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ORIGINAL ARTICLE
Year : 2022  |  Volume : 67  |  Issue : 3  |  Page : 211-215
A comparative study of the efficacy of intralesional 5 fluorouracil vs combination of 5 fluorouracil with triamcinolone acetonide in keloids


1 Department of Dermatology, Venereology and Leprosy, Father Muller Medical College, Mangalore, Karnataka, India
2 Professor and Vice Dean, Father Muller Medical College, Mangalore, Karnataka, India
3 Professor and Hod, Father Muller Medical College, Mangalore, Karnataka, India
4 Professor, Father Muller Medical College, Mangalore, Karnataka, India

Date of Web Publication22-Sep-2022

Correspondence Address:
Rochelle C Monteiro
Department of Dermatology, Venereology and Leprosy, Father Muller Medical College, Mangalore, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.IJD_485_19

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   Abstract 


Context: Keloids are defined as scars that invade the adjacent tissues and rarely regress. In recent years, antimitotic drugs have been used in the management of keloids with promising results. This study highlights the effectiveness of 5-fluorouracil (5-FU) in keloids. Aims: To study the efficacy of intralesional 5-FU in keloids as a solo agent and in combination with triamcinolone acetonide and to study the side effects of both the drugs. Methods and Materials: A total of 30 patients with keloids were randomly allocated into two groups. Group A received 50 mg/mL of 5-FU intralesionally. Group B patients received a combination of 40 mg/mL of intralesional triamcinolone acetonide and 50 mg/mL of 5-FU. The patients were observed for immediate and delayed complications and the treatment was continued for a total of 3 months. Statistical Analysis Used: ANOVA, Mann–Whitney test, Fisher's test, Chi-square test. Results: The patients in both groups showed a significant reduction in the size and thickness of the lesions. The reduction in the length of keloid was highly significant in both the groups but in comparison, there was no statistically significant difference in the reduction of lesions among both the groups. Hence, both modalities of treatment can be claimed to be equally efficacious. The therapeutic response was good to excellent in most patients with only one patient opting out of the therapy in the 5-FU group due to the inability to tolerate the pain. The common side effects noted were pain, itching, ulceration, burning sensation, and bulla formation. Conclusions: 5-FU, both as a single agent or in combination with steroids is equally efficacious in reducing the keloid size. The side effects are lesser with the combination group.


Keywords: 5-Fluorouracil, intralesional injection, keloids, triamcinolone acetonide


How to cite this article:
Monteiro RC, Bhat R, Martis J, Kamath H G. A comparative study of the efficacy of intralesional 5 fluorouracil vs combination of 5 fluorouracil with triamcinolone acetonide in keloids. Indian J Dermatol 2022;67:211-5

How to cite this URL:
Monteiro RC, Bhat R, Martis J, Kamath H G. A comparative study of the efficacy of intralesional 5 fluorouracil vs combination of 5 fluorouracil with triamcinolone acetonide in keloids. Indian J Dermatol [serial online] 2022 [cited 2022 Sep 27];67:211-5. Available from: https://www.e-ijd.org/text.asp?2022/67/3/211/356738





   Introduction Top


Dermal injury results in excess scar tissue formation during the process of wound healing. Clinically, keloids are defined as scars that invade the adjacent tissues and rarely regress.[1] Despite the high prevalence of keloids in the general population, the mechanisms of its pathogenesis are poorly understood, which reflects in the absence of a single effective means of treatment and frustrating outcomes both for the clinician and patient. In recent years, antimitotic drugs like bleomycin, mitomycin-c, interferon-γ, and retinoic acid have been used in the management of keloids with promising results. This study highlights the effectiveness of 5-fluorouracil (5-FU) in keloids in comparison to the traditionally used triamcinolone acetonide.


   Methods Top


After obtaining appropriate permission from the institutional ethics committee and registration of the study with the CTRI (REF/2017/09/015484), a total of 30 newly clinically diagnosed patients with keloids were included in the study. A sample size of 15 per group was included in the study at 95% confidence interval and 80% power based on a similar study[2] and based on the formula n = 2 (zα + zβ)22/(x–1-x–2)2. The confirmation of diagnosis by biopsy was avoided as biopsy itself can precipitate further keloidal formation. Written informed consent was obtained. The patients who belonged to the age group 20–60 years, who were willing to participate in the study were included. The previously treated patients, patients unwilling for the study and follow-up, and those who did not fit into the prescribed age group were excluded from the study. A complete medical history, history of injury, and progression of lesions were documented. The patients thus recruited were randomly allocated into groups A and B by the lottery method. The group A patients received 50 mg/mL of 5-FU intralesionally using a 27-gauge insulin syringe. The group B patients received a combination of 40 mg/mL intralesional triamcinolone acetonide and 50 mg/mL of 5-FU, 0.1 mL of each solution in a ratio of 1:1 was injected similarly as group A. The drugs were injected 1 cm apart intralesionally. The patients were observed for immediate and delayed complications. The patients were asked to report back if any other side effects occurred in the next 48 h. The procedure was repeated at fortnightly intervals for the 1st month, and monthly, till the lesions showed complete flattening, till the level of the surrounding tissue, for a maximum of 3 months. At each visit, the patients were assessed for pain, bulla formation, edema, ulceration, secondary infection, flattening, reduction in keloid size measured as the length and breadth in centimeters, and recurrence. The clinical photographs were obtained at the first and last visit. At the end of the study period, the response to treatment was assessed clinically and compared photographically in terms of flattening of the lesions, categorized as excellent (76–100%), good (51–75%), fair (25–50%), and poor (0–24%). A statistical analysis was done as follows: to compare week 0 to week 10 changes within the group, chi-square with Friedmans chi-square test was performed. The comparison of the changes between the groups was performed by the Mann–Whitney test. All the patients were further followed up for 6 months.


   Results Top


Out of a total of 30 patients, 17 belonged to the male gender and 13 to the female gender. Group A had 10 males and 5 females, and group B had 7 males and 8 females. A total of 14 patients gave a history of trauma prior to the onset of the lesions. The male to female distribution in both groups was statistically insignificant. Two patients dropped out of the study in group A and one was lost to follow-up in group B. At the end of week 10, the patients in both groups showed a significant reduction in the size and thickness of the lesions. The reduction in the length of keloid was highly significant in both groups [Table 1] and [Table 2], emphasizing the fact that both the treatment modalities were efficacious. However, in comparison, there was no statistical significance in the reduction of the lesions among both groups [Table 3]. Hence, both the modalities of treatment can be claimed to be equally efficacious [Figure 1],[Figure 2]a and [Figure 2]b. The therapeutic response was good to excellent in most patients [Graph 1] with only one patient opting out of the therapy in the 5-FU group due to the inability to tolerate the pain.
Figure 1: (a and b) Pre- and post-treatment images of a patient with keloid belonging to group 1 showing significant flattening of the lesion

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Figure 2: (a and b) Pre- and post-treatment images of a patient with keloid belonging to group 2 showing a significant reduction in the size of the keloid

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Table 1: Comparison in the reduction of the keloid size between both groups at each visit

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Table 2: Pairwise comparison of the clinical improvement in the lesions showing statistically significant improvement

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Table 3: Change in the dimensions of the keloid in comparison to the baseline

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The common side effects noted were pain, itching, ulceration, burning sensation, and bulla formation. The patients in group A had a higher incidence of severe pain, burning sensation, following injection and two patients developed bulla out of which one was followed by ulceration over the lesion. For the patients who had pain following injection, tablet paracetamol 650 mg was advised. In comparison, the adverse effects in the combination group were lesser in frequency and severity; mild itching being the commonest. The pain was not seen in the combination group. Thus, a combination reduces the severity of adverse effects, although the rate of regression of the lesions may be slower.

On follow-up, after 6 months, none had a recurrence of the lesions, and most of them had achieved flattening of the lesions. There were no reports of any systemic side effects. Further follow-up was not possible, as all the patients were not willing to report back repeatedly after the resolution of the lesions. However, we had instructed them to report back in case of recurrence.


   Discussion Top


Mitosis is the basis for cell proliferation so blocking any of the phases of mitosis results in the cessation of cell proliferation and initiation of apoptosis. The antitumor drugs which have been used in the treatment of keloids include 5-fluorouracil, bleomycin, mitomycin-c, interferon-γ, and retinoic acid.[3],[4]

5-FU is a pyrimidine analog which probably acts by interference with Transforming Growth Factor (TGF)-β signaling and the resultant activation of type I collagen gene expression. It has been found to have an inhibitory effect on the human fibroblast cell lines in culture[5] and it also inhibits proliferation and myofibroblast differentiation in the Dupuytren fibroblasts in vitro.[6] It is inexpensive, easily available, with a well-established safety profile. The pharmacokinetic studies have revealed that 5-FU remains in the soft tissue for less than 10 days. Once taken up in the bloodstream, it is degraded within 20 min and the toxic metabolites are excreted by the kidney. The toxicity of the drug is related to its intravenous use and not seen with subcutaneous dosing. Thus, the benefit of its antimitotic profile can be safely used in keloids without the associated adverse effects. This property also allows for higher dosing of the drug in intralesional dosing. The systemic side effects of 5-FU, viz., anemia, leucopenia, thrombocytopenia, or adverse effects on reproductive functions have not been noted with the intralesional dosing[7] Fitzpatrick and Manuskiatti, in a four-arm study involving 5-FU, intralesional steroid, steroid with 5-FU, and 585 nm pulse-dyed laser, noted that the 5-FU-only group performed as well as all other groups with the benefit of a faster resolution and avoidance of the side effects of steroid injection.[8] In another study, which involved biopsy for efficacy evaluation, more than 75% of the patients showed good to excellent improvement, with only one out of 20 patients claiming inefficacy. In addition, there was histopathologic evidence showing diminution in the amount and nodular concentric arrangement of hyalinized collagen fibers, less prominent vascularity, reduction of Ki-67 expression, which is a marker of cellular proliferation, and slight reduction of TGF-β expression.[9] Haurni et al.[7] too reported very promising results with the 5-FU injections with a very low recurrence rate. Our findings were similar with respect to the efficacy of 5-FU, showing a rapid onset of action and comparable efficacy to the combination group. However, the side effect profile did not match the previous studies. Although not seen immediately after injection, a majority of the patients complained of severe pain a few hours after the injection, a few even necessitating the use of oral analgesics. The pain varied from burning to pricking type and lasted for a few hours. In contrast, the individuals in the combination group hardly showed any discomfort after the injection. Since we were comparing the side effects between the groups, we did not quantify the pain using any scale but noted it as present or absent. Although not used in this study, a combination of lignocaine 2% injection in a 1:1 ratio with 5-FU can help minimize the pain and achieve the same efficacy. The need for oral analgesics can be ameliorated.

Intralesional corticosteroid injections for keloids and scars have been used since the mid-1960s, with triamcinolone being the most commonly used one.[10] The corticosteroids act by inhibiting the inflammation, causing vasoconstriction which disrupts oxygen and nutrient supply to the keloid, and it also has an antimitotic effect on the fibroblasts and keratinocytes.[11] It can also suppress the vascular endothelial growth factor expression, inhibit fibroblast proliferation, and induce scar regression.[12] Despite this age-old proven efficacy, the drawback of the steroids are the local side effects like subcutaneous fat atrophy, telangiectasia, hypopigmentation, and more importantly, the high incidence of recurrence noted on the stoppage of therapy.[13],[14] Hence, the present consensus is to use steroids in combination with antimitotic agents or other modalities like cryotherapy or Pulsed dye laser (PDL).[3] In our patients on the corticosteroid and 5-FU combination, we did not note any atrophy or hypopigmentation until the follow-up period. Also, compared to the 5-FU group, the incidence of immediate side effects too was minimal, hence, from the patient comfort point of view, this modality was superior. It provided the efficacy of the steroids and 5-FU at the same time minimizing the side effects. Probably because of the steroid action, the incidence of pain was nil in this group. We have found better efficacy and lesser side effects with the combination group. So, irrespective of the duration of the keloid, or age/sex of the patient, we recommend a combination therapy. 5-FU has a higher efficacy and reduces the side-effects which can be caused when the steroids are used alone, while the addition of the steroids nullifies the pain caused by 5-FU. Thus, in both ways, the combination is highly synergistic.

The limitations of this study are the short follow-up period; ideally, long-term follow-up would have been advisable. We limited the period of the study and the number of patients due to the difficulty in tracking the patients for follow-up and the problems of drop-out in the long-term studies. Also, the third arm with steroid alone would have been ideal, but since we are aware of the efficacy of steroids in reducing keloids, and the recurrence rates being higher, we chose a two-arm study.

This study highlights the efficacy of antimitotic drugs in the management of keloids. As in the current scenario, there is no single available modality of choice in this area. It is worth exploring our options in the antitumor group of drugs so that we can achieve high levels of therapeutic success in the management of keloids.

Acknowedgements

Mrs. Sucharita Suresh, Department of Statistics, Father Muller Medical college Dr. Saurabh kumar, Professor and HOD, Department of Community medicine, KAHER's JGM Medical college, Hubballi, Karnataka.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Bran GM, Goessler UR, Hormann K, Riedel F, Sadick H. Keloids: Current concepts of pathogenesis (Review). Int J Mol Med 2009;24:283-93.  Back to cited text no. 1
    
2.
Farahnaz FN, Jamshid N, Koroush A. Comparison of therapeutic response of keloids and hypertrophic scars to cryotherapy plus intralesional steroid and bleomycin tattoo. Indian J Dermatol 2005;50:129-32.  Back to cited text no. 2
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3.
Xi-Qiao W, Ying-Kai L, Chun Q, Shu-Liang L. A review of the effectiveness of antimitotic drug injections for hypertrophic scars and keloids. Ann Plast Surg 2009;63:688-92.  Back to cited text no. 3
    
4.
Shridharani S, Magarakis M, Manson PN, Singh NK, Basdag B, Rosson GD, et al. The emerging role of antineoplastic agents in the treatment of keloids and hypertrophic scars: A review. Ann Plast Surg 2010;64:355-61.  Back to cited text no. 4
    
5.
de Waard JW, de Man BM, Wobbes T, Van der linden CJ, Hendriks T. Inhibition of fibroblast collagen synthesis and proliferation by levamisole and 5-fluorouracil. Eur J Cancer 1998;34:162-7.  Back to cited text no. 5
    
6.
Jamec B, Linge C, Grobbelaar AO, Smith PJ, Sanders R, McGrouther DA, et al. The effect of 5-fluorouracil on Dupuytren fibroblast proliferation and differentiation. Chir Main 2000;19:15-22.  Back to cited text no. 6
    
7.
Haurani JM, Foreman K, Yang JK, Siddiqui A. 5-Fluorouracil treatment of problematic scars. Plast Reconstr Surg 2009;123:139-48.  Back to cited text no. 7
    
8.
Manuskiatti W, Fitzpatrick RE. Treatment response of keloidal and hypertrophic sternotomy scars: Comparison among intralesional corticosteroid, 5-fluorouracil, and 585-nm flashlamp-pumped pulsed-dye laser treatments. Arch Dermatol 2002;138:1149-55.  Back to cited text no. 8
    
9.
Kontochristopoulos G, Stefanaki C, Panagiotopoulos A, Stefanaki k, Argyrakos T, Petridis A, et al. Intralesional 5-fluorouracil in the treatment of keloids: An open clinical and histopathologic study. J Am Acad Dermatol 2005;52:474-9.  Back to cited text no. 9
    
10.
Chen MA, Davidson TM. Scar management: Prevention and treatment strategies. Curr Opin Otolaryngol Head Neck Surg 2005;13:242-7.  Back to cited text no. 10
    
11.
Reed BR, Clark RA. Cutaneous tissue repair: Practical implications of current knowledge, II. J Am Acad Dermatol 1985;13:919-41.  Back to cited text no. 11
    
12.
Wu WS, Wang FS, Yang KD, Huang CC, Kuo YR. Dexamethasone induction of keloid regression through effective suppression of VEGF expression and keloid fibroblast proliferation. J Invest Dermatol 2006;126:1264-71.  Back to cited text no. 12
    
13.
Nouri K, Vidulich K, Rivas MP. Lasers for scars: A review. J Cosmet Dermatol 2006;5:14-22.  Back to cited text no. 13
    
14.
Fitzpatrick RE. Treatment of inflamed hypertrophic scars using intralesional 5-FU. Dermatol Surg 1999;25:224-32.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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