|Year : 2012 | Volume
| Issue : 1 | Page : 19-25
A randomized controlled trial comparing the efficacy of intralesional 5-fluorouracil versus triamcinolone acetonide in the treatment of keloids
Avinash Prabhu1, H Sreekar2, Rajesh Powar1, VM Uppin3
1 Department of Plastic Surgery, J.N. Medical College and KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Belgaum, Karnataka, India
2 Department of Plastic Surgery, CMC, Vellore, Tamil Nadu, India
3 Department of General Surgery, J.N. Medical College and KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Belgaum, Karnataka, India
|Date of Web Publication||21-May-2012|
Department of Plastic Surgery, KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Nehru Nagar, Belgaum - 590 010, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Effective keloid management is still a distant dream in spite of many recent modalities being tried for the same. Although many treatment protocols have shown efficacy of varying degrees, there are few systematic randomized trials comparing them. Objective: To compare the efficacy of intralesional 5-Fluorouracil versus Triamcinolone acetonide in the treatment of Keloids. Materials and Methods: This randomized controlled trial was conducted on 30 patients with keloids, randomly divided into two groups of 15 each, treated with intralesional 5-fluorouracil (Group A) or triamcinolone acetonide (Group B). The groups were compared for reduction in the size of keloid, pain relief, and the incidence of adverse effects. Statistical analysis was done using the unpaired student t- test and test of proportion. Results: The reduction in the size of the keloid was found to be significantly better in Group B (71.23%) than in Group A (57.48%) with a P value of 0.04. The difference in the reduction of pain, as assessed by the visual analog scale, between Groups A (18%) and B (24%), was found to be insignificant (P value - 0.47). Although the incidence of complications in Group A was three times higher than those in Group B, the difference was not statistically significant (P value - 0.13). Conclusion: Reduction in the size of the keloid, which was the main aim of this study was significantly better in those treated with triamcinolone acetonide than those treated with 5-fluorouracil. The other parameters like reduction of pain and the incidence of adverse effects were comparable in both the groups.
Keywords: Intralesional 5-flurouracil, intralesional triamcinolone acetonide, keloid
|How to cite this article:|
Prabhu A, Sreekar H, Powar R, Uppin V M. A randomized controlled trial comparing the efficacy of intralesional 5-fluorouracil versus triamcinolone acetonide in the treatment of keloids. J Sci Soc 2012;39:19-25
|How to cite this URL:|
Prabhu A, Sreekar H, Powar R, Uppin V M. A randomized controlled trial comparing the efficacy of intralesional 5-fluorouracil versus triamcinolone acetonide in the treatment of keloids. J Sci Soc [serial online] 2012 [cited 2018 Jun 22];39:19-25. Available from: http://www.jscisociety.com/text.asp?2012/39/1/19/96466
| Introduction|| |
Keloids are aberrations of wound healing, the exact pathogenesis of which is not very well understood. Extensive research has not found any medication for preventing them. The end point of wound healing following injury to the skin is formation of scar tissue. Keloids result from an uncontrolled overgrowth of this dense fibrous scar tissue. This tissue extends beyond the borders of the original wound, does not regress spontaneously, and tends to recur after excision. The term keloid, meaning 'Crab Claw,' was first coined by Alibert in 1806, in an attempt to illustrate the way the lesion expands from the original scar into the normal tissue. 
Keloid management has been a constant disappointment to many surgeons. Although keloids occur with a considerable frequency, no single therapeutic modality has been determined experimentally to be very effective for treating them. Effective keloid management still remains a distant dream in spite of many recent modalities being tried for the same. Although many treatment protocols have shown efficacy of varying degrees, there are very few systematic randomized trials comparing them in a given community. Thus, controversy continues to exist regarding the treatment of keloids. The high recurrence rate of keloids has initiated a wide variety of treatments, such as, compression therapy, intralesional injections of corticosteroid, 5-fluorouracil, methotrexate, bleomycin, radiotherapy, cryosurgery, laser therapy,  tamoxifen,  and tacrolimus.  Recent therapies such as pulsed dye laser, interferon α2b, and cultured epithelial autografts have also been used. 
Although, the results are not very encouraging, intralesional steroids are still widely used, more due to lack of a better option. , 5-fluorouracil is one of the newer drugs being used for the treatment of keloid, apparently with a similar degree of success.  Even as the effectiveness of these drugs has been shown in independent studies, they have not yet been compared in a systematic clinical study. The objective of this study is to compare the efficacy of 5-fluorouracil and triamcinolone acetonide in the treatment of keloids, in terms of volume reduction, symptomatic improvement in terms of pain relief (by visual analog scale), and incidence of adverse reactions.
| Materials and Methods|| |
This study was conducted at KLES Dr. Prabhakar Kore Hospital and Medical Research Center, Belgaum, from July 2008 to June 2010. Approval for this study was obtained from the Institutional Ethical Committee. The patients who were diagnosed with keloid were included in the study after due consent. All patients with keloids, irrespective of age of patient, size or site of the keloid were included in the study. Pregnant and lactating mothers and patients with concomitant illnesses like renal failure, hepatic failure, acid peptic disease, diabetes, and hypertension, and immunocompromised patients, were excluded from the study. The sample size of 30 patients was randomized into two groups. Group A - 15 patients treated with intralesional 5-fluorouracil and Group B - 15 patients treated with intralesional triamcinolone acetonide. Patients were divided into these groups by a randomization coding system derived from a computer-generated randomization table. Written informed consent was taken. Details of the patients, like name, age, sex, address, family history, presenting complaints, and history related to the keloid were recorded in the proforma.
During each visit, the size of the keloid was recorded in millimeters using the Vernier's calipers, in terms of length, breadth, and height. The color of the keloid was noted and classified depending on its darkness compared to the surrounding skin. The consistency of the keloid was classified as either hard, soft or consistency similar to the surrounding skin. The clinical appearance was classified into the atrophic, hypertrophic or nodular categories. Pain was recorded using the visual analog scale (VAS), at each visit. Other features like skin atrophy, erythema, ulceration, skin necrosis, hypopigmentation or hyperpigmentation, and other features were also recorded. This protocol was followed for every patient over all the visits.
The strength of triamcinolone acetonide used for this study was 40 mg / ml, with up to a maximum of 2 ml being used per dose. Similarly 5-fluorouracil at 50 mg / ml up to 2 ml was used. The injections were scheduled at weekly intervals for four consecutive weeks. Subsequently, the patients were instructed to follow up at monthly intervals for six months. After instructing the patient regarding the procedure, the solution was loaded in an insulin syringe. The keloid was cleaned thoroughly with a spirit swab and the needle of the insulin syringe was inserted into the substance of keloid and the solution pushed with adequate pressure till minimal blanching was seen. This was repeated at multiple sites on the keloid.
Statistical analysis for the change in volume of the keloid, taken in percentages, was done using the unpaired student t-test. The same test was also used for changes in the visual analog scale. A P value less than 0.05 was considered to be significant. Statistical analysis for significance of difference between age, sex, site of keloid, color, appearance, consistency, and appearance between the two groups was done using the Chi Square test.
| Observations and Results|| |
A total of 30 patients satisfied the selection criteria, of which one patient opted to discontinue the treatment due to increased pain. The statistical analysis was thus carried out on 29 patients. The clinical presentations of both the groups were as shown in [Table 1] and [Table 2]. On analyzing both groups A and B statistically, they were found to be comparable. The groups were then analyzed for different parameters like relief of pain, using the visual analog scale, reduction in volume, and adverse reaction [Table 3] and [Table 4]. Analysis of the symptomatic relief in pain was assessed by the visual analog scale, and a comparison between the two groups was done [Table 5]. There was a mean decrease in pain of 18.33% in patients treated with 5-flurouracil, with a standard deviation of 15.61. In the patients treated with triamcinolone acetonide it was 24.00 and 17.45%, respectively. On comparison with the unpaired student-t test the difference between the two groups was found to be insignificant (P value 0.4679).
|Table 3: Analyses of symptomatic relief in pain, volume, and adverse effect in the 5-fluorouracil group|
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|Table 4: Analyses of symptomatic relief in pain, volume, and adverse effect in the triamcinolone acetonide group|
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The decrease in the volume of the keloid was also analyzed and compared [Table 6]. The mean reduction in volume in the 14 patients treated with 5-flurouracil was 57.48% with a standard deviation of 16.21 [Figure 1]. The maximum decrease was 81.21% and minimum was 36.2% [Figure 2]. In the 15 patients who were treated with triamcinolone acetonide, the mean reduction in volume was 71.23%, with a standard deviation of 18.01 [Figure 3]. The maximum decrease in volume was 91.64% and minimum was 38.01% [Figure 4]. On analysis by the unpaired student- t test, the reduction in volume was significantly more in the keloids treated with triamcinolone acetonide than those treated with 5-flurouracil (P value 0.0402).
|Figure 1: Chest wall keloid before intralesional 5-fluorouracil treatment|
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|Figure 2: Chest wall keloid after intralesional 5-fluorouracil treatment|
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|Figure 3: Chest wall keloid following intralesional triamcinolone acetonide treatment|
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The adverse effects in the treatment with 5-fluorouracil and triamcinolone acetonide are shown in [Table 7]. Three out of 14 patients (21.43%) initiated for treatment with 5-flurouracil had complications. The complications were in the form of ulceration (one patient) [Figure 5], increased pruritis (one patient), and increased pain (one patient). Only one out of the 15 patients treated with triamcinolone acetonide (6.7%) had a complication, in the form of increased pruritis. Although the incidence of adverse effects in the 5-flurourcil group was higher, on comparing the two groups with the test of proportion, this difference was found to be statistically insignificant (P value 0.1247).
| Discussion|| |
Keloids and hypertrophic scars are benign conditions, in which there is excessive proliferation of dermal fibroblasts.  Patients often present with severe itching, tenderness, pain, sleep disturbance, anxiety, depression, disruption of daily activities, and esthetic concerns. However, the basis for keloid and hypertrophic scar formation has not been fully understood.  It has been noted in literature that the fibroblasts that present in keloid and hypertrophic scar tissue produce increased amounts of collagen compared to the normal fibroblasts. Thus, suppression of this uncontrolled fibroblast activity in keloid and hypertrophic scar may be essential in their treatment. 
There is no universally accepted treatment for keloids.  Multiple therapeutic modalities, with variable success, have been reported, with intralesional steroids and 5-fluorouracil being two among them. An intralesional steroid injection is more commonly used. It is used either alone or as an adjunct to cryosurgery or surgical excision  or in combination with 5-fluorouracil. 
Corticosteroids reduce fibroblast proliferation, collagen synthesis, and glycosaminoglycan synthesis, and suppress pro-inflammatory mediators. , The most commonly used corticosteroid is triamcinolone acetonide. It has been reported that the fibroblasts that are been treated with triamcinolone acetonide result in a reduction on TGF β expression and an increase in β FGF production. The dosage and treatment interval have varied from 10 to 40 mg / ml, given at an interval of three to six weeks. Complications seen with the use of intralesional triamcinolone are skin atrophy, hypopigmentation or hyperpigmentation, telangiectasis, and ulceration.  5-flurouracil is a pyrimidine analog, with antimetabolite activity, which inhibits fibroblast proliferation and also has an inhibitory effect on TGF β-induced expression of the type-1 collagen gene. The dosage is 50 mg / ml, once a week. However, several studies in the literature suggest that the overall efficacy is not better than other modalities and significant side effects such as ulceration, hyperpigmentation, pain, pruritis, and a burning sensation make 5-flurouracil less appealing.  According to literature, fibroblast regression is dependent on the duration of exposure to the drug and the dose. It has been observed that intralesional 5-flurouracil given once a week or once every two weeks is effective for keloids and hypertrophic scars. ,,
In our study all the patients had complaints of swelling. Some also came with various combinations of complaints including pruritis and pain. Pain is an important symptom in patients with keloids. In our study, pain was evaluated using the visual analog scale. The pain was assessed before initiating the treatment and subsequently at each visit. On a scale of 0 to 100 there was on an average 18% improvement in patients treated with 5-flurouracil, as compared to 24% in the triamcinolone acetonide group, at six months. This difference was found to be insignificant (P value - 0.468) on analysis with the unpaired student- t test. Although patients in both the groups were relieved of pain to a great extent, the two drugs were comparable in doing so. According to Mutalik S, improvement was first seen in the form of reduction of pain and pruritis, followed by flattening of the lesion. 
The size was evaluated in terms of the volume at presentation and the change following treatment at follow-up after six months. In the group treated with 5- fluorouracil there was, on an average, 57.48% reduction in size as compared to 71.23% in the triamcinolone acetonide group. This difference was statistically significant (P value - 0.04) on an analysis with the unpaired student t-test. In studies evaluating intralesional triamcinolone acetonide there were volume changes ranging from 50 - 100%. ,, The effectiveness of 5-fluorouracil, as evaluated in other studies, has ranged from a 50 - 70% change in keloid size.  Our study showed similar reduction in size on treatment with 5-flurouracil.
Darzi MA observed that intralesional triamcinolone acetonide produced symptomatic relief in 72% and complete flattening in 64% of the lesions.  However, Kill J noticed complete flattening of the lesions and cessation of itching in 52 (100%) of the cases.  The study conducted by Nanda S observed more than 50% improvement in the size in almost 80% of cases that were been treated with 5-flurouracil. The side effects that they noticed were, in the form of pain at the site of injection in 100% of the patients, ulceration in 21.4%, and a burning sensation in 7.1%. Kontochristopoulos G reported more than 50% improvement in size in 85% of the patients, with complication of pain in 100%, hyperpigmentation in 100%, and ulceration in 30% of the cases that were being treated with 5-fluorouracil. 
In our study, the adverse effects of the treatment modalities were also compared. In the 5-flurouracil group there was a case each with complaints of increased pain, pruritis, and ulceration during the course of the treatment. In one of the patients being treated with 5- fluorouracil, the course had to be terminated due to untrollable pain and this case was excluded from the statistical analysis. These adverse effects may be directly related to the drug. In the triamcinolone acetonide group there was only one patient who complained of increased pruritis.
Similar results have been observed by Nanda S  and Kontochristopoulos G  with respect to pain and ulceration. We could not explain the cause for an increase in pruritis. The pruritis in keloids is believed to be due to the increased release of histamine from the mast cells, which are abundant in the healing wound.  Although there was three times higher incidence of adverse affects in the 5-flurouracil group, this difference was found to be statistically insignificant on analysis with the test of proportion (P value - 0.1247).We did not find any case of recurrence in six months of the follow-up period.
To our knowledge this is the first randomized clinical trial to compare these two drugs in the treatment of keloid. However, to have a more concrete conclusion, a large sample size needs to be studied.
| Conclusion|| |
Our study concludes that in terms of volume reduction of keloids, both triamcinolone acetonide and 5-fluorouracil have a significant action. However, when compared, triamcinolone acetonide has a statistically better outcome. Both 5- fluorouracil and triamcinolone acetonide are effective in reducing the pain associated with keloids. There is statistically no significant difference between the two drugs in reducing pain. Although 5-fluorouracil was found to have three times more complications as compared to triamcinolone acetonide, the difference was statistically insignificant.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]
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