [0.19, 0.80]
0.01 0.1 1 Favors [experimental]
10 100 Favors [control]
Figure 2. Forest plot of comparison: steroid versus control, incidence of moist desquamation at week 5. df: degrees of freedom, Fixed: Fixed Effect, M–H: Mantel–Haenszel.
control arm, however, only the study by Farhan et al. and Miller et al. showed significant results (TABLE 3) [18,20]. There was no difference in pain between treatment groups in all three studies. The study by Schmuth et al. and by Miller et al. assessed quality of life in their patients. They both utilized Skindex to assess skin-related mental issues [17,20]. Schmuth et al. noted that the control group had deterioration in all dimensions while only four of seven dimensions worsened in the steroid
group [17]. The study by Miller et al. reported a mean Skindex score of 1.4 for the steroid arm and 1.7 for the placebo arm [20]. Although both studies did not demonstrate a significant difference between treatment groups with regards to quality of life, they both suggested a trend toward a more favorable outcome in patients treated with topical steroids. Adverse events due to the medication were reported only by Schmuth et al. They noted itching in three patients (dexpanthenol n = 1; methylprednisolone n = 2), burning in one
Table 3. Primary and secondary outcomes. Outcome
Bostrom et al. (2001) [16] MMF versus placebo
Schmuth et al. (2002) [17] methyl versus dex
Farhan et al. (2003) [18] beta versus placebo
Shukla et al. (2006) [19] beclo versus no tx
Omidvari et al. (2007) [1] Beta vers us pet
Miller et al. (2011) [20] MMF versus placebo
Beta 0% Placebo 2.9%
Beclo 13.3% No tx 36.6%
Beta 0% Pet 6%
MMF 4.8% Placebo 4.9%
1.3 ± 0.3 versus 1.5 ± 0.3
1.2 ± 0.85 versus 1.3 ± 0.80
Primary outcomes Incidence of moist desquamation
MMF 16% Placebo 40%
Secondary outcomes ARD scores (mean + SD)
1.8 ± 0.7 versus 2.3 ± 0.63
Quality of life
1.6 ± 0.25 versus 2.2 ± 0.4
1.0 ± 0.37 versus 1.4 ± 0.56
1.4 versus 1.7 (p = 0.07)
methyl: 4 out of 7 worsened dex: 7 out of 7 worsened
Patient-reported symptoms Pruritus
Less in MMF, p = 0.087
Less in beta, p < 0.05
1.5 versus 2.2 (p = 0.002)
Burning
Less in MMF, p = 0.069
Less in beta, p < 0.05
1.5 versus 2.1 (p = 0.02)
Pain
No difference
No difference
2.1 versus 2.5 (p = 0.11)
Beclo: Beclomethasone; Beta: Betamethsone; Dex: Dexpanthenol; Methyl: Methylprednisolone; MMF: Mometasone furoate; No tx: No treatment; Pet: Petrolatum; SD: Standard deviation.
646
Expert Rev. Clin. Pharmacol. 6(6), (2013)
Topical corticosteroid therapy for the prevention of acute radiation dermatitis
Study (year)
Steroid Control Standard mean difference Mean SD Total Mean SD Total Weight IV, fixed, 95% CI Year
Bostrom et al. (2001) [16] Schmuth et al. (2002) [17] Farhan et al. (2003) [18] Omidvari et al. (2007) [1] Miller et al. (2011) [20]
1.8 1.6 1 1.3 1.2
0.7 0.25 0.37 0.3 0.85
24 10 38 19 84
2.3 2.2 1.4 1.5 1.3
0.63 0.4 0.56 0.3 0.8
Total (95% CI) 175 Heterogeneity: Chi2 = 13.99, df = 4 (p = 0.007); I2 = 71% Test for overall effect: Z = 4.33 (p
