Superficial radiation therapy for nonmelanoma skin cancer: A review

The high prevalence of nonmelanoma skin cancer (NMSC) has become a global health‐care burden. Various modalities have been established to treat NMSC, with surgery being the mainstay approach. Superficial radiation therapy (SRT) has been in use for over a century to treat various conditions. Recent discussion among the dermatological community has promoted the use of SRT for the treatment of NMSC.


| INTRODUCTION
Skin cancer is the most common malignancy in the United States.
Current estimates reveal that one in five Americans will develop skin cancer in their lifetime. Skin cancer can affect anyone, regardless of skin color. Squamous cell carcinoma (SCC), SCC in situ (SCCis), and basal cell carcinoma (BCC) are the most common skin cancer types and are highly treatable. 1,2 Epidemiological studies indicate that the incidence of nonmelanoma skin cancer (NMSC) has increased over the past few decades. 3 Rogers et al. 4  General's Call to Action to Prevent Skin Cancer. 5 This initiative aimed to educate the general population about the risk factors associated with skin cancers along with a series of strategies to help prevent skin cancer development. Sun exposure is unequivocally the most wellknown risk factor for acquiring skin cancers in general. Other individual risk factors include immunosuppression, genetic predisposition, age, and Fitzpatrick skin type I and II. 6 The vast majority of patients with NMSC have a good prognosis.
Early detection and treatment of NMSC are imperative for long-term survival. A study in Germany showed the 5-year absolute survival (AS, proportion of patients who survived after 5 years of initial diagnosis) and relative survival (RS, observed survival divided by survival of age-and sex-matched general population) for BCC were 87.1% and 102.9%. The AS and RS for SCC were 77.6% and 93.6%. 7 A single institution retrospective study found the risk of SCC metastasis was 3.7% and the risk of disease-specific death was 2.1%. Tumors with a diameter of 2 cm or more, invasive tumors beyond the fat, poor differentiation, perineural invasion, and certain location (ear, temple, or anogenital) carry a poor prognosis. 8 Currently, there are a variety of treatment options. The surgical approach (either excision with standardized margin or Mohs micrographic surgery) is considered the mainstay treatment. 9 Other approaches include radiation, electrodessication and curettage, cryotherapy, photodynamic therapy, and topical medications such as imiquimod and 5-fluorouracil. 10 The choice of the most appropriate treatment should be based on the patient's preference and suitability, tumor characteristics, providers' expertise, and availability of local services. 10,11 Radiation therapy (RT), one of the oldest treatment modules, includes superficial RT (SRT), brachytherapy, and external beam radiation. 11,12 Mechanistically, RT works primarily by causing lethal damage to target cells via DNA damage, resulting in population reduction and functional impairment of target cells. 13 Exposing cells to ionizing radiation activates a variety of complex signaling cascades that may result in cell cycle arrest or cellular apoptosis. Cellular radiation exposure also results in the activation of various DNA repair mechanisms, which combat the cytolytic effects of RT. Additionally, radiation-treated cells can exert downstream effects on untreated neighboring cells, a concept known as the bystander effect. 14 The dosing of RT is defined by the International Unit known as Gray (Gy) and centiGray (cGy, 1 Gy = 100 cGy). Fraction is defined as the dose delivered per treatment session. A typical treatment scheme for SRT might be a total dose of 4500 cGy, delivered in 300 cGy doses, for a total of 15 fractions. In this case, the treatment duration will be over a 5-8-week period, with fractions given two to three times per week. The determination of fractions and treatment dosing is based on the patient's age and tumor size. 15 Recently, there has been a renewed advocacy for the use of SRT in managing NMSC due to its accessibility in the office setting, promising cure rate, excellent cosmetic results, precise computerized system, and low recurrence rate. SRT utilizes electromagnetic energy generated from X-rays or photons to target the rapidly dividing tissues. Radiation oncologists classically utilize high-energy megavoltage photons in the range of 6-25 mV through the use of a linear accelerator (LINAC) to manage internal malignancy. The LINAC uses microwave technology to accelerate electrons to collide with a heavy metal and produce high-energy X-rays. These high-energy X-rays are customized as they exit the machine to meet the therapeutic needs of the patient's tumor. The beam comes out of a part of the accelerator called a gantry, which can be rotated around the patient.
Radiation can be delivered to the tumor from different aspects by rotating the gantry. 16 In contrast, SRT delivers a relatively lower energy range from 50 to 150 kVp (kV peak), which focuses on the skin and spares deeper structures. 15 A survey of dermatologic programs in the United States and Canada in 1986 by Kingery found that only 12% of respondents used X-ray therapy and 81% included instruction in RT. 17 Another survey in 2006 with 87 dermatology residency programs showed that only 10% of programs are familiar with X-ray or Grenz-ray equipment. Once again, 80% of dermatology programs included the theory and practice of RT in their curriculum. 18 In 2016, a survey was conducted concerning residency training on RT. Seventy-nine out of 80 respondents (99%) reported that SRT equipment was not available for them or that they did not know whether SRT was available. Sixty-five percent (52/80) reported no didactic or practical exposure to SRT. Seventy-six percent (61/80) reported they did not feel prepared to discuss SRT with patients as a viable option for NMSC. Fifty-nine percent (47/80) reported they would like to learn more about SRT as an alternative. The majority of residents also reported a need for more training in RT. These responses reveal both an education gap and a desire to learn more about SRT in managing NMSC. 19 Considering the educational gaps about SRT and the fact that SRT is the most affordable among all RT options, it is imperative to educate clinicians about the knowledge and clinical use of SRT.
Classically, SRT has been the standard of care in the office setting and has been studied and developed by dermatologists for over 100 years. 19 Until the 1980s, the propensity toward Mohs micrographic surgery and reduction in the manufacturing of SRT devices resulted in decreased utilization of SRT. 19 Recently, SRT was endorsed by many dermatologists because of the ease of use in an office setting, cost-effectiveness, innovative computerized system, and fractionation methodology, as well as the new consensus agreement. Most importantly, several studies have demonstrated the efficacy and safety profile of SRT in managing keloid scars, another commonly encountered condition in dermatology practices. [20][21][22] In this article, the author hereby presents an in-depth review of the clinical evidence and the future of SRT.

| COMPARISON OF RADIATION TREATMENT MODALITIES FOR SKIN CANCER
Historically, there have been three main modalities in treating skin cancer through radiation. SRT, used by dermatologists in the office setting, ranges from 75 to 125 kV and is used for lesions that are less than 5 mm in thickness; megavoltage electron beam therapy is able to penetrate 6 mm in depth and uses electron beams in the range of 6-20 MeV. 23

| Electron beam therapy (EBT)
EBT works by directing a beam of electrons at a low, well-defined energy level toward a lesion. 27 The radiation is generated via the LINAC and classically administered by radiation oncologists. EBT allows the uniform radiation dose to be delivered both laterally and distally, which allows the clinician to target superficial lesions without affecting the normal skin. Six to 20 MeV were used primarily in treating skin conditions. 28 The addition of a material, called bolus, which is placed on the skin to build up the surface dose is required. 29

| Brachytherapy
Brachytherapy involves the placement of radioactive material directly on a target lesion. 30 Depending on the anatomical location of the tumor, radiation sources in brachytherapy are generally placed into a body cavity (interstitial) or on the body surface (surface mold). 30 During the past decade, a novel brachytherapy called electronic brachytherapy has been developed that uses miniaturized X-ray sources instead of radionuclides to deliver high doses of radiation.
The advantages of electronic brachytherapy include low exposure to vital organs at risk, reduced dose to clinicians, no leakage radiation in the off state, less shielding required, and no radioactive waste. Most of these systems operate between 50 and 100 kVp and are widely used in the treatment of skin cancer. 25 These systems are in fact SRT systems with the source slightly closer to the patient.

| SRT
SRT has been used for over a century by dermatologists to treat superficial tumors. 19,31 In SRT, a 50-150 kV X-ray machine generating low-energy photons is used, which is absorbed within the first 5 mm of skin tissue. The source-to-skin distance in superficial SRT is generally between 10 and 30 cm. 31 Seventy-five kilovolts is applied to 1-2 mm lesions, whereas 100 kV is applied to 3-5 mm lesions. 31 The SRT device is smaller and less expensive to conduct procedures than EBT, as X-rays are used rather than a LINAC. Furthermore, a bolus is not needed for SRT as opposed to EBT. 26 SRT deposits energy in a uniform fashion and requires lower doses. 32 The SRT applicator ranges from 10 to 180 mm, which allows precise targeting of the lesions. 33 Several studies have compared the clinical results of SRT and EBT. Mendenhall et al. 34 examined patients with SCC and BCC on their head and neck that were treated with EBT or SRT. Patients treated with SRT had local control rates that were noninferior to those treated with EBT and the authors attributed it to the tendency to underdose to the tumor with the latter. Lovett et al. 35   • SRT should be the first option for treating appropriate types of NMSC in appropriate patients due to its comparable cure rates to surgery and possible superior cosmetic results in certain locations.
Contraindications to the use of SRT include aggressive tumor type or deep tissue invasion, previously irradiated sites, and organ transplant recipients.
• SRT is superior to EBT for treating most cases of NMSC as SRT has a smaller penumbra (1 mm) than EBT (8-10 mm). SRT is also superior to electronic brachytherapy due to being more costeffective and its ability to vary energies from 50 to 100 cGy and employ larger spot sizes.
• SRT is most appropriate for primary BCC, SCC, SCCis, and certain cases of cutaneous lymphomas and Kaposi sarcoma.
Other forms of aggressive tumors (tumors with perineural invasion, cutaneous T-cell lymphomas, Merkel cell carcinoma, dermatofibrosarcoma protuberans) should be treated with other forms of RT.
• The radiation margin should be similar to the surgical margin. The penumbra is only 1 mm.
• Certain anatomical areas are more suitable for SRT, notably, below the knee, nasal alar rim, ear, perioral, and periorbital areas.
• Certain patients are more suitable for treatment with SRT than surgery due to local skin conditions, advanced age, pre-existing medical conditions, or their own preferences.
• Patient safety is warranted, including shielding, positioning, and immobilization.
• Optimal energy and fractionation schedules for treating NMSC lead to superior outcomes. The more fractions in the treatment scheme, the fewer short-and long-term adverse events will be seen. The patient's preferences should be discussed before treatment to determine the treatment schedule, such as whether they prioritize outcome and cosmesis (more fractions) versus less frequent office visits (less fractions). A suggested treatment algorithm is outlined in Table 3.
• Constant evaluation of the treatment site is vital. A pause or change in the treatment algorithm should be executed when medical personnel sees significant ulceration, swelling, or pain.
• No study has assessed whether the use of topical treatments for radiation dermatitis during and/or after SRT affects treatment outcomes, but such treatments can possibly reduce cure rates as it is hypothesized that inflammation from RT is the mechanism of curing NMSC. Radiation dermatitis management is based on the severity of the damaged skin.

ACKNOWLEDGMENTS
Authors thank to Shari Sanchez for their administrative support.

CONFLICT OF INTEREST
Mark S. Nestor is a consultant to Sensus Healthcare.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
Written consent was obtained from all patients whose photos were included in this article. F I G U R E 4 An 80-year-old-male patient was treated with superficial radiation therapy on his left nasal ala (left to right). 1. Before radiation; 2. Ultrasound image of the basal cell carcinoma before radiation; 3. posttreatment #15