A modified nonsurgical treatment of keloids: Cocktail therapy

The high recurrence rate after nonsurgical treatment of keloid is a major challenge for clinicians. Although there are many existing treatment options, how to optimize and upgrade the existing options and make a reasonable combination of utilization is our concern. The aim of this study is to provide a comprehensive non‐surgical treatment for keloid—cocktail therapy.


| INTRODUC TI ON
Keloid is recognized by the medical community as a disease similar to benign skin tumor with poor treatment effect, and the pathogenesis is not clear.Any single treatment has obvious limitations and a very high recurrence rate.Clinicians are increasingly inclined to multi-means comprehensive treatment, such as carbon dioxide fractional laser combined with drug injection, 1 botulinum toxin combined with corticosteroid, 2 pulsed dye laser (PDL) combined with verapamil in the treatment of keloid, 3 and so on.This array of treatments speaks to the difficulty in obtaining satisfactory results.
In addition, comprehensive treatment does not mean that all treatment methods are used indiscriminately, which not only increases the treatment cost of patients, but also does not produce "a whole greater than the sum of the parts."Just like a cup of palatability cocktail, the base should be proportioned and added at the right time.Our team has been committed to finding a more suitable nonsurgical comprehensive treatment for a long time.From May 2018 to December 2018, a total of 152 keloids were selected from 80 outpatients were treated with "cocktail therapy".After long-term follow-up observation, the treatment effect was satisfactory, which is reported as follows.lection according to the color response of patients with keloid treatment adjusted at any time, to immediately postoperative mild purpura as the standard).The DCD dynamic cold spray system is cooled for 20 ms, and the spot overlap is maintained by 20%-30%.
After treatment, cool water bag was applied to the treatment area for 60 min.After local anesthesia for keloid, drug A was uniformly injected into keloids in stratified layers with an injection volume of about 0.1 mL/cm 3 .Along the edge of the lesion, drug B is added to the area, and the injection method is the same as above.Patients were treated at 4-week intervals.
Treatment Stage II: After the keloid is completely soft and flat, local electron beam irradiation can be performed, which is divided into two times.And drug B was injected into the lesions within 24 h before the first irradiation.The injection of drug B is about 0.2 mL/ cm 2 .One week later, the second irradiation was performed.
The irradiation range of electronic line exceeds 1 cm outside the skin lesion, and the irradiation depth varies according to the different thickness of the skin, usually 0.5-1 cm.The radiation energy was 6-7 MeV electron wire and the dose is Dt18Gy/2 f.The equivalent 0.5-1 cm film was placed on the skin of the patient's irradiation area to increase the skin irradiation dose, and the equivalent biological dose BED reached 30-40 Gy.After irradiation, patients are advised to avoid friction in the treatment area and do not scrub with detergent within 7 days.
Treatment stage III, which is 4 weeks after the end of treatment stage II, patients were injected with drug B every 4 weeks.The injection of drug B is about 0.5 mL/cm2.As the color of keloid gradually changed from dark red to light, the treatment interval could be gradually lengthened to 5, 6, 8, 12, 24 weeks, etc., until the lesions turned white and close to the skin color.
Once the keloid in the III stage hardens locally, it enters the IV stage of treatment, that is, drug A is injected every 4 weeks, and after the keloid is softened, it enters the III stage again.(Figure 1).

| Clinical effect
Recurrence refers to the occurrence of one or more of the following conditions in keloid after treatment: the keloid becomes red, hard, raised skin surface, and the appearance of clinical symptoms such as itching/pain.The keloid status of patients was evaluated at 16 months after the end of III treatment.Evaluation criteria: (1) Cure: keloid is completely smooth and softened, the color is white or close to the skin color, pain, itching, and other symptoms disappeared; (2)   Significant effect: keloid softening, poor flatness, slightly red color, occasional itching, pain, and other symptoms; (3) Ineffective: keloid no change, clinical symptoms did not improve.

| Adverse reaction
The occurrence of adverse reactions during treatment and follow-up were recorded, such as skin atrophy, black scab caused by local damage, pigmentation around skin lesions, telangiectasia on skin lesions, radiation dermatitis, and other adverse reactions.

| RE SULTS
In this study, the age of the patients ranged from 19 to 53 years old, with an average age of (34.04 ± 8.42) years.There were 43 females and 37 males with an average medical history of (15.96 ± 10.05) years.Fifty-five percent of the patients relapsed or could not be controlled after receiving various treatments.Keloid is distributed in the forechest with obvious hyperemia and obvious infiltrative zone at the edge, accompanied by itching and pain.Eighty patients did not withdraw and all completed the study on time.In Stage I, the patients received an average of (3.5 ± 1.07) times of treatment.In Stage III, patients received an average of (8.27 ± 2.93) treatments.The incidence of receiving IV stage treatment is 45.4%.Sixteen months after the end of treatment, the effective rate was 100% and the cure rate was 92.8%.

| The incidence of adverse reactions
In Stage I treatment, the incidence of telangiectasia was 11.2%, and no other adverse reactions occurred; in Stage II treatment, the incidence of radiation dermatitis was 12.5%, and no other adverse reactions were found; in Stage III treatment, the incidence of skin pigmentation was 48.7%, which could return to normal after stopping treatment.
During the treatment of IV, no adverse reactions were found.

| Typical cases
Typical cases: We report three representative cases, as shown in Figures 2-4.All patients included in the study signed the informed consent and have been reviewed by the Medical Ethics Committee.

| DISCUSS ION
595 nm PDL can selectively destroy the hyperplastic and dilated microvessels in the superficial layer of keloids, 4 thereby reducing the supply of nutrients for their disorderly growth and inhibiting their proliferation ability.In this study, 595 nm PDL was used as the first step of treatment because the ability of invasive growth and recurrence of keloid partly depends on the hyperplasia and dilation of superficial blood vessels. 5,6However, PDL is not enough to significantly reduce the size of the scar, and local drug injection should be The adverse reactions after TAC injection are usually manifested as telangiectasia, depigmentation, and skin atrophy in the treatment area.For keloids that are already flat, if continued injection, there is a great risk of skin atrophy, which is why many clinicians choose to stop injection therapy, resulting in a high recurrence rate of keloid in nonsurgical treatment of keloids.
How to solve the high recurrence rate after keloid treatment is a major challenge for clinicians.The cure criteria of keloid in this study are as follows: keloid pain, itching, and other symptoms disappear, completely smooth and soften, and the color is white or close to the skin color.We need to realize that flattening keloids is not the end of treatment, it is only a stage (such as Stage I treatment in this study).
According to our clinical experience, the pathological structure of keloid has not changed substantially at this stage, if left unchecked, it will soon relapse.For keloid, which is already soft but still red, that is, the III stage in this study, the treatment should focus on inhibiting vascular dysplasia and dilatation.According to the treatment experience of our team, for keloids initially entering a flat and soft state, if the injection of TAC + FU is suddenly replaced by a single injection of a lower concentration of FU, the recurrence rate can be as high as 90%. 8,9Although increasing the concentration of FU injection can reduce the recurrence rate to a certain extent, it will also increase the risk of ulceration and necrotic scab in the injection area, and there is no much benefit after weighing the pros and cons.Therefore, in this study, it is possible to proceed from Stage I to Stage III treatment, that is, keloids receiving a single FU injection need to receive local electron irradiation (Stage II treatment) beforehand.Electron irradiation can effectively inhibit the proliferation of local fibroblasts and induce cell aging and apoptosis, thereby inhibiting the proliferation of keloid capillaries and greatly reducing the recurrence rate of keloid. 10 an antitumor drug, FU can be used as a radiosensitizer in the treatment of tumor diseases to improve the efficacy of radiotherapy. 11,12 view of this characteristic of FU, this study was flexibly applied to the radiotherapy process of keloid, achieving the antitumor effect of electron wire enhancing drugs, and FU enhanced the killing ability of radiation on "tumor cells", forming a special sensitization mechanism that promoted each other and greatly inhibited the recurrence ability of keloid.It is well prepared for the treatment of keloid by single injection of low concentration FU in Stage II.
In the early stage of III, when the treatment interval is about 4 weeks, there are signs of recurrence of keloid, and timely tonics are needed.For the local redness and hardening of keloid, it is necessary to enter the IV stage of treatment, and then return to the III stage of treatment after the keloids soften again.In this study, the recurrence rate was 45.4%, indicating that radiotherapy is not the end point of keloid treatment.For recurrence with only color change, recurrence can be inhibited only by injection of low concentration of FU (4.2 mg/mL).With the continuous accumulation of treatment, the vitality of keloid gradually decreased.After the injection of the same amount of FU as the previous treatment, there will be temporary color deposition in and around the injection area, which also means that we can extend the treatment interval, such as 6 weeks, 12 weeks, or even 24 weeks.In this study, we determined that the patients with keloid who had not relapsed 16 months after the last treatment were completely cured, with a cure rate of 92.8%.For patients with keloid, small skin damage may lead to retaliatory growth of keloid, so in this study, in order to reduce the risk of treatment, tissue biopsy and other more invasive procedures were not used to evaluate the curative effect and keloid character changes, and the relevant contents will be further verified by experiments in the future.For keloids with infection or contracture, symptomatic treatment should be given before the treatment of this scheme.

F I G U R E 1
Treatment flow chart.F I G U R E 2 (A) Patient A, before the treatment.(B) Follow-up was performed 12 months after completion of Phase II therapy (For the keloid located above, surgical resection plus electron beam irradiation was selected).(C) 16 months after the end of the nonsurgical treatment, the patient took a follow-up photo at home. the main part of the treatment plan.TAC, as the most widely used injection drug in clinical practice, has been regarded as the first-line drug in the treatment of keloids for many years.It can not only relieve the discomfort symptoms such as pruritus and pain, but also significantly reduce the size of scars, making them soft and flat. 7

F
I G U R E 4 (A) Patient C, before the treatment.(B) Follow-up was performed 12 months after completion of Phase II therapy.(C) 16 months after the end of the treatment, the patient took a follow-up photo at home.F I G U R E 3 (A) Patient B, before the treatment.(B) Follow-up was performed 18 months after completion of Phase II therapy.| 3099 LIU et al.