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BURN SURGERY AND RESEARCH

Optimizing Radiotherapy for Keloids


A Meta-Analysis Systematic Review Comparing Recurrence Rates
Between Different Radiation Modalities
Peter Mankowski, MD, MSc,* Jonathan Kanevsky, MD, CM,* Jared Tomlinson, MD,*
Alina Dyachenko, MSc,† and Mario Luc, MD*

electron beam, or brachytherapy. Brachytherapy has been demonstrated


Background: The high recurrence rate of keloids has lead to the use of multiple
to be superior to other radiation options for control of keloid recur-
treatment adjuncts to improve cosmetic outcomes after surgery. To date, there has
rence.3,4 However, previous meta-analyses comparing the success of
been no single, standardized modality agreed upon to produce the best results.
these treatments left the ideal treatment modality in question.1,5 Thus,
The purpose of this study was to review the radiation-based treatments (brachy-
the aim of this systematic review is to consolidate the current reports
therapy, electron beam and X-ray) used for keloid management and compare
of keloid radiotherapy treatments and summarize the outcome of differ-
their outcomes.
ent radiation treatment modalities by meta-analysis.
Methods: A literature review was performed from 1942 to October 2014 using
the databases: PubMed database of the National Center of Biotechnology Infor-
mation, MEDLINE, Biosis, Embase, Google scholar, and Cochrane database. Ar- METHODS
ticles were reviewed for case numbers, patient demographics, keloid location,
A review of the literature from 1942 to 2014 was performed
follow up, radiation modality, dose, keloid recurrence, and complications.
through October 2014 using the databases: PubMed database of the Na-
Results: A total of 72 studies met the inclusion criteria representing 9048 keloids.
tional Center of Biotechnology Information, MEDLINE, Biosis,
These studies were categorized by treatment: brachytherapy, electron, or X-ray.
Embase, Google scholar, and Cochrane database. All relevant studies
Meta-analysis demonstrated that radiotherapy after surgery had less recurrence
describing the use of radiotherapy for the treatment of keloids were in-
when compared to radiotherapy alone (22% and 37%, respectively, P = 0.005).
cluded without exclusion based on treatment regimen. Keywords used
Comparison between modalities revealed that postoperative brachytherapy
to search the literature include “keloid,” “radiotherapy,” and “radiation
yielded the lowest recurrence rate (15%) compared with X-ray and electron beam
therapy.” References cited by the retrieved literature were also reviewed.
(23% and 23%, respectively; P =0.04, P = 0.1). Subgroup analysis by location
Inclusion criteria for the study required the use of radiotherapy for the
demonstrated chest keloids have the highest recurrence rate. The most commonly
treatment of keloids with a reported recurrence rate or clearly defining
reported side effect of radiotherapy was changes in skin pigmentation.
parameters used to measure the success of radiotherapy treatment. Stud-
Conclusions: The results of this study reinforce postoperative radiotherapy as
ies were excluded if they failed to clearly report the parameters of their
effective management for keloids. Specifically, brachytherapy was the most ef-
technique or if they failed to quantify the success of their treatment
fective of the currently used radiation modalities.
(Fig. 1). Case series/reports were not included (patient, n <10). All arti-
Key Words: keloid, meta-analysis, radiotherapy, brachytherapy, recurrence cles reviewed were published in English. Articles were reviewed for
(Ann Plast Surg 2017;78: 403–411)
their case number, patient demographic, keloid location, follow up, eti-
ology, surgery inclusion, radiation type, dose, keloid recurrence, resolu-
tion, and reported complications.
K eloids arise from excessive collagen deposition that extend beyond
the margins of an original injury and are thought to occur from an
imbalance in normal wound healing.1,2 These growths are known for
Recurrence rate was obtained from each study as a percentage of
the number of keloids that recurred over the total treatment group size.
a recurrence rate above 50% when treated by excision alone.2 Many For each of the selected studies, the recurrence rate was verified or com-
treatments in various combinations have been applied to keloid man- puted if necessary. If a gradient was used by a study to measure recur-
agement with a stepwise algorithm having been previously described rence, only keloids that did not show any level of recurrence where
by Ogawa.3 used to calculate the total rate. To allow for comparison of the amount
Postoperative radiotherapy is 1 treatment option that has shown of radiotherapy administered between studies, biological effective dose
to be more effective than either surgery or radiation monotherapy and (BED) was calculated for each study in accordance with Kal and Veen.6
is commonly applied after keloid management is refractory to nonsurgi- Calculation of BED values used a tissue specific alpha/beta ratio that
cal options such as corticosteroid injection, laser, or cryotherapy.1,3 The represents the relationship of cell survival to radiotherapy. For skin,
approach of postoperative radiotherapy can include superficial X-ray, values of both 10 and 2.08 have been reported in the literature and there-
fore BED calculations where completed using both values.1 For studies
where a range of Gray values were reported, an average BED was cal-
culated and used to represent the study. For studies where the total ke-
Received April 5, 2016, and accepted for publication, after revision December 12, 2016.
From the *Division of Plastic and Reconstructive Surgery, and †St. Mary’s Research
loid population contained subgroups of keloids that received different
Centre, University of McGill Health Centre, Montreal, Quebec, Canada. fractionation dosing schedules, we broke the study population into indi-
Conflict of interest and sources of funding: none declared. vidual treatment groups for meta-analysis comparison.
Presentation at a meeting: Organization: Association of plastic and aesthetic surgery of To proceed with statistic analysis the recurrence rates from the
Quebec. Place: Mont Tremblant, Quebec, Canada Date: February 28, 2015.
Supplemental digital content is available for this article. Direct URL citations appear in
multiple studies were pooled in a binomial meta-analysis.7,8 We tested
the printed text and are provided in the HTML and PDF versions of this article on the study homogeneity of the pooled studies and depending on whether
the journal’s Web site (www.annalsplasticsurgery.com). homogeneity was accepted or rejected, we planned to use a fixed or the
Reprints: Peter Mankowski, MD, MSc, 401-1290W 11 Avenue, Vancouver, British random effect model for meta-analysis comparison to calculate the
Columbia, Canada. E-mail: peter.mankowski@mail.mcgill.ca.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
summary keloid recurrence rate and its 95% confidence interval (95%
ISSN: 0148-7043/17/7804–0403 CI). We used the Q statistic to test between study homogeneity: homo-
DOI: 10.1097/SAP.0000000000000989 geneity was rejected when the Q statistic P value was less than 0.10.

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Mankowski et al Annals of Plastic Surgery • Volume 78, Number 4, April 2017

FIGURE 1. Overview of literature systematic review. Multiple modalities, either X-ray or electron beam therapy was used. Monotherapy,
radiotherapy alone. Postexcisional, radiotherapy after surgical excision of the keloid.

The binomial meta-analysis was then repeated separately for each com- I2 > 64% and P value Q statistics <0.0001). The studies homogeneity
parison of interest1: monotherapy versus post-keloid excision,2 radio- was always rejected, and the random effect models for meta-analysis
therapy modality type and3 by keloid location. Finally, a mixed effect were used for each comparison.
logistic meta-analysis was performed to statistically compare the keloid
recurrence rates by reporting a combined odds ratio (OR) and 95% CI Radiotherapy Monotherapy Compared With
for each of the above covariates. Postexcisional Radiotherapy
Dose-response curves using the calculated BED values were
created to assess the relationship between radiation dose and recur- Of the 98 treatment groups, 22 groups were treated by radiother-
rence rate. A dose response curve was created for each alpha/beta apy alone and 71 groups were treated by surgical excision first followed
value used to calculate BED for each postexcisional treatment modality. by radiotherapy (postexcisional radiotherapy). The remaining groups
Forest plots were obtained for each radiation treatment modality. The were classified as receiving either preoperative radiotherapy or both
meta-analysis was conducted using the R 3.1 software.9 preoperative and postoperative radiotherapy but these groups had a
sample size too small for effective comparison.
Meta-analysis was performed to compare the recurrence rates
RESULTS of keloids treated with radiation therapy with and without surgery. Re-
currence rates were reported based on patient follow up which ranged
A total of 1410 studies where found using our keyword search
0 to 16 years. The average minimum follow up between all studies was
methodology. Based on title and abstract screening, 411 studies re- 14.4 months. A significantly higher recurrence rate of 37 ± 12% was
ceived complete review and 72 studies were identified that met the in- identified with radiation monotherapy compared with 22 ± 4% when
clusion criteria (Fig. 1). Publications were deconstructed to represent
radiation was applied after surgical excision (OR, 2.43; 95%CI,
individual treatment groups representing a unified treatment regimen
1.31–4.49; P=0.0046)
(eg, multiple radiotherapy dosing schedules composing different treat-
ment groups within one study). From the collected studies, 98 treatment
groups representing a total of 9048 keloids qualified for meta-analysis. Efficacy of Multiple Radiotherapy Modalities
These treatment groups included 20 brachytherapy, 21 electron beams, The 98 treatment groups were classified into 5 different categories
and 42 X-rays. (Figure 1 and Supplemental digital content 1, http://links.lww.com/SAP/
Assessment of overall consistency of effects across the evaluated A220, which summarizes all studies included in the meta-analysis).10–76
studies was low (I2 = 92%). When the studies were segregated by differ- An initial meta-analysis was performed to compare recurrence between
ent subgroups the datasets had a high degree of heterogeneity (always treatment modalities. A recurrence rate of 34%, the highest of all

TABLE 1. Meta-Analysis Comparison of Keloid Recurrence Rate by Radiation Modality Including Both Radiation Monotherapy
and Postexcisional Radiotherapy Treatment Groups

Treatment Modality (n = 98) No. Studies Recurrence Rate (95% CI) % of Variation (I2) OR (95% CI) P
Electron 21 21 % (15–30) 90.9% 1.53 (0.69–3.39) 0.2936
X-ray 42 34 % (26–43) 94.2% 3.12 (1.56–6.24) 0.0013
Brachytherapy 20 17 % (13–22) 85.1% 1 reference

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Annals of Plastic Surgery • Volume 78, Number 4, April 2017 Meta-Analysis of Keloid Radiotherapy Modalites

FIGURE 2. Meta-analysis of postexcisional radiation brachytherapy for the treatment of keloids.

FIGURE 3. Meta-analysis of postexcisional X-ray radiation therapy for the treatment of keloids.

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Mankowski et al Annals of Plastic Surgery • Volume 78, Number 4, April 2017

FIGURE 4. Meta-analysis of postexcisional electron beam radiation therapy for the treatment of keloids.

treatment modalities, was identified with X-ray radiotherapy. Both (34%) of all the location groups and were significantly more likely to
brachytherapy and electron beam modalities showed decreased rates recur compared to keloids localized to the ear (12%; P = 0.0025). Re-
of recurrence when compared to X-ray (21% and 17%, respectively, currence rates compared between the other treatment groups were noted
Table 1). The difference between electron and brachytherapy was to be nonsignificant (Table 3).
noted to be nonsignificant.
Meta-analysis was then performed again including only post- Complication Profile of Postexcision Radiotherapy
excisional radiotherapy studies (Figs. 2, 3, and 4). The lowest recur- Of the total keloid population, 59.2% (5356) were collected from
rence rate of 15% was found for brachytherapy with 23% for electron studies with documented posttreatment complication rates. A total of 37
beam and 23% for X-ray therapies. Recurrence rate comparison be- complication types were described. The 5 most common complications
tween X-ray and brachytherapy was statistically significant (OR, 1.94; represented multiple classifications of pigmentation changes with a
P =0.04, Table 2) and statistically insignificant between electron beam collective total occurrence of 32.5% (erythema, transient hyperpig-
and brachytherapy (OR, 1.81; P =0.10, Table 2). Dose-response curves mentation, hyperpigmentation, hypopigmentation, and unspecified
and regression analysis (R2) was used to quantify the strength of associ- pigmentation changes). Both infection and wound dehiscence occurred
ation between recurrence and treatment modality (Figs. 5, 6, and 7). in less than 1% of cases (0.85% and 0.32%, respectively; Figure 8).
Brachytherapy demonstrated the highest R2 value of 0.39 with electron
beam and X-ray having similar R-squared values (0.15).
DISCUSSION
Subgroup Analysis of Recurrence Rate by Location
A subgroup analysis of 33 treatment groups was performed to Postexcisional Radiotherapy
assess the relationship between keloid location and recurrence rate. Radiation monotherapy of keloids is currently used for very
Each treatment group consisted of keloids localized to one of 5 possible large or nonresectable lesions. In accordance with current management
categories (chest and trunk, upper extremity, lower extremity, head, and practices, we initially demonstrated that postexcisional radiotherapy
neck or ears). Chest and trunk keloids had the highest rate of recurrence was more successful at reducing keloid recurrence compared to

TABLE 2. Meta-Analysis Comparison of Keloid Recurrence Rate by Radiation Modality for Postexcisional Radiotherapy Treatment

Treatment Modality (n = 71) No. Studies Recurrence Rate (95% CI) % of Variation (I2) OR (95% CI) P
Electron 18 23 % (17–31) 87.1% 1.81 (0.89–3.69) 0.1002
X-ray 27 23 % (16–3) 92.5% 1.94 (1.01–3.72) 0.0465
Brachytherapy 17 15 % (12–2) 76.7% 1 reference

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Annals of Plastic Surgery • Volume 78, Number 4, April 2017 Meta-Analysis of Keloid Radiotherapy Modalites

FIGURE 5. The relationship of the recurrence rate of keloids treated with postexcisional brachytherapy as function of the BED.

FIGURE 6. The relationship of the recurrence rate of keloids treated with postexcisional X-ray therapy as function of the BED.

FIGURE 7. The relationship of the recurrence rate of keloids treated with postexcisional electron beam therapy as function of the BED.

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Mankowski et al Annals of Plastic Surgery • Volume 78, Number 4, April 2017

TABLE 3. Meta-Analysis Comparison of Keloid Recurrence Rate by Anatomical Location

Location (n = 36) No. Studies Recurrence Rate (95% CI) % of Variation (I2) OR (95% CI) P
Chest and trunk 9 34 % (23–47) 85.7% 4.46 (1.73–11.51) 0.002
Ear 12 12 % (7–22) 77.0% 1 reference
Head and neck 5 9 % (5–15) 23.2% 1.07 (0.33–3.43) 0.916
Extremity 7 16 % (1–25) 1.5% 1.37 (0.45–4.14) 0.5743

radiotherapy alone (22% and 37%, respectively). A previous meta- recurrence rate when compared to electron beam and X-ray therapy by
analysis cited a similar recurrence rate for radiation monotherapy of meta-analysis (23%, P = 0.10 and 23%, P = 0.04 respectively, Table 2).
43%; however, they noted postexcisional radiotherapy to be less effica- The dose-response relationship of brachytherapy keloid recurrence was
cious with recurrence rate of 32%.5 This improvement in keloid control also noted to be the strongest of the three modalities (Fig. 5). Of the 3
with postexcisional radiotherapy is most likely attributed to the increas- modalities, brachytherapy is unique in offering a focused in situ deliv-
ing popularity of the technique that has allowed for a greater sampling ery and less toxicity to adjacent tissue.77 Thus, brachytherapy is capable
of studies for our analysis. Additionally, postexcisional radiotherapy is of the highest targeting of keloid tissue compared with the external mo-
improving with recent reports demonstrating improved recurrence rates dalities. However, although multiple case series have suggested brachy-
with shorter, stronger dosing fractionation schedules.1 therapy is superior to other external beam modalities, few controlled
comparisons have been completed.10,77,78 In a recent cohort study of
258 keloids, Yossi et al79 found an 18.5% greater control with brachy-
Comparison Between Radiotherapy Modalities therapy over external beam after 5-year follow-up (73.5% and 55%).
Of the 3 most commonly used radiation modalities for post- However, their difference in recurrence rate was not significant,
excisional radiotherapy, brachytherapy (15%) was found to have a lower and it was suggested that a larger sample size was required to show

FIGURE 8. Rate of treatment complications from radiotherapy management of keloids. Adverse outcomes were reported for a
proportion of the studies reviewed representing a subpopulation of 5356 keloids. The incidence obtained from the studies reviewed
for each complication was then used to calculate the total percentage of each treatment complication within the population of keloids
with complications reported. Minor adverse events with a rate of occurrence less than 0.01% were not included in the figure.

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Annals of Plastic Surgery • Volume 78, Number 4, April 2017 Meta-Analysis of Keloid Radiotherapy Modalites

the significance of brachytherapy over electron beam.79 Here, we were No accounts of neoplastic processes were reported in any of the
able to reinforce the superiority of brachytherapy of maintaining control reviewed studies. The association of cancer as an adverse outcome of
of keloid recurrence compared with X-ray external beam therapy. keloid radiation was originally identified by Ragoowansi et al81 who
Larger studies with comparable keloid dosing profiles and locations found 5 case reports of malignancies arising in patients who previously
are required to tease apart the subtle difference between electron and received radiotherapy for keloid management. However, a subsequent
brachytherapy control of keloids. analysis of these cases by Ogawa et al82 noted that these previous re-
For the 2 external radiation modalities, X-ray and electron beam, ports did not include their dosing regimens or shielding techniques
similar control of keloid recurrence was noted. Additionally, the dose- and therefore it is difficult to quantify the true associated neoplastic risk.
response association for both external beam modalities was found to It was concluded that the risk developing a neoplasm from keloid radio-
be similar when the alpha/beta value was 2.08 (Figs. 6 and 7). Our con- therapy was low and the majority of radiation oncologists considers the
clusion is different from Flickinger,1 who compared electron beam and technique acceptable.82
X-ray kilovoltage radiation by multivariate regression analysis and
found that electron was superior to X-ray. Flickinger1 attributed the im-
proved control of keloids by electron therapy to the superficial penetra- CONCLUSIONS
tion profile of the modality allowing for maximal dose to be delivered at The use of postexcisional radiotherapy for the treatment of ke-
the keloid site. They suggest a 95% control rate of non-earlobe keloids loids is superior to radiation monotherapy. Currently used radiation
with total postoperative radiotherapy doses of 23.4 to 24.8 Gy.1 These modalities are capable of achieving rates of recurrence of approxi-
dose estimates have however been unsuccessful at achieving 95% con- mately 20% regardless of the type of radiation chosen. Of these,
trol in subsequent cohort studies.11,79 Here, the ability of X-ray and brachytherapy is a promising option using an interstitial source of radi-
electron beam therapy to achieve similar recurrence rates suggest that ation to achieve optimal targeting of keloid tissue. Adverse outcomes
variation between the penetrance profiles of either modality does not associated with the technique are primarily associated with change
significantly contribute to keloid control with the doses previously in pigmentation.
used. A previous dose-response analysis by Kal and Veen6 suggested
a dose of greater than 30 Gy for 90% control of keloid recurrence with
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