Non-melanoma skin cancer treated with high-dose-rate brachytherapy: a review of literature

Purpose

The incidence of skin cancer has been increasing over the past 30 years and currently 2-3 million new cases are diagnosed worldwide every year. Non-melanoma skin cancer (NMSC) is the most common skin malignancy (95%) and in recent years its incidence has been increasing rapidly, even in young populations [1,2]. The development of NMSC is due to a combination of environmental, genetic, and phenotypic factors [3,4]. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the two most common subtypes: about 75-80% of all NMSC are characterized by the presence of BCC, 15-20% of these malignancies present SCCs, while 1% show a mixed phenotype [5]. There are different treatment options for NMSC such as surgery, cryotherapy, laser therapy (recommended only for shallow and early SCC), topical chemotherapy, photodynamic therapy, and radiotherapy (RT). Surgical excision is the most frequent treatment due to its low rates of recurrence, reported less than 5% [6,7,8,9,10]. In addition, RT is often used to treat NMSC and, specifically, different techniques can be used such as superficial X-rays, electron beams, megavoltage photons, and low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy (BT). Usually, the treatment options are chosen based on the institutional resources and the specialist’s experiences.
Electronic brachytherapy (EBT) is a new technique of radiotherapy, which delivers low-energy radiation at a high-dose-rate through an applicator placed on the skin. Due to introduction of new devices that are compatible for use with the equipment of EBT (such as Xoft® Axxent®, Zeiss® INTRABEAM® and Elekta® Esteya®) and the commercialization of electronic BT, has attracted considerable interest in the BT treatment of small skin tumors in last years.
Compared to the other radiotherapy technique, HDR-BT might be a better therapeutic option due to essential advantages such as high radiation dose concentration into the clinical target volumes (CTV), rapid dose fall-off at target periphery, optimal sparing of normal tissues in sensitive structures, shorter treatment time, and the use of hypofractionated course [11,12,13,14,15,16,17].
High-dose-rate BT is often delivered in the form of a surface mold but can also be delivered through use of a custom mold, Leipzig applicator, Valencia applicator, or a variety of other techniques. Moreover, HDR brachytherapy technique allows to treat with curative doses some localizations (such as cancer on face skin, near eyes and nose) with excellent and good cosmetic outcomes [18,19,20,21,22,23,24,25,26].

The role of HDR brachytherapy using ¹⁹²Ir source and surface applicators

The development in the late 1960s of the HDR bra­chytherapy afterloader, a robotic controller for automated insertion and removal of the radioactive source through catheters placed in or near the tumor, greatly improved radiation protection and simplified the delivery of the source. Most of NMSC brachytherapy today is delivered with HDR brachytherapy afterloaders using ¹⁹²Ir. While there is little level I evidence for traditional radiotherapy in the management of NMSC, there is no level I evidence for HDR brachytherapy. However, several retrospective and prospective studies with excellent results and adequate follow-up have been reported [19,20,21,22,23,24,25,26].
At first, Svoboda et al. [18] in 1995 published a data of 106 lesions (76 patients) treated with high-dose-rate micro­selectron afterloader using expanded silicone rubber molds and ¹⁹²Ir source.
In the study, we used different hypofractionated regimens (12-22 Gy given in a single fractions, 27-30 Gy/3 fractions, 30 Gy/5 fractions, 40 Gy/10 fractions, 46 Gy/10 fractions, and 50 Gy given in 15 fractions), and no recurrences were observed after a median follow-up of 9.6 months. Only G1-G2 acute and late toxicity was observed, and 94.4 % of lesions had an excellent and good cosmetic outcome.
In 1999, Köhler-Brock et al. [19] described the outcome of 520 lesions treated with HDR-BT using Leipzig applicators. The dose prescribed was 30-40 Gy in 5-10 fractions with a local control of 92% after 10 years’ of follow-up. One year later, Guix et al. [20] described a standardized surface mold technique prospectively utilizing HDR brachytherapy in 236 NMSC lesions, and achieved 5-year local control of 98% with excellent treatment tolerance and no severe early or late complications. Similar results were reported by other authors [19,20,21,22,23,24,25,26,27,28,29,30] in their retrospective studies. Despite the potential interest in BT for the treatment of non-melanoma skin cancer, there are not a lot of randomized controlled trials, systematic reviews, and/or metanalyses in literature.
The aim of this review was to systematically evaluate the available literature data regarding the local control, toxicity, and cosmetic outcomes in patients affected by non-melanoma skin cancer and treated with HDR-BT.

Material and methods

Search strategy

In May 2016, we conducted a comprehensive literature search of the following electronic databases: PubMed, Web of Science, Scopus, and Cochrane library. The databases were searched with a combination of key words for non-melanoma-skin cancer treated with HDR-BT; “skin cancer”, “high dose rate brachytherapy”, “squamous cell carcinoma”, “basal cell carcinoma”, and “non melanoma skin cancer “.

Study selection

In this systematic review, we included randomized trials, non-randomized trials, prospective studies, retrospective studies, and case series in patients affected by NMSC treated with HDR-BT. Single case reports and small case series with less than 20 cases were excluded. Moreover, we excluded studies reporting on patients with diagnoses different from NMSC skin cancer and studies reporting only palliative intent of skin cancer. In case of duplicated datasets (e.g. multiple articles from the same study group or institution, related to the same treatment on the same cohort of patient), we included only the work with the longest follow-up and the greatest number of patients.

Data extraction and analysis

Data extraction was performed by one reviewer and checked by a second reviewer. Two reviewers independently studied the abstracts and full text of all retrieved papers to select suitable articles for the assessment; disagreement about study to be included in this review were resolved by discussion between two reviewers who selected independently the publications for the evaluation.
We obtained the following information from each report: author identification, year of publication, medical center, study design characteristics, study population, number of patients, age, sex, histological diagnoses, BT technique, total dose, dose for fraction, delivered dose, local control, toxicity, functional cosmetic outcome, and follow-up time. Finally, in order to compare clinical outcome of different modalities of fractionated regimens used (total dose and dose for fraction), the biological effective dose (BED) was calculated.
Regarding late and acute toxicities or cosmetic events, all studies selected for this review used CTCAE v4.0 (Common Terminology Criteria for Adverse Events) toxicity scales [27], or Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) scales [31].

Statistical analysis

Before data performing, an exploration phase of the data was carried out; the categorical data were described by frequency and percentage, whereas continuous data by mean, median, and range. If necessary, after data exploration, analysis and calculation of frequencies, median, and range was performed due to description of end- points of the review.
All analyses were performed using the SPSS 22 technology.

Results

Our searches generated a total of 85 results, and through a process of screening, 10 publications were selected for the review. Of 65 studies excluded for this review, 22 were excluded due to duplicate data, 30 were excluded because they were not clinical trials but consisted in review (24), letter to editor (1) or book chapter (5). Finally, 23 studies were excluded because they did not fulfil the inclusion criteria: different treatment technique (such as use of low dose rate BT, interstitial BCT, EBRT with LINAC), little number of patients, palliative treatment, and diagnoses of melanoma skin cancer in majority of patients. Therefore, 10 studies fulfilled the inclusion criteria and were included in our review. The flowchart of systematic literature search process is shown in Figure 1.
Overall, in 10 studies analyzed in this review, 1977 lesions (1870 patients) were treated; of them, the majority of lesions 65% consisted in BCC, 32.5% were SCC, and the reaming 2.5% consisted in mixed phenotype such as Kaposi’s sarcoma, lymphomas, melanomas, and Bowen’s disease. The median age of patients treated was 72 years old, and 61% (1141) of patients were male and 39% (729) were female. The characteristics of these studies included in the review are summarized in Table 1 and Table 2.

Doses and fractionation

Comparing with external beam radiation, HDR-BT has an advantage regarding deep and superficial doses. In fact, during HDR-BT, the dose remains on the surface and does not penetrate deeply with optimal sparing of normal tissues due to dose concentration into the clinical target volumes (CTV) and rapid dose fall-off at target periphery [10,11,12,13,14,15,16,17]. Published studies have mainly reported standard fractionation and hypofractionated brachytherapy regimens in patients treated with HDR-BT, and the biological effective dose (BED) was often calculated due to define the total dose and dose for fractions regimen for a better local control and acceptable late and acute toxicity [19,20,21,22,23,24,25,26,33,34,35,36,37].
Biological effective dose is an inherent part of the linear quadratic (LQ) model of radiation effects and estimates the true biological dose delivered by a particular combination of dose per fraction and total dose to a given tissue characterized by a specific a/b ratio. It is calculated by the equation BED = nd [1 + d(/)] where n – the number of fractions, d – the dose/fraction, and / – radio-sensitivity coefficients at the dose at which the linear and quadratic components (for early or late cell damage, respectively) of cells killed are equal [38,39]. The a/b ratios vary based on the tumor type. For example, squamous cell cancers with high cell proliferation are characterized by 10-30 / ratio, while breast cancer shows lower values (4-5 Gy) as well in prostate cancer (0.8-2.5 Gy) and melanoma malignancies [39,40]. For NMSC, the alpha/beta ratios are approximately 10 Gy [39]; for SCC lesions, the / value is lower and it is reported at a value of 8.5 in different data in literature [41]. From the previous equation, it is evident that the BED will increase proportionally to the dose per fraction and inversely proportional to the / ratio. If the total dose is kept constant, the BED will increase if the dose per fraction is increased. For these reasons, it is important to perform BED calculations before clinical decisions since different histological classes of cancers have different a/b ratios, leading to different clinical responses, despite not changing the total dose.
Conventional fractionated regimes were reported by Guix et al. [20] data of 136 patients affected by NMSC and received a total dose of 60-65 Gy in 33 to 36 fractions. In this study, the mean age of patients was 67 years old (range, 23-91), 5 years local control for all patients was 98%.
Hypofractionated HDR brachytherapy regimens, which reduce the number of treatment fractions, compared with the conventional regimen that involves around 30 and 35 fractions, have been shown to achieve very good local control without increased side effects or reduced cosmetic results. Moreover, conventional fractionated regimens have different disadvantages such us higher number of sessions, overall treatment duration, moving the patient to the hospital, which can lead to an increase of overall costs effective therapy.
Different hypofractionated regimens with very good local control has been reported in literature [19,20,21,22,23,24,25,26,27,28,37,41,42]. Most commonly hypofractionated course described consist in a total dose of 30-40 Gy, delivered in 5-10 fractions once/ twice per week (Köhler-Brock et al. [19]), 36 Gy in 12 fractions (Gauden et al. [23]), 47-57 Gy delivered in 3 times weekly (Arenas et al. [42]), 40-50 Gy delivered in 7-8 fractions 2/3 time at week (Ghaly et al. [22], Delishaj et al. [26]), 42 Gy in 6 fractions delivered twice weekly (Tormo et al. [25]). Other hypo­fractionated regimes reported in some studies consist in 50-60 Gy given in 8-10 fractions and 50-60 Gy delivered in 5-6 fractions two time a week (Skowronek et al. [21]).

Local control

An excellent local control in patients with NMSC and treated with HDR-BT has been shown in different studies, and the local control rate is variable reported with a wide range from 83.3% [24] to 98-100% [18,22,25,26]. The main factors that may influence local control consist of total dose prescription, doses for fractions, dimension and depth of lesion, and histological type. Kanikowski [24] reported a recurrences rate of 16.7% after a median follow-up of 12 months in 497 patients with skin cancer treated by brachytherapy between November 1999 till April 2008 (Table 1 and 2). However, this study included patients who received palliative brachytherapy and patients previously treated with external beam radiation, which reported recurrences after treatment. The data reported by Skowronek et al. [21] showed a recurrences rate of 8.9% (179 lesions treated) after a median follow-up of 12 months but this study included 8 patients with skin metastases and receiving BT with palliative intent.
Köhler-Brock et al. [19] reported a recurrence rate of 8% of 520 lesions treated with HDR-BT using Leipzig applicators at the doses of 30-40 Gy in 5-10 after, 10 years follow-up. The study included Kaposi’s sarcoma, melanomas, and skin metastases. Finally, other studies [20,22,23,25,26] including patients affected by NMSC treated with definitive HDR-BT, reported excellent local control rate of 98-100%.
Overall, the median of local control rate after HDR brachytherapy in 10 studies analyzed was 97%.

Adverse events and cosmetic results

As reported in the literature, HDR brachytherapy treatment is very well tolerated with excellent cosmetic results despite applicators used (Lippizing applicators, Valencia applicators or custom made surface molds), total doses, and dose for fractions. Moreover, excellent cosmetic outcomes and acceptable acute and late side events were observed even in elderly patients using hypofractionated regimen of 40-50 Gy delivered in 8-10 fractions 2-3 time weekly [19]. As shown in Table 3, the most common early side-effects due to HDR-BT treatment are erythema, edema, rash dermatitis, pruritus, desquamation, and in rare cases ulceration. Late side effects appear, as per definition, 6 months after HDR-BT treatment and often consist of atrophy, pigmentation change, hair loss, telangiectasia fibrosis, and in rare cases ulceration (Table 3). RTOG morbidity scoring criteria [31].
According to toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Orga­nization for Research and Treatment of Cancer (EORTC), scale G1-G2 acute toxicities after HDR-BT varies widely from 24.5% [18] to 91.1% [24]. G3 RTOG/EORT acute toxicities has been reported in several studies in literature and they differ from 0% [19,20,22,23,25,26] to 40.3%, as reported by Arenas et al. [42]. Acute G4 toxicity was reported only in one study with a frequency of 2.2% [42]. The incidence of late toxicity reported in literature is lower than the incidence of acute toxicity. G1-G2 late toxicities differ from a minimum of 0.84% [20] to a maximum of 54% [21].
Overall, three studies [21,24,42] reported G3 late toxicity with frequencies of 2.2%, 3.4%, and 4.9%, respectively; G4 late toxicity was described only by Arenas et al. [42] data in 0.8% of lesions treated as shown in Table 2. In Table 4, we present a cosmetic rating scale [31].
Finally, as reported in many studies in literature, the treatment of NMSC with HDR BT is associated with excellent cosmetic outcomes even in elderly patients, as reported in our previous study [19,20,21,22,23,24,25,26,27]. On average, an excellent cosmetic result was reported from approximately 62% [23] to 98-100% [20,22,25]; a good cosmetic result from 0-2% [20,25] to 26% [23]; a fair result from 0% [25] to 13% [27], and, finally, a poor cosmetic result was reported in a range wide from 0% [24,25,26] to 5.5% [23]. Overall, an excellent and good cosmetic outcome consisted of 94.8% of cases.

Discussion

Surgery is often the primary treatment for NMSC lesions due to low rates of recurrence reported [6,7,8,9,10]. However, surgical treatment is an invasive procedure, and in elderly patients is not always feasible because of comorbidities, performance status, or lesion location (near the eyes, nose, and on facial skin). Typically, RT is the treatment of choice in this class of patients since surgery might be accompanied with functional or cosmetic deficits. The development of new devices for small skin tumor treatment and the introduction of commercial electronic BT have attracted considerable interest for BT as a skin cancer treatment. Despite the new technologies available, few studies have focused on the treatment of NMSC with HDR-BT and hypofractionated regimes seems to be a valid option for the treatment of NMSC with very good local control, toxicity, and cosmetic result [19,20,21,22,23,24,25,26,33,34,35,36,37,43,44]. In 1999, Köhler-Brock et al. [19] described the outcome of 520 lesions treated with HDR-BT using Leipzig applicators. The dose prescribed was 30-40 Gy in 5-10 fractions, and after 10 years’ of follow-up, local control was 92% of the cases; only G1-G2 late and acute toxicities were observed. One year later, Guix et al. [20] reported the results of 236 NMSC lesions treated with HDR-BT using custom-made surface molds, and after five years of follow-up, the local control was 98%. In addition, Gauden et al. [23] published the data of 236 lesions, and the local control was 98% after 36 months of follow-up. The total dose prescribed was 36 Gy in 12 fractions, and no G3 or higher late or acute toxicities were observed.
Hypofractionated course appears effective with very good local disease control and have different advantages such us little number of fractions, overall shorter time of duration, reduction of times for moving the patient to the hospital, and feasible outpatient treatment regimen, which can lead to reduction of overall costs effective therapy [36]. Comparable outcomes were reported by Bhatnagar [37], Tormo et al. [25], and Ballester-Sánchez et al. [28] with the use of hypofractionated course and Valencia applicators or HDR electronic BT with surface applicators, which resulted in excellent local control, cosmetic results, and very low-grade toxicities. More recently, we reported our data [26] of 57 lesions in elderly patients receiving hypofractionated regimes at the dose of 40-50 Gy in 8-10 fractions (using Valencia applicator) with excellent local control, cosmetic results with no G3 or higher acute or late toxicity. Finally, Haseltine et al. [29] reported the data of 61 patients treated with HDR brachytherapy, hypofractionated external beam radiation therapy (EBRT), or standard fractionation EBRT in patients affected by NMSC. After a median follow-up of 30 months, the local control was 81% and 2-year overall survival was 89%. There was no statistical difference in local control, overall survival, cosmetic outcome, or toxicity between treatment modalities.

Conclusions

As seen in our review, HDR-BT, through use of a custom mold, Leipzig applicator, Valencia applicator, or a variety of other techniques, is an alternate radiation modality that may be valuable for treatment of selected NMSCs. Typically, HDR-BT is the treatment of choice in patients, in which surgery is not feasible because of comorbidities, performance status, or lesion location, and surgery might be accompanied with functional or cosmetic deficits. Overall, the hypofractionated course appears to be effective with very good local disease control. Moreover, this cost-effective therapy shows high compliance and a feasible outpatient treatment regimen, essential in elderly patients. Finally, more data with large-scale randomized/prospective controlled trials and longer follow-up are needed to assess the efficacy and safety of HDR-BT, and to compare it directly with external beam therapy as well as the differential cure rates of subtypes of BCC versus SCC.

Disclosure

Authors report no conflict of interest.

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