Comparative Study Between Intralesional Injection of Bleomycin and 5-ﬂuorouracil in the Treatment of Keloids and Hypertrophic Scars

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Original article Comparative study between intralesional injection of bleomycin and 5-ﬂuorouracil in the treatment of keloids and hypertrophic scars

⇑ Ahmed M. Kabel a,b, , Hanan H. Sabry c, Neveen E. Sorour c, Fatma M. Moharm d

a Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif, Saudi Arabia b Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt c Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Benha University, Egypt d Dermatology specialist, Samannoud Central Hospital, Ministry of Health, Egypt

Received 13 May 2015; accepted 4 July 2015 Available online 26 July 2015

Abstract

The aim of this work was to evaluate the efficacy and safety of intralesional injection of 5-fluorouracil and bleomycin in the treatment of keloids and hypertrophic scars. One hundred and twenty patients were divided into the following groups: group IA was injected intralesionally with 5-fluorouracil; group IB was injected intralesionally with a combination of triamcinolone acetonide and 5-fluorouracil; group II was injected intralesionally with bleomycin. Patients underwent follow up by photographing and Vancouver scar scale system. There was a significant improvement in the Vancouver scar scale in group II compared to group I after treatment. There was hyperpigmentation, pain and ulceration in all the studied groups. Pain was significantly decreased in group IB compared to that in group IA, ulceration was significantly decreased in group II than in group I while pain after injection was increased in group II than in group I. Relapse occurred in 12 patients of group IA, 14 patients of group IB and no relapse occurred in group II. So, intralesional injection of bleomycin was more effective and better in remission than intralesional 5-fluorouracil injection in the treatment of keloids and hypertrophic scars regardless of patient’s age, sex, disease duration or site of the lesion. Ó 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords: Bleomycin; Fluorouracil; Keloids; Hypertrophic scars

1. Introduction tissue. A keloid scar is benign, non-contagious and some- times accompanied by severe itching, sharp pains and Keloids and hypertrophic scars are characterized by changes in texture. In severe cases, it can aﬀect movement excessive deposition of dermal collagen with resultant scar of skin and may ulcerate. The probability of recurrence of keloids after surgical removal is high, usually greater than 50% (Hunasgi et al., 2013; Maghrabi and Kabel, 2014). ⇑ Corresponding author at: Department of Clinical Pharmacy, College of Pharmacy, Taif University, Al-Haweiah, P.O. Box 888, Zip Code Five-Fluorouracil (5-FU) is a pyrimidine analog, which 21974, Saudi Arabia. Tel.: +20 1009041488, +966 564833526. is used in the treatment of cancer. It is also used in oph- E-mail address: [email protected] (A.M. Kabel). thalmic surgery, speciﬁcally to augment trabeculectomy Peer review under responsibility of King Saud University. in patients deemed to be at high risk for failure. 5-FU acts as an anti-scarring agent in this regard, since excessive scarring at the trabeculectomy site is the main cause for failure Production and hosting by Elsevier of the surgery (Rothman et al., 2000). Recent trials have

http://dx.doi.org/10.1016/j.jdds.2015.07.003 2352-2410/Ó 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). A.M. Kabel et al. / Journal of Dermatology & Dermatologic Surgery 20 (2016) 32–38 33 used 5-FU topically for treating hypertrophic scars and 2.2.3. Exclusion criteria some types of basal cell carcinomas of the skin. Some stud- Pregnancy, lactation, chronic renal failure and any ies had used 5-FU intralesionally in the treatment of abnormalities of liver function tests or complete blood keloids and hypertrophic scars alone or mixed with triam- count. cinolone acetonide (TAC). The latter is thought to decrease pain and inflammation (Davison et al., 2009). 2.2.4. Groups Bleomycin is a glycopeptide antibiotic that is widely The patients were divided into the following groups: used as an anti-cancer agent. The drug is used in the treat- Group (IA): included thirty patients who were injected ment of Hodgkin lymphoma, squamous cell carcinomas intralesionally with 5-FU at a concentration of 50 mg/ml. and testicular cancer, as well as in the treatment of plantar Initially, local anesthetic Mepivacaine HCl 3% was admin- warts (Lewis and Nydorf, 2006). Also, bleomycin has been istered at the lesion site. Then, the patients were injected tried intralesionally to treat keloids and hypertrophic scars. intralesionally with 5-fluorouracil at a concentration of The commonest complication of bleomycin injection was 50 mg/ml, multiple injections were given at 1 cm intervals hyperpigmentation, which was seen in 75% of patients on average, 0.2–0.4 ml/cm2. The maximum dose was 2 ml (Saray and Gu¨leç, 2005). This work was a trial to evaluate per session with a two week interval (Kontochristopoulos the efficacy and safety of intralesional injection of et al., 2005). 5-fluorouracil and bleomycin in the treatment of keloids Group (IB): included thirty patients who were injected and hypertrophic scars. intralesionally with a mixture of 0.1 ml of 40 mg/ml TAC and 0.9 ml of 5-FU (50 mg/ml). Initially, local anesthetic 2. Methods (Mepivacaine HCl 3%) was administered at the lesion site. Then, the patients were injected intralesionally with a mix- 2.1. Location ture of 0.1 ml of 40 mg/ml triamcinolone acetonide and 0.9 ml of 5-FU (50 mg/ml), multiple injections were given This study was conducted at dermatology, venereology at 1 cm intervals on average, 0.2–0.4ml/cm2. The maximum and andrology department, faculty of medicine, Benha dose was 2 ml per session with a two week interval (Asilian University, Egypt. This study was approved by the et al., 2006). Research Ethics Board at Benha University. This work Group (II): included sixty patients who were injected complied with the principles laid down in the Declaration intralesionally with bleomycin at a concentration of of Helsinki. 1.5 IU/ml. Initially, local anesthetic (Mepivacaine HCl 3%) was administered at the lesion site. Then, multiple 2.2. Study design intralesional injections of bleomycin at a dose of 0.5–1 ml/cm2 with a maximum dose of 4 ml per session 2.2.1. Equipments using insulin syringe were administered with a two week interval (Espanã et al., 2001). A 1 ml insulin syringe with a fixed 30 gauge needle. All patients were subjected to complete history taking Mepivacaine HCl 3% (Mepacaine ampoule, Alexandria and dermatological examination included site, size, shape, Pharmaceutical Co., Egypt). color and consistency of the lesion. Investigations into Five-fluorouracil (Fluorouracil 250 mg ampoule, blood count, liver and kidney functions were done before Biosynthesis Pharmaceutical Co., Egypt). treatment and then at a monthly interval during therapy. Bleomycin (Bleocip 15 mg vial, Cipla Co. Ltd, Verna The patients were informed about the nature of each pro- industrial state, Goa, India). cedure, expected number of treatments and also expected Triamcinolone acetonide (Kenacort vial, Bristol-Myers side effects of the procedure. Follow up of the patients Squibb). was performed by the Vancouver scar scale system after stopping the treatment for 12 months. This study was conducted on one hundred and twenty patients with keloids and hypertrophic scars of varying 2.3. Assessment of the clinical response sizes and durations selected from the Dermatology and Andrology outpatient clinic of faculty of medicine, Benha Assessment of keloids was done at the beginning of the University, Egypt. treatment, at 4, 8, and 12 weeks, and during the follow up period. The assessment included clinical changes in the 2.2.2. Inclusion criteria keloids by photographs and by reporting any side effects A minimum age of 15 years, acceptable pretreatment that the patients experienced. Clinical assessment was car- laboratory studies (complete blood cell count, serum ried out using Vancouver scar scale that includes vascular- chemistries, urine analysis, and pregnancy test) and a ity, pigmentation, pliability and height. The results were written consent was taken from each patient before the recorded from (0) to (14) where (0) reflected normal skin study. (Baryza and Baryza, 1995). The clinical improvement was 34 A.M. Kabel et al. / Journal of Dermatology & Dermatologic Surgery 20 (2016) 32–38 judged on the basis of a decrease in vascularity, pigmenta- 4.46 ± 1.55 after treatment with a mean total improvement tion and height as well as softening of the scar and of 55%. In group II, the mean Vancouver scar scale in all improvement of symptoms. patients before treatment was 9.32 ± 1.46 and it was 2.7 ± 0.95 after treatment with a mean total improvement 2.4. Statistical analysis of 73%. The mean value of group II after treatment was statistically significant compared to that of group I after Data were presented as mean ± standard deviation treatment (Figs. 2–5). (SD). An ANOVA and Student’s t-test were used for eval- uating the statistical significance of differences in means. 3.3. Correlation between age, sex, disease duration and Pearson’s correlation coefficient (r) was applied to correlate clinical response between the parameters. A P value of less than 0.05 was considered to be statistically significant. There was no correlation between age, sex, disease duration and clinical response in all groups (Table 1). 3. Results 12 The ages of the patients ranged from 16 to 54 years with Before mean values of (29.87), (32.07) and (31.5) in group (IA), 10 (IB) and (II) respectively The duration of the lesions ranged After 8 from 4 months to 23 months. The most commonly affected sites were chest, shoulder, back, forearm and neck. 6

3.1. Number of sessions required for patient groups 4

2 In group IA, the numbers of intralesional injections of 5-FU received ranged from 4 to 6 sessions. In group IB, 0 the numbers of intralesional injections of 5-FU mixed with 5-FU 5-FU+TAC Bleomycin TAC ranged from 5 to 6 sessions. In group II, the numbers Figure 2. Vancouver scar scale in the studied groups. of intralesional injections of bleomycin received ranged from 2 to 6 sessions. The diﬀerence was statistically significant compared to that of group I (IA and group IB). This means that bleomycin is more eﬀective than 5FU alone or mixed with TAC (Fig. 1).

3.2. Vancouver scar scale in the studied groups

In group IA, the mean Vancouver scar scale in all patients before treatment was 9.67 ± 1.35 and it was 4.47 ± 1.3 after treatment with a mean total improvement of 54%. In group IB, the mean Vancouver scar scale in all patients before treatment was 9.67 ± 1.63 and it was

Figure 3a. Case 7 keloid before treatment, Vancouver scale score = 12. 80

70 5FU 60 5FU+TAC

50 Bleomycin

% 40

0 23456 Figure 3b. Keloid after 6 sessions of treatment with 5-FU, Vancouver Figure 1. The number of sessions required for the studied groups. scale score = 6, 50% improvement. A.M. Kabel et al. / Journal of Dermatology & Dermatologic Surgery 20 (2016) 32–38 35

Figure 4a. Case 14 hypertrophic scar before treatment, Vancouver scale score = 11. Figure 5b. Hypertrophic scar after 6 sessions of 5FU +TAC, Vancouver scale score = 5, 54.55% improvement.

Table 1 Correlation between clinical response and age, sex and disease duration in all studied groups. Parameter Pearson value P-value Age À0.0002 0.999 Sex 0.215 0.1 Disease duration À0.103 0.432

100 5FU

90 5FU+TAC Bleomycin 80 Figure 4b. Hypertrophic scar after 5 sessions of bleomycin, Vancouver scale score = 2, 81.82% improvement. 70 60

% 50

0 Hyperpigmentation Ulceration Pain

Figure 6. Side eﬀects in patients of the studied groups.

3.5. Relapse in the studied groups

Regarding relapse, there was relapse in 12 patients Figure 5a. Case 20 hypertrophic scar before treatment, Vancouver scale (40%) of group IA, in 14 patients (46.67%) of group IB score = 11. and no relapse occurred in any patients of group II (Table 2). 3.4. Side effects in the studied groups 4. Discussion Regarding side effects, there was hyperpigmentation, pain and ulceration in all the studied groups. However, Keloids and hypertrophic scars are fibrotic conditions pain was significantly decreased in group IB compared to that represent a model of altered wound healing with group IA, ulceration was significantly decreased in group overproduction of extracellular matrix and marked II than in group I, while pain after injection was increased proliferation of fibroblasts. Their exact etiology and in group II than in group I (Fig. 6). pathophysiology is still poorly understood. No single 36 A.M. Kabel et al. / Journal of Dermatology & Dermatologic Surgery 20 (2016) 32–38

Table 2 TAC/5-FU combination in the treatment of keloids and Relapse of keloids & hypertrophic scars in all studied groups. hypertrophic scars. He reported a 9-year experience admin- Time of relapse Group IA Group IB Group IC istering more than 5000 injections of 5-FU to more than (month) N % N % N % 1000 patients. He found that by mixing 1 mg/ml TAC with 1 2 6.67 4 13.33 0 0.00 5-FU, the efficacy was improved and injections were less 2 0 0.00 4 13.33 0 0.00 painful. Also, he found that injection at weekly intervals 3 6 20.00 2 6.67 0 0.00 was better than monthly. He used pulsed dye laser in com- 4 2 6.67 0 0.00 0 0.00 bination with 5-FU injection .The results of his study were 5 0 0.00 0 0.00 0 0.00 over 90% improvement in most patients . The difference 6 2 6.67 4 13.33 0 0.00 between the present study and that of Fitzpatrick (1999) Total 12 40.00 14 46.67 0 0.00 may be due to the use of pulsed dye laser (PDL) in combination with 5-FU injection. Also, the results of the present study were in agreement therapeutic modality is best for all keloids (Butler et al., with those of a study by Asilian et al. (2006) in which 69 2008; Trisliana Perdanasari et al., 2014). The aim of this patients of keloids and hypertrophic scars were randomly study was to evaluate the efficacy and safety of intrale- assigned into three groups. In one group, intralesional sional injection of 5-fluorouracil and bleomycin in the TAC was used, in the second intralesional TAC+5-FU treatment of keloids and hypertrophic scars. It was not was used, in the third TAC+5-FU injections were followed possible to use a double-blind study design in this study by pulsed-dye laser. All groups showed an acceptable due to difference in the storage precautions of bleomycin improvement in nearly all measures, but in comparison from that of 5-FU as bleomycin is stored at 4 °C while between groups, there was a statistically more significant 5-FU should not be freezed. improvement in the TAC+5-FU and TAC+5-FU + PDL Five-fluorouracil is an anti-metabolite that suppresses groups. Also, Darougheh et al. (2007) had given a combi- cell division and produces growth arrest at any stage of nation of intralesional TAC and 5-FU to twenty patients the cell cycle. It has been shown to inhibit fibroblast prolif- with keloids and hypertrophic scars at weekly intervals eration. So, it has been used intralesionally to treat keloids for 8 weeks. A good to excellent improvement was reported and hypertrophic scars with good therapeutic results by 55% of the patients as evidenced by an acceptable (Asilian et al., 2006). improvement in nearly all parameters except pruritus and In the present study, intralesional injection of 5-FU percentage of itching reduction. resulted in a significant improvement in vascularity, pliabil- In the present study, multiple intralesional injections of ity and height while worsening in the pigmentation. These bleomycin produced a significant improvement in vascular- results were in agreement with Nanda and Reddy (2004) ity, pliability and height while worsening pigmentation who had given intralesional 5-FU (50 mg/ml) to 28 patients compared to 5-FU injection. These results were in agree- with keloids at weekly intervals. The total dose ranged ment with those of Saray and Gu¨leç (2005) who used der- from 0.5 to 2 ml per session with a maximum number of mojet injection of bleomycin to treat 14 patients with 12 sessions and follow-up was done at 24 weeks. The keloids and hypertrophic scars that had not responded to improvement was more than 50% in the majority of the intralesional injection of TAC. 73% of the lesions showed patients. Also, the results in the present study are in agree- complete flattening, 7% showed highly significant flatten- ment with Kontochristopoulos et al. (2005) who treated ing, 13% showed significant flattening and 7% showed twenty patients once weekly with intralesional injections moderate flattening. of 5-FU (50 mg /ml) at 0.2–0.4 ml/ cm2. Injections were Espanã et al. (2001) used intralesional bleomycin injec- spaced at a 1 cm interval. The maximum dose was 2 ml tion to treat keloids and hypertrophic scars in 13 patients per session. All patients were followed up for 12 months, using multiple puncture method. The dose applied was or until recurrence was noted. Of the twenty patients, 17 2 ml/cm2 with a maximum of 6 ml per session. Complete (85%) showed more than 50% improvement. Moreover, flattening was seen in 6 patients, highly significant flatten- Gupta and Kalra (2002) treated twenty-four patients with ing (>90%) was observed in 6 patients, and significant flat- keloids with intralesional injections of 50–150 mg 5-FU tening (75–90%) in 1 patient. Also, Aggarwal et al. (2008) per week for a maximum of 16 injections. One third of used bleomycin by multiple superficial puncture technique the patients showed more than 75% flattening of the to treat fifty patients with keloids and hypertrophic scars. keloids. Overall, about half of the patients showed more Three applications were given at an interval of fifteen days than 50% flattening of the treated keloids. The difference followed by a fourth and final application two months after in the present study and that in Gupta and Kalra (2002) the last application. This resulted in complete flattening in may be due to the difference in the number of sessions 22 patients (44%), significant flattening in 11 patients and the dose used. (22%), adequate flattening in 7 patients (14%) and no flat- In group IB of the present study, the improvement was tening in 10 patients (20%). The difference between the pre- better than that in group IA but the difference was statisti- sent study and that of Aggarwal et al. (2008) may be due to cally non significant. Fitzpatrick (1999) was the first to use the difference in the methods of injection. It could be A.M. Kabel et al. / Journal of Dermatology & Dermatologic Surgery 20 (2016) 32–38 37 concluded that intralesional injection of bleomycin is more (60%) and pain at the injection site was present in 10 effective than the superficial puncture techniques. patients (33.33%). The side effects in group IB were nearly Naeini et al. (2006) treated 45 patients with keloids and the same as group IA except for pain which was signifi- hypertrophic scars. They were divided into two groups; cantly decreased in group IB. In a study by Darougheh group A was treated by bleomycin tattoo, group B was et al. (2007), no adverse effects were seen in the treated with cryotherapy combined with intralesional TAC+5-FU group. In group II of the present study, hyper- TAC. They were given four therapeutic sessions at a one- pigmentation was present in 42 patients (70%), ulceration month interval. Therapeutic response in lesions less than was present in 14 patients (21.33%) and pain at the injec- 100 mm2 was higher than 88% in both groups but in larger tion site was present in all patients (100%). lesions, the response to bleomycin was significantly better In a study by Espanã et al. (2001), four patients had skin than cryotherapy combined with TAC. type II and nine patients had skin type III. They detected In the present study, there was recurrence during the fol- slight residual hyperpigmentation in two patients with skin low up period in 12 (40%) patients of group IA and in 14 type III. In the present study, all patients had skin types (46.67%) patients of group IB. These results were in agree- III, IV and V. The difference between the present study ment with those of Kontochristopoulos et al. (2005) who and that of Espanã et al. (2001) may be due to the differ- noted recurrence in 47% of patients who responded to ence in skin types of patients in the two studies. treatment within 1 year. However, Nanda and Reddy In conclusion, intralesional injection of bleomycin was (2004) observed no recurrence of symptoms or the lesion more effective and better in remission than intralesional during the follow-up period of 24 weeks in any of the 5-FU injection in the treatment of keloids and hyper- patients. trophic scars regardless of patient’s age, sex, disease dura- In group II, there was no recurrence during the follow tion or site of lesion. up period. This was in agreement with that of Saray and Gu¨leç (2005) who followed up their patients for 19 months Conflict of interest after treatment and observed no recurrence of the lesions. Also, Bodokh and Brun (1996) used bleomycin infiltration None of the authors have a conflict of interest to report. and observed no recurrence in any patients. On the other hand, Espanã et al. (2001) observed recurrence in 15% of References patients 10 months after the last infiltration of bleomycin. In the present study, no correlation between clinical Aggarwal, H., Saxena, A., Lubana, P.S., Mathur, R.K., Jain, D.K., 2008. response and age, sex or duration of keloids was found. Treatment of keloids and hypertrophic scars using bleomycin. Cosm. This was in line with that of Nanda and Reddy (2004) Dermatol. 7, 43–49. who observed no correlation between duration of keloid Asilian, A., Darougheh, A., Shariati, F., 2006. New combination of and response to treatment. Also, Naeini et al. (2006) found triamcinolone, 5-Fluorouracil, and pulsed-dye laser for treatment of keloid and hypertrophic scars. Dermatol. Surg. 32, 907–915. no correlation between location or duration of lesions Baryza, M.J., Baryza, G.A., 1995. The Vancouver scar scale: an and the therapeutic response. On the contrary, administration tool and its interrater reliability. J. Burn Care Kontochristopoulos et al. (2005) found a correlation Rehabil. 16, 535–538. between duration of keloids and recurrence. He observed Bodokh, I., Brun, P., 1996. Treatment of keloids with intralesional that the response was low in older lesions. bleomycin. Ann. Dermatol. Venereol. 123, 791–794. Butler, P.D., Longaker, M.T., Yang, G.P., 2008. Current progress in Regarding the side effects in the present study, there keloid: research and treatment. J. Am. Coll. Surg. 206, 731–741. were hyperpigmentation, ulceration and pain. In group Darougheh, A., Asilian, A., Shariatic, F., 2007. Intralesional triamci- IA, hyperpigmentation was present in 20 patients nolone alone or in combination with 5-fluorouracil for the treatment of (66.67%), ulceration was present in 18 patients (60%) and keloid and hypertrophic scars. Clin. Exp. Dermatol. 34, 219–223. pain at the injection site was present in 22 patients Davison, S., Dayan, J., Clemens, M., Sonni, S., Wang, A., Crane, A., 2009. Efficacy of intralesional 5-fluorouracil and triamcinolone in the (73.33%). Nanda and Reddy (2004) found that pain, burn- treatment of keloids. Aesthetic Surg. J. 29, 40–46. ing sensation and ulceration were the main adverse effects. Espanã, A., Solano, T., Quintanilla, E., 2001. Bleomycin in the treatment Pain was found in 100% of patients, ulceration was found of keloids and hypertrophic scars by multiple needle punctures. in 20% of patients and burning sensation in 7% of patients. Dermatol. Surg. 27, 23–27. The difference may be due to performing the injection with- Fitzpatrick, R.E., 1999. Treatment of inflamed hypertrophic scars using intralesional 5-FU. Dermatol. Surg. 25, 224–232. out local anesthesia. Also, Kontochristopoulos et al. (2005) Gupta, S., Kalra, A., 2002. Efficacy and safety of intralesional 5- found that pain, hyperpigmentation and ulceration were fluorouracil in the treatment of keloids. Dermatology 204, 130–132. the main adverse effects. Pain was found in all patients as Hunasgi, S., Koneru, A., Vanishree, M., Shamala, R., 2013. Keloid: a case the injection was done without local anesthesia, ulceration report and review of pathophysiology and differences between keloid was observed in 6 out of 20 patients and hyperpigmenta- and hypertrophic scars. J. Oral Maxillofac. Pathol. 17 (1), 116–120. Kontochristopoulos, G., Stefanaki, C., Panagiotopoulos, A., Stefanaki, tion in all patients. K., Argyrakos, T., Petridis, A., et al., 2005. Intralesional 5-fluorouracil In group IB, hyperpigmentation was present in 18 in the treatment of keloids: an open clinical and histopathologic study. patients (60%), ulceration was present in 18 patients J. Am. Acad. Dermatol. 52, 474–479. 38 A.M. Kabel et al. / Journal of Dermatology & Dermatologic Surgery 20 (2016) 32–38

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