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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 6  |  Page : 1251-1255

Single-fraction radiation: A promising adjuvant therapy to prevent keloid recurrence


Department of Radiation Oncology, Amrita Institute of Medical Sciences, Amrita University, Kochi, Kerala, India

Date of Web Publication28-Nov-2018

Correspondence Address:
K Sruthi
Department of Radiation Oncology, Amrita Institute of Medical Sciences, Amrita University, Kochi - 682 041, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_20_17

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 > Abstract 


Introduction: Keloids are characterized by collection of atypical fibroblasts with excessive deposition of extracellular matrix components. Keloids are prone to high recurrence (50%–80%) with unimodality treatment. Radiation is a promising approach among the adjuvant modalities in vogue though consensus is lacking on dose-fractionation schedule.
Aim: The present study aimed to analyze the efficacy of single-fraction high-dose adjuvant radiotherapy to prevent keloid recurrence.
Materials and Methods: Details of patients treated for keloids using external beam radiation therapy from January 2011 to December 2016 were retrieved from electronic medical records and radiation therapy charts and analyzed.
Results: Thirty-seven keloid lesions in thirty patients were analyzed. Keloids received radiation within 24–72 h postsurgery using 6 MeV electron beam. 45.9% of keloids were in the chest wall. Dose ranged between 5 Gy and 12 Gy in 1–3 fractions. Eight Gy was used in 78.4%. The single fraction was preferred in 91.9%. Good cosmesis was achieved in all except three who had wound dehiscence. Median follow-up was 32.67 months. 16.2% had recurrence. Median time to recur was 13.6 months, and median recurrence-free interval 21.23 months. Among those who received 8 Gy single fraction, 73.4% remained recurrence-free at 5 years.
Conclusion: Albeit a retrospective analysis, ours is the only study in literature offering 8 Gy single dose, using electrons, as a postoperative adjuvant treatment to prevent recurrence in keloids. Our recurrence rates were similar to that quoted in published series. This hence can be validated in further studies as it is cosmetically acceptable, safe, painless, and cost-effective with good patient compliance.

Keywords: Adjuvant therapy, electron beam radiation, keloids


How to cite this article:
Sruthi K, Chelakkot PG, Madhavan R, Nair RR, Dinesh M. Single-fraction radiation: A promising adjuvant therapy to prevent keloid recurrence. J Can Res Ther 2018;14:1251-5

How to cite this URL:
Sruthi K, Chelakkot PG, Madhavan R, Nair RR, Dinesh M. Single-fraction radiation: A promising adjuvant therapy to prevent keloid recurrence. J Can Res Ther [serial online] 2018 [cited 2019 Sep 16];14:1251-5. Available from: http://www.cancerjournal.net/text.asp?2018/14/6/1251/211660




 > Introduction Top


Keloids are characterized by a collection of atypical fibroblast with excessive deposition of extracellular matrix components.[1] Pathologically, keloids contain relatively acellular centers and thick, abundant collagen bundles that form nodules in the deep dermal portion of the lesion. Keloids can occur on any part of the body, but they typically, occur on the earlobes, shoulders, chest, and back.[2],[3] Many factors have been implicated in keloid formation. However, the commonly known causative factors are piercing, trauma, surgical scars, acne scars, and chickenpox scars.[1],[3]

Keloids are prone to high rates of recurrence with unimodality treatment. Nearly 50%–80% recurrence rates have been documented. Many adjuvant treatments are in vogue in an attempt to contain these lesions. Radiation is one promising treatment modality, but there is no consensus on dose fractionation schedule.[4] Common treatment options include intralesional steroids, interferon and fluorouracil injections, laser therapy, cryotherapy, silicone gel sheets applications, surgical excision, external radiation therapy, and brachytherapy.[1],[5] According to the international advisory panel on scar management, surgical excision with postoperative radiation therapy is considered the most efficacious treatment.[6]

In an established keloid, the cells are no longer rapidly proliferating, and they have already laid down collagen, so radiotherapy is not very effective at shrinking it. Radiotherapy can slow down both normal wound healing and the overblown or unrestrained healing response that occur in the development of a keloid. If radiotherapy is administered after excision of a keloid, it can slow down and limit wound healing to normal levels by killing a substantial portion of the rapidly proliferating fibroblasts.[7] The German patterns of care study series reported only 11.4% keloid recurrences from 880 cases undergoing postoperative radiotherapy.[8]


 > Materials and Methods Top


We, in this study, focused on patients with keloids treated with external beam radiation, in our tertiary care center, from January 2011 to December 2016. Details of these patients were retrieved from the electronic medical records and radiation therapy records. The data obtained were analyzed for site-wise distribution of keloids, radiation dose used, and complications of treatment, recurrence-free interval, and failure patterns. Telephonic interview was taken for those patients who could not come to the hospital for follow-up.

SPSS (Statistical Package for the Social Sciences) for Windows, Version 17.0. Chicago: SPSS Inc was used for the analysis and descriptive statistics. Pearson Chi-square test, Spearman correlation, and Pearson's correlation were used. Kaplan–Meier survival curve for the recurrence-free pattern was plotted.


 > Results Top


The study included 37 keloid lesions in thirty patients. After surgical removal of the keloid lesions, all patients had received radiotherapy within 24–72 h of surgery. Written informed consent had been obtained before the delivery of radiotherapy. The planned target volume included the operative scar with a margin of 1 cm. The patients were treated with 6 MeV electron beam with a linear accelerator, at 100 cm source to skin distance [Figure 1]. Appropriate bolus was used on the keloid surgical scar when necessary. Surrounding organs at risk and normal tissue tolerance dose were respected by appropriate shielding of the area of concern with lead. Radiation dose ranged between 5 Gy and 12 Gy in 1–3 fractions. A single fraction of 8 Gy was used for 29 keloids (78.4%) while 10 Gy as a single fraction was used for 4 keloids (10.8%). The majority of the lesions were treated with a single fraction (91.9%) while two fractions were used for one patient (2.7%) and three fractions in two cases (5.4%).
Figure 1: Electron beam treatment field in a patient receiving adjuvant radiation for keloid of left ear lobe

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The median follow-up was 32.67 months, with the maximum being 70.7 months. The median age at presentation was 37 years (range: 21–77), and 67.6% were male. Seventeen of the keloids were in the chest wall (45.9%) followed by eight in the ear (21.6%). Six (16.2%) were in the limbs and two each (5.4%) in the abdomen, breast/axilla, and neck. Six MeV electron beam was used for all the 37 lesions. The dose was prescribed to 80% isodose reference line in 83.3% and to 90% in 16.2%.

Electron beam therapy was given within 24–48 h after surgery. Twenty-five patients (83.3%) were treated within 24 h and the rest within 48 h of surgery. Most of the patients (91.9%) did not have any posttreatment complications. Postoperative wound dehiscence was noted in three cases (8.1%). Recurrence of the keloid was noted in six cases (16.2%) and the median time to recur was 13.6 months. The median recurrence-free interval was 21.23 months. At 5 years, 75.5% of patients were recurrence free [Figure 2]. All recurrences were noted within 24 months. Although not statistically significant, a striking difference in 5-year recurrence free interval was observed based on gender; females faring better with 87.5%, compared to males (68.2%, P = 0.194). All keloid lesions of ear, abdomen, breast/axilla remained failure free at 2 years. 82.35% of chest wall, 87.5% of ear, 50% of neck, and 83.3% of limb lesions remained failure free at 5-years. Among those who received a dose of 8 Gy or more, there was no recurrence after 24 months, with 73.8% of patients remaining recurrence free at 5 years. Pearson 2-tailed correlation study showed a correlation coefficient of 0.639 between the dose of radiation and the pattern of recurrence. Analysis on the basis of number of fractions showed 71.4% of patients who received single fraction to be recurrence-free at the end of 5 years. Among those who received 8 Gy single fraction 4 patients had recurrence (13.8%), and 73.4% remained recurrence-free at 5 years [Figure 3]. No long-term complications were noted in these patients.
Figure 2: Kaplan–Meier curve showing the recurrence-free interval after radiation treatment

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Figure 3: Kaplan–Meier curve showing the recurrence-free interval with 8 Gy single fraction

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 > Discussion Top


Keloid is defined as an exuberant scar unique to human being, which is usually triggered by skin trauma.[9] Keloid is similar to benign tumor in their biological behaviors such as aggressive growth beyond the original boundary of skin injury and invasion into normal tissue. Keloid patients possess-specific diathesis, including genetic predisposition and gene mutation, abnormal levels of hormones, growth factors and cytokines, and strong inflammatory response.[9]

Keloids represent a pathologic response to dermal injuries resulting in firm, rubbery tumors with a shiny surface appearance that grow beyond initial wound boundaries. Keloid scarring is unique to human beings, and it occurs predominantly on the chest, back, shoulders, and earlobes, whereas it rarely occurs on the soles or palms. One plausible explanation stems from the fact that humans have different sebaceous glands than other mammals and that these higher risk areas of the human body may have higher concentrations of sebaceous glands. The so-called “sebum hypothesis” proposes that the sebum released by the sebaceous glands onto the skin surface may come into contact with T-cells after cutaneous injury and cause an inflammatory reaction that leads to keloid progression.[10]

Management of hypertrophic scars, keloid disease, and striae distensae in dark pigmented skin remains a clinical challenge. There are various treatment modalities; however, there is no single therapy that is advocated for hypertrophic scars, keloid disease, or striae distensae.[11] Treatment modalities for keloids and hypertrophic scars include compression garments, radiation, excision, intralesional injections, cauterization, cryotherapy, laser surgery, and silicone gel dressings. It is difficult to assess the efficacy of the existing treatment modalities due to lack of controlled, comparative studies.[12]

Injection of corticosteroids is frequently employed as first-line therapy for keloids. Successful application of steroid injections requires injection into the scar itself, which can be a painful procedure for the patient. The side effects can include skin atrophy, depigmentation, telangiectasias, atrophy of subcutaneous tissue and fat, skin necrosis, ulcerations, and cushingoid features.[6],[13]

Radiation has been used for the treatment of keloids since the late 1800s, and there are multiple radiation protocols for keloid treatment, which vary in the type of beam used and the use of radiation as monotherapy or adjuvant therapy. The most common use of radiation is as adjuvant postoperative treatment although this has not been evaluated in a randomized, prospective controlled trial. Success rates have been recorded in the range of 67% to 98%.[14],[15]

Radiation suppresses collagen synthesis in keloids or hypertrophic scars. This is mediated by the inhibition of transforming growth factor-beta 1 release from fibroblasts. Otherwise, histamine released from mast cells stimulates the proliferation of fibroblasts. Radiation inhibits histamine release from mast cells, which in turn inhibits the proliferation of fibroblasts. Thus, the mechanism by which radiation inhibits keloids or hypertrophic scars is by suppression of fibroblast proliferation and inhibition of collagen synthesis.[16],[17]

Radiation increases the expression of p53 downstream genes, p21 and p27, in primary keloid fibroblasts. In addition, irradiation induces the expression of p21 and p16, which regulated cell proliferation, differentiation, and senescence. The induction of cellular senescence has been considered an important molecular target to halt keloid lesion progression and recurrence. Thus, radiation may prevent the recurrence of keloids by controlling fibroblast proliferation, arresting the cell cycle, and inducing premature cellular senescence.[18]

There is no consensus as to the type of beam, the energy of the beam, or the dose of radiation. In our study, all the patients were treated with electron beam therapy. Electron beams are delivered using high-energy linear accelerators. Lower energies of electron beams such as 4–6 MeV achieve high dose at the required depth while sparing the critical deeper structures. Dose homogeneity is easily achieved and has a shorter treatment time.[19]

Various dose ranges and multiple fractionation schedules are used for adjuvant radiation for keloids. Flickinger in his radiobiological analysis of keloid radiotherapy says that postoperative keloid radiotherapy requires moderately high doses for optimal technique to be effective. The relatively low α/β ratio of 1.12–2.86 (mean 2.08) for keloids indicates that hypofractionated radiation therapy is the best strategy.[7]

Sakamoto et al. studied the dose-response relationship and dose optimization in 194 postoperative keloids in 119 patients.[20] The total dose ranged from 16 Gy in 8 fractions to 40 Gy in 8 fractions and a mean biologically effective dose of 33.5 Gy. Kilo-voltage X-rays (55 or 100 kVp) or electron beams (4 or 6 MeV) were used. This study quoted a relapse rate of 11% for dose greater than 20 Gy while it was 43% for lower doses. They proposed 20 Gy in five fractions as the optimal dose for the postoperative radiation therapy of keloids. Sakamoto et al. study also showed a relapse rate of 33% at 36 months.[20] Kim et al. in a retrospective study over 11 years suggested a dose of 15 Gy of radiation in three fractions following keloidectomy for earlobe keloids.[21]

In our study, with a dose of 8 Gy in a single fraction, 73.4% of patients were recurrence-free at 5 years. Among those treated with 8 Gy single fraction, the recurrence rate was 13.8%. Similarly, in contrast to Sakamoto's observation, our overall recurrence rate was conspicuously lower rates for doses <:20 Gy; 16.2% versus 43%.[20] This also substantiates Flickinger's observation that fractionated treatment in keloids has little advantage.[7]

Lee and Park. in their study evaluating the treatment outcome and factors associated with occurrence and recurrence in the postoperative electron beam radiotherapy for keloids stated that radiotherapy must be initiated within 72 h of surgical excision as the proliferation phase occurs 2 or 3 days after an injury. Six of the seven patients who recurred in their study received radiation 72 h after the surgery (P < 0.0001).[22] All our patients were treated within 72 h after surgical excision with 83.3% being within 24 h. And hence, no correlation was obtained between the pattern of recurrence and delay in initiation of radiation treatment.

Van Leeuwen et al. in a systematic review of 33 articles of surgical excision with adjuvant irradiation for keloid scars noted the mean time for recurrence after treatment to be 14.8 months (range: 2–36 months). In addition, a lower mean recurrence rate for the single-fraction protocols (12 ± 8.8) was seen compared to the mean recurrence rate within the total external radiation group (22.2 ± 16). In addition, no complications were described, and good results were achieved in terms of scar quality and patients' satisfaction.[23]

Pontoriero et al. treated 62 patients with keloids with postoperative orthovoltage irradiation to a total dose of 12 Gy in three consecutive days, at 4 Gy per fraction; 24 h after surgery and noted a 16% clinical relapse.[24] Speranza et al. noted a relapse rate of 15% in their series.[25] With a dose of 8 Gy single fraction, our relapse rate was 13.8%, which is comparable to these studies.

The median time to recur in our study was 13.61 months, and all the recurrences were seen within 24 months. This was similar to the German patterns of care study of 880 cases which reported 11.4% recurrences, all within 2 years of therapy.[8] Song et al. also describes a similar approach with adjuvant single-fraction radiotherapy for intractable keloids, using 10 Gy dose within 72 h of surgical excision. Their mean follow-up period was 20 months, and there was no recurrence. However, the study included only 16 keloid lesions from 12 patients.[26]

No relation was seen between the recurrence rates and the site of the keloid in the study by Pontoriero et al.[24] Flickinger, on the other hand, observed that keloids of earlobe had a significantly lower recurrence rate,[7] as also did Ogawa et al.[15] Of the eight patients with earlobe keloids only one had recurrence with 87.5% remaining recurrence free at 5 years. We also observed that all keloid lesions of the abdomen and breast/axilla and 82.35% of the chest wall and 83.3% of the limb lesions were failure at 5 years.

Side effects of radiation can be divided into acute and late, the former occurring within the first 7–10 days and the latter occurring several weeks after exposure. Acute reactions include erythema, hyperpigmentation, epilation, and desquamation. Late complications range from scarring, permanent pigmentation/depigmentation, and atrophy, to dermal fibrosis and ulceration.

Speranza et al. have analyzed the toxicity profiles in their descriptive study of 234 patients receiving adjuvant radiation after excision using a total of 15 Gy in three 5-Gy daily fractions of orthovoltage radiotherapy within 24 h for keloids. Acute toxicities such as skin redness (54.2%) and skin peeling (24%) were observed. The late toxicities were telangiectasia, (27%) and permanent skin discoloration (62%).[25] Interestingly, we did not observe any skin changes either in the immediate posttreatment period or as late sequelae.

The main deterrent for surgeons to consider radiation as an adjuvant treatment for keloids is the fear of radiation-induced carcinogenesis. Ogawa et al. in a literature search evaluating radiation-associated carcinogenesis between 1901 and 2009 found only five reported cases, one of which was a likely malignant transformation of keloid.[14] In the remaining four cases, the radiation doses and documentation of appropriate protection of surrounding tissue were inconsistent, and the authors concluded that the risk of carcinogenesis attributable to keloid radiation therapy is very low when surrounding tissues, including the thyroid and mammary glands, especially in children and infants, are adequately protected and that radiation therapy is acceptable as a keloid treatment modality.[14]


 > Conclusion Top


Radiation as an adjuvant therapy in the postoperative period within 48 h is a cosmetically acceptable, safe, painless, cost-effective treatment with good patient compliance to prevent keloid recurrence. Albeit a retrospective analysis, ours is the only study in literature that has offered 8 Gy in a single fraction, using electrons as a postoperative adjuvant treatment to prevent recurrence in keloids. Recurrence rates observed in our study were similar to that quoted in the published series and hence can be validated in further studies.

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

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Marneros AG, Krieg T. Keloids – Clinical diagnosis, pathogenesis, and treatment options. J Dtsch Dermatol Ges 2004;2:905-13.  Back to cited text no. 1
    
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Brissett AE, Sherris DA. Scar contractures, hypertrophic scars, and keloids. Facial Plast Surg 2001;17:263-72.  Back to cited text no. 2
    
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Lee JY, Yang CC, Chao SC, Wong TW. Histopathological differential diagnosis of keloid and hypertrophic scar. Am J Dermatopathol 2004;26:379-84.  Back to cited text no. 3
    
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Jung JY, Roh MR, Kwon YS, Chung KY. Surgery and perioperative intralesional corticosteroid injection for treating earlobe keloids: A korean experience. Ann Dermatol 2009;21:221-5.  Back to cited text no. 5
    
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Mustoe TA, Cooter RD, Gold MH, Hobbs FD, Ramelet AA, Shakespeare PG, et al. International clinical recommendations on scar management. Plast Reconstr Surg 2002;110:560-71.  Back to cited text no. 6
    
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Flickinger JC. A radiobiological analysis of multicenter data for postoperative keloid radiotherapy. Int J Radiat Oncol Biol Phys 2011;79:1164-70.  Back to cited text no. 7
    
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Kutzner J, Schneider L, Seegenschmiedt MH. Radiotherapy of keloids. Patterns of care study – Results. Strahlenther Onkol 2003;179:54-8.  Back to cited text no. 8
    
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Qu M, Song N, Chai G, Wu X, Liu W. Pathological niche environment transforms dermal stem cells to keloid stem cells: A hypothesis of keloid formation and development. Med Hypotheses 2013;81:807-12.  Back to cited text no. 9
    
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Fong EP, Chye LT, Tan WT. Keloids: Time to dispel the myths? Plast Reconstr Surg 1999;104:1199-202.  Back to cited text no. 10
    
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Ud-Din S, Bayat A. New insights on keloids, hypertrophic scars, and striae. Dermatol Clin 2014;32:193-209.  Back to cited text no. 11
    
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Mutalik S. Treatment of keloids and hypertrophic scars. Indian J Dermatol Venereol Leprol 2005;71:3-8.  Back to cited text no. 12
[PUBMED]  [Full text]  
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Roques C, Téot L. The use of corticosteroids to treat keloids: A review. Int J Low Extrem Wounds 2008;7:137-45.  Back to cited text no. 13
    
14.
Ogawa R, Yoshitatsu S, Yoshida K, Miyashita T. Is radiation therapy for keloids acceptable? The risk of radiation-induced carcinogenesis. Plast Reconstr Surg 2009;124:1196-201.  Back to cited text no. 14
    
15.
Ogawa R, Miyashita T, Hyakusoku H, Akaishi S, Kuribayashi S, Tateno A. Postoperative radiation protocol for keloids and hypertrophic scars: Statistical analysis of 370 sites followed for over 18 months. Ann Plast Surg 2007;59:688-91.  Back to cited text no. 15
    
16.
Caccialanza M, Piccinno R, Schiera A. Postoperative radiotherapy of keloids: A twenty-year experience. Eur J Dermatol 2002;12:58-62.  Back to cited text no. 16
    
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Rosen EM, Goldberg ID, Myrick KV, Levenson S. Radiation survival properties of cultured vascular smooth muscle cells. Radiat Res 1984;100:182-91.  Back to cited text no. 17
    
18.
Ji J, Tian Y, Zhu YQ, Zhang LY, Ji SJ, Huan J, et al. Ionizing irradiation inhibits keloid fibroblast cell proliferation and induces premature cellular senescence. J Dermatol 2015;42:56-63.  Back to cited text no. 18
    
19.
Guix B. Radiotherapy concepts for keloids: Current options and clinical results. Radiother Oncol 2004;71:s15.  Back to cited text no. 19
    
20.
Sakamoto T, Oya N, Shibuya K, Nagata Y, Hiraoka M. Dose-response relationship and dose optimization in radiotherapy of postoperative keloids. Radiother Oncol 2009;91:271-6.  Back to cited text no. 20
    
21.
Kim K, Son D, Kim J. Radiation therapy following total keloidectomy: A retrospective study over 11 years. Arch Plast Surg 2015;42:588-95.  Back to cited text no. 21
    
22.
Lee SY, Park J. Postoperative electron beam radiotherapy for keloids: Treatment outcome and factors associated with occurrence and recurrence. Ann Dermatol 2015;27:53-8.  Back to cited text no. 22
    
23.
van Leeuwen MC, Stokmans SC, Bulstra AE, Meijer OW, Heymans MW, Ket JC, et al. Surgical excision with adjuvant irradiation for treatment of keloid scars: A systematic review. Plast Reconstr Surg Glob Open 2015;3:e440.  Back to cited text no. 23
    
24.
Pontoriero A, Potami A, Iati G, Comitini S, Venza M, Settineri N, et al. Post-operative radiotherapy of keloids. A 10-years experience of kilovoltage irradiation. Int J Radiat Res 2015;13:201-4.  Back to cited text no. 24
    
25.
Speranza G, Sultanem K, Muanza T. Descriptive study of patients receiving excision and radiotherapy for keloids. Int J Radiat Oncol Biol Phys 2008;71:1465-9.  Back to cited text no. 25
    
26.
Song C, Wu HG, Chang H, Kim IH, Ha SW. Adjuvant single-fraction radiotherapy is safe and effective for intractable keloids. J Radiat Res 2014;55:912-6.  Back to cited text no. 26
    


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