Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 1, pp. 245–251, 2009Copyright � 2009 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/09/$–see front matter

doi:10.1016/j.ijrobp.2008.12.066

BIOLOGY CONTRIBUTION

DOSE–EFFECT RELATIONSHIPS FOR RECURRENCE OF KELOID AND PTERYGIUMAFTER SURGERY AND RADIOTHERAPY

HENK B. KAL, PH.D., RONALD E. VEEN, M.D., PH.D., AND INA M. JURGENLIEMK-SCHULZ, M.D., PH.D.

Department of Radiotherapy, University Medical Center Utrecht, Utrecht, The Netherlands

Purpose: To show radiation dose–response relationships for recurrence of keloid and pterygium after radiother-apy following surgery.Methods and Materials: Using PubMed, we performed a retrospective review of articles reporting incidences and/or dose–response relationships for recurrence of keloid and pterygium after radiotherapy following surgery. Theirradiation regimens identified were normalized by use of the linear–quadratic model; biologically effective doses(BEDs) were calculated.Results: For keloid recurrence after radiotherapy following keloid removal, with either teletherapy or brachyther-apy, the recurrence rate after having delivered a BED greater than 30 Gy is less than 10%. For pterygium recur-rence after bare sclera surgery and 90Sr b-irradiation, a BED of about 30 Gy seems to be sufficient also to reducethe recurrence rate to less than 10%.Conclusions: Most of the doses in the radiotherapy schemes used for prevention of keloid recurrence after surgeryare too low. In contrast, the doses applied in most regimens to prevent pterygium recurrence are too high. A schemewith a BED of 30 to 40 Gy seems to be sufficient to prevent recurrences of keloid as well as pterygium. � 2009Elsevier Inc.

LQ–BED model, Pterygium recurrence, Keloid recurrence, Fibroblasts, Radiotherapy after surgery.

INTRODUCTION

Keloids are benign fibrous dermal tumors that develop after

skin injury such as surgery or earlobe piercing. They belong

to the group of hyperproliferative diseases, such as pterygium

of the eye and Dupuytren disease. Keloid formation is due to

excessive collagen synthesis and decreased collagen degrada-

tion (1). Characteristically, the scar tissue extends beyond the

borders of the original wound. The scar does not improve with

time, and besides its unattractive visual effect, it may cause

tingling, burning, and itching. Treatment by surgery alone is

followed by recurrence in 60% to 80% of the cases (2). Com-

bination therapy is likely the optimal strategy. Methods of

treatment include intralesional steroids, 5-fluorouracil, inter-

feron, pulsed dye laser, compression with silicone sheeting,

topical tacrolimus and imiquimod, and radiotherapy (3–5).

There is no consensus about the optimal treatment. Surgical

excision followed by radiotherapy provides good results as

described in the literature. However, no consensus has been

reached on the total dosage, fractionation, or optimal timing

of the delivery of radiotherapy. Kal and Veen (6) reviewed

the literature for the recurrence rates of keloids after surgical

excision followed by radiotherapy. They concluded that an

2

optimal treatment probably is an irradiation scheme resulting

in a biologically effective dose (BED) of at least 30 Gy.

Pterygium is a complex benign disease of the supporting

orbital tissue that can cause impairment of visual function.

It belongs to the group of hyperproliferative diseases. It is as-

sociated with ultraviolet (UV) radiation, immuno-inflamma-

tory processes, genetic factors, and virus infection. For

example, UV radiation induces secretion of cytokines, and

these may activate pterygium fibroblasts, resulting in over-

growth of the conjunctiva. Pterygium typically develops be-

tween the ages of 20 and 50 years, with the greatest incidence

in dusty, hot, and dry regions in latitudes between 0� and 30�

(7, 8). Bare sclera surgery alone results in high relapse

rates—a reason to combine surgery with other treatment mo-

dalities. After surgery, therapy can include topical corticoste-

roids, thiotepa, mitomycin C, b-irradiation, and cautery.

Jurgenliemk-Schulz et al. (9) reviewed the literature for post-

operative radiotherapy and reported that treatment with

a BED of 25 Gy or greater resulted in a low relapse rate.

In this study we reviewed the literature from the past 6 years

and updated the dose–response relationships as described by

Kal and Veen (6) and Jurgenliemk-Schulz et al. (9).

Reprint requests to: Henk B. Kal, Ph.D., Department of Radiother-apy, University Medical Center Utrecht, Q00.118, Heidelberglaan100, 3584 CX Utrecht, The Netherlands. Tel: (+31) 88-755-3136;Fax: (+31) 88-755-5850; E-mail: H.B.Kal@UMCUtrecht.nl

45

Conflict of interest: none.Received Nov 17, 2008, and in revised form Dec 15, 2008.

Accepted for publication Dec 29, 2008.

246 I. J. Radiation Oncology d Biology d Physics Volume 74, Number 1, 2009

Table 1. Recurrence rate, treatment scheme, and BED of radiotherapy for prevention of keloids after surgery

Reference No. of keloids Recurrence rate (%) Dosage and type of radiation Overall treatment time (d) BED (Gy)

Cosman and Wolff (2) 76 36 2 � 4 Gy 14 Mean, 10.6*4 � 2 Gy*X-rays (assumed to be 100 kV)

Edsmyr et al. (14) 53 11 1,200 Rz 1 30.845- and 100-kV X-rays

Levy et al. (15) 35 12 5 � 3 Gy 12–14 Mean, 18*6 � 3 Gy100-kV X-rays

Malaker et al. (16) 31 19.4 20 Gy 1 22192Ir LDR

Ollstein et al. (17) 68 21 3 � 5 Gy <6 26.5100-kV X-rays

Sallstrom et al. (18) 124 8 3 � 600 Rz 3 37.250-kV X-rays

Bertiere et al. (19) 38 13 16 Gy <2 17.6LDR

Lo et al. (20) 14 43 8 Gy 5 14.477 13 10 Gy 5 2041 10 12 Gy 5 26.417 18 15 Gy 5 37.5

1.5- to 3.5-MeV electrons41 61 3 � 2 Gy 3–10 8.05

Doornbos et al. (21) 71 29.6 3 � 3 Gy 13.212 25 3 � 4 Gy 1927 14.8 3 � 5 Gy 25.6

120-kV X-rays20 20 4 � 5 Gy 12 17.5*

Supe et al. (22) 44 35 4 � 5 Gy 26 7.5*90Sr beta rays

Meythiaz et al. (23) 54 7.5 10 � 300 R 10 44*50-kV X-rays

Clavere et al. (24) 38 36.8 12–15 Gy 1 16.5LDR

Chaudhry et al. (25) 36 2.8 3 � 6 Gy <6 34.1100-kV X-rays

Maalej et al. (26) 114 13 20.4 Gy 1 22.4192Ir LDR

Guix et al. (27) 147 3.4 4 � 3 Gy 1 15.6HDR

Caccialanza et al. (28) 88 5.7 6 � 5 Gy 33 30.9*31 16.1 5 � 5 Gy 26 27.8*

50-kV X-raysOgawa et al. (29) 147 32.7 3 � 5 Gy 4 22.5

4-MeV electronsRagoowansi et al. (30) 80 16 10 Gy 1 24.1

100-kV X-raysMalaker et al. (31) 47 12.8 4 � 4 Gy 4 22.4

60CoNarkwong and Thirakhupt (32) 16 12.5 3 � 5 Gy 2 22.5

192IrOgawa et al. (33) 28 0 2 � 5 Gy 1 15

35 22.5 3 � 5 Gy 2 22.558 30 4 � 5 Gy 3 30

4-MeV electronsAkita et al. (34) 38 21.1 6 � 3 Gy, linear accelerator 18 12.4*Bischof et al. (35) 60 15 4 � 4 Gy 4 22.4

6-MeV electronsVan de Kar et al. (36) 32 71.9 3 � 4 Gy/4 � 3 Gy, X ray 3–4 18.3Veen and Kal (37) 9 44.4 1 � 4 + 2 � 3 Gy 1 13.4

18y 0 3 � 6 Gy 1 28.838 2.6 1 � 6 + 2 � 4 Gy 1 20.8

192Ir HDRDe Lorenzi et al. (38) 30 20.9 2 � 7 Gy 1 23.8

192Ir HDR(Continued )

Dose–effect relationships for recurrence of keloid and pterygium d H. B. KAL et al. 247

Table 1. Recurrence rate, treatment scheme, and BED of radiotherapy for prevention of keloids after surgery (Continued )

Reference No. of keloids Recurrence rate (%) Dosage and type of radiation Overall treatment time (d) BED (Gy)

Arneja et al. (39) 25 8 3 � 5 Gy 2 22.5192Ir HDR

Abbreviations: BED = biologically effective dose; LDR = low dose rate; HDR = high dose rate.* Corrected for overall treatment time.y Updated results.z For BED calculation, we applied 1 R = 0.96 cGy.

METHODS AND MATERIALS

Using PubMed, we performed a retrospective review of studies

reporting incidences or dose–response relationships for recurrence

of keloid and pterygium after radiotherapy following surgery.

Studies were included if the follow-up time was at least 1 year.

Studies were excluded when the recurrence rate could not be related

to a specific radiation dose or the number of cases per dose group

was smaller than 10.

For comparison of the different radiation doses and schedules that

have been described in the literature, BEDs were calculated by use

of the linear–quadratic (LQ)–BED concept. The occurrence of a bi-

ologic effect (E) depends on the dose in a linear and quadratic fash-

ion: E = n(ad + bd2), with n being the number of fractions, d being

the dose per fraction, and a and b being parameters that determine

the initial slope and curvature of the underlying cell survival curve.

From that equation, the BED can be calculated as follows: BED =

nd[1 + d/(a/b)] (10, 11).

For regimens with different overall treatment times, a correction

for proliferation can be applied. For proliferating normal tissues,

values of 0.8 to 1.3 Gy/d are frequently applied (12, 13). We applied

a value of 1 Gy/d for treatment times greater than 7 days. Pterygia

were treated especially with 90Sr b-radiation, whereas keloids

were treated with a diversity of radiation modalities: kilovolt X-

rays, 90Sr beta rays, 192Ir gamma rays, and megavolt electrons.

Corrections for differences in relative biologic effectiveness were

applied as described by Kal and Veen (6).

It is widely accepted that the a/b is equal to about 10 Gy for acute-

reacting tissues; it is in the range of 1 to 3 Gy for late-reacting tis-

sues. For keloid and pterygium as acute-reacting tissues, we applied

a/b equal to 10 Gy.

It is the strength of the LQ–BED concept that for a specific isoef-

fect, the BED values are equal for treatments with different fraction-

ation regimens.

Curve fitting was applied by use of Microsoft Excel (Microsoft

Corp., Redmond, WA) for logarithmic and linear fitting.

RESULTS

We identified 27 articles regarding keloid recurrence (2,

14–39), of which 19 (2, 14–31) were described earlier (6).

Table 1 shows the recurrence rate of keloids after radiation

therapy and the calculated BED values. The total number

of keloids in these studies was 1,945.

In most of the reports the total radiation dose administered

to the keloids was given within 1 week after surgery. In six

reports the overall treatment time exceeded 1 week (2, 15,

22, 23, 28, 34); as a consequence, the BED was corrected

for overall treatment time. In Fig. 1 the data points of the re-

currence rates as a function of the BED are shown. At a BED

equal to 0 Gy (i.e., after surgery only), the range of recur-

rences is 60% to 80% (2). The data points were fitted by a log-

arithmic function as indicated in the figure.

The resulting dose–effect relationship suggests that for

a BED less than 30 Gy, the radiation dose is suboptimal.

For a BED of 30 Gy or greater, the incidence of keloid recur-

rence is less than 10%.

Eighteen studies regarding pterygium recurrence were

identified (7, 8, 40–55), of which 14 (7, 8, 40–51) were de-

scribed earlier (9). Table 2 shows the recurrence rate and

the calculated BED values, taking into account the overall

treatment time. The total number of pterygia in these studies

was 5,662.

A linear dose–effect relationship for a/b equal to 10 Gy has

been constructed (Fig. 2). From the figure, it is clear that the

doses applied in most regimens to prevent pterygium recur-

rence are too high. A scheme with a BED of 30 to 40 Gy seems

to be sufficient to keep the recurrence rate lower than 10%.

DISCUSSION

Keloids and pterygia are benign diseases for which multi-

ple treatment modalities exist to prevent recurrence. The

most commonly used treatments for keloids include intrale-

sional steroid injections, surgery, cryotherapy, laser therapy,

radiotherapy, and application of silicone gel sheets. Other

treatments with variable success rates include imiquimod,

5-fluorouracil, bleomycin, retinoids, calcium channel

0

10

20

30

40

50

60

70

80

0 10 20 30 40 50

BED (Gy)

Recu

rren

ce rate (%

)

Fig. 1. Keloid recurrence after surgery and radiotherapy as a func-tion of the biologically effective dose (BED). The data points werefitted with a logarithmic function.

248 I. J. Radiation Oncology d Biology d Physics Volume 74, Number 1, 2009

Table 2. Pterygium recurrence after 90Sr b-therapy after surgery

Reference N Recurrence rate (%) Dosage BED (Gy)

Wilder et al. (7) 284 12 8 � 3 Gy 25.2Monteiro-Grillo et al. (8) 20 5.4 3 � 10 Gy 60.0Monteiro-Grillo et al. (8) 80 19 6 � 10 Gy 92.0De Keizer (40) 18 0 3 � 10 Gy 54.0Alaniz-Camino (41) 483 4.3 4 � 7 Gy 47.6MacKenzie et al. (42) 685 12 1 � 22 Gy 70.4Beyer (43) 127 10.2 1 � 30 Gy 120.0Wesberry and Wesberry (44) 171 8 1 � 20 GY 60.0Parayani et al. (45) 677 1.7 6 � 10 Gy 92.0Schultze et al. (46) 49 8.6 5 � 6 Gy 48.0Fukushima et al. (47) 391 8.6 1 � 30 Gy 107.0Amano et al. (48) 61 23 2 � 10.8 Gy 42.9Nishimura et al. (49) 367 11.8 4.5 � 8.9 Gy 57.6Smith et al. (50) 52 5.8 5 � 5 Gy 37.5Pajic et al. (51) 97 2 4 � 12.5 Gy 99.5Bekibele et al. (52) 31 6.5 1 � 25 Gy 87.5Isohashi et al. (53) 1,253 7.7 3 � 10 Gy 46

1 � 15 + 2 � 10 Gy 63.5Mean, 54.7

Mourits et al. (54) 44 11 1 � 25 Gy 87.5Viani et al. (55) 737 9.9 5 � 7 Gy 29.5

7 � 5 Gy 36.5Mean, 33.0

Abbreviations: N = number of patients; BED = biologically effective dose.

blockers, mitomycin C, and interferon alfa-2b. No single

treatment has proven widely effective. In fact, recurrence af-

ter treatment is generally the norm. Combination therapy is

likely the optimal strategy. Surgical excision followed by ra-

diotherapy provides good results in the literature. With re-

spect to pterygium, it would seem that a single satisfactory

method of removing pterygium with minimal complications

and a low recurrence rate has not yet been identified. After

surgery alone, high incidences of recurrence have been ob-

served—a reason to combine surgery with other treatment

modalities such as brachytherapy or local chemotherapy.

Surgical resection followed by b-irradiation, despite a variety

of doses administered, results in an acceptable recurrence

rate. However, as for keloids, no consensus has been reached

on the total dosage, fractionation, or optimal timing of the de-

livery of radiotherapy. Dose-finding studies have not been

performed.

In this report we analyzed the reported recurrence rates of

keloids and pterygia after postoperative radiation therapy us-

ing the LQ–BED concept with the aim to normalize the radio-

therapy doses into BEDs to be able to construct dose–effect

relationships.

The resulting dose–effect curve for keloid recurrence is

shown in Fig. 1.

Several authors reported that no statistically significant

correlation was observed between the results of radiation

therapy and the anatomic site (21, 28, 30, 56, 57). However,

Ogawa et al. (29) and Wagner et al. (58) reported that the re-

currence rate in the sites with high stretch tension, such as the

chest wall, was statistically higher than that in sites without

high stretch tension, such as the neck and earlobes. This

would at least partly explain the low recurrence rates

observed by several authors (33, 39). Kal and Veen (6) ana-

lyzed the available data on keloid recurrences as a function of

the BED with respect to recurrences in the face and neck re-

gion and those in other parts of the body, and they concluded

that the recurrence rates in the sites with high stretch tension

seem to be higher than those in the sites without stretch ten-

sion. However, because of the scatter of the data points, no

statistical significance was reached. In addition, regardless

of the technique for brachytherapy implants, the fractionation

dose and/or overall treatment time may play a role in why

higher recurrence rates were found for keloids in high stretch

regions, such as the chest wall and scapular and suprapubic

0

10

20

30

40

50

0 20 40 60 80 100 120 140

BED (Gy)

Recu

rren

ce rate (%

)

Fig. 2. Pterygium recurrence after surgery and radiotherapy asa function of the biologically effective dose (BED). The BED wascalculated with a/b equal to 10 Gy; a correction for repopulationof 1 Gy/d for each day in excess of 7 days was applied. The datapoints were fitted with a linear function.

Dose–effect relationships for recurrence of keloid and pterygium d H. B. KAL et al. 249

regions, than in regions without high stretch tension, such as

the earlobe.

Figure 1 indicates that a BED of at least 30 to 40 Gy should

be applied to keep the recurrence rate lower than 10%. A

BED of 30 to 40 Gy can be obtained with, for instance, a sin-

gle acute dose of 13 to 15 Gy, two fractions of 8.5 to 10 Gy or

three fractions of 6 to 7.5 Gy, or a single dose of 27 Gy

applied at a low dose rate. The radiation treatment should

be administered within 2 days after surgery.

For the prevention of pterygium recurrence after surgery,90Sr b-irradiation has a long history as a treatment modality

in ophthalmology. 90Sr treatment is performed with an oph-

thalmic applicator (59) and is therefore a convenient and

practical radiation method and has the advantage of minimal

tissue penetration. It has consistently been shown to be effec-

tive. However, no consensus has been reached on the total

dosage, fractionation, or optimal timing of the delivery of

radiotherapy.

From Fig. 2, it is clear that for a BED of 30 Gy or greater,

the mean recurrence rate of pterygium is lower than 10%. It

also indicates that most of the treatments that have been re-

ported in the literature are applied with doses above this

BED value. On the basis of a review of the literature, Hirst

(60) concluded that the most commonly administered physi-

cal dose is 15 Gy in either a single dose or divided doses. We

advocate a single dose of 13 to 15 Gy, which is equivalent to

a BED of 30 to 40 Gy. For equal effectiveness, when fraction-

ated radiotherapy is used, the total dose should be higher, for

example, 17 to 20 Gy in two fractions. It would be worth-

while to conduct a randomized trial comparing schemes

with a BED of 30 to 40 Gy with currently used schemes

with higher BED values. If the results at the lower dose are

equal to those at the higher dose schemes, high-dose applica-

tion should be abandoned (i.e., the principle of keeping the

dose as low as reasonably achievable).

With respect to the timing of the radiotherapy, Isohashi

et al. (53) reported that b-irradiation immediately given after

surgery, within 2 h, resulted in a higher recurrence rate than

when given with an interval of more than 2 h, even in pa-

tients who received identical doses. Other reports indicated

a better control rate in patients treated 1 to 3 days after sur-

gery than in those treated more than 3 days after surgery.

Similar to the findings for keloids, it is likely that a longer

delay in delivering the radiotherapy results in a higher recur-

rence rate (6).

Keloids are composed of intrinsically normal polyclonal

fibroblasts, which respond to an abnormal extracellular sig-

nal, resulting in increased production of scar tissue (61).

An important extracellular factor to induce pterygium is

UV radiation. UV radiation induces secretion of cytokines,

and these may activate pterygium fibroblasts, resulting in

overgrowth of the conjunctiva. Thus, in both keloid and

pterygium formation, activated fibroblasts play an important

role. Therefore it is worthwhile to determine whether the

dose–effect relationships derived for keloid and pterygium

are similar. In Fig. 3 all data points found for keloid and

pterygium recurrence are shown. The fact that the data points

0

10

20

30

40

50

60

70

80

0 20 40 60 80 100 120 140

BED (Gy)

Recu

rren

ce rate (%

)

Fig. 3. Keloid (diamonds) and pterygium (squares) recurrence ratesafter surgery and radiotherapy as a function of the biologically effec-tive dose (BED).

overlap and supplement each other is obvious and may indi-

cate that the curve through the points represents a dose–effect

relationship for activated fibroblasts. This indicates that the

doses applied to keloids are mostly not sufficient and should

have a BED of at least 30 to 40 Gy. In contrast, the doses ap-

plied in most radiotherapy regimens to prevent recurrence of

pterygium are too high; a BED of 30 to 40 Gy might also be

sufficient. In addition, this relatively low dose will reduce or

even avoid the risk of late complications.

Treatment of benign diseases frequently poses questions

about the risk of tumor induction in the normal tissues that

are also irradiated. De Lorenzi et al. (38) reviewed the liter-

ature; no case of radiation-induced cancer after brachyther-

apy of keloids has been reported. Out of more than 6,500

patients treated with external radiotherapy, only 5 cases of

potential and doubtful radiation-induced cancers have been

described (30). This is not surprising because with postoper-

ative brachytherapy and carefully applied teletherapy, only

a small volume of normal tissue is involved. An example

of how to calculate the risk of fatal-tumor induction after ra-

diotherapy of the keloid scar is as follows: The irradiated skin

area is about 10 cm2, that is, 0.05% of the whole skin area of

about 2 m2 (20,000 cm2). The risk of inducing a fatal skin

tumor is 2 � 10�4 Gy�1 (62). The risk of inducing a fatal

tumor with a single dose of 13 Gy, therefore, is as follows:

(10/20,000) � 13 � (2 � 10�4) = 1.3 � 10�6. For compari-

son, the risk of inducing a fatal tumor by a computed

tomography scan of the chest with an effective dose of 9.5

mSv is almost similar: (9.5 � 10�3) � 5 � 10�2 (63), that

is, 4.8 � 10�6 (the risk of a radiation-induced fatal tumor

is 5 � 10�2 Sv�1) (62).

A similar calculation can be performed for the risk of a fatal

tumor in the fat or muscle tissues. The International Commis-

sion on Radiological Protection provided risk factors for

a number of organs but not for fat or muscle tissues (62).

The risk factor for the ‘‘remainder’’ (total of all organs for

which no risk factor is yet known) is 0.5 � 10�2 Sv�1.

Here again, the volume treated is very small compared

250 I. J. Radiation Oncology d Biology d Physics Volume 74, Number 1, 2009

with the total body volume; hence, the risk of a radiation-in-

duced fatal tumor has the same order of magnitude as was

calculated for fatal skin tumors. Thus, as a consequence of

the small volume that is irradiated, the risk of a radiation-

induced tumor is negligible. For treatment of pterygium, as

a result of the use of 90Sr electrons with a rapid falloff of

the dose, the treated volume is very small and tumor induc-

tion is also negligible.

In conclusion, most doses in radiotherapy schemes used

for keloid recurrence prevention after surgery are too low.

A dose with a BED of at least 30 to 40 Gy should be applied.

In contrast, the doses applied in most regimens to prevent

pterygium recurrence are too high. A scheme with a BED

of 30 to 40 Gy seems to be sufficient also. For keloids and

pterygia, a single-dose regimen can be applied. The risk of

radiation-induced fatal tumors is negligible.

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