Retrospective Analysis of Treatment of Unresectable Keloids with Primary Radiation Over 25 Years

Clinical Oncology (2004) 16: 290–298 doi:10.1016/j.clon.2004.03.005

Original Article Retrospective Analysis of Treatment of Unresectable Keloids with Primary Radiation Over 25 Years K. Malaker*, K. Vijayraghavan†, I. Hodson†, T. Al Yafi‡ †Princess Norah Oncology Centre, Jeddah, Saudi Arabia; ‡Department of Radiation Oncology Cancer Care Manitoba, Manitoba, Canada; §Department of Plastic Surgery, King Khalid National Guard Hospital, King Abdulaziz Medical City, Jeddah, Saudi Arabia ABSTRACT: Aims: The purpose of the study was to review retrospectively the role of primary radiotherapy for unresectable keloids. Materials and methods: Kilovoltage X-rays and mega-voltage electron beams were used to irradiate large bulky unresectable keloids. A total of 3750 cGy was given in five once-weekly fractions, over a period of 5 weeks. Eighty-six keloids in 64 patients were treated between 1977 and 2002. Results: Ninety-seven per cent of this cohort had significant regression, and 3% had partial regression 18 months after completing radiotherapy. Both acute and long-term reactions were acceptable, and so far none of the patients have been reported as having cancer of any sort. Sixty-three per cent of the patients surveyed were very happy with the outcome of their treatment. Conclusion: Unresectable bulky symptomatic keloids can be satisfactorily treated with hypo-fractionated radiotherapy primarily using either kilovoltage X-rays or electron beams without significant short- or long-term side-effects. Malaker K. et al. (2004). Clinical Oncology 16, 290–298  2004 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Unresectable keloids, primary radiotherapy Received: 21 July 2003

Revised: 18 February 2004

Introduction

The success of postoperative radiotherapy for the treatment of keloids is well documented [1–4]; however, primary radiotherapy has so far been a failure with either external beam [5–8] or interstitial irradiation [9,10] (Table 1). Large recurrent keloid after repeated surgery, post-burn keloids, lacerated wound and multiple acneinduced keloids are usually unresectable because of the inability to obtain a primary closure or multiplicity (as in acne). Resection under these conditions inevitably results in recurrence. Because of their bulk and size, intra-lesional steroid infiltration is impractical and ineffective, as the amount of steroids needed to cover a large volume may not be tolerated by the patient [16,17]. During surgical excision, avascular physiologically inactive collagen and chondroitin sulphate protoglycan containing fibrous tissues are removed [18]. During postoperative radiotherapy, active well-oxygenated fibroblasts [19] in the scar are destroyed. This results in a high degree of control and good cosmetic effect. When radiotherapy is given as primary modality, the bulk of Author for correspondence: Professor Kamal Malaker, MD. Ph.D., Chairman, Princess Norah Oncology Centre, King Abdulaziz Medical City, National Guard Health Affairs, P.O. Box 9515, Jeddah 21423 Kingdom of Saudi Arabia. Tel +966 2 6240000 (ext. 4082); Fax: + 966 2 6247242; E-mail: [email protected] 0936-6555/04/040290+9 $30.00/0

Accepted: 19 February 2004

collagen remains unaffected. Intra-keloidal fibroblasts, which have a poor growth rate [20] and thrive in a hypoxic environment [21–23], respond poorly to standard radiotherapy fractionation and dose. An unpublished study by Malaker and Das (Radiation Oncology Department Manitoba Cancer Foundation, present Cancer Care Manitoba, Winnipeg Canada April, 1988) compared the vascularity of keloids with normal skin. They studied the number of blood vessels per field, patency of blood vessels, thickness of vascular wall and inter-vascular distance. It has been suggested that inter-vascular distance of 200 µm or more is likely to produce interstitial hypoxia [24]. The investigators also studied the number of blood vessels less than 200 µm from the nearest vessel and others more than 200 µm distant from the nearest blood vessel. They examined three specimens of keloid with adjacent normal skin from three different patients. Fifty pairs of fields were studied for each specimen to a total of 300 fields. In this histopathological study, there were (1) 2–8 times more blood vessels (median 3.40 times) in the normal skin than in keloids; (2) 4–9 times more vascular patency (median 4.85) in normal skin than in keloids; (3) an average thickness of vascular walls in keloids between 2–2.5 times that of normal skin; and (4) 88% of inter-vascular distance more than 200 µm in

 2004 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Reference

Technical detail

Total dose (r)/fractions (F)/time

1 Belisario et al., 1957 [11] 1200 r/3 F/HVL 1.5 mm AL 2 Arnold and Graver, 140 KV. 5 ma, no filter, HVL 1959 [12] 2 mm AL, FSD 2.5 cm

1200 r/3 F/1 month (1) 450–1200 r/3 F/1 month; repeat 2–4 times (2) 1000–3000 r/2–6 F/10–30 days

3 Van den Brenk and Minty, 1960 [10]

Not available

400–1000 r single dose or 1000–3000 r/3 F/2–9 months

4 Van den Brenk and Minty, 1960 [10]

Radium plaques, radon moulds Not available or interstitial needle implants with or without additional X-rays None available 800 r/4 F/4–8 weeks

5 Cosman et al., 1961 [36] 6 Edsmyr et al., 1974 [13] 7 Inalsingh, 1974 [14]

45 Kv, 10 ma 0.5 mm AL filter or 100 Kv, 8 ma 1.70 mm AL filter 60–90 Kv; no filtration; lead cut-out to shield all but the keloid area

Number of cases

Results

10 (1) 20

5/10 good improvement (1) Fair (good results) 13/20 (65%) (2) 39 (2) Fair (good results) 33/39 (84.6%) Single dose 56; Single dose 9/56 (16%); good fractionated dose response 4/28 (14%) 28 23 Good response 1/23 (4.3%); partial response 11/23 (47.8%) 5

Success 2/5 (40%)

500–2400 r/1–14 post op. days

17

400 r single dose monthly; number of treatments depended on clinical response

76

Total regression 2/17 (11.8%); amelioration of symptoms 14/17 (82.3%) Symptomatic success

Comments Mild telangiectasia

Three cases of radionecrosis with single dose Radionecrosis: four patients with severe atrophy (11); disturbance of bone growth (3) Radiotherapy given primarily in the preoperative setting 92.4% of patients were black No regression

RETROSPECTIVE ANALYSIS OF TREATMENT OF UNRESECTABLE KELOIDS WITH PRIMARY RADIATION

Table 1 – Literature survey for primary radiotherapy for treatment of keloids [1]

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keloids, whereas only 27% of normal skin had an inter-vascular distance more than 200 µm. These histopathological features indicate the possible existence of a hypoxic state in the keloidal matrix. These findings have now to some extent been supported by other studies [5,14,25]. Differences of partial oxygen pressure between normal skin and a hypertrophic scar have further emphasised the hypoxic state [26]. Martin et al. have shown experimentally that fibroblasts, which constitute part of keloids, evolve from a highly differentiated clone capable of surviving in an extreme hypoxic environment [16]. These fibroblasts have an efficient radiation damage-repair mechanism [27–29]. It is conceivable that keloidal fibroblasts residing in a hypoxic environment are relatively radioresistant [30]. It is also conceivable that some form of chemical disintegration by radiation [31,32] or radiolysis of tightly packed keloidal collagen [33,34] would improve local oxygenation by simple diffusion, thus making constituent cells in the keloidal matrix relatively radiosensitive. Furthermore, severe skin atrophy is common when superficial X-rays using single 1900–2000 R fractions are applied to treat skin cancers. This led us to postulate that, in a similar fashion, keloidal atrophy may be achieved by using large fractions of radiotherapy of appropriate energy. However, single large fractions have so far failed to achieve flattening of the keloid [5,35,36].

Materials and Methods

Individuals were treated over a period of 3 decades (1977–2002), using a uniform radiotherapy technique and dose, and involved two major institutions: Manitoba Cancer Treatment and Research Foundation, Winnipeg, Canada, and Princess Norah Oncology Centre, Jeddah, Saudi Arabia. We treated 86 lesions in 64 patients. Twenty-six men and 38 women aged between 18–58 years were treated. Most presented to the radiotherapy clinic 5–36 months after sustaining their injury. The anatomical distribution and underlying trauma responsible for inducing keloids are listed in Table 2. Technique

Before delivering radiotherapy, the keloid-cutaneous junctions with a 2-mm margin is accurately marked (Fig. 1b) by inspection, palpation and with the help of a magnifying glass. A lead cut-out is made to fit the skin marking. The thickness of the lead is determined by the quality of the X-ray beam or electron energy. Lesions thicker than 1 cm were treated with 250 kVp X-rays or with 6–9 MeV electrons. When an electron beam was used, the energy was determined according to the thickness of the lesion with appropriate skin build-up, and a wider field than superficial or ortho-voltage. The most common electron beam energy used was 3–6 MeV. On

Table 2 – Anatomical sites and nature of trauma that might have provoked formation of keloids in this group of 64 patients Anatomical site Abdomen Pelvis Chest Upper limb Lower limb Shoulder Gluteal Perineum

Type of trauma Laparotomy Pelvic surgery Sternotomy Vaccination Road traffic accident Surgery Acne Injection site Abscess

Total

Male Female

Number of keloids

6 1 6 4 2 3 2 2 1

12 9 2 9 1 2 0 2 0

21 13 12 20 3 7 2 7 1

27

37

86

rare occasions, electron-beam energies up to 9 MeV had to be used. The maximum dimensions of lesions were as follows: 3.5 cm (height: range 0.6–3.5 cm); 14 cm (length: range 4–14 cm); and 4.2 cm (width: range 1–4.2 cm). The dose was 3750 cGy applied to each lesion in five once-weekly fractions, at 750 cGy per fraction. Electrons were prescribed at 100% isodose with appropriate bolus. The time, dose, fractionation (TDF) of this regimen is 99, whereas the TDF (based on the nominal standard dose model) of normal skin tolerance is 115 [60], which makes this regimen acceptable in 1977, the concept of biological equivalent dose (BED) based on the linear-quadratic model [37] was not in use, dose equivalence being based on TDF. Conversion of the above TDF-equivalent fractionated doses into BED (based on linear quadratic model) gives values of 100 and 117, respectively, for the current regimen and normal skin tolerance, based on
/=3 Gy for late normal tissue complications. Again, this favours the course of radiotherapy applied in this study. Method of Assessment

Response was assessed on the basis of symptomatic relief, degree of flattening of the lesion on palpation and clinical photography taken at regular intervals, initially with Polaroid cameras and, for the past 7–8 years, with digital cameras. Response to the therapy has been classified as follows: Significant response: complete symptomatic relief and, or almost, complete flattening of the lesion; Partial response: Significant symptomatic relief with 25–75% height reduction; Stable: moderate symptomatic relief and no or minimal height reduction; Progression: symptomatic deterioration, nil or some increase in height. Results

We intended to carry out this technique prospectively; however, this was not possible for the following reasons: some of the investigators relocated, the length of time had elapsed to accumulate enough analysable patients

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RETROSPECTIVE ANALYSIS OF TREATMENT OF UNRESECTABLE KELOIDS WITH PRIMARY RADIATION

Table 3 – Response to radiotherapy* Response Complete Partial Stable Progression

24 weeks

52 weeks

76 weeks

260 weeks

72/80 (90%) 8/80 (10%) 0 0

78/80 (97%) 2/80 (2.5%) 0 0

68/70 (97%; 10 lost to follow-up) 2/70 (3%; 10 lost to follow-up) 0 0

36/36 (100%) 0/36 0 0

*Response to primary radiotherapy given to relatively large unresectable keloids. By 18 months, 97% of patients treated had complete response. At 5 years, 36 patients were followed up. They were all in complete remission.

Table 4 – Reaction scoring* Parameters Erythema Dry Desquamation Moist Desquamation Ulceration Pigmentation De-pigmentation Epilation Oedema Fibrosis Atrophy Telangiectasia Carcinogenesis

2 weeks (%)

4 weeks (%)

12 weeks (%)

24 weeks (%)

52 weeks (%)

76 weeks (%)

260+ weeks

0 58

0 6

– 6

– –

– –

– –

– –

0

0

0

–

–

–

–

0 93 0 100

0 93 0 100

0 58 4 100

– 40 2 100 0 0 6 6

– 12.5 3.1 100 0 0 9 12.5

– 12.5 0 100 0 0 9 15.5 0

– – – – – – – – 0+66

*Acute and delayed reaction after primary hypofractionated radiotherapy for unresectable keloids. Thirty-six out of 54 patients (67%) who had completed 5 years or more since treatment, who could be traced for follow-up, did not have any evidence of malignancy locally or otherwise. — Reactions/symptoms were no longer evident.

who could benefit from this treatment, and two centres were involved. Thus, the data had to be collected and analysed retrospectively. Response to treatment was intended to be monitored monthly for the first 3 months, and then at 3, 6, 12 and 18 months. Acute and chronic toxicities were scored using RTOG toxicity scale. Acute reactions were recorded at 2–3 weeks after completing radiotherapy, and chronic reactions were monitored up to 18 months after completing treatment. Most acute and subacute reactions had settled by 6–9 months. Patients were monitored every 3 months, and follow-up was scheduled regularly from 6 months onwards at 6-monthly intervals. Follow-up compliance started to decline 6 months after completing radiotherapy. However, we were able to maintain follow-up for 36 out of 54 patients for 5 or more years. Table 3 shows that, by 18 months, 97% of treated lesions had regressed significantly and 3% partially. Table 4 indicates that the main acute reactions were epilation (100%), pigmentation (93%) and dry desquamation (58%) at 2 weeks (reducing to 6% by 1 month). By 18 months, the most common delayed reactions were epilation (100%), telengiectasia (15.5%) and atrophy (9%). Fifty-four cases reached the fifth anniversary or more of their therapy, but only 36 members of this group could be followed up clinically. None had developed any form of cancer, either locally or otherwise.

Table 5 – Index of patient satisfaction* Parameter Very satisfied Satisfied Can live with it No comment

Number of responders

%

23/36 9/36 4/36 0/36

64 25 11 0

*Thirty-six patients responded to a questionnaire aimed at establishing the degree of satisfaction with the outcome of their treatment.

Other investigators have had similar experiences [38–40]. This cohort of patients was physically well, and often neglected to keep follow-up appointments of Noncompliance of patients on mid- and long-term follow-up [41–43], especially by some communal groups [44], has been documented by other investigators. Most of our patients had sought medical treatment because of poor cosmesis. An ‘unmarked’ questionnaire was distributed to 36 traceable patients to assess their degree of satisfaction with the outcome of the treatment. Table 5 gives details of the patient response to this questionnaire. Sixty-four per cent of patients who participated in the survey said they were ‘very satisfied’, 25% said they were ‘satisfied’ and 11% said they ‘can live with the outcome’ of the treatment. Thus a high degree of patient satisfaction was achieved in the responding (66.6% of total)

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Fig. 2 – Post-hysterectomy supra-pubic keloid of 6 months’ duration, with severe itching, in a 36-year-old female staff nurse; (b) this shows the patient in (a) 6 months after primary radiotherapy for a post-hysterectomy supra-pubic keloid; shows complete response.

group of patients who would not have been treated with any degree of satisfaction in the past. Figure 2a shows an extensive post-hysterectomy, suprapubic keloid in a 42-year-old woman. This lesion was twice excised before the woman was referred for radiotherapy. This was a typical lesion with variable thickness. Figure 2a shows the thicker (3.5 cm) suprapubic portion of the lesion, which was treated with a 250 kV X-ray beam: the upper section of the lesion was less prominent (1–1.5 cm thick), and therefore was treated with a 100 kV X-ray beam. Figure 2b shows the result of treatment 6 months after radiotherapy. Figure 3a shows a 36-year-old woman who developed severe

Fig. 1 – (a) Massive post-hysterectomy abdominal keloid. The inferior part is bulky and thicker, treated with 250 Kv X-rays. The superior longitudinal part is relatively thinner and was treated with 100 Kv X-rays; (b) abdominal post-hysterectomy keloid noted in patient in (a), 6 months after primary radiotherapy treatment. Significant physical and symptomatic improvement.

RETROSPECTIVE ANALYSIS OF TREATMENT OF UNRESECTABLE KELOIDS WITH PRIMARY RADIATION

Fig. 3 – (a) Extensive acne-induced keloid of the right deltoid region in a 28-year-old white man. Note the mapping technique for lead cut-out; (b) 1 year after definitive primary radiotherapy treatment for patient in (a) showing complete response. Note the ‘shiny glistening’ appearance of the lesion, treated by 100 Kv X-rays.

symptomatic keloid after caesarian section. The lesion was surgically excised, and no postoperative adjuvant radiotherapy was given. Within 6 months of primary excision, the woman developed severe symptomatic recurrence of her keloid. Figure 3b shows the result of radiotherapy 1 year after completion, and she remains free from recurrence. Figure 1a shows a 28-year-old white man who presented with multiple symptomatic acne with keloid formation on the right deltoid region. Figure 1a also indicates the mapping of keloidal lesions used for lead cut-out for this technique. Figure 1b shows significant (complete) flatness of the lesion with glistening surface 1 year after therapy. Figure 4a shows a Saudi Arabian man with an acne-induced keloid in the right scapular region. This lesion was treated by electron beam. To deliver adequate dose to the mapped lesion, a much larger field had to be used, compared with photon fields. Figure 4b shows significant flattening of the lesion 1 year after treatment.

295

Fig. 4 – (a) A Saudi-Arabian man with acne-induced keloid in the right scapular region; (b) 1 year after radiotherapy, complete flattening of the lesion with residual radiation pigmentation is seen. Treated by 6 Mev electron beams with lead cut-out and wax build-up on the lesion only.

Discussion

Major advances have been made in the understanding of the molecular basis of wound healing and keloid formation. Rubin et al. [45] reviewed the cellular biological basis of keloid formation and prevention of the process at various stages of wound healing. The place of immediate postoperative radiotherapy for prevention of keloid formation is well explained on the basis of recent scientific advances. Postoperatively, 500 cGy single dose or 1200 cGy in fractionated dose achieves around 80% long-term control [46]. Radiotherapy as primary treatment using 150 cGy weekly for 10 weeks to total dose of 1500 cGy or 300–500 cGy per fraction three times weekly to a total dose of 2000 cGy has virtually had no effect, with a follow-up of between 3 months and 7 years. (Table 1) [1]. Studies using higher total doses with standard fractionation have not been carried out and, even if they had, we have reasons to believe it would not have been effective, as discussed below.

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The targets for radiation damage in keloids are still poorly understood. Excessive production of collagen by a specialised clone of fibroblasts outstrips the increase in local collagenase production, which maintains the balance of fibroblastic activity [26,46]. Histologically, mature keloids are thick, tightly packed bundles, nodules, or both, of collagenous tissue with sparsely distributed fibroblasts present in the ground substance of mucinous matrix [5,47]. This matrix is scantily vascularised. Factors that might contribute to the radioresistance of keloidal fibroblasts have been demonstrated by Malaker and Das (unpublished data) and recently supported by other investigators [23,25]. Therefore, it is not surprising that the dose used so far for primary radiotherapy for keloids has remained ineffective. The basis for a protracted fractionated course of radiotherapy is differential tumour-cell killing taking advantage of the ‘4R’ phenomenon. In matured keloid, active formation of collagen and chondroitin ceases, and active fibroblasts are replaced by a slow growing hypoxic clone of fibroblasts in significantly reduced numbers. In this biological milieu, it is highly unlikely that standard fractionated radiotherapy would be able to take advantages of the classical ‘4R’ phenomenon. A parallel situation can be drawn in case of desmoid tumours, with very different results of radical fractionated radiotherapy as a primary mode of treatment. The long-term local control of desmoid tumours after fractionated courses of 50–60 Gy is around 80% [48,49]. Whereas keloid formation is a reactive self-limiting process, desmoid tumours, although mostly a benign condition, are neoplastic. In spite of desmoids and keloids sharing some common histopathological features, they are entirely different entities from a radiobiological point of view. The cellular contents of desmoids are the target of radiotherapy. On the other hand, the keloidal contents seem to be a poor target for standard fractionated radiotherapy, as the bulk constitutes radiobiologically inert collagen, chondroitin and hypoxic fibroblasts. Unless these are surgically removed, consideration must be given to tackle this collagen/ chondroitin complex with ionising radiation. Ionising radiation can cause disintegration of chemical compounds by the process of radiolysis [31,33,50]. High radiation dose is needed to achieve radiolysis of simple proteins like albumin [24,51]. Collagen and chondroitin are complex glyco-proteins with molecular weight around 100 000 [6,12,52]. To induce radiolysis in vitro in collagen, high doses of radiation exposure are needed [20,38]. By using 60Co radiation, Tjiri [51] showed that reducible cross links per hydroxy proline residue was strikingly high in bone collagen at high-dose 10 000–15 000 cGy compared with a lower dose. It seems that to achieve any form of response with primary radiotherapy, induction of radiolysis of keloidal collagen and destruction of fibroblasts are needed. In-vitro experimental evidence suggests that a fraction size of about 500 cGy will be effective in inducing a radiolysis [7,16,53]. However, in-vivo experiments with rat skin

show that the radiolytic process starts minimally from 50–250 cGy.[54] Radiolytically recoiled collagen fibrils return to normal shape and size 4–6 weeks after radiation [9,13,55]. A dose of 750 cGy applied weekly for 5 weeks, now, on the basis of above experiments carried out after we started our regimen of radiotherapy, explains why this preferred dose is high enough to induce radiolysis of the keloidal collagen, and an interfraction time of 7 days is short enough to prevent any post-radiation recovery of fibroblasts or recoiling of any damaged collagen. It has been suggested that radiolysis of collagen may trigger increased production and activity of collagenase, which leads to disintegration of keloidal collagen in the process [7]. Radiation-induced vasculopathy may also have a role to play. As indicated above, keloidal blood vessels are thick and relatively scanty. Radiationinduced vascular damage would produce further hypoxia leading to increased production of toxic-free radicals [56,57]. These free radicals would enhance collagen degradation by lysis of the helical parts of the collagen fibrils [9]. The fibroblasts within the poorly vascularised keloidal matrix are biologically quiescent. Further radiation-induced vascular damage, even in the hypoxic environment, could bring about further destruction of the fibroblast population. It is postulated that reduction of the keloidal mass could improve nutrition and oxygenation of the residual fibroblast population, making these cells more vulnerable to fractionated radiotherapy. However, it is unclear which, if any, of these factors are actively responsible for the clinical response achieved using the radiotherapy regimen as described in this study. The possibility of radiation-induced malignancies was considered, and the risk is clearly explained to each patient [27,58]. The risk of second malignancy seems to be less with the high dose of radiation used in this study [35,58]. An extensive literature survey and recent reports [38–40], have failed to identify any radiation-induced malignancy after treatment of keloids. Nevertheless, the existence of the risk is well-appreciated [27,59]. We believe that this regimen using primary radiation is a practical and viable technique to treat unresectable mature keloids, which have been traditionally untreatable and thought to be radio-resistant. Acknowledgements. The author wishes to thank Ms Marlene Chambers, Radiotherapy Nurse of Cancer Care, Manitoba, Mrs Rene Cornellissen, Radiation Oncology Staff Nurse, Dr Henry Weatherburn, Chief Medical Physicist and Mrs Noura Pellicci of Medical Secretariat of Princess Nora Oncology Centre for secretarial assistance.

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RETROSPECTIVE ANALYSIS OF TREATMENT OF UNRESECTABLE KELOIDS WITH PRIMARY RADIATION

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