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GEC-ESTRO ACROP recommendations in skin brachytherapy

Open AccessPublished:February 15, 2018DOI:https://doi.org/10.1016/j.radonc.2018.01.013

      Abstract

      Purpose

      The aim of this publication is to compile available literature data and expert experience regarding skin brachytherapy (BT) in order to produce general recommendations on behalf of the GEC-ESTRO Group.

      Methods

      We have done an exhaustive review of published articles to look for general recommendations.

      Results

      Randomized controlled trials, systemic reviews and meta-analysis are lacking in literature and there is wide variety of prescription techniques successfully used across the radiotherapy centers. BT can be delivered as superficial application (also called contact BT or plesiotherapy) or as interstitial for tumours thicker than 5 mm within any surface, including very irregular. In selected cases, particularly in tumours located within curved surfaces, BT can be advantageous modality from dosimetric and planning point of view when compared to external beam radiotherapy. The general rule in skin BT is that the smaller the target volume, the highest dose per fraction and the shortest overall length of treatment can be used.

      Conclusion

      Skin cancer incidence is rising worldwide. BT offers an effective non-invasive or minimally invasive and relative short treatment that particularly appeals to elder and frail population.

      Keywords

      The incidence of skin cancer has been rising over the past decades. World Health Organization (WHO) estimates that currently 2–3 million non-melanoma skin cancers (NMSC) occur globally each year with one in every three cancers diagnosed being a skin cancer []. These data are most likely underestimated. The incidence rates in Europe varied between 40–130/100,000 person-years for basal cell carcinoma (BCC) and 8–30/100,000 person-years for squamous cell carcinoma (SCC) respectively [
      • Lomas A.
      • Leonardi-Bee J.
      • Bath-Hextall F.
      A systematic review of worldwide incidence of nonmelanoma skin cancer.
      ]. A trend in increasing incidence in older population has been confirmed [
      • Eisemann N.
      • Waldmann A.
      • Geller A.C.
      • et al.
      Non-melanoma skin cancer incidence and impact of skin cancer screening on incidence.
      ]. It is expected that NMSC may soon start to represent a major public health problem and pose a significant burden to any health care system. Many patients with NMSC referred for radiotherapy are older, frail, have unresectable tumours or contradictions to surgery due to advanced age or co-morbidities. This issue already introduces a bias in data analysis and comparison with other treatment methods. Various radiotherapy techniques have been developed to treat skin cancer: superficial and orthovoltage X-rays, electron and megavoltage photon treatment, and brachytherapy (BT) in all the modalities: low dose rate (LDR), high dose rate (HDR), pulsed dose rate (PDR), and electronic BT. Due to logistics of LDR application, this modality has been gradually abandoned. The treatment choice is usually based on institutional resources and specialist experience and should consider local control, cosmesis, toxicity and convenience/expected compliance of the treatment.
      BT is an appropriate and effective treatment option for selected skin cancers, mainly NMSC that are not better served by surgical removal, non-radiotherapy treatment modalities, or external beam radiotherapy (EBRT) [
      • Alam M.
      • Nanda S.
      • Mittal B.B.
      • Kim N.A.
      • Yoo S.
      The use of brachytherapy in the treatment of nonmelanoma skin cancer: a review.
      ]. There are several advantages of HDR and PDR BT when compared with EBRT that should be considered in the decision making process. BT is usually delivered as a hypofractionated course, three or two times a week, rather than daily, which translates into fewer treatment visits for a patient, particularly useful for elderly and frail patients. The dose is delivered in a short period of time. Computer-based treatment planning allows for an optimized dose distribution. A rapid fall in dose beyond radioactive source makes it possible for increased tumour control while sparing the surrounding tissue and shorter overall treatment duration reduces risk of tumour cell repopulation. There are no randomized controlled trials, systemic reviews and meta-analysis in literature regarding skin BT and there is wide variety of prescription techniques successfully used across the radiotherapy centers [
      • Delishaj D.
      • Rembielak A.
      • Manfredi B.
      • et al.
      Non-melanoma skin cancer treated with high-dose-rate brachytherapy: a review of literature.
      ]. All the recommendations in this paper have a level of evidence IV (LOE IV: based in retrospective cohort studies, no prospective studies); and grade of recommendation B (GOR B: Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended) [].

      Modalities of BT applications in skin

      Current skin applications in brachytherapy can be classified in two modalities [
      • Joslin C.A.
      • Flynn A.
      High dose-rate brachytherapy in the treatment of skin tumors, in principles and practice of brachytherapy using afterloading systems.
      ,
      • Skowronek J.
      Brachytherapy in the treatment of skin cancer – an overview.
      ]:
      • Superficial, also called contact brachytherapy or plesiotherapy.
      • Interstitial, with the insertion of plastic tubes or rigid needles.
      Superficial modalities involve moulds and flaps for larger lesions, and radionuclide based shielded applicators and electronic based shielded applicators for small volume lesions. Interstitial BT is applied to deeper located and/or very irregular tumours.
      An excellent review of those different modalities and details on the applicators from physics point of view have been published by the American Brachytherapy Society (ABS), with an updated review of relevant papers on skin BT [
      • Ouhib Z.
      • Kasper M.
      • Perez Calatayud J.
      • et al.
      Aspects of dosimetry and clinical practice of skin brachytherapy: the American Brachytherapy Society working group report.
      ].

      Superficial brachytherapy

      Surface moulds

      Mould BT is a technique of delivering BT by an applicator that is usually custom made and designed to provide a more constant and reproducible frame for source positioning. Mould can be used for flat surfaces and irregular shapes. A customized mould can be constructed from specialized polymers, acrylic resin, wax (such as those used in dentistry) or a thermoplastic material or similar in which the catheters are embedded [
      • Joslin C.A.
      • Liversage W.E.
      • Ramsey N.W.
      High dose rate treatment mould by afterloading technique.
      ,
      • Sabbas A.M.
      • Kulidzhanov F.G.
      • Presser J.
      • et al.
      HDR Brachytherapy with surface applicators: technical considerations and dosimetry.
      ] (Fig. 1). Moulds fit to the external patient surface and the catheters must remain in the exact position as closely as possible to tumour surface to provide adequate dose coverage of tumour volume and increase the distance to other normal surrounding structures. In postoperative BT the gradient can overdose the skin, therefore the catheters must be placed at a few mm of distance from the skin, preferably 5 mm. Conformal custom moulds are often utilized for complex shapes and irregular surfaces like the earlobe or nose. An irreversible hydrocolloid can be used for making impression. Cerrobend alloy or thin lead is chosen for shielding purposes [

      Bahadir Ersu. Custom Made Mold Brachytherapy, Basal Cell Carcinoma, Dr. Vishal Madan (Ed.), ISBN: 978-953-51-0309-7, InTech; 2012. Available from: http://www.intechopen.com/books/basal-cell-carcinoma/custommade-mold-brachytherapy.

      ]. A thermoplastic mask with catheters embedded in wax or resin is useful for an accurate reproducibility for extensive lesions of the scalp. Low-cost 3D printers are a promising solution for the customization of the HDR BT applicators but regulatory materials’ approval is required for clinical application [
      • Ricotti R.
      • Vavassori A.
      • Bazani A.
      • et al.
      3D-printed applicators for high dose rate brachytherapy: dosimetric assessment at different infill percentage.
      ]. Published studies involving mould technique have shown good local control and cosmesis [
      • Svoboda V.H.
      • Kovarik J.
      • Morris F.
      High dose-rate microselectron moulds in the treatment of skin tumours.
      ,
      • Amendola B.
      • et al.
      Cosmesis outcomes in patients with non melanoma skin cancer (NMSC) treated with HDR.
      ,
      • Montero A.
      • Hernanz R.
      • Capuz A.B.
      • et al.
      High-dose-rate (HDR) plesiotherapy with custom-made moulds for the treatment of non-melanoma skin cancer.
      ,
      • Guix B.
      • Finestres F.
      • Tello J.I.
      • et al.
      Treatment of skin carcinomas of the face by high-dose-rate brachytherapy and custom-made surface molds.
      ,
      • Skowronek J.
      • Chichel A.
      • Piotrowski T.
      HDR brachytherapy of skin cancer - the Wielkopolski Cancer Centre’s experience.
      ,
      • Maroñas M.
      • Guinot J.L.
      • Arribas L.
      • et al.
      Treatment of facial cutaneous carcinoma with high-dose rate contact brachytherapy with customized molds.
      ,
      • Jumeau R.
      • Renard-Oldrini S.
      • Courrech F.
      High dose rate brachytherapy with customized applicators for malignant facial skin lesions.
      ] (see separate file for table).
      Figure thumbnail gr1
      Fig. 153 year old with 12 months non-healing ulceration on the left middle finger. Biopsy confirmed SCC. No bony invasion. Prior unsuccessful treatment with cryotherapy. On examination: 2.1 cm × 3.1 cm lesion. Skin US 1.9 mm total tumour depth, 3.6 mm from the top of the tumour to bone. Treatment: Skin HDR brachytherapy 37.5 Gy in 8 fractions, treatment twice a day over 4 days. Results at 18 month follow-up. (Example of surface moulds and flaps).
      The dose prescription point with moulds is usually 3–5 mm under the skin surface but in case of advanced tumours with deep ulcer or deep dermis infiltration, it should be at least 3–5 mm under the deepest point of a given tumour, defined by an appropriate imaging, therefore interstitial BT or EBRT should be considered in such cases.
      The ABS in 2001 made specific recommendations for head-and-neck cancer patients [
      • Nag S.
      • Cano E.R.
      • Demanes D.J.
      • Puthawala A.A.
      • Vikram B.
      The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for head-and-neck carcinoma.
      ]:
      • 1.
        Superficial (<5 mm thick) tumours can be treated with fractionated HDR using moulds.
      • 2.
        Suitable sites for mould therapy include scalp, face, pinna, lip, buccal mucosa, maxillary antrum, hard palate, oral cavity, external auditory canal, and the orbital cavity after exenteration.
      • 3.
        A total HDR dose equivalent to about 60 Gy LDR (prescribed at 5 mm depth) is recommended. The actual HDR dose per fraction and number of fractions can be varied to suit individual situation (site and treatment volume). HDR can be used as a boost to 45–50 Gy EBRT (LDR equivalent doses of 15–30 Gy).

      Surface flaps

      In case of non-excessive surface irregularity, commercially available flaps may be used. These consist of regular layers of silicon-based material or linked pellets of 10 mm in thickness or diameter in which the catheters are embedded. Ten mm inter-catheter distance and a minimum of 5 mm distance to the skin are assured. Typical prescription depth with flaps is less than 5 mm under the skin. The available flaps are the Freiburg™ flap (Elekta Instrument AB, Stockholm, Sweden), the H.A.M.™ (Mick Radio-Nuclear Instruments and Eckert & Ziegler BEBIG, Berlin, Germany), and the Catheter Flap set™ (Varian Medical Systems, Palo Alto, CA, USA). Parallel equidistant plastic tubes can be taped to a bolus to obtain a hand-made flap that is fixed to the skin or scalp in every fraction.
      • Surface moulds and flaps are indicated on regular surfaces. Flaps are convenient in larger volume lesions.
      • Customized moulds can be adapted to irregular surfaces like nose, pinna, hand and fingers.
      • Dose is prescribed to 3–5 mm under the skin surface.
      • A distance from the source to the skin of 5 mm is recommended to obtain homogeneity on the surface of the skin, and avoid an overdosage.

      Superficial radionuclide based shielded applicators

      In case of small lesions, on regular and plane surfaces, adequately sized applicators were developed specifically for this purpose. The Leipzig type™ applicator is cup-shaped and made of tungsten with the HDR source at its vertex [
      • Niu H.
      • Hsi W.C.
      • Chu J.C.
      • Kirk M.C.
      • Kouwenhoven E.
      Dosimetric characteristics of the Leipzig surface applicators in the high dose rate brachytherapy.
      ]. Different diameters, from 10 mm to 30 or 45 mm are available (Elekta or Varian). Although the main disadvantage of these applicators can be non-flat dose distribution delivering an inhomogeneous dose on the target volume, and relatively large penumbra [
      • Perez-Calatayud J.
      • Granero D.
      • Ballester F.
      • Crispin V.
      • van der Laarse R.
      Technique for routine output verification of Leipzig applicators with a well chamber.
      ,
      • Perez-Calatayud J.
      • Granero D.
      • Ballester F.
      • Puchades V.
      • Casal E.
      • Soriano A.
      • et al.
      A dosimetric study of Leipzig applicators.
      ,
      • Fulkerson R.K.
      • Micka J.A.
      • LA De Werd
      Dosimetric characterization and output verification for conical brachytherapy surface applicators. Part I. Electronic brachytherapy source.
      ], several studies have shown the clinical efficacy of this approach [
      • Köhler-Brock A.
      • Prager W.
      • Pohlmann S.
      • Kunze S.
      The indications for and results of HDR afterloading therapy in diseases of the skin and mucosa with standardized surface applicators (the Leipzig applicator).
      ,
      • Gauden R.
      • Pracy M.
      • Avery A.M.
      • Hodgetts I.
      • Gauden S.
      HDR brachytherapy for superficial non-melanoma skin cancers.
      ,
      • Arenas M.
      • Arguis M.
      • Diez-Presa L.
      • et al.
      Hypofractionated high-dose-rate plesiotherapy in nonmelanoma skin cancer treatment.
      ,
      • Evans M.D.C.
      • Yassa M.
      • Podgorsak E.B.
      • et al.
      Surface applicators for high dose rate brachytherapy in AIDS-related Kaposi’s sarcoma.
      ]. The prescription depth usually depends on the depth of the skin tumour infiltration, usually no more than 4 mm.
      The Valencia™ applicator (Elekta) was developed from the Leipzig™ applicator by adding a flattening filter to homogenize the dose distribution, resulting in significant improvement of the useful beam and penumbra [
      • Granero D.
      • Perez-Calatayud J.
      • Gimeno J.
      • et al.
      Design and evaluation of a HDR skin applicator with flattering filter.
      ,
      • Granero D.
      • Perez-Calatayud J.
      • Ballester F.
      • Ouhib Z.
      Radiation leakage study for the Valencia applicators.
      ]. It is cup-shaped and made of tungsten, with two sizes of 20 mm (VH2) and 30 mm (VH3) of diameter. The 40 mm (VH4) and 50 mm (VH5) are under development. Lesion size must not exceed 15 or 20 mm for VH2 and VH3 with a minimum of 5 mm of margin and 1–2 mm extra from CTV-PTV due to setup uncertainty. The template la Fe-ITIC™ has been developed specifically for marking the added Planning Target Volume (PTV) on skin and helps to avoid interfraction set-up errors [
      • Villalba S.R.
      • Perez-Calatayud J.
      • Bautista J.A.
      • et al.
      Novel simple templates for reproducible positioning of skin applicators in brachytherapy.
      ]. Because of the filter-induced attenuation, the treatment times are higher and can take from 5 to 15 min. The typical prescription depth is 3 mm with a skin surface dose of around 135% [
      • Tormo A.
      • Celada F.
      • Rodríguez S.
      • et al.
      Non melanoma skin cancer treated with HDR Valencia applicator: clinical outcomes.
      ,
      • Delishaj D.
      • Laliscia C.
      • Manfredi B.
      • et al.
      Non-melanoma skin cancer treated with high dose rate brachytherapy and Valencia applicator in elderly patients: a retrospective case series.
      ,
      • Ghaly M.
      • Byrnes R.
      • Zinkin H.
      • et al.
      Role of HDR brachytherapy with standardized surface applicators in the treatment of superficial malignant skin lesions.
      ]. Valencia™ applicators have a removable 1 mm thick plastic cover cap in close contact with the patient skin. The overtreatment without the cap for the first millimeter of skin goes up to a factor of 2.8. Depth of the area to be treated must not exceed 3–4 mm what delivers 80–90% of the dose to a depth of 5 mm, due to a gradient of 10% per mm. Skin high frequency ultrasound of the lesion or surgical bed to define the depth of PTV is recommended. Immobilization during every session of BT can be obtained with an articulated arm, tape or thermoplastic mask (see separate file for tables).

      Electronic based shielded applicators

      In order to reduce the treatment time and to avoid dependence on HDR equipment and a brachytherapy facility, several electronic solutions have been implemented, leading to development of electronic based applicators [
      • Skowronek J.
      Brachytherapy in the treatment of skin cancer – an overview.
      ]. Currently, three major electronic applicator systems can be used for skin cancer. The Axxent™ (Xoft Inc, San Jose, USA) has a 50 kV electronic source and is used mainly for the intracavitary treatments. For skin treatments, the source needs to be mounted on special applicators with flattening filter [
      • Fulkerson R.K.
      • Micka J.A.
      • DeWerd L.A.
      Dosimetric characterization and output verification for conical brachytherapy surface applicators. Part II. High dose rate Ir-192 sources.
      ]. Another device is the 50 kV Intrabeam™ (Carl Zeiss, Oberkochen, Germany), with the specifically developed skin applicator [
      • Schneider F.
      • Clausen S.
      • Tholking J.
      • Wenz F.
      • Abo-Madyan Y.
      A novel approach for superficial intraoperative radiotherapy (IORT) using a 50 kV X-ray source: a technical and case report.
      ,
      • Goubert M.
      • Parent L.
      Dosimetric characterization of INTRABEAM(R) miniature accelerator flat and surface applicators for dermatologic applications.
      ]. The third system is Esteya™ (Elekta, Stockholm, Sweden) [
      • Garcia-Martinez T.
      • Chan J.P.
      • Perez-Calatayud J.
      • Ballester F.
      Dosimetric characteristics of a new unit for electronic skin brachytherapy.
      ,
      • Pons O.
      • Ballester R.
      • Celada F.
      • Candela C.
      • Garcia T.
      • Llavador M.
      • et al.
      Clinical implementation of a new electronic brachytherapy system for skin brachytherapy.
      ], compact and dedicated specifically for skin BT. It has a 69.5 kV electronic source and a dose gradient that is slightly shallower (8% per mm) than with Leipzig™, Valencia™ and Axxent™ systems (12% per mm). The dose rate allows for shorter treatment times, lasting approximately one third of the Valencia applicator times. The design of Esteya™ has significantly improved radiation leakage [
      • Ballester-Sánchez R.
      • Pons-Llanas O.
      • Candela-Juan C.
      • et al.
      Electronic brachytherapy for superficial and nodular basal cell carcinoma: a report of two prospective pilot trials using different doses.
      ,
      • Bhatnagar A.
      Non melanoma skin cancer treated with electronic brachytherapy: results at 1 year.
      ,

      Bhatnagar A. Electronic brachytherapy for the treatment of non-melanoma skin cancer: results up to 5 years. In: Proceedings of the 73th annual meeting of the American Academy of Dermatology; 2015 march 20–24; San Francisco, USA.

      ,

      Dogget S, Willoughby M, Mafong E et al. Electronic brachytherapy for non-melanoma skin cancer: report of first 565 lesions. In: Proceedings of the 73th annual meeting of the American Academy of Dermatology; 2015 march 20–24; San Francisco, USA.

      ,

      Strimling RB, Jones CL, Schaeffer J et al. Initial experience of electronic brachytherapy for the treatment of 494 non-melanoma skin cancer (NMSC) lesions in 297 patients. In: Proceedings of the 73th annual meeting of the American Academy of Dermatology; 2015 march 20–24; San Francisco, USA.

      ,
      • Paravati A.J.
      • Hawkins P.G.
      • Martin A.N.
      • et al.
      Clinical and cosmetic outcomes in patients treated with high-dose-rate electronic brachytherapy for nonmelanoma skin cancer.
      ,
      • Goyal U.
      • Kim Y.
      • Tiwari H.A.
      • Witte R.
      • Stea B.
      A pilot study of ultrasound-guided electronic brachytherapy for skin cancer.
      ] (see separate file for table).
      • Superficial radionuclide or electronic based shielded applicators are indicated mainly for small volume lesions on regular surfaces.
      • They always must be in complete contact with the surface, fixed without pressing the skin and be immobilized.
      • Dose is usually prescribed to 3–4 mm depth.
      • Skin high frequency ultrasound of the lesion or surgical bed to define the depth of CTV is recommended in skin tumours.

      Interstitial brachytherapy

      Interstitial BT is indicated in cases when other radiotherapy techniques, including surface BT, are not suitable for a good dose coverage of the tumour, in particular, when the thickness is more than 5 mm and/or the tumour is in curved surfaces as in the face. The implantation procedure requires general or local anaesthesia. Often the flexible implant tubes are inserted using rigid introducers, 8–12 mm apart, and secured by fixation buttons or sutured to the skin (Fig. 2). Some authors use rigid metallic needles. Definition of the catheter positions follows the rules of the Paris system that in HDR and PDR becomes Stepping Source Dosimetry System (SSDS) [

      Van der Laarse R, De Boer R. Computerized high dose rate brachytherapy treatment planning. Brachytherapy HDR-LDR. In: Proceedings Brachytherapy Meeting: Remote afterloading. State of the Art. Ed. Martinez, Orton and Mould; 1990, pp. 170–183.

      ]. Plastic tubes are the first choice in not plain areas, since they allow a better, more flexible coverage of the target; however, the implant with the metallic needles offer a better and more stable implant geometry. For lesions with a thickness of 10 mm or less, a single-plane implant might be adequate with catheters embedded at half distance within the target. The catheters should be 3–4 mm beneath the skin surface to avoid telangiectasia, skin necrosis, or delayed healing along the source positions. If more than one plane of catheters are needed, separation of at least 5–7 mm should be considered between planes. Sometimes, for dose optimization on the external surface of the target, an additional plane of catheters outside the body can be necessary, adding a tissue equivalent bolus between the catheters in the air and the skin. Individual blocks or distance keepers can minimize the surrounding normal tissue dose.
      • Interstitial brachytherapy is indicated in cases with tumour thickness of 5 mm or more, and in irregular surfaces.
      • Interspace between catheters 8–12 mm. Several planes outside the skin can be used with external fixation adding bolus material in the empty spaces.
      • Catheters must be at least 3 mm under the skin surface to avoid late toxicity.
      • A CT scan with marks is necessary to define the CTV plus margins.
      Figure thumbnail gr2
      Fig. 2Extensive interstitial implant to treat an SCC in the columella.

      BT applications in skin – special considerations

      Nose and ear

      Due to very irregular shape of nose and ear, BT in such locations is often delivered with flexible plastic tubes, custom mould or interstitial technique. With interstitial LDR implants, 60 Gy was defined as the optimal dose [
      • Crook J.M.
      • Mazeron J.J.
      • Marinello G.
      • et al.
      Interstitial iridium 192 for cutaneous carcinoma of the external nose.
      ] with a local control over 96% [
      • Debois J.M.
      Cesium-137 brachytherapy for epithelioma of the skin of the nose: experience with 370 patients.
      ,
      • Ducassou A.
      • David I.
      • Filleron T.
      • Rives M.
      • Bonnet J.
      • Delannes M.
      Retrospective analysis of local control and cosmetic outcome of 147 periorificial carcinomas of the face treated with low-dose rate interstitial brachytherapy.
      ], good aesthetic result over 90% and 2% of complications with no Grade 3 complications. The results of interstitial HDR BT as primary treatments for nasal vestibule carcinomas were compared with surgery [
      • Bussu F.
      • Tagliaferri L.
      • Mattiucci G.
      • et al.
      Comparison of interstitial brachytherapy and surgery as primary treatments for nasal vestibule carcinomas.
      ], without differences in locoregional control and survival; but the functional, aesthetic outcome and the degree of satisfaction of the patients were significantly better following HDR BT, with often superior organ preservation and cosmesis. Computed tomography-based surface mould BT for superficial lesions on irregular surfaces such as nose [
      • Maroñas M.
      • Guinot J.L.
      • Arribas L.
      • et al.
      Treatment of facial cutaneous carcinoma with high-dose rate contact brachytherapy with customized molds.
      ] and ear [
      • Allan E.
      • Stanton A.
      • Pye D.
      • et al.
      Fractionated high dose rate brachytherapy moulds – a precise treatment for carcinoma of the pinna.
      ], is a highly conformal method with good homogeneity, with normal tissue sparing ability in high doses superior to EBRT [
      • Kuncman Ł.
      • Kozłowski S.
      • Pietraszek A.
      • et al.
      Highly conformal CT based surface mould brachytherapy for non-melanoma skin cancers of earlobe and nose.
      ].

      Eyelid

      The gold standard of NMSC of eyelid is surgery with good tumour control and preservation of the functional structures. However, if functional structure preservation is not possible, interstitial BT plays an important role. Often, BT is performed as an implant using LDR or HDR and results in high local control rates. The most common late toxicities are conjunctivitis and kerato-conjunctivitis sac, epilation, eyelid malocclusion, pruritus, burn pain, and pigmentation changes. With LDR, doses of 60 Gy for BCC and 70 Gy for SCC achieved a local control rate over 96% with 18% local side effects (significantly more frequent in recurrent lesions) [
      • Daly N.J.
      • de Lafontan B.
      • Combes P.F.
      Results of the treatment of 165 lid carcinomas by iridium wire implant.
      ,
      • Krengli M.
      • Masini L.
      • Comoli A.M.
      • et al.
      Interstitial brachytherapy for eyelid carcinoma. Outcome analysis in 60 patients.
      ]. HDR BT for eyelid targets was reported in small number of patients with local control rates over 94% [
      • Martinez-Monge R.
      • Gomez-Iturriaga A.
      High dose rate brachytherapy in lower eyelid cancer.
      ,
      • Mareco V.
      • Bujor L.
      • Abrunhosa-Branquinho A.N.
      • et al.
      Interstitial high-dose-rate brachytherapy in eyelid cancer.
      ,
      • Azad S.
      • Chouhary V.
      Treatment results of high dose rate interstitial brachytherapy in carcinoma of eyelid.
      ]. In 2015, a systematic review analysed six publications and concluded that BT is well tolerated, the local control is high (median: 95.2%), the toxicity is acceptable and the functional-cosmetic outcome is good [
      • Frakulli R.
      • Galuppi A.
      • Cammelli S.
      • et al.
      Brachytherapy in non melanoma skin cancer of eyelid: a systematic review.
      ]. Special care needs to be considered when upper outer eyelid is treated due to location of lacrimal glands and late complications with dry eye. Usually eyelid treatment requires internal shielding of the eye. The minimum bolus thickness that is needed to neutralize backscatter, above and below the shielding was 0.5 mm and 1 mm respectively [
      • Lliso F.
      • Granero D.
      • Perez-Calatayud J.
      • Carmona V.
      • Pujades M.C.
      • Ballester F.
      Dosimetric evaluation of internal shielding in a high dose rate skin applicator.
      ]. (see separate file for table).

      Extremities

      NMSC located at extremities represents a clinical challenge in radiotherapy. In areas of poor vascularisation and subjected to constant trauma, such as extremities, radiotherapy may cause prolonged healing, poorly treatable ulcerations and even necrosis, requiring subsequent surgical intervention (anterior tibial locations) or impaired hand function due to risk of radiation damage to tendons, joints and bones. BT can be applied safely over bones or cartilage where traditional EBRT may be less safe [
      • Alam M.
      • Nanda S.
      • Mittal B.B.
      • Kim N.A.
      • Yoo S.
      The use of brachytherapy in the treatment of nonmelanoma skin cancer: a review.
      ]. There are only handful of publications in the literature on the use of BT in NMSC located over extremities. Usually extremities’ locations are included with other sites, and outcomes are analysed together. Leipzig applicators for HDR BT have been used on extremities [
      • Gauden R.
      • Pracy M.
      • Avery A.M.
      • Hodgetts I.
      • Gauden S.
      HDR brachytherapy for superficial non-melanoma skin cancers.
      ], to a total dose of 36 Gy in 3 Gy per fraction given daily over 2 weeks, prescribed to 3–4 mm, and local control in 98% of cases. Grade 2 acute skin toxicity 34% with good or excellent cosmesis in 88%, and late skin hypopigmentation changes in 5%. Customized moulds, on the hand, arm or lower limbs for HDR superficial BT can be made, with total dose ranging from 12 to 50 Gy given in 1–15 fractions [
      • Svoboda V.H.
      • Kovarik J.
      • Morris F.
      High dose-rate microselectron moulds in the treatment of skin tumours.
      ], on the dorsum of the hand and fingers with 40–45 Gy on the skin surface in eight fractions given on 5 consecutive days [
      • Frakulli R.
      • Galuppi A.
      • Cammelli S.
      • et al.
      Brachytherapy in non melanoma skin cancer of eyelid: a systematic review.
      ]. The cosmetic result and preserved hand function are good for most patients [
      • Somanchi B.
      • Stanton A.
      • Webb M.
      • Loncaster J.
      • Alan E.
      • Muir L.T.
      Hand function after high dose rate brachytherapy for squamous cell carcinoma of the skin of the hand.
      ]. Large moulds to cover more than a half the circumference of the forearm (60 Gy in 2 Gy per fraction) [
      • Rudoltz M.S.
      • Perkins R.S.
      • Luthmann R.W.
      • Fracke T.D.
      • Green T.M.
      • Eaglstein N.F.
      • et al.
      High-dose-rate brachytherapy with a custom surface mold to treat recurrent squamous cell carcinomas of the skin of the forearm.
      ] or the hand (50 Gy in 10 fractions, 3 fractions per week) [
      • Fabrini M.G.
      • Perrone F.
      • De Liguoro M.
      • Cionini L.
      High-dose-rate brachytherapy in a large squamous cell carcinoma of the hand.
      ], result in satisfactory cosmetic outcome. Marjolin's ulcer, an aggressive ulcerating form of SCC presenting in an area of previously traumatized, chronically inflamed or scarred skin (40% can occur on the lower limbs) has been treated with 45–47.5 Gy in 10 or 11 fractions [
      • Joslin C.A.
      • Flynn A.
      High dose-rate brachytherapy in the treatment of skin tumours. Chapter 29 p.389 in “Principles and practice of brachytherapy using afterloading systems” by Joslin CAF, Flynn A and Hall EJ.
      ], with poor healing or superficial necrosis. Considerable care is necessary when considering dose fractionation regimes for lower limb locations, and increased fractionation is advised.

      Frail and elder patients

      BT has proven to be effective in the elderly in many application sites. Reported side effects and local control of cancer after BT remain the same regardless of patients’ age [
      • Montemaggi P.
      • Guerrieri P.
      Brachytherapy in the elderly.
      ]. Delishaj et al. retrospectively analysed an elderly group of patients (median age 84 years) with NMSC treated with HDR BT and Valencia™ applicator in 8–10 daily fractions with high compliance for older patients [
      • Delishaj D.
      • Laliscia C.
      • Manfredi B.
      • et al.
      Non-melanoma skin cancer treated with high dose rate brachytherapy and Valencia applicator in elderly patients: a retrospective case series.
      ]. Another fractionation schedule of 42 Gy in 6–7 fractions delivered twice a week (median age 78 years) also proved excellent results and facilitated good compliance [
      • Tormo A.
      • Celada F.
      • Rodríguez S.
      • et al.
      Non melanoma skin cancer treated with HDR Valencia applicator: clinical outcomes.
      ]. Recent ABS report provided a detailed summary of 19 published protocols for skin cancer BT [
      • Ouhib Z.
      • Kasper M.
      • Perez Calatayud J.
      • et al.
      Aspects of dosimetry and clinical practice of skin brachytherapy: the American Brachytherapy Society working group report.
      ], median age of patient’s falls into “elderly” category, and local controls were in the range of 90–100%. A study with Esteya™ applicator showed an effective, simple, safe and comfortable treatment for nodular and superficial BCC in patients with a mean age of 79 years [
      • Ballester R.
      • Pons O.
      • Candela C.
      • et al.
      Efficacy and safety of electronic brachytherapy for superficial and nodular basal cell carcinoma.
      ]. Similar encouraging results in patients treated with electronic BT [
      • Bhatnagar A.
      Non melanoma skin cancer treated with electronic brachytherapy: results at 1 year.
      ]. In general, it is acceptable that more hypofractionated treatments can be used in older and frail patients, even in large size areas, at the cost of reduced cosmetic result.

      Keloids

      BT to prevent keloid formation is effective, especially useful in complex and irregular surfaces. The excision should be as close to the lesion as possible to avoid further damage to surrounding tissues. Catheter(s) needs to be placed at least 4 mm deep from the skin surface and below the approximation sutures. Fixation buttons are used to secure catheter(s) in place. Careful consideration needs to be given to closure the scar over the catheter. If the wound is 4 cm long and/or 3 cm wide, subdermal sutures every 1–2 cm are required to approach the margins and to avoid tension in the skin. Intradermal continuous suture with 4–0 silk is preferable with adhesive reinforced skin closures. CTV definition includes 4 mm around the surgical wound and around the catheter, beyond each of the ends of the scar. The prescribed dose is at 4–5 mm from the center of the source, using dose points optimization. It is very important to start treatment as soon as possible after surgery, if possible 90 min after surgery, and always before 24 h, to avoid the regrowth of the keloid. Different fractionations have been used and there is not a standard recommended schedule [
      • Escarmant P.
      • Zimmermann S.
      • Amar A.
      • et al.
      The treatment of 783 keloid scars by iridium 192 interstitial irradiation after surgical excision.
      ,
      • Arnault J.P.
      • Peiffert D.
      • Latarche C.
      • et al.
      Keloids treated with postoperative iridium 192* brachytherapy: a retrospective study.
      ,
      • De Cicco L.
      • Vischioni B.
      • Vavassori A.
      • et al.
      Postoperative management of keloids: Low-dose-rate and high-dose-rate brachytherapy.
      ,
      • Guix B.
      • Henríquez I.
      • Andrés A.
      • Finestres F.
      • Tello J.I.
      • Martínez A.
      Treatment of keloids by high-dose-rate brachytherapy: a seven-year study.
      ,
      • Garg M.K.
      • Weiss P.
      • Sharma A.K.
      • et al.
      Adjuvant high dose rate brachytherapy (Ir-192) in the management of keloids which have recurred after surgical excision and external radiation.
      ,
      • Veen R.E.
      • Kal H.B.
      Postoperative high-dose-rate brachytherapy in the prevention of keloids.
      ,
      • Arneja J.S.
      • Singh G.B.
      • Dolynchuk K.N.
      • et al.
      Treatment of recurrent earlobe keloids with surgery and high-dose-rate brachytherapy.
      ,
      • Van Leeuwen M.C.
      • Stokmans S.C.
      • Bulstra A.E.
      • et al.
      High-dose-rate brachytherapy for the treatment of recalcitrant keloids: a unique, effective treatment protocol.
      ,
      • Jiang P.
      • Baumann R.
      • Dunst J.
      • et al.
      Perioperative interstitial high-dose-rate brachytherapy for the treatment of recurrent keloids: feasibility and early results.
      ,
      • Hafkamp C.J.
      • Lapid O.
      • Dávila Fajardo R.
      • et al.
      Postoperative single-dose interstitial high-dose-rate brachytherapy in therapy-resistant keloids.
      ]. A systematic review of published papers [
      • van Leeuwen M.C.
      • Stokmans S.C.
      • Bulstra A.E.
      • et al.
      Surgical excision with adjuvant irradiation for treatment of keloid scars: a systematic review.
      ] showed that the mean total radiation dose for studies investigating external radiation and HDR brachytherapy was the same (external, 13.5 ± 3.3 Gy; HDR, 13.7 ± 2.6 Gy) and higher when using LDR brachytherapy (19.3 ± 1.2 Gy). HDR brachytherapy was associated with the lowest mean recurrence rate (HDR: 10.5 ± 15%; LDR: 21.3 ± 2.1%; external: 22.2 ± 16%) (Table 1)
      • Keloids are effectively managed with HDR BT placing a single catheter during the surgery.
      • The catheter must be at least 4 mm under the skin.
      • Dose prescription 4–5 mm from the source.
      • Start as soon as possible, the first session should be on the same day as surgery.
      • Doses of 5–6 Gy × 3 fractions or 5 Gy × 4 fractions are recommended.
      Table 1Results of Brachytherapy in keloids.
      AuthorYearN. lesionsDose rateDose × fractionsPrescriptionTotal doseStart sessionFollow up (months)Local control
      Escarmant P et al.
      • Escarmant P.
      • Zimmermann S.
      • Amar A.
      • et al.
      The treatment of 783 keloid scars by iridium 192 interstitial irradiation after surgical excision.
      1993570LDR5 mm20 Gy<24 h82 months79%
      Arnault JP et al.
      • Arnault J.P.
      • Peiffert D.
      • Latarche C.
      • et al.
      Keloids treated with postoperative iridium 192* brachytherapy: a retrospective study.
      200955LDR5 mm18 GyWithin 7 h84 months76.4%
      De Cicco L et al.
      • De Cicco L.
      • Vischioni B.
      • Vavassori A.
      • et al.
      Postoperative management of keloids: Low-dose-rate and high-dose-rate brachytherapy.
      201446

      50
      LDR

      HDR


      4Gy × 3
      16 Gy

      12 Gy
      <24 h69.6%

      62%
      Guix B et al.
      • Guix B.
      • Henríquez I.
      • Andrés A.
      • Finestres F.
      • Tello J.I.
      • Martínez A.
      Treatment of keloids by high-dose-rate brachytherapy: a seven-year study.
      2001147 periop

      22 radical
      HDR5 Gy × 4

      5 Gy × 6
      4 mm20 Gy

      30 Gy
      Within 1 h, 3times a day8496.6%

      86.4%
      Garg MK et al.
      • Garg M.K.
      • Weiss P.
      • Sharma A.K.
      • et al.
      Adjuvant high dose rate brachytherapy (Ir-192) in the management of keloids which have recurred after surgical excision and external radiation.
      200417 recurrences after RTHDR5 Gy × 310 mm15 Gy<24 h

      Twice a day
      2688%
      Veen RE et al.
      • Veen R.E.
      • Kal H.B.
      Postoperative high-dose-rate brachytherapy in the prevention of keloids.
      20079

      38

      7
      HDR4 Gy + 3 Gy × 2

      6 Gy + 4 Gy × 2

      6 Gy × 3
      10 Gy

      14 Gy

      18 Gy
      Within 6 h55%

      97%

      100%
      Arneja JS et al.
      • Arneja J.S.
      • Singh G.B.
      • Dolynchuk K.N.
      • et al.
      Treatment of recurrent earlobe keloids with surgery and high-dose-rate brachytherapy.
      200825 earHDR5 Gy × 33–6 mm15 Gy<24 h

      Twice a day
      3692%
      VanLeeuwen MC et al.
      • Van Leeuwen M.C.
      • Stokmans S.C.
      • Bulstra A.E.
      • et al.
      High-dose-rate brachytherapy for the treatment of recalcitrant keloids: a unique, effective treatment protocol.
      201467HDR6 Gy × 212 GyWithin 4 h and 24 h3396.9%
      Jiang P et al.
      • Jiang P.
      • Baumann R.
      • Dunst J.
      • et al.
      Perioperative interstitial high-dose-rate brachytherapy for the treatment of recurrent keloids: feasibility and early results.
      201632HDR6 Gy × 35 mm18 Gy<24 h

      Twice a day
      2994%
      Hafkamp CJ et al.
      • Hafkamp C.J.
      • Lapid O.
      • Dávila Fajardo R.
      • et al.
      Postoperative single-dose interstitial high-dose-rate brachytherapy in therapy-resistant keloids.
      201729HDR13 Gy × 113 Gy<24 h5375.9%

      Brachytherapy dose calculation and planning

      Most current treatment planning systems used for BT dose calculation are based on American Association of Physics in Medicine (AAPM) TG-43 dosimetric parameters where scatter defect is not considered [
      • Rivard M.J.
      • Coursey B.M.
      • DeWerd L.A.
      • et al.
      Update of AAPM task group No. 43 Report: a revised AAPM protocol for brachytherapy dose calculations.
      ]. Differences at the prescription depth, between TG-43 and Monte Carlo calculations, were negligible for Ir-192, therefore no bolus over the mould is required. The Freiburg™ flap is composed of small spheres or ‘‘pellets’’, the scatter defect plus interpellet air gap effect is smaller than 5%. In surface HDR BT with mould/flaps, a lead shield covering the implants reduce dose to radiosensitive organs, then, the backscatter overdose can be avoided by just adding a few mm of bolus to the lead [
      • Lliso F.
      • Granero D.
      • Perez-Calatayud J.
      • Carmona V.
      • Pujades M.C.
      • Ballester F.
      Dosimetric evaluation of internal shielding in a high dose rate skin applicator.
      ]. The Leipzig™ and Valencia™ applicators are equipped with an attachable plastic cap to be placed during fraction delivery to prevent secondary electrons from reaching the skin surface. Users must check always that the plastic cap is in place because if the cap is not used, the skin dose is 2.5 and 10 times higher for the Valencia™ and Leipzig™ applicators respectively [
      • Granero D.
      • Candela-Juan C.
      • Vijande J.
      • et al.
      Technical Note: Dosimetry of Leipzig and Valencia applicators without the plastic cap.
      ].
      The ABS report includes some treatment planning and clinical practice recommendations and there is a specific section dedicated to recommendations in commissioning and QA [
      • Ouhib Z.
      • Kasper M.
      • Perez Calatayud J.
      • et al.
      Aspects of dosimetry and clinical practice of skin brachytherapy: the American Brachytherapy Society working group report.
      ]. The AAPM joined with the European Society for Therapeutic Radiation and Oncology (ESTRO) have in progress a Task Group (TG-253) to include recommendations for quality management. In an interstitial implant, the PTV equals the CTV. Expansion of at least 5 mm from GTV to CTV is required in cases of superficial applicators. For radionuclide-based BT and electronic BT applicators, an extra margin of approximately 1–2 mm (PTV) should be added to account for any misalignment. Excellent results are obtained comparing electronic BT and Mohs surgery [
      • Patel R.
      • Strimling R.
      • Doggett S.
      • et al.
      Comparison of electronic brachytherapy and Mohs micrographic surgery for the treatment of early-stage non-melanoma skin cancer: a matched pair cohort study.
      ]. A very useful method for applicators setup is the use of templates, as the template La Fe/ITIC™ for the superficial shielded applicators [
      • Villalba S.R.
      • Perez-Calatayud J.
      • Bautista J.A.
      • et al.
      Novel simple templates for reproducible positioning of skin applicators in brachytherapy.
      ]. Once the GTV is drawn, with graduated rules, it is possible to select the applicator size according the required margin taking into account the useful beam. An air gap between the applicator and the skin surface can result in significant underdosage. Too much pressure on the applicator can cause tissue compression resulting in possible overdosage or hypoxic change to the target tissue. Additional shielding might be necessary over the eyes, inside the lip, or in the nasal cavity with appropriate lead thickness and paraffin (or other bolus material). Currently, most users are relying on hand calculation or a library plan for the dose distribution for the Leipzig™ and Valencia™ applicators, a phantom generated plan for these applicators, that does not use CT data.
      In interstitial BT and surface moulds, CT imaging is the recommended standard for reconstruction of catheters and the target area, using CT wire markers with minimal distortion to define the target at surface. The CT images should be contiguous and no more than 2-mm thick in the axial plane for good target and catheter reconstruction. High-resolution US systems with frequency transducers preferably higher than 18 MHz are recommended for cutaneous lesions as they provide better detail of the skin surface, but there is some uncertainty for tumours smaller than 3 mm. Dermoscopy can detect more accurately the lateral borders in BCCs than clinical examination alone [
      • Caresana G.
      • Giardini R.
      Dermoscopy-guided surgery in basal cell carcinoma.
      ].
      Recommended margins for prescription in NMSC (CTV):
      • BCC 5 mm margin for well defined lesions, 7–10 mm margin for poorly defined, large, infiltrative, morphoeic and/or sclerotic types of BCC.
      • SCC at least 10 mm margin, if the lesion is <20 mm it is necessary to add a margin of 10–15 mm, for lesions >20 mm the margin of 15–20 mm is usually required (NCCN squamous cells cancer guidelines 2016 version 1).
      • Merkel cell carcinoma: at least 20–30 mm peripheral margin, deep margin at least 5–10 mm below visible extension (by imaging).
      • Post-operative cases: whole surgical site to be included. Peripheral and deep margins as per histopathology report from surgery.
      • An extra margin is needed (PTV) to account for any misalignment for radionuclide and electronic based shielded applicators and for flaps.

      Brachytherapy doses and fractionation

      With LDR the prescribed dose was 60 Gy at the 85% reference isodose, covering the minimum target dose (peripheral dose), at dose rates between 45–70 cGy/h to be delivered in 4–6 days. Although doses up to 70 Gy were given in some large tumours, without unacceptable sequelae, the increase in cosmetic damage was greater than the gain in local control expected from a dose increase above 60 Gy. With PDR similar doses to LDR are recommended. With interstitial HDR BT, high dose per fraction is used, twice a day, separated at least 6 h between fractions. With PDR similar doses are recommended. In case of PDR/HDR because the SSDS system, the reference isodose is 90%. Depending on the volume to be treated and the organs at risk, the chosen dose per fraction is between 2.5 and 4 Gy, in order to finish the treatment in one–two weeks.
      When using contact BT, the schedule is similar to electron beam, and 3–5 Gy per fraction 2–3 days per week in 4–5 weeks is effective [
      • Montero A.
      • Hernanz R.
      • Capuz A.B.
      • et al.
      High-dose-rate (HDR) plesiotherapy with custom-made moulds for the treatment of non-melanoma skin cancer.
      ]. In large areas such as scalp, 2–3 Gy per day fractionation is preferable [
      • Ozyar E.
      • Gurdalli S.
      Mold brachytherapy can be an optional technique for total scalp irradiation.
      ,
      • Semrau S.
      • Kunz M.
      • Baggesen K.
      • et al.
      Successful treatment of field cancerization of the scalp by surface mould brachytherapy.
      ,
      • Wittych J.
      • Banatkiewicz P.
      • Wachowicz M.
      Angiosarcoma of the scalp: a case report.
      ]. In small epithelial tumours, 5–7 Gy per fraction 2–3 days per week can be recommended [
      • Alam M.
      • Nanda S.
      • Mittal B.B.
      • Kim N.A.
      • Yoo S.
      The use of brachytherapy in the treatment of nonmelanoma skin cancer: a review.
      ]. For old and fragile patients, higher doses per fraction, 9–10 Gy but only once a week have been used, even a single dose of 20 Gy. With skin surface applicators the chosen dose is 5 Gy × 8 fractions or 7 Gy × 6 fractions twice a week [
      • Ballester-Sánchez R.
      • Pons-Llanas O.
      • Candela-Juan C.
      • et al.
      Electronic brachytherapy for superficial and nodular basal cell carcinoma: a report of two prospective pilot trials using different doses.
      ]. In cases of very thin skin or with underlying cartilage, such as the nose, lower doses per fraction probably allow better cosmetic long-term results [
      • Arenas M.
      • Arguis M.
      • Diez-Presa L.
      • et al.
      Hypofractionated high-dose-rate plesiotherapy in nonmelanoma skin cancer treatment.
      ]. No clear recommendations can be made due to the great variety of published schedules and the prescribed dose is based more on experience that on evidence [
      • Likhacheva A.O.
      • Devlin P.M.
      • Shirvani S.M.
      • et al.
      Skin surface brachytherapy: a survey of contemporary practice patterns.
      ,

      Guinot JL, Perez-Calatayud J, van Limbergen E. The GEC-ESTRO Handbook of Brachytherapy 2nd edition. Chapter 31: Skin cancer brachytherapy. DOVE platform ESTRO.

      ]. The total dose depends on the chosen dose per fraction. Some extra fraction can be added with gross tumour, or can be reduced in postoperative indications. Commonly used regimens are presented in Table 2.
      Table 2Different effective doses and fractionation for superficial brachytherapy.
      AuthorYearN. patientsN. FractionsDose per fractionTotal doseDays per weekFractions per dayPrescriptionApplicator
      Svoboda et al.
      • Svoboda V.H.
      • Kovarik J.
      • Morris F.
      High dose-rate microselectron moulds in the treatment of skin tumours.
      1995130120 Gy20 Gy11SurfaceMould
      39–10 Gy27–30 Gy11SurfaceMould
      104 Gy40 Gy51SurfaceMould
      Guix et al.
      • Guix B.
      • Finestres F.
      • Tello J.I.
      • et al.
      Treatment of skin carcinomas of the face by high-dose-rate brachytherapy and custom-made surface molds.
      200013633–361.8 Gy59.4–64.8 Gy515 mmMould
      Skowronek et al.
      • Skowronek J.
      • Chichel A.
      • Piotrowski T.
      HDR brachytherapy of skin cancer - the Wielkopolski Cancer Centre’s experience.
      2005179510 Gy50 Gy115 mmMould/flap
      125 Gy60 Gy215 mmMould/flap
      Maroñas et al.
      • Maroñas M.
      • Guinot J.L.
      • Arribas L.
      • et al.
      Treatment of facial cutaneous carcinoma with high-dose rate contact brachytherapy with customized molds.
      20115111 or 124 Gy44–48 Gy313 mmMould/flap
      183 Gy54 Gy313 mmMould
      57 Gy35 Gy213 mmMould
      Arenas et al.
      • Arenas M.
      • Arguis M.
      • Diez-Presa L.
      • et al.
      Hypofractionated high-dose-rate plesiotherapy in nonmelanoma skin cancer treatment.
      201513173 Gy51 Gy315 mmMould
      Allan et al.
      • Allan E.
      • Stanton A.
      • Pye D.
      • et al.
      Fractionated high dose rate brachytherapy moulds – a precise treatment for carcinoma of the pinna.
      19982885–5.5 Gy40–44 Gy522–3 mmMould
      RembielakUnpublished data84.7–5 Gy37.6–40 Gy425 mmMould
      Arenas et al.
      • Arenas M.
      • Arguis M.
      • Diez-Presa L.
      • et al.
      Hypofractionated high-dose-rate plesiotherapy in nonmelanoma skin cancer treatment.
      201510115–193 Gy45–57 Gy313–5 mmLeipzig
      Köhler-Brock et al.
      • Köhler-Brock A.
      • Prager W.
      • Pohlmann S.
      • Kunze S.
      The indications for and results of HDR afterloading therapy in diseases of the skin and mucosa with standardized surface applicators (the Leipzig applicator).
      199952085 Gy40 Gy216–8 mmLeipzig
      310 Gy30 Gy116–8 mmLeipzig
      Ghaly et al.
      • Ghaly M.
      • Byrnes R.
      • Zinkin H.
      • et al.
      Role of HDR brachytherapy with standardized surface applicators in the treatment of superficial malignant skin lesions.
      20086785 Gy40 Gy21VariableLeipzig
      Gauden et al.
      • Gauden R.
      • Pracy M.
      • Avery A.M.
      • Hodgetts I.
      • Gauden S.
      HDR brachytherapy for superficial non-melanoma skin cancers.
      2013236123 Gy36 Gy513–4 mmLeipzig
      Tormo et al.
      • Tormo A.
      • Celada F.
      • Rodríguez S.
      • et al.
      Non melanoma skin cancer treated with HDR Valencia applicator: clinical outcomes.
      2014786–76–7 Gy42 Gy213–4 mmValencia
      Delishaj et al.
      • Delishaj D.
      • Laliscia C.
      • Manfredi B.
      • et al.
      Non-melanoma skin cancer treated with high dose rate brachytherapy and Valencia applicator in elderly patients: a retrospective case series.
      20158485 Gy40 Gy2 or 313–4 mmValencia
      It has been proposed to express these doses in Biological Equivalent Dose (BED), but the total time of treatment is variable, therefore BED is not a useful tool to compare different duration schemes, but in interstitial treatments. Take into account that in surface treatments, the doses to the skin surface are always higher than the prescribed dose, and they can change depending on the bolus width and the depth of prescription. If the dose gradient is considered, the biological effect is still higher [
      • Hannoun-Levi J.M.
      • Chand-Fouche M.E.
      • Dejean C.
      • Courdi A.
      Dose gradient impact on equivalent dose at 2 Gy for high dose rate interstitial brachytherapy.
      ]. A study of these variables is mandatory to achieve a consensus on the ideal doses required in skin surface BT. Meanwhile the dose on the skin surface should be recorded to correlate the outcome with late side effects.
      • Recommended BT schedules for surface moulds and flaps:
      • o
        3 Gy per fraction, 17–18 fractions, 3 times a week, total dose 51–54 Gy.
      • o
        4 Gy per fraction, 10–12 fractions, 3 times a week, total dose 40–48 Gy.
      • o
        5 Gy per fraction, 10–12 fractions, twice a week, total dose 50–60 Gy.
      • o
        5 Gy per fraction, 8 fractions, twice a day, daily, total dose 40 Gy.
      • o
        Higher doses per fraction, once a week.
      • For Leipzig applicator
      • o
        3 Gy per fraction, 17–18 fractions, 3 times a week, total dose 51–54 Gy.
      • o
        5 Gy per fraction, 8 fractions, twice a week, total dose 40 Gy.
      • o
        10 Gy per fraction, 3 fractions, once a week, total dose 30 Gy.
      • For Valencia, Esteya and Xoft applicator
      • o
        7 Gy per fraction, 6 fractions, twice a week, total dose 42 Gy.
      • o
        5 Gy per fraction, 8–10 fractions twice a week, total dose 40–50 Gy.

      Conclusions

      • (a)
        Available data confirm that brachytherapy is an efficient and well tolerated treatment that offers excellent cosmesis and low toxicity for skin cancer patients. Variety of available skin BT schedules offers options of shorter overall length of the treatment, with better patience compliance, particularly in the elderly group, the vast majority of patients treated with skin BT.
      • (b)
        Carefully tailored BT is a good alternative, if not the treatment of choice for those lesions that cannot be safely removed by surgery.
      • (c)
        The majority of publications in the field of skin BT is single institution and involves a relatively small number of patients. Despite very promising results, randomized controlled trials, systemic reviews and meta-analysis are lacking in literature.
      • (d)
        HDR and PDR can be used in interstitial implants twice daily, usually 2.5–4 Gy per fraction, or 0.8–1 Gy per pulse in PDR technique.
      • (e)
        In skin tumours with a depth of <5 mm, non-invasive contact BT through flaps, moulds, superficial radionuclide or electronic based shielded applicators without anaesthesia are effective.
      • (f)
        In small size tumours, Leipzig™, Valencia™ applicators or electronic devices yield excellent results with high doses per fraction (5–7 Gy) delivered once or twice a week.
      • (g)
        In extensive flat lesions, flaps or customized moulds with embedded or taped plastic tubes at a distance from skin of at least 3–5 mm to avoid overdose on the skin, can be used at 3–5 Gy per fraction daily or every other day.
      • (h)
        No standard schedule can be recommended and total doses are based on experience. The dose on the skin surface should be recorded to correlate the outcome with late side effects.

      Disclaimer

      ESTRO cannot endorse all statements or opinions made on the guidelines. Regardless of the vast professional knowledge and scientific expertise in the field of radiation oncology that ESTRO possesses, the Society cannot inspect all information to determine the truthfulness, accuracy, reliability, completeness or relevancy thereof. Under no circumstances will ESTRO be held liable for any decision taken or acted upon as a result of reliance on the content of the guidelines.
      The component information of the guidelines is not intended or implied to be a substitute for professional medical advice or medical care. The advice of a medical professional should always be sought prior to commencing any form of medical treatment. To this end, all component information contained within the guidelines is done so for solely educational and scientific purposes. ESTRO and all of its staff, agents and members disclaim any and all warranties and representations with regard to the information contained in the guidelines. This includes any implied warranties and conditions that may be derived from the aforementioned guidelines.

      Conflict of interest

      The authors declare that they have no competing interests.
      None of the authors has any financial and personal relationships with other people or organisations that could inappropriately influence (bias) of this work.

      Appendix A. Supplementary data

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