April 2020 HSC Section 4 - Plastic and Reconstructive Problems

Annals of Plastic Surgery • Volume 83, Number 2, August 2019

Keloid Excision and Adjuvant Treatments

CONCLUSIONS We employed the novel statistical tool of network meta-analysis in order to evaluate the effect of different adjuvant treatments following keloid excision. “ Excision + radiation ” seems to have significantly less recurrences than “ excision only ” or “ excision + 1 adjuvant drug. ” However, future randomized trials are necessary in order to draw more confident conclusions and help guide clinical decision making. REFERENCES 1. Sun LM , Wang KH, Lee YC. Keloid incidence in Asian people and its comorbid- ity with other fibrosis-related diseases: a nationwide population-based study. Arch Dermatol Res . 2014;306:803 – 808. 2. Alster TS , Tanzi EL. Hypertrophic scars and keloids: etiology and management. Am J Clin Dermatol . 2003;4:235 – 243. 3. Slemp AE , Kirschner RE. Keloids and scars: a review of keloids and scars, their pathogenesis, risk factors, and management. Curr Opin Pediatr . 2006;18: 396 – 402. 4. Sephel GC , Woodward SC. Repair, regeneration, and fibrosis. In: Rubin E, ed. Rubin's Pathology . Baltimore, MD: Lippincott, Williams & Wilkins; 2001: 84 – 117. 5. Mahdavian Delavary B , van der Veer WM, Ferreira JA, et al. Formation of hyper- trophic scars: evolution and susceptibility. J Plast Surg Hand Surg . 2012;46: 95 – 101. 6. He Y , Deng Z, Alghamdi M, et al. From genetics to epigenetics: new insights into keloid scarring. Cell Prolif . 2017;50. 7. Chike-Obi CJ , Cole PD, Brissett AE. Keloids: pathogenesis, clinical features, and management. Semin Plast Surg . 2009;23:178 – 184. 8. Bijlard E , Kouwenberg CA, Timman R, et al. Burden of keloid disease: a cross- sectional health-related quality of life assessment. Acta Derm Venereol . 2017; 97:225 – 229. 9. Walliczek U , Engel S, Weiss C, et al. Clinical outcome and quality of life after a multimodal therapy approach to ear keloids. JAMA Facial Plast Surg . 2015;17: 333 – 339. 10. WolframD , Tzankov A, Pulzl P, et al. Hypertrophic scars and keloids — a reviewof their pathophysiology, risk factors, and therapeutic management. Dermatol surg . 2009;35:171 – 181. 11. Ogawa R . Keloid and hypertrophic scars are the result of chronic inflammation in the reticular dermis. Int J Mol Sci . 2017;18. 12. Zhu Z , Ding J, Tredget EE. The molecular basis of hypertrophic scars. Burns trauma . 2016;4:2. 13. Lee TY , Chin GS, KimWJ, et al. Expression of transforming growth factor beta 1, 2, and 3 proteins in keloids. Ann Plast Surg . 1999;43:179 – 184. 14. Marneros AG , Krieg T. Keloids — clinical diagnosis, pathogenesis, and treatment options. J Dtsch Dermatol Ges . 2004;2:905 – 913. 15. Arno AI , Gauglitz GG, Barret JP, et al. Up-to-date approach to manage keloids and hypertrophic scars: a useful guide. Burns . 2014;40:1255 – 1266. 16. Shridharani SM , Magarakis M, Manson PN, et al. The emerging role of antineo- plastic agents in the treatment of keloids and hypertrophic scars: a review. Ann Plast Surg . 2010;64:355 – 361. 17. O'Brien L , Pandit A. Silicon gel sheeting for preventing and treating hypertrophic and keloid scars. Cochrane Database Syst Rev . 2006;1:Cd003826. 18. Anzarut A , Olson J, Singh P, et al. The effectiveness of pressure garment therapy for the prevention of abnormal scarring after burn injury: a meta-analysis. J Plast Reconstr Aesthet Surg . 2009;62:77 – 84. 19. Abdel Hay R , Shalaby K, Zaher H, et al. Interventions for acne scars. Cochrane Database Syst Rev . 2016;4:CD011946. 20. Gauglitz GG , Korting HC, Pavicic T, et al. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med . 2011;17:113 – 125. 21. Del Toro D , Dedhia R, Tollefson TT. Advances in scar management: prevention and management of hypertrophic scars and keloids. Curr Opin Otolaryngol Head Neck Surg . 2016;24:322 – 329. 22. Rouse B , Chaimani A, Li T. Network meta-analysis: an introduction for clinicians. Intern Emerg Med . 2017;12:103 – 111. 23. Moher D , Liberati A, Tetzlaff J, et al. Preferred Reporting Items for Systematic Re- views and Meta-analyses: the PRISMA statement. PLoS Med . 2009;6:e1000097. 24. Hoaglin DC , Hawkins N, Jansen JP, et al. Conducting indirect-treatment-comparison and network-meta-analysis studies: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 2. Value health . 2011;14: 429 – 437.

Radiation therapy has been utilized for treating keloids for over a century. 54 The effectiveness of postexcision radiation therapy in reducing keloid size has been demonstrated by multiple studies. 55 – 58 A 2015 study found that radiation affects keloid formation by decreasing fibroblast proliferation through inhibition of histamine release from mast cells and suppressing collagen synthesis through inhibition of TGF- β 1. 56 The most commonly used forms of radiation therapy for keloids are brachytherapy and electron beam radiation. In a retrospective review of 612 patients with 892 keloids treated between 1992 and 2006 with postexcision brachytherapy, Viani et al 59 reported a recurrence-free re- sponse rate of 87.6%with a median follow-up of 61 months. These authors additionally reported that keloids secondary to burns and those that pre- viously received any treatment were the most likely to recur following excision and brachytherapy. Ogawa et al 60 reported a 4% recurrence rate at 18 months in 174 lesions among 145 patients who underwent ex- cision and radiation. However radiation therapy is associated with adverse effects that must be considered, such as carcinogenesis (eg, especially fibrosarcoma, thyroid carcinoma, and breast carcinoma). A review by Ogawa et al 54 reported a very low rate of carcinogenesis attributable to radiation therapy for keloids. Radiation therapy is regarded as a safe option when carefully applied in select patients. Excision-induced injury can often start the process of keloid recurrence. In this study, the results from the comparison in dyad 1 cor- roborates this point. Current thinking in the field is that recurrence rates can be reduced when excision is combined with pre-excision or postexcision adjuvant therapies. There is currently no standard of care for combination treatment regimens involving excision. Possible adjuvant therapies include intralesional injection of corticosteroids, radiation, silicone sheet gel sheets, pressure garments, and skin grafting. These therapies can also be used as monotherapies. Excision therapy often results in reduction of scar size and volume, symptomatic relief of pain and pruritus, and cosmetic improvement. Intralesional injection of corticosteroids, compression, and silicone sheeting may reduce scar volume by as much as 50% in some patients. 61 Corticosteroids work by inhibiting fibroblast proliferation and reducing collagen and glycosaminoglycan synthesis. Intralesional injection of tri- amcinolone acetonide is the most commonly used treatment for keloids and hypertrophic scars. 62 The investigators reported, on average, an 83% reduction in pruritus and pain among 94 patients with 109 keloids and a reduction in size by 4 weeks following intralesional corticosteroid injection. While these rates appear to be promising, intralesional injec- tions are associated with multiple adverse effects. These include dermal atrophy and hypopigmentation or hyperpigmentation. Hypopigmentation is particularly seen in African Americans and individuals with darker skin tones. For some patients who fail intralesional corticosteroid therapy, 5-FU is used instead; 5-FU has been shown to induce macrophage ap- optosis and inhibit TGF- β signaling, 63 which is important for type I collagen synthesis and keloid formation. Our study is not without limitations. The small sample size in the literature we found limited our ability to discern more precise treatment effects of each tested modality. Because of this, we cannot conclusively state that excision + radiation is superior to the other modalities we analyzed, although the analysis shows a trend toward this conclu- sion. Additionally, despite the fact that keloids affect millions of people worldwide, there is an ostensible lack of randomized trials that severely limits our ability to draw safe conclusions; the area of keloid therapy and care is in great need of higher-level evidence studies. A large variety of treatment modalities for keloids now exist. This is beneficial to patients, whose keloids manifest themselves in a wide variety of forms and etiologies and thus require tailored thera- pies. This large variety, however, adds to the challenge of identifying the treatments that are most effective for reducing the risk of recur- rence. We recommend future randomized controlled trials testing a small set of treatments as a strategy to better delineate the effectiveness of keloid therapies.

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