Strontium-90 brachytherapy following intralesional triamcinolone and 5-fluorouracil injections for keloid treatment: A randomized controlled trial

Background Keloid disease is hard to fully eradicate. Recurrence and other unsatisfactory results were found in many patients. No current therapeutic modality has been determined to be most effective for treating keloid scars. Intralesional corticosteroid injections is most commonly recommended for primary management of small and young keloids as well as hypertrophic scars. However, it’s difficult for patients to adhere to long-term triamcinolone acetonide injection therapy because of the pain, inconvenience or complications including hormonal imbalance or irregular menstruation. Objective We aimed to determine whether and how Strontium-90 brachytherapy as an adjuvant radiation could affect keloid recurrence after intralesional triamcinolone and 5-fluorouracil injections. Methods We included keloid patients from March 2019 to September 2019 and randomly allocated them to two groups after 3 intralesional triamcinolone and 5-fluorouracil injections at 3 weeks interval. The experimental group received Strontium-90 brachytherapy at a total dose of 15-20Gy, while the control group didn’t receive any adjuvant treatment. We performed both Vancouver Scar Scale scoring and Color Doppler ultrasound examination to monitor and evaluate lesions regularly. A one-year follow-up was completed for each patient. Results 31 patients who had 42 keloids in total were recruited. We found intralesional triamcinolone and 5-fluorouracil injections could effectively reduce the thickness and modify the hardness of small and young keloids. Strontium-90 brachytherapy reduced the one-year recurrence rate from 85.7 percent to 44.4 percent after 3 intralesional triamcinolone and 5-fluorouracil injections. The lesions’ thickness or elasticity was not affected by Strontium-90 brachytherapy. Conclusion Strontium-90 brachytherapy as an adjuvant radiation could effectively reduce small sized keloids recurrence after intralesional triamcinolone and 5-fluorouracil injections. It worked by enhancing the lesions’ stability post-injection. Trial registration The clinical trial registration number: ChiCTR2000030141. Name of trial registry: Chinese Clinical Trial Registry (http://www.chictr.org.cn/)


Background
Keloid is a disease caused by abnormal proliferation of fibroblasts and accumulation of extracellular matrix. The clinical manifestations are hard protruding scars on the skin, often accompanied by itching and pain. The main difference from ordinary scars is that the size of the lesion exceeds the scope of the original injury, and it grows in a crab-like shape to the surrounding area without shrinking by itself.
In the past, keloids were mainly evaluated by the Vancouver Scar scale(VSS). The Vancouver Scar Scale mainly judges the thickness, hardness, color, and blood flow of keloids by doctors' faceto-face consultation, and makes subjective scores accordingly. However, the evaluation of different doctors varies greatly. Later, some people introduced color Doppler ultrasound, three-dimensional CT and other methods to objectively evaluate the characters of keloids. Based on the reports, we use color Doppler to score the blood supply of keloids, and shear wave elastography to evaluate the hardness of keloids.
The treatment of keloids includes surgical resection, radiation therapy, glucocorticoid injection, cryotherapy, silicone gels, etc. So far, no method alone can get a satisfactory cure rate. Clinical treatment is based on a combination of multiple methods, such as surgery combined with radiotherapy, surgery combined with injection, etc. Injection therapy for keloid patients is a firstline treatment. According to Wu, intralesional injection of glucocorticoid combined with small dose of 5-FU can effectively block the blood vessels and reduce the volume of the keloid. However, the complications of injection include Cushing syndrome, acne, severe pain during injection. Repeated injections over a long period of time have caused many patients to give up. According to the literature, the recurrence rate of surgery combined with radiation exposure varies greatly from 20% to 80%. According to articles by Ogawa, after a comprehensive treatment of surgery and radiation irradiation, the recurrence rate of the earlobe is about 5%, the chest, shoulder and back is about 30%, and the recurrence rate of other parts of the body is between the two. between. The specific method of radiation exposure has also been controversial. Brachytherapy of radiation and electron beam irradiation are the commonly used methods. The irradiation plan includes a single large-dose irradiation and multiple small-dose irradiations.
Researchers in this subject adopt the method of injecting drugs firstly into keloid's base and then injecting into the parenchyma, hoping to obtain a better clinical effect. After 2-3 injections which ensure the flatness of keloid, Sr90 brachytherapy is applied. This research aims to observe and evaluate the clinical effects and side effects of this method.

Purpose
Researchers use a combination of basal and intralesional injection, hoping to obtain better clinical efficacy while reducing the pain. After injection, brachytherapy with Sr90 isotope is applied.
By comparing with the control group, the effects, complications and recurrence rate were observed, in order to evaluate the clinical effect of the treatment. Patients with keloids larger than 9 cm 2 or thicker than 4mm.
3.1.3 Collect the patient's information, including gender, age, VSS, and color Doppler results; 3.1.4 Included patients were allocated equally to either the experimental group or the control group using the block randomization method. The conventional injection technique was performed in the control group, while the modified injection technique was performed in the experimental group.
3.1.5 The VSS was evaluated before the injection, 1, 2, and 3 months after the injection; Color Doppler was used to evaluate the thickness, hardness, and blood flow rate of the keloid before the injection and the third month after the injection; The pain degree was evaluated after each injection; side effects and recurrence are followed up to 1 year.
3.2 Part 2 3.2.1 Based on an estimated effect size of d = .83, alpha level = .05 (one-tailed as direction was hypothesised), power = .80, we estimated that we would require a total of n =19 lesions per group and therefore aimed to recruit 21 lesions per group based on a 10% dropout rate. Patients with keloids larger than 9 cm 2 or thicker than 4mm.

Inclusion
3.2.3 Collect the patients' information, including gender, age, VSS, and color Doppler results; 3.2.4 Included patients after injection were randomly divided into experimental group and control group. The experimental group received 90Sr isotope radiotherapy with a total dose of 15-20Gy, and the control group no longer received radiotherapy after injection. VSS scoring was performed 3 weeks after the last injection and monthly after the brachytherapy completion or any time when patients visited for recurrence concern. Color Doppler ultrasound examination was performed 3 weeks after the last injection and 6、12 months after the brachytherapy completion. Patients' subjective symptoms including itching and pain were recorded. If a patient's VSS thickness score increased by 1 after the whole treatment course was completed, the follow-up would be ended and we would perform an VSS assessment and color Doppler ultrasound examination as an endpoint evaluation before re-injection. Complications such as hyperpigmentation, menstrual disorders, local depression, skin ulceration, and Cushing syndrome were recorded during the follow-up.