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Brachytherapy - (2014) -

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Postoperative management of keloids: Low-dose-rate and high-dose-ratebrachytherapy

Luigi De Cicco1, Barbara Vischioni2, Andrea Vavassori3,*, Federica Gherardi3,Barbara Alicia Jereczek-Fossa3,4, Roberta Lazzari3, Federica Cattani5, Stefania Comi5,

Francesca De Lorenzi6, Stefano Martella6, Roberto Orecchia2,3,41Division of Radiotherapy, Ospedale di Circolo di Busto Arsizio, Varese, Italy

2Division of Radiation Oncology and Radiobiology, National Center for Oncological Hadrontherapy CNAO, Pavia, Italy3Division of Radiotherapy, European Institute of Oncology, Milano, Italy

4University of Milan, Milano, Italy5Division of Medical Physics, European Institute of Oncology, Milano, Italy

6Plastic and Reconstructive Surgery, European Institute of Oncology, Milano, Italy

65

ABSTRACT PURPOSE: We report the experience of the

Received 24 Octo

accepted 10 January 2

Conflict of interes

The study was co

Ripamonti, 435, Mila

* Corresponding a

of Oncology, Via R

57489037; fax: þ390

E-mail address: a

1538-4721/$ - see fro

http://dx.doi.org/10

66676869707172737475767778798081

Radiation Oncology Department of the EuropeanInstitute of Oncology in Milan, Italy, on the adjuvant low-dose-rate (LDR) and high-dose-rate(HDR) interstitial brachytherapy. Brachytherapy might be useful to improve keloids recurrence rateor reduce keloids treatment side effects instead of external beam radiotherapy.METHODS AND MATERIALS: Data on 70 consecutive patients treated after complete keloidsurgical excision were retrospectively analyzed. First, 31 patients and 46 keloids were treated withadjuvant LDR brachytherapy and the following 39 patients and 50 keloids underwent HDR treat-ment. Median delivered dose of LDR therapy was 16 Gy; HDR median dose was 12 Gy. Sixty-four keloids (66.7%) were symptomatic at diagnosis with pain, itching, or stress.RESULTS: Fourteen relapses over 46 treated keloids (30.4%) were observed in the LDR groupand 19of 50 keloids (38%) in the HDR group ( p 5 0.521). Recurrence rate was significantly higherin males ( p 5 0.009), in patients younger than 44 years ( p! 0.0001), for arms, neck, and chestwall anatomic sites ( p 5 0.0001) and for symptomatic keloids ( p 5 0.017). Aesthetic outcomewas better in case of larger keloids (O8 cm) ( p 5 0.064). Symptomatic relief was achieved in92% of HDR patients and only 68% of LDR patients ( p 5 0.032).CONCLUSIONS: Postoperative brachytherapy is an effective treatment for keloids. In our study,LDR and HDR treatments resulted in similar recurrence rate. Better symptomatic relief was re-ported in case of HDR treatment compared with the LDR regimen. � 2014 American Brachyther-apy Society. Published by Elsevier Inc. All rights reserved.

8283

Keywords: Keloids; Brachytherapy; Hypertrophic scar

8485

86878889

Introduction

Keloidal scars (keloids) are benign lesions resultingfrom exuberant production of extracellular matrix by

BRACHY800_proof ■ 02–

ber 2013; received in revised form 9 January 2014;

014.

t: None.

nducted at the European Institute of Oncology, Via

n 20141, Italy.

uthor. Division of Radiotherapy, European Institute

ipamonti, 435, Milan 20141, Italy. Tel.: þ3902-

2-94379227.

ndrea.vavassori@ieo.it (A. Vavassori).

nt matter � 2014 American Brachytherapy Society. Publis

.1016/j.brachy.2014.01.005

909192939495969798

polyclonal fibroblasts, usually responding to a skin trauma,even if a spontaneous origin is possible.

Clinically, the main symptoms are pain, burning, itching,or stress. Aesthetic and cosmetic appearances might influ-ence the patient perception of keloid presence, with animpairment of both psychological and physical domainsof quality of life (1, 2).

Surgical excision alone results in a recurrence rate up to80% (3). For this reason, several adjuvant treatments havebeen evaluated to improve outcomes, such as topical orinjective corticosteroid, injective interferon, continuouspressure, laser therapy, silicone gel sheeting, topical tacro-limus, flurandrenolide or imiquimod, cryotherapy, oral

11–2014 07:33:51

hed by Elsevier Inc. All rights reserved.

Q4

Table 1

Keloids characteristics according to the brachytherapy dose rate

Keloids

LDR,

n 5 46

(47.9%)

HDR,

n 5 50

(52.1%)

Total,

n 5 96

(%)

Site

Neck 4 (8.7) 1 (2) 5 (5.2)

Chest wall d 2 (4) 2 (2.1)

Arms 1 (2.2) 4 (8) 5 (5.2)

Sternal area 5 (10.9) 9 (18) 14 (14.6)

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155156157158159160161162163

methotrexate or colchicines, and radiotherapy (4). Surgeryand adjuvant radiotherapy lead to a recurrence rate of about20e25%, ranging from 2.8% to 61% (5e9).

In this study, we report on a series of keloids treated withbrachytherapy at the Radiation Oncology Department ofthe European Institute of Oncology of Milan, Italy. Thelocal control rates, aesthetic outcome, and symptomatic re-lief of low-dose-rate (LDR) and high-dose-rate (HDR)adjuvant interstitial brachytherapy are presented.

Breast 31 (67.4) 20 (40) 51 (53.1)

Abdomen 3 (6.5) 10 (20) 13 (13.4)

Ear lobe 2 (4.3) 4 (8) 6 (6.2)

Etiology

Surgery 37 (80.4) 43 (86) 80 (83.3)

Piercing d 2 (4) 2 (2.1)

Trauma 2 (4.3) d 2 (2.1)

Acne 1 (2.2) d 1 (1)

Unknown 6 (13) 5 (10) 11 (11.5)

Previous treatment 17 (37) 17 (34) 34 (35.4)

Surgery 11 (23.9) 11 (22) 22 (22.9)

Injective corticosteroid 4 (8.7) 4 (8) 8 (8.3)

Laser 6 (13) 1 (2) 7 (7.3)

Topical corticosteroid 2 (4.3) 3 (6) 5 (5.2)

Topical noncorticosteroid

creams

d 2 (4) 2 (2.1)

Silicone gel sheeting d 2 (4) 2 (2.1)

Cryotherapy d 1 (2) 1 (1)

LDR brachytherapy d 1 (2) 1 (1)

Unknown 1 (2.2) d 1 (1)

Length

Median (range), cm 8 (1e42) 8.75 (1.25e32) 8 (1e42)

O8 cm 22 (47.8) 25 (50) 47 (49)

#8 cm 24 (52.2) 25 (50) 49 (51)

Symptoms at diagnosis

Presence 27 (58.7) 37 (74) 64 (66.7)

Absence 14 (30.4) 13 (26) 27 (28.1)

Unknown 5 (10.9) d 5 (5.2)

LDR 5 low-dose rate; HDR 5 high-dose rate.

Chest wall: thorax excluding breast and sternal area.

164165166167168169170171172173174175176177178179180181182183184185186187188189190191192193194195196197198199200201202203204205206207208209210

Methods and materials

From April 1999 through May 2008, 79 consecutivepatients with 114 keloids, after obtaining a written consent,underwent complete surgical excision and adjuvant brachy-therapy at our institute. First, 38 patients and 61 keloids,from April 1999 to March 2004, were treated by LDRbrachytherapy (LDR group) and the following 41 patientsand 53 keloids, from October 2004 to October 2008, under-went HDR brachytherapy (HDR group). Seven patients inthe LDR group and 2 patients in the HDR group were lostat follow-up; therefore, the data of 70 patients and 96 ke-loids are presented.

All but 1 patient was Caucasian. Median age was43 years in LDR group and 45 years in HDR group; medianage was 44 years in all.

General characteristics of the keloids according to thebrachytherapy treatment they received (HDR or LDR) aresummarized in Table 1. The lesions were localized at thebreast (53.1%), sternal area (14.6%), abdomen (13.4%),ear (6.2%), arm (4.2%), neck (5.2%), and chest wall(excluding breast and sternal area) (2.1%). Keloids etiologywas surgery, piercing, trauma, and acne in 80 (83.3%), 2(2.1%), 2 (2.1%), and 1 (1%) lesions, respectively, and un-known in 11 (11.5%). A previous treatment had been per-formed in 35.4% of all cases: surgical excision in 22(22.9%), injective corticosteroid in 8 (8.3%), laser therapyin 7 (7.3%), topical corticosteroid in 5 (5.2%), topical un-specified noncorticosteroid creams in 2 (2.1%), siliconegel sheeting in 2 (2.1%), cryotherapy in 1 (1%), LDRbrachytherapy in 1 (1%), and unknown in 1 (1%) keloids;some lesions had been successively treated with more thanone technique. Median length of treated scars was 8 cm(range, 1e42), and this value was used as threshold for sta-tistical analysis. Sixty-four keloids (66.7%) were symptom-atic at diagnosis with pain, itching, or stress.

Treatment started with a proper and complete surgicalexcision, performed with the same technique in the two treat-ment groups, to remove all the keloid tissues without the useof catgut sutures and electrocoagulation to avoid trauma tothe wound bed. During the surgical procedure, at the endof the scar excision, the applicator guide for brachytherapy(a standard flexible 5- or 6-F dedicated plastic tube), was in-serted as deep as possible through the center of the wound,usually about 4e5 mm deep in the derma where the keloid

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originates. The patient was then transferred to the RadiationOncology Department to perform either standard X-ray orCT simulation with nonradioactive wire or dummy sourcesto visualize and verify the exact position of the applicator.Brachytherapy dosimetry was done using the Plato Systemversion 14.2.6, Nucletron (an Elekta company; Elekta AB,Stockholm, Sweden), for HDR treatment planning and Nu-cletron Planning System version 11 for LDR treatment plan-ning. LDR therapy was carried out placing an 192Ir wire inthe plastic catheter (manual afterloading) for a median timeof 39 h (range, 24.25e63.25 h). HDR treatment used an 192Irstepping source (micro-Selectron; Nucletron).

Surgical wound was considered as the target volume, andthe irradiation started within 4e6 h after surgery in all but 1patient, who started 2 days later. LDR median delivered dosewas 16 Gy (range, 12e18 Gy), prescribed at a median dis-tance from the source of 5 mm (range, 4e7 mm). HDR me-dian delivered dose was 12 Gy (range, 9e12 Gy) in fourfractions of 3 Gy b.i.d., with at least 6 h in-between, pre-scribed at a median distance from the source of 4 mm (range,

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Table 2

Prognostic factors in keloids brachytherapy

Prognostic

factors

Number

of

keloids

Recurrence,

N 5 33

(34.3%)

Univariate,

p

Multivariate,

p

Gender

Male 13 9 (69.2) 0.009 !0.0001

Female 83 24 (28.9)

Age (yr)

O44 46 7 (15.2) !0.0001 !0.0001

!44 50 26 (52)

Brachytherapy dose rate 0.521 0.355

LDR 46 14 (30.4)

HDR 50 19 (38)

Previous treatment 0.263 0.195

Yes 34 9 (26.5)

No 61 24 (39.3)

Site 0.0001 !0.0001

Neck 5 5 (100)

Chest wall 2 2 (100)

Arms 5 4 (80)

Sternal area 14 7 (50)

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4e7 mm) to reduce skin surface dose and toxicity; afterinitial dose prescription, a planning optimization followed.

After the treatment completion, the plastic catheter,together with the source only in the LDR group, wasremoved. No complication, such as bleeding or scar infec-tions, occurred during treatment or after catheter removal.

In the HDR group, 2 patients completed only three of thefour planned treatment fractions, in one case because of theaccidental removal of the catheter and in the other onebecause of the patient refusal.

To assess symptomatic outcome, at the first clinical eval-uation before keloids surgical removal and then at everyfollow-up visit after treatment, each referred symptom,pain, itching, or stress was scored according to a three-grades scale: 1 for mild, 2 for moderate, and 3 for severeintensity. At the end, the three values were added uptogether, resulting in a number ranging from 3 to 9. Symp-tomatic relief was achieved in case of a score reduction at aconsecutive visit.

Breast 51 8 (15.7)

Abdomen 13 6 (46.2)

Ear lobe 6 1 (16.7)

Keloid length, cm 0.671 0.799

#8 49 18 (36.7)

O8 47 15 (31.9)

Symptoms at diagnosis 0.017 0.041

Presence 64 28 (43.8)

Absence 27 5 (18.5)

LDR 5 low-dose rate; HDR 5 high-dose rate.

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Statistical analysis

The KaplaneMeier analysis was performed to estimatethe rates of relapse as time function using the log-rank testfor the univariate analysis and the Cox proportional hazardmodel for the multivariate analysis, with gender, age,keloid brachytherapy rate (LDR vs. HDR), location, etiol-ogy, previous therapy, size, and symptoms at diagnosis, ascovariates examined. Recurrence was defined as the pres-ence of a new keloid in a previously treated site (both alongthe scar or only at its extremity). For analyses of time tolocal failure, treatment was considered to have failed iflocal recurrence was diagnosed. The chi-square test wasperformed for the analysis of the treatment outcome data.Statistical evaluation was carried out using the SPSS 13.0statistical software program package (SPSS, Chicago, IL)at a significance level of 0.05 (two sided).

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Results

Over a median follow-up time of 28months (range, 3e108months), 33 treated keloids (34%) relapsed. The relapse ratewas 30.4% (14 relapses on 46 keloids) and 38% (19 of 50)in the LDR and HDR groups of patients, respectively( p5 0.521). One of the 2 HDR patients who did not completethe therapy relapsed. One patient died because of an accidentand was free of recurrence at the death.

Table 2 shows the results of the univariate analysis of prog-nostic factors for keloid treatment outcome. To compare thetwo treatments, we have calculated the median deliveredHDR dose at 5 mm that was of 7.68 Gy in total (1.92 Gy perfraction). The median biologically effective dose (BED),calculated according to Kal and Veen (10), was 17.3 Gy(range, 13e19.7 Gy) and 9.1 Gy (range, 6.9e9.1 Gy) for theLDR and HDR treatments, respectively.

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The actuarial cumulative hazard risk incidence of recur-rence for the all series of keloids and for the two differenttreatment modalities is shown in Fig. 1. Recurrence ratewas significantly higher in males ( p 5 0.009) and patientsyounger than 44 years ( p! 0.0001). There was a statisti-cally significant correlation between keloids relapse rateand their anatomic site. Recurrences were more frequentat arms, neck, and chest wall ( p 5 0.0001). Keloid lengthand a previous treatment history were not related to relapserate. Keloids with symptoms at diagnosis showed higherrelapse rate compared with asymptomatic ones( p 5 0.017). In the multivariate logistic regression anal-ysis, male gender ( p 5 0.015), younger age ( p 5 0.052),the presence of symptoms at diagnosis ( p 5 0.001), andthe keloids treatment sites of neck, chest wall, and arms( p!0.0001) were statistically associated with an increasedlocal failure rate (Table 2).

Aesthetic patient judgment on treatment result in termsof patient cosmetic perception was regarded as ‘‘good’’ incases of both good and excellent outcome or ‘‘bad’’ for un-satisfactory outcome. Aesthetic outcome after therapy didnot differ between the LDR and HDR therapy groups( p 5 0.497); good cosmetic results were obtained in 60%and 56% of LDR and HDR keloids, respectively. It was un-known in one case of the LDR group. No statistically sig-nificant correlation between aesthetic results and keloidanatomic site ( p 5 0.269), previous treatment history

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Fig. 1. (a) Cumulative hazard risk of keloid failure after adjuvant brachy-

therapy. (b) Cumulative hazard risk of keloid failure after HDR or LDR

adjuvant brachytherapy. HDR 5 high-dose rate; LDR 5 low-dose rate.

Table 3

Aesthetic outcome in keloids brachytherapy Q6

Evaluated

factors

Number of

keloids

evaluated

Good

aesthetic

outcome (%) Chi square

Gender p 5 0.572

Male 13 6 (46.2)

Female 82 49 (59.8)

Age (yr)

O44 45 29 (64.4)

!44 50 26 (52)

Brachytherapy dose rate p 5 0.497

LDR 45 27 (60)

HDR 50 28 (56)

Previous treatment p 5 0.750

Yes 34 20 (58.8)

No 60 35 (58.3)

Location p 5 0.269

Neck 5 2 (40)

Chest wall 2 2 (100)

Arms 5 2 (40)

Sternal area 14 5 (35.7)

Breast 50 32 (58.2)

Abdomen 13 7 (53.8)

Ear lobe 6 6 (100)

Keloid length, cm p 5 0.064

#8 49 23 (46.9)

O8 46 32 (69.6)

Symptoms at diagnosis p 5 0.195

Presence 63 32 (50.8)

Absence 27 18 (66.7)

LDR 5 low-dose rate; HDR 5 high-dose rate.

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( p 5 0.750), or the presence of symptoms at diagnosis( p 5 0.195) was observed. Instead, aesthetic outcomewas better for larger keloids (O8 cm) ( p-value that trendedtoward significance, p 5 0.064) (Table 3).

Symptomatic relief was achieved in 81.2% of the ke-loids with symptoms at diagnosis. Relief was achieved in91.7% and 67.9% of symptomatic keloids after HDR andLDR therapy, respectively ( p 5 0.032). Other factors, suchas anatomic site and previous treatment history, did notappear to have an influence on the relief of patients’ symp-toms (data not shown).

Late toxicity was recorded: in the LDR group, 7 (15.2%)keloids showed, in the treated area, skin telangiectasia, 5(10.8%) hyperpigmentation, and 15 (32.6%) skin fibrosis.In the HDR group, 11 (22%) keloids showed hyperpigmen-tation and 11 (22%) skin fibrosis; no patient showed skintelangiectasia.

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Discussion

With a relapse rate of 30.4% and 38%, respectively, wehave shown the efficacy of LDR and HDR brachytherapy inpreventing keloid relapse after surgical removal. Irradiationstarted within 4e6 h after surgery in all but 1 patient, evenif contradictory data have been reported on time to start

BRACHY800_proof ■ 02

adjuvant radiotherapy after keloids excision and local con-trol rate (10).

We are aware that our series has several limitations,including its retrospective character, patient heterogeneity,and short follow-up. This makes the interpretation of the re-ported results somehow difficult. However, we suggest tohave provided promising data on the efficacy of brachyther-apy for postoperative treatment of keloids. Our report alongwith other series leads to the hypothesis that the combina-tion of surgery and adjuvant brachytherapy may reducelocal failure rate.

Previous published data show recurrence rates rangingfrom 2.8% to 61% for keloids after surgery and radiationtherapy, respectively (6, 8, 10). Different radiotherapy tech-niques have been used to treat keloids. For example, in caseof kilovolt X-rays treatment with three fractions of 6 Gy,the recurrence rate reported was 2.8% (11), 16% at 5 yearswith a single fraction of 10 Gy (12), and 61% in case ofthree fractions of 2 Gy (13).

According to the linear-quadratic model, BED of radia-tion follows this fashion: BED 5 nd [1 þ d/(a/b)], where nis the number of fractions, d is the dose per fraction, a andb are the parameters that determine the initial slope and de-gree of curvature of the underlying cell survival curve (14,15). The a/b ratio has been previously considered 10 Gy forkeloids (10). The newly published radiobiological analysisof literature data on postoperative external beam

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radiotherapy by Flickinger (16) supports the hypothesis of alow a/b ratio of 2.08 Gy for keloids. If this is true, the useof large dose per fraction as in HDR brachytherapy mightbe of benefit for patients compared with LDR treatment.

Compared with the published data, the BED in ours se-ries are too low to have higher control rates. Kal and Veen,assuming an a/b 5 10 Gy, sustained need of a BED of atleast 30 Gy (10). In our series, with an a/b ratio of10 Gy, the calculated median BED values were 17.3 and9.1 Gy for HDR and LDR treatments, respectively. Onthe other side, by taking into account the new a/b ratiofor keloids of 2.08 Gy, median BED of LDR and HDRtreatments in our series were 22.3 and 29.3 Gy, respec-tively, whereas the reported calculated BED for effectivetreatment might be 69.9 Gy if three of six fractions or103.6 Gy if 7.5 Gy were used as suggested by Kal et al. (9).

The previously reported results on interstitial brachy-therapy treatments can be hardly compared because ofdifferent implantation technique and different prescriptiondistances from source axis leading to differences in treatedtissue and radiation dose delivered. In general, brachyther-apy, because of rapid dose fall off, absence of lateral pen-umbra, and high conformal treatment of surgical bed,leads to a major normal tissues sparing than external radio-therapy. In our report, we have attempted the comparisonbetween the two different dose-rate regimens of interstitialbrachytherapy with the same surgical and catheter posi-tioning techniques and comparable doses (but differentBED). In our study, no difference in control rate betweenthe two treatment modalities was observed. HDR brachy-therapy, compared with LDR, allows a dose distributionoptimization and, because of remote afterloading, leads toabsence of radiation exposure of the assisting staff, anoutpatient treatment, and, overall, a cost reduction.

Our control rate with LDR treatment, with a mediandose of 16 Gy prescribed at a median distance from thesource of 5 mm, was 70%, similar to the 79% achievedby Escarmant et al. (17)with a treatment dose of 20 Gyor the 76.4% achieved by Arnault et al. (8) with a doseof 17.9 Gy, prescribed at the same distance.

A similar HDR brachytherapy treatment was previouslydescribed by Guix et al. (18) with four fractions of 3 Gyand with a local control rate of 96.6%. In this series, the to-tal administered dose was calculated at 10 mm from thesource axis, that is, taking into account exponential dosefall off, more than twice our delivered dose, that couldexplain the different efficacy of the treatment described inthis report.

Concerning prognostic factors, differently from previousliterature data, male gender (5) and younger age (17) wereassociated with higher recurrence rate. According to Ogawaet al. and Wagner et al. (19, 20), the recurrence rate washigher at the chest wall but in our series arms and neck lo-cations, too. The presence of symptoms at diagnosis wasalso related to statistically significant higher rate of relapse;it was never previously reported. All these data, if

BRACHY800_proof ■ 02–

confirmed on a larger number of patients, could lead totreatment personalization (e.g., planned dose), accordingto the presence of these factors.

A better aesthetic improvement could be possiblyachieved with higher BED (21). Recurrence rate andaesthetic outcome do not differ in the two treatment groupsof our series, whereas symptomatic relief was better afterHDR therapy. According to our knowledge, this interestingdifference has not been previously reported, definitely itwarrants further investigation.

No malignant neoplasm was detected in our series dur-ing follow-up time, even if this was too short. The risk ofcarcinogenesis attributable to keloid radiation therapy isconsidered very low, and radiation therapy acceptable asa keloid treatment modality, but surrounding tissues,including the thyroid and mammary glands, should beadequately protected (22).

In conclusion, brachytherapy for keloids adjuvant treat-ment after surgical excision is an effective and safe treat-ment. Use of low brachytherapy doses make partiallyexplain relatively high relapse rates observed in our series.Definitely, further prospective investigation is warranted toestablish the optimal dose and dose rate that should be usedin the postoperative treatment of this benign condition.

Conclusions

Postoperative brachytherapy is an effective treatment forkeloids. In our study, LDR and HDR treatments resulted insimilar recurrence rate. Better symptomatic relief was re-ported in case of HDR treatment compared with the LDRregimen.

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–11–2014 07:33:53

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