Postoperative Carbon Ion Radiotherapy for Keloids: A Preliminary Report of 16 Cases and Review of the Literature

Objectives. Radiotherapy for the management of keloids was first introduced in 1906, yet 107 years later optimal protocol has not yet been established. Most studies have been conducted using x-ray, β-ray, or γ-ray. However, for high linear energy transfer radiation, clinical data are scarce. The aim of this study was to examine the efficacy and safety of postoperative carbon ion radiotherapy for keloids. Material and Methods. Case records of 16 patients with 20 keloids, who were given postoperative carbon ion radiotherapy with 16GyE/8 fractions in the therapy terminal at the Heavy Ion Research Facility in Lanzhou at the Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China, were retrospectively reviewed. Results. In a mean follow-up period of 29.7 months (range 24.3-35.3 months), overall survival and 95% success rates were achieved. No grade 3 or higher toxicity and complication occurred, and none of the 16 patients presented with local or systemic malignancy during the follow-up period. Conclusion. Here, the first evidence of postoperative carbon ion radiotherapy for keloids is provided. Surgical excision and immediate postoperative carbon ion radiotherapy is well tolerated and should be considered as a potential curative treatment modality of keloids in certain cases.

Radiotherapy for the management of keloids was first introduced in 1906,¹ yet 107 years later optimal protocol has not yet been established. Previous protocol included external irradiation using superficial^2-11 and orthovoltage^12-14 x-ray and β-ray,^11,12,15-20 and brachytherapies using β-ray^21-23 and γ-ray.^24-31 Most studies have been conducted using x-ray, β-ray, or γ-ray, but for high linear energy transfer (LET) radiation, clinical data are scarce.

  Carbon-ion beams are generally characterized by a high LET, an energy deposition peak (Bragg peak) at the end of their tracks, and an increased relative biological effectiveness (RBE) within the peak region.³² Carbon ion radiation therapy (C-ion RT) was initiated at the Heavy Ion Research Facility (Lanzhou, China) in 2006 and has been used to treat more than 120 patients with a large histological variety of benign or malignant tumors. Of those patients, 16 with keloids were enrolled who were not indicated for curative surgery or who had declined surgery. In this report, the authors describe their experiences treating keloids using a combination of surgery and postoperative C-ion RT, and the efficacy and safety of such treatment.

Case presentation. A total of 16 patients treated at the Gansu Provincial Cancer Hospital (Lanzhou, China) were included in the study (Table 1 and continued). All cases of keloids met the clinical criteria for the diagnosis of keloid.³³ Patients were selected for radiation therapy based on 1 or more of the following criteria: evidence of extensive keloid disease, repeated failed surgical procedures, and anticipated failure of compliance to intralesional injection (triamcinolone acetonide) therapy.

  Surgical treatment. Local anesthesia (1% xylocaine) was administered during all surgical procedures. A fusiform excision was made approximately at the center of the keloid. The keloid rind flap, which consists of epidermis and thin dermis overlying the keloid, was raised from the fibrous keloid core. After raising the flap completely, the keloid core was excised. After trimming the redundant keloid rind flap, defects were resurfaced with the flap. All excised keloids were sent for independent histological examination to confirm the diagnosis. The skin sutures were removed 14 days after the operation.

  Carbon ion radiotherapy. A carbon ion beam of 100 MeV/u was supplied by the Chinese Academy of Sciences (Beijing, China). Carbon beams with maximum energy of 100 MeV u-1 were used for this skin carcinoma radiotherapy. Two- and 3-dimensional conformal layer-stacking irradiation methods realized by the passive beam delivery system were used within the C-ion RT. Beam weights (physical absorbed doses) of each Bragg peak are optimized by iterative technique or genetic algorithm. A broad beam algorithm based on the ray-tracing technique was used for dose distribution calculation in the treatment plan. Sixteen patients with a combined 20 keloids were treated with 2 Gy C-ion RT after surgical excision. All patients received a total dose of 16 Gy on consecutive days, beginning on the day of surgery. The time interval between keloid excision and delivery of the first radiotherapy fraction was less than 24 hours in all cases. Thereafter, no other treatments were performed for any of the patients.

  Follow-up. Fifteen of the 16 patients were followed up by clinical examination every 2 months for the first 6 months after C-ion RT and every 3 to 6 months thereafter. One patient could not return to the hospital for follow-up, and the determination of recurrence was made by telephone interview. The local findings were documented focusing on the presence or absence of keloid recurrence, dehiscence, acute and late complications (eg, infections, delayed wound healing), and cosmetic results. Recurrence was defined as the presence of a new keloid scar in the treated location. Toxicities were classified according to Common Terminology Criteria for Adverse Events (CTCAE) v3.0.34. The results of treatment were considered “good,” “improved,” or “failure” according to the scoring system of Enhamre and Hammar³⁴ in which “good” and “excellent” were combined as “good.” (Table 2). Keloid recurrence was defined as a regrowth of scar tissue that surpassed the margins of the wound created on lesion removal at day 1.The patients are currently being followed, with > 24 months since therapy. A literature review was done to compare the results of this study with other studies. All major articles reporting on the radiotherapy of keloids are summarized in Table 3 Part 1, Part 2, Part 3, and Part 4.

All patients were alive at the last observation date and no patient was lost to follow-up. The mean observation period was 29.7 months (range: 24.3-35.3 months). Surprisingly, at the time of last follow-up, 95% of keloids were without any evidence of recurrence. Only 1 recurrent keloid was observed within 6 months of postoperative radiation.

 No delayed wound healing or late complications were seen. There was no other grade 3 or higher toxicity of radiotherapy and none of the 16 patients presented with local or systemic malignancy during the follow-up period.

  Treatment results were rated by 12 patients (75%) as good, 2 patients (12.5%) as improved, and 2 patients (12.5%) as not satisfied, presumably because of cosmetic outcomes, although only 1 of these patients relapsed.

  Of the studies reviewed in the literature, most were retrospective studies. Only 1 randomized, prospective study was located.9 Five of 40 studies combined keloids with hypertrophic scars.^{15,20,21,39,40} Twenty-four of 40 studies used x-ray radiation, 11 used electron radiation, and 6 employed γ-ray radiation. There was no study that employed heavy ion radiation protocol. Several studies employed radiation in children, while others declined to irradiate keloids in children. There was no standardization of total dosage and fractionation in the reviewed studies. The follow-up period to determination of recurrence varied, the minimum being 1 month in 1 study. There was no study that reported grade 3 or higher toxicity of radiotherapy. Furthermore, there was no malignancy during the follow-up period.

Keloids are benign growth of fibrous tissue developing from an abnormal healing response to a cutaneous injury, extending beyond the original borders of the wound or inflammatory response.^1-4 The large number of treatment options is a reflection of the poor quality of research on this topic, with no single proven best treatment or combination of treatments. The reason for this lies in the fact that keloid scars are particularly refractory to these therapeutic modalities. Until now, there have been no uniform criteria for therapy of keloids.

  Surgical excision without any after-treatment may lead to keloid recurrence, and it has been reported that the recurrence rate is between 45% and 100%.^35-37 A combination of surgery and postoperative radiation therapy is considered to be the most efficacious treatment available for severe keloids, according to the International Clinical Recommendations on Scar Management, although it should be noted that this notion has not yet been tested by randomized controlled trials.³⁸

  Many types of radiation (including x-, β-, and γ-rays) have been used for the treatment of keloids.^1-31 The success rate for postoperative keloid radiotherapy using x-ray is 47%-100%, but this increases to 63.0%-95.3% if radiation employed γ-ray.²⁹ Several studies show a 64%-87% success rate with electron radiation.⁴⁰ Among them, the only 100% success rate was reported by Ramakrishnan et al in 1974⁴¹ however, a follow-up period was not mentioned.

  The 5% recurrence rate in the current study is less than most recurrence rates found in the literature. The mechanisms underlying this phenomenon might be due to ionic deposition of energy densely along their tracks, with the high local concentration of radiation damage from high-LET radiation causing greater impact compared to low-LET radiation.⁴²

  Kovalic and Perez⁵ and Doornbos et al⁶ have graphically demonstrated that most recurrences are seen within the 24 months following excision of the keloid and immediate postoperative radiotherapy. Kovalic and Perez⁵ reported that 13% of recurrences were seen after 24 months. Doorbos et al⁶ reported that 98% of the recurrences in their series were seen within this period as well. As such, the minimum period from excision and postoperative radiotherapy to determination recurrence should be 24 months.

  In the current study, none of the patients presented with malignancy during the follow-up period and there was no other grade 3 or higher toxicity of radiotherapy. Despite the potential risks of malignancy, there are only 3 reports in the literature of malignancies arising from the treatment of keloids with radiotherapy, and the causal relation was questionable. Hoffman⁴³ reported a case of carcinoma arising in the thyroid of a 19-year-old man 8 years after receiving x-ray treatment of 12 Gy to his chin. Botwood et al⁴⁴ reported a case of a patient who developed bilateral breast carcinomas almost 30 years after treatment of chest wall keloids with radiotherapy. Bilbey et al⁴⁵ reported a case of a 36-year-old woman who received radiotherapy to a chest wall keloid (dose unknown) when she was 13 years old, and who subsequently developed both a hypoplastic right breast and a poorly differentiated ductal carcinoma in situ with lymph node metastases. This patient also developed a localized pleural mesothelioma directly beneath the area of previous radiotherapy, although it is suspected she may have received a dose that exceeds today’s standards.

  The study has several strengths. First, all patients were observed for at least 24 months after treatment. Second, all excised keloids were sent for independent histological examination to confirm the diagnosis. Third, the study provides the first evidence that C-ion RT after surgical excision could be considered a potential novel treatment modality for keloids, with great efficiency and safety. The major limitation of the present study is the modest sample size. The positive results in this study need to be replicated in larger sample size studies with greater power. Furthermore, future studies focusing on optimal total dosage and fractionation of C-ion RT for keloids are needed.

Affiliations: Yingtai Chen, MD is from the Cancer Hospital/Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; and Gansu Provincial Cancer Hospital, Lanzhou, China. Feng Dong, MD; Xiaohu Wang, MD; Jijun Xue, MD; Liying Gao MD; Qiuning Zhang, MD; and Xuezhong Chen, MD are from Gansu Provincial Cancer Hospital, Lanzhou, China. Hong Zhang, PhD is from the Department of Radiology, Institute of Modern Physics, Lanzhou, China.

Address correspondence to:
Xuezhong Chen, MD
President
Gansu Provincial Cancer Hospital
2 Xiaoxihu East Street
Lanzhou, Gansu 730050
chief.chenxuezhong@163.com

Disclosure: The authors disclose no financial or other conflicts of interest.