32. Keloids - The GEC-ESTRO Handbook of Brachyterapy

SECOND EDITION

The GEC ESTRO Handbook of Brachytherapy

PART II: CLINICAL PRACTICE 32 Keloids Peter Niehoff, Erik Van Limbergen

Editors Bradley Pieters Erik Van Limbergen Richard Pötter

Peter Hoskin Dimos Baltas

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32 Keloids

Peter Niehoff, Erik Van Limbergen

1. Summary 2. Introduction

3 3 3 4 4 4 5 5

9. Dosimetry

6 6 6 6 8 8 9

10. Dose, dose rate and fractionation

3. Anatomical Topography

11. Monitoring

4. Pathology 5. Work up

12. Results

13. Adverse Events 14. Key messages 15. References

6. Indications, Contra-indications 7. Tumour, target volumes and organs at risk

8. Technique

1. SUMMARY

Keloids, characterized by abnormal scar tissue growth beyond the wound boundaries, pose both cosmetic and functional challenges for patients. This chapter explores the utilization of brachytherapy in the treatment of keloids, an evolving therapeutic approach aimed at addressing the underlying pathophysiological mechanisms of keloid formation. Brachytherapy involves the precise delivery of localized radiation to the keloid tissue. The rationale lies in its ability to modulate fibroblast activity, inhibit collagen synthesis, and impede cellular proliferation. This targeted radiation approach is designed to minimize damage to surrounding healthy tissues. The success of treatment may be influenced by factors such as radiation dose, duration, and patient-specific variables such as bleeding and infection.

2. INTRODUCTION

• Laser, prolonged local compression (several months), retinoic acid or silicone gel, but results are not very encouraging. • Cryotherapy in combination with glucocorticoids • Post-operative radiotherapy (external beam, orthovoltage, electrons or brachytherapy) following excision of a keloid is regularly used to prevent the keloid regrowing and even non-excised keloid lesions can be reduced in thickness with a fractionated course of radiotherapy [2].

Keloids are benign tumours of the skin that most commonly occur after a local injury to the skin. In rare cases they can occur after microtraumas such as insect bites or medical injections. Typically, a keloid scar can appear after a local trauma: surgical excision, ear piercing, vaccination, skin burn or infection. Keloids occur mainly in the Asian and African coloured population. There is also a familial genetic predisposition to keloid growth [1]. Keloids should be distinguished from hypertrophic scars, which have a better prognosis. While hypertrophic scars are always limited to the area of injury, keloids grow beyond the incision or trauma area. Preferential locations are the ears, the presternal and the deltoid region. In addition to the high psychological burden due to the unattractive cosmetic appearance, especially in the facial area, patients often suffer from burning, pain, itching or tingling. A variety of treatments can be used: • Surgery alone, the risk of local recurrence is about 2/3 of the cases after surgery alone. • Surgery followed by post operative injection of corticosteroids. The risk of recurrence remains high in about a third of the patients [2].

3. ANATOMICAL TOPOGRAPHY

Keloids can appear in the skin everywhere on the body (Fig. 32.1 and 32.2). However, they are most common on the auricles or in areas of the body with high skin tension, such as deltoid region, scapula or sternum area. Improvement of cosmetic appearance is the main reason for treating a keloid, the resulting cosmetic effect of re excision (always a longer scar) must be anticipated before a decision for treatment is taken. Also, the presence of radiosensitive tissues in the neighbourhood of the keloid must be critically evaluated. [3, 4].

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4. PATHOLOGY

5. WORK UP

The pathogenesis of keloids has not yet been conclusively explained. The classical model of wound healing distinguishes 3 overlapping phases. In the inflammatory phase (days 1-3), growth factors, macrophages and inflammatory processes are activated. The proliferation phase begins on day 2-3 and can last up to 6 weeks. In this phase, fibroblasts are formed and angiogenesis is activated. In the late proliferation or granulation phase from day 8 onwards, granulation tissue is formed by myofibroblasts and collagen bundles. The processes in the inflammatory phase should be influenced at an early stage. The first irradiation fraction should be given within 24 hours after excision of the keloid [3, 5]. In one extensive overview of the literature van Leeuwen et al. [6] suggested however that better outcome was observed for external beam radiotherapy when started within 7 hours as compared to longer duration. Conversely, this was not seen in series treated with LDR or HDR brachytherapy.

Because of the increased risk of long-term side effects and cancer induction, keloids should only in extreme conditions be treated in children. In adolescents completion of growth should be documented by measuring length. Further there is no specific work up except general examination to determine if there is no contra indication for local excision. A complete skin examination is recommended to detect other potential lesions.

6. INDICATIONS, CONTRA-INDICATIONS

The main indication for treatment is in patients with recurrence of a keloid and patients with large keloids. Active skin infections present a contraindication. Because of the different pathogenesis of keloids occurring after a burn, it is generally not recommended to treat them with radiotherapy.

Figure 32.1 Keloid of the right ear lobe pre and 15 months post treatment

Figure 32.2 : Keloid after breast reconstruction before and after treatment

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3. Planning target volume (PTV) covers at least the CTV for interstitial techniques. 4. For mould techniques the PTV includes the CTV and a 0.5 cm position uncertainty margin in all directions. Image based treatment planning is strongly recommended to determine the exact position of the catheter and, adjust the target volume if necessary. In this way, underdosing and hot spots can be avoided. [9, 12].

Simple surgical excision of keloids can result in recurrence rates of 60% to 80% [7, 8]. The recurrence rate for postoperative radiotherapy is significantly lower at an average of 22% which rises to 37% for radiotherapy alone. In a recent metanalysis perioperative brachytherapy showed the lowest recurrence rate of 15%, while X-ray and electron beam treatment have a recurrence rate of 23% [9]. The German guideline for the treatment of pathological scars states a 1.2-2 times higher recurrence rate for external beam radiation techniques compared to brachytherapy [2]. In a meta analysis by Kal et al. different dose concepts were evaluated, the authors found that from a BED of 30Gy the risk of recurrence is less than 10% [10, 11]. Before perioperative brachytherapy, the physical and psychological suffering due to the keloid should be discussed with the patient. Patients should be informed of the possible secondary estimated risk of malignancy (1/50,000) and the risk of recurrence. Because of the effect on tissue growth and possible cancer induction, brachytherapy should not be carried out in children, except in very critical situations where the risk is considered worthwhile. In the published series of adult patients, no increased incidence of cancer induction has been reported until now.

8. TECHNIQUE

The technique for irradiating keloids with brachytherapy was initially described by Nicoletis and Chassagne in 1967 [13]. Plastic tubes are recommended because they adapt easily to curvatures in the scar. The keloid resection and the insertion of the brachytherapy catheter is possible under local anesthesia or general anesthesia. Typically, immediately after keloid excision, a blind end plastic tube should be positioned along the centre of the scar subcutaneously 3-5 mm deep. The scar is then closed with a non-soluble suture. It is necessary that the plastic catheters cover the entire scar length. The catheter should extend 5 mm beyond both ends of the scar for optimal coverage of the PTV. In large excision wounds it is advocated that the wound is closed with subcutaneous sutures to approximate the wound edges before inserting the plastic tube. The surgical skin sutures are usually intradermal, the epidermis is not pierced but closed by adhesive strip. Careful positioning of the plastic tube, avoidance of infection and/or bleeding in the scar is extremely important to prevent recurrences. We recommend therefore as a final step to cover the entire scar with a compression bandage and to leave only one end of the plastic catheter free for connecting to the afterloading machine (Fig 32.3).

7. TUMOUR, TARGET VOLUMES AND ORGANS AT RISK

For interstitial brachytherapy, it is recommended to implant the catheter at a depth of 5 mm. The target volume for interstitial brachytherapy after keloid excision consists of the margins around the excision along the entire surgical scar and a 5 mm safety margin in all directions to capture the relevant fibroblast population. 1. Gross target volume (GTV) includes the whole scar. 2. Clinical target volume (CTV) including the scar and 5mm of the affected skin.

Figure 32.3. Situation during positioning of the catheter 5 mm deep (left picture) and after closure (right picture)

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TABLE 32.1 LISTS DIFFERENT HDR DOSE SCHEDULES AND FRACTIONATION REGIMENS WITH CORRESPONDING BED AND EQD2 (α/β VALUES OF 10 GY) Fractionation schedule BED 10 EQD2 10 3 x 6 Gy 28.8 Gy 24.0 Gy 4 x 3 Gy 15.6 Gy 13.0 Gy 2 x 7 Gy 23.8 Gy 19.8 Gy 1 x 8 Gy 14.4 Gy 12.0 Gy 3 x 5 Gy 22.5 Gy 18.8 Gy 1 x 13 Gy 29.9 Gy 24.9 Gy 2 x 6 Gy 19.2 Gy 16.0 Gy

Another technique reported by Xiaoping (36) uses a postoperative mould irradiation. Other, less common and seldom used techniques are contact brachytherapy with Sr 90 applicators [14].

In the retrospective analyses by Kal et al. it was calculated that with a BED 10 of more than 30 Gy (25 Gy EQD2 10 ) the recurrence rate would be less than 10 % [10]. Bijlard et al. recommend a BED 10 of 19.2 Gy (2 x 6 Gy) based on their retrospective analysis, which corresponds to an EQD2 10 of 16 Gy. Here the recurrence rate was also less than 10%. A common HDR fraction schedule is 3 x 6 Gy at 5 mm depth starting a least within 7 hours after surgery [6] and two fractions the following day. Other frequently used schedule is 2 x 7 Gy at 5 mm, starting the day of surgery and a second dose the day after, and single dose schedules (1 x 13 Gy at 5-7 mm) is also described [15]. Important is to prescribe the dose in relation to the depth in which the catheter is placed. For the postoperative mould application, the doses range from 12 Gy in 3-4 fractions to 20 Gy in 4 fractions.

9. DOSIMETRY

For image guided brachytherapy the reference isodose should cover the PTV as described before. For interstitial brachytherapy without imaging the reference isodose should be least at 5 mm from the scar, encompassing a target volume as described above with a total length equal to the affected skin length. Therefore, the first and last source position should be 5 mm beyond the surgical scar, and that the isodose distribution at the end of the target volume should be wide enough to cover the wounds made at the puncture site. We recommend keeping equal dwell times over the whole source trajectory and not to use geometrical optimization to create a cylindrical instead of a cigar-like shape of the prescription isodose. Hot spots at entrance and exit points should be avoided, because they will lead to hyperpigmentation of the skin at entrance and exit points of the source. For the mould application the distance of the reference isodose is at 5 mm depth.

11. MONITORING

The implant site should be carefully monitored during the stay in the department. No acute side effects besides normal wound healing are to be expected. Extreme care should be taken to keep the wound sterile and avoid additional trauma and Infection. Also, bruising and loosened stitches have been associated with recurrence risk of the keloid [3]. Removal of the skin suture is carried out one week after leaving the hospital.

10. DOSE, DOSE RATE AND FRACTIONATION

The optimal dose and fractionation regimen for the treatment of keloids is still unclear. The literature recommends a minimum dose of 20 Gy BED 10 and 30 Gy BED 10 [10, 11], This corresponds to an EQD2 of 20.4 Gy and 25 Gy for an α/β value of 10 Gy based on the assumption that keloids behave like acutely reacting tissue (see table 32.1). One of the most widely used treatment regimens is 3 x 6 Gy at 5 mm, which corresponds to a BED 10 of 28.8 Gy (24 Gy EQD2 10 ).

12. RESULTS

Almost all the data in the literature is based on retrospective monocentric analyses. Table 32.2 lists the outcome of brachytherapy for keloids by dose rate technique and method of application. Only a few institutes have reported a standardised procedure.

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TABLE 32.1 LISTS DIFFERENT HDR DOSE SCHEDULES AND FRACTIONATION REGIMENS WITH CORRESPONDING BED AND EQD2 (α/β VALUES OF 10 GY) Author Patients/Keloids (N) Brachytherapy Method Local recurrence (%) Good cosmetic results (%)

Ir LDR 12- 15 Gy

Clavere [26]

43 / 51

Unknown

35

88

Ir LDR 20 Gy

Escarmant [3]

43 / 51

Interstitial

21

80

Ir LDR 15-20 Gy

Gerbaulet [27]

157 / 201

Unknown

25

75

Ir LDR 20 Gy

Malaker [16]

30

Interstitial

17

Ir LDR 15-20 Gy

Nicoletis [13]

20

Unknown

15

Sr/Y HDR 14 Gy (1x 14 Gy) Ir HDR 18 Gy (unknown) Ir HDR 18 Gy (3x6Gy) 5mm Ir HDR 12-18 Gy (3x4 -3x6Gy) 5mm

Wagner [14]

139 / 166

Contact

20

80

Arnault [28]

87/138

Unknown

23.6

Ns

Jiang [29]

29/29

Interstitial

17

91

Bijlard [19]

149/226

Interstitial

8,3

Ns

Ir HDR 12 Gy 5mm

Barragan [18]

51/61

Interstitial

4.9

81

C0 60 HDR 15 Gy (3x5 Gy) 5mm

Manjunath [20]

50/71

Interstitial

4%

NS

HDR 12 Gy (3x4Gy)

Fuenmajor [22]

14/14

Mould

21%

NS

Ir HDR 8 Gy (1x 8Gy) 5mm Ir HDR 18 Gy (3x 6 Gy) 5mm Ir HDR 15 Gy Gy (3x5 Gy) Ir HDR No surgery 18 Gy 6x3 Gy Surgery 12 Gy 4x3 Gy 10mm Ir HDR

Anderson [12]

14/20

Interstitial

0

NS

Daurade [30]

38/67

Interstitial

6%

62

Bautista [23]

80/85

Mould

5

90

Kuribayashi [21]

21/36

Mould / Contact

9.7

NS

13.6 4

77 97

Guix [17]

169

Mould / Interstitial

Interstitial LDR – Brachytherapy Escarmant et al (8) published one of the largest patient populations for LDR. 570 patients were retrospectively studied. The average dose given was 19.14 Gy (range 8-30 Gy). The recurrence rate was 21% with disappearance or reduction in symptoms in 80% of cases, and good cosmetic results in 75% of patients. Other authors as Malaker and Nicoletis reported recurrence rates of 15-17% with dose of 20 Gy [13, 16]. Interstitial HDR – Brachytherapy Guix [17] published an HDR patient collective of 169 patients with a recurrence rate of 4% for the combined surgery and BT treated patients. For the patients treated with brachytherapy without surgery the recurrence rate was 13.6%. Barragan [18] reported a 5% recurrence rate with perioperative brachytherapy.

Bijlard et al. [19] reported the data of 3 different fractionation schedules with a recurrence rate of 8.3% for interstitial brachytherapy using 1 catheter in 5 mm depth. Manjutnath et al used Co-60 instead of Ir-192 and reported a recurrence rate of 2% after 5 months [20]. Overall, the local recurrence rate is between 2.4% and 20% and good cosmetic results are obtained in 60% to 91%. Superficial HDR – Brachytherapy Kuribayashi et al. [21] report recurrence rates of 9.7% for superficial brachytherapy with a dose of 3-4 x 5 Gy and a total dose of 15-20 Gy. The authors used 2 plastic tubes with a spacer to achieve a distance of 3 mm to the skin. The recurrence rate in keloids of the earlobes also treated with surface therapy was 21% reported by Fuenmayor et al. [22] Bautista Hernandez et al. [23] observed a recurrence rate of 5%

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13. ADVERSE EVENTS

in their series. They used surface brachytherapy with the Leipzig applicator and customised moulages. Bhattacharya et al. [24] reported a recurrence rate of 6%, they used superficial double layer moulds and electron beam radiotherapy. Scalfani [25] compared corticosteroids and radiation therapy: the recurrence rate was 33% for surgery + steroid injection, and 12.5% for surgery and radiation therapy. For external irradiation following excision, the control rates are between 73 - 93 % reported by Kovalic (113 keloids) [4], 93% by Durosinmi (454 keloids) [9] to 97.6% by Borok (393 keloids) [8] In an extensive retrospective overview of the literature Kal et al. [10, 11] reported a recurrence rate of < 10% if a minimum dose of 30 Gy BED10 (corresponding to 25 Gy EQD210) was applied. In an extensive overview of reported series in the literature, van Leeuwen et al found that the time interval between surgery and external beam irradiation was better if administered within 7 hours (16.8 %) instead of longer duration 7-24 (28.4 %) or over 24 hours (21.5%.) [6]. However, no differences were noted for HDR BT cases; 10.7 % (< 7h) versus 10 % (7-24 h). In case of LDR brachytherapy the numbers are: 22.3% (< 7h) versus 19.4% (7-24h).

Side effects that can occur are infections. Postoperative bleeding should be avoided, since they influence recurrence and bad cosmetic outcome rate For the figures of cosmesis see table 32.1. Other reported side effects are hyperpigmentation, hypopigmentation, and overstretched scars. Cancer induction estimated risk in adults is estimated about1/50000, but not yet well reported in the published studies.

14. KEY MESSAGES

• Postoperative brachytherapy prevents keloid recurrences • Recurrences and large keloids are the main indications for postoperative brachytherapy • The clinical target volume (CTV) includes the scar and 5mm of the affected skin. • The reference isodose should be least at 5 mm from the scar • A minimum EQD2 10 of 20 Gy-25 Gy is recommended

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15. REFERENCES

25. Sclafani, A.P., et al., Prevention of earlobe keloid recurrence with postoperative corticosteroid injections versus radiation therapy: a randomized, prospective study and review of the literature. Dermatol Surg, 1996. 22(6): p. 569-74. 26. Clavere, P., et al., Postoperative interstitial radiotherapy of keloids by iridium 192: a retrospective study of 46 treated scars. Dermatology, 1997. 195(4): p. 349-52. 27. Gerbaulet A, H.-M.C., Breton C, et al. Role of LDR brachytherapy in keloid scars. Radiother Oncol 1999; 53 (suppl 1): abstract 34., Role of LDR brachytherapy in keloid scars. Radiother Oncol, 1999. 53: p. abstract 34. 28. Arnault, J.P., et al., Keloids treated with postoperative Iridium 192* brachytherapy: a retrospective study. J Eur Acad Dermatol Venereol, 2009. 23(7): p. 807-13. 29. Jiang, P., et al., Efficacy and the toxicity of the interstitial high-dose-rate brachytherapy in the management of recurrent keloids: 5-year outcomes. Brachytherapy, 2018. 17(3): p. 597-600. 30. Daurade, M., et al., Efficacy of Surgical Excision and Brachytherapy in the Treatment of Keloids: A Retrospective Cohort Study. Adv Skin Wound Care, 2020. 33(11): p. 1-6.

1. Mankowski, P., et al., Optimizing Radiotherapy for Keloids: A Meta-Analysis Systematic Review Comparing Recurrence Rates Between Different Radiation Modalities. Ann Plast Surg, 2017. 78(4): p. 403-411. 2. Nast, A., et al., J Dtsch Dermatol Ges, 2021. 19(2): p. 312-327. 3. Escarmant, P., et al., The treatment of 783 keloid scars by iridium 192 interstitial irradiation after surgical excision. Int J Radiat Oncol Biol Phys, 1993. 26(2): p. 245-51. 4. Kovalic, J.J. and C.A. Perez, Radiation therapy following keloidectomy: a 20-year experience. Int J Radiat Oncol Biol Phys, 1989. 17(1): p. 77-80. 5. Goutos, I. and R. Ogawa, Brachytherapy in the adjuvant management of keloid scars: literature review. Scars Burn Heal, 2017. 3: p. 2059513117735483. 6. van Leeuwen, M.C., et al., Surgical Excision with Adjuvant Irradiation for Treatment of Keloid Scars: A Systematic Review. Plast Reconstr Surg Glob Open, 2015. 3(7): p. e440. 7. Brown, J.R. and J.H. Bromberg, Preliminary studies on the effect of time-dose patterns in the treatment of keloids. Radiology, 1963. 80: p. 298-300. 8. Borok, T.L., et al., Role of ionizing irradiation for 393 keloids. Int J Radiat Oncol Biol Phys, 1988. 15(4): p. 865-70. 9. Durosinmi-Etti, F.A., T.A. Olasinde, and E.O. Solarin, A short course postoperative radiotherapy regime for keloid scars in Nigeria. West Afr J Med, 1994. 13(1): p. 17-9. 10. Kal, H.B. and R.E. Veen, Biologically effective doses of postoperative radiotherapy in the prevention of keloids. Dose-effect relationship. Strahlenther Onkol, 2005. 181(11): p. 717-23. 11. Kal, H.B., R.E. Veen, and I.M. Jürgenliemk-Schulz, Dose-effect relationships for recurrence of keloid and pterygium after surgery and radiotherapy. Int J Radiat Oncol Biol Phys, 2009. 74(1): p. 245-51. 12. Anderson, E.M., et al., Interstitial high-dose-rate brachytherapy in the treatment of keloids: Moving toward a volumetric approach. Brachytherapy, 2021. 20(1): p. 185-188. 13. Nicoletis, C. and D. Chassagne, Interstitial irradiation by iridium 192 in the prevention of recurrence after surgical excision of keloid cicatrices. Ann Chir Plast, 1967. 12(3): p. 237-42. 14. Wagner, W., et al., Results of scar keloid prevention using contact irradiation with strontium 90. Rontgenpraxis, 1989. 42(7): p. 248-52. 15. Hafkamp, C.J.H., et al., Postoperative single-dose interstitial high-dose-rate brachytherapy in therapy-resistant keloids. Brachytherapy, 2017. 16(2): p. 415-420. 16. Malaker, A., F. Ellis, and C.H. Paine, Keloid scars: a new method of treatment combining surgery with interstitial radiotherapy. Clin Radiol, 1976. 27(2): p. 179-83. 17. Guix B, F.F., Tello JI, et al., Seven year experience of HDR brachytherapy as treatment of keloids. . Radiother Oncol, 1999. 53: p. abstract 40. 18. Barragán, V.V., et al., Perioperative interstitial high-dose-rate brachytherapy for keloids scar. J Contemp Brachytherapy, 2022. 14(1): p. 29-34. 19. Bijlard, E., et al., Optimal High-Dose-Rate Brachytherapy Fractionation Scheme After Keloid Excision: A Retrospective Multicenter Comparison of Recurrence Rates and Complications. Int J Radiat Oncol Biol Phys, 2018. 100(3): p. 679-686. 20. Manjunath, K.N., et al., Efficacy of Surgical Excision and Adjuvant High-dose Rate Brachytherapy in Treatment of Keloid: Our Experience. J Cutan Aesthet Surg, 2021. 14(3): p. 337-343. 21. Kuribayashi, S., et al., Post-keloidectomy irradiation using high-dose-rate superficial brachytherapy. J Radiat Res, 2011. 52(3): p. 365-8. 22. Fuenmayor, P., et al., Outcomes of Surgical Excision and High-Dose-Rate Brachytherapy for Earlobe Keloids. World J Plast Surg, 2021. 10(1): p. 78-84. 23. Bautista Hernandez, Y., et al., Surface brachytherapy in the treatment of keloid scars in Mexico. Rep Pract Oncol Radiother, 2020. 25(1): p. 133-138. 24. Bhattacharya, N., K. Bhattacharya, and T.C. Chandran, Treatment of Keloids with Surgery and Immediate Postoperative Radiotherapy: Knowledge Gained Over 17 Years. Indian J Plast Surg, 2023. 56(3): p. 251-259.

ACKNOWLEDGMENTS The authors of this chapter are much indebted to Alain Gerbaulet, author of the original version of the chapter on Keloids in the first edition of the GEC ESTRO Handbook of Brachytherapy 2002.

AUTHORS

Peter Niehoff Department of Radiotherapy Sana Klinikumn Offenbach Germany

Erik Van Limbergen Department of Radiation Oncology University Hospital Gasthuisberg Leuven Belgium