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Department of Biochemistry, Florida Atlantic University College of Medicine, Boca Raton, FLDepartment of Dermatology, Florida Atlantic University College of Medicine, Boca Raton, FL
Nonmelanoma skin cancers (NMSCs) are the most common type of human malignancy. Although surgical techniques are the standard treatment, radiation therapy using photons, electrons, and brachytherapy (BT) (radionuclide-based and electronic) has been an important mode of treatment in specific clinical situations. The purpose of this work is to provide a clinical and dosimetric summary of the use of BT for the treatment of NMSC and to describe the different BT approaches used in treating cutaneous malignancies.
Methods and Materials
A group of experts from the fields of radiation oncology, medical physics, and dermatology, who specialize in managing cutaneous malignancies reviewed the literature and compiled their clinical experience regarding the clinical and dosimetric aspects of skin BT.
Results
A dosimetric and clinical review of both high dose rate (192Ir) and electronic BT treatment including surface, interstitial, and custom mold applicators is given. Patient evaluation tools such as staging, imaging, and patient selection criteria are discussed. Guidelines for clinical and dosimetric planning, appropriate margin delineation, and applicator selection are suggested. Dose prescription and dose fractionation schedules, as well as prescription depth are discussed. Commissioning and quality assurance requirements are also outlined.
Conclusions
Given the limited published data for skin BT, this article is a summary of the limited literature and best practices currently in use for the treatment of NMSC.
). Although NMSC has a low mortality rate, its incidence continues to rise and it significantly affects quality of life. The most common histology of NMSC is basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).
The primary goals of any treatment of NMSC are to cure the lesion with preservation of function and to optimize cosmesis. Treatment options include surgery, radiation therapy, and topical agents, with surgical techniques such as Mohs micrographic surgery, electrodessication, and curettage being the most frequently used. Historically and at present, radiation therapy has an important role in the management of NMSC as outlined in the following sections, especially in functional preservation.
A variety of radiation therapy techniques have been used to treat NMSC. These techniques include superficial x-rays (which have largely been supplanted by more advance techniques), orthovoltage x-rays, megavoltage x-rays, electron beam irradiation, and radionuclide-based brachytherapy (BT). Electronic brachytherapy (eBT) is a newer technology administering high-dose-rate (HDR) BT with the use of a low energy x-ray source and therefore requires minimal shielding (
The indications for and results of HDR afterloading therapy in diseases of the skin and mucosa with standardized surface applicators (the Leipzig® Applicator).
The goal of this report is to provide a review of the dosimetry and clinical aspects of NMSC skin BT. It provides an overview of the typical BT modalities for NMSC including a standard reference for treatment planning and prescription. Skin BT including eBT should be performed only by authorized users (AUs) and qualified medical physicists (QMPs) as defined by agreement states and federal regulatory agencies. These regulations may vary from one state to another, and it is the responsibility of the institution to adhere to the local requirements. Individuals without such training, credentials, or with jurisdictional scope of practice limitations should not be performing this procedure.
Surface applicators have been used in radiotherapy because the turn of the 20th century. Applicators such as wax and paraffin skin custom molds were developed and used with radium needles or radon seeds to cure skin cancer (
The introduction of teletherapy and concerns over radiation exposure from BT had a negative impact on the use of BT, and a generation of radiation oncologists had limited exposure to BT in managing skin cancer.
Over the past 40 years, radiotherapy for NMSC has largely consisted of superficial and orthovoltage x-rays and electron beam therapy. Electron beam therapy often requires templates and lead cutouts, the construction of which can be messy and uncomfortable for the patient when using skin collimation for a better dose coverage. When using this modality, output factors and percent depth dose (PDD) measurements need to be performed. This entire process can be time consuming and cumbersome for the department. Moreover, if collimation is done at a distance from the skin, penumbra should be considered. Typically, additional collimation at skin with lead inserts is required to improve penumbra. In the treatment of small fields, electron dosimetry requires special attention because the PDD and output change significantly according to the specific block shape and size. HDR BT, despite the more heterogeneous dose distribution, presents several advantages, particularly for irregular surfaces and challenging setups.
With the incorporation of HDR BT and remote afterloaders in the 1960s, there has been a renewed interest in BT for cutaneous malignancies. Reports of older published series mainly done in European facilities with wide experience in BT showing efficacy in treating skin cancer (
) has led to recent interest and growth in new techniques. Several innovative applicators have been introduced to the BT community, and the use of skin BT has significantly increased (
The primary tools available to evaluate NMSC lesions are (1) clinical history, (2) clinical examination, and (3) histopathologic classification.
1.
Clinical history: Clinical history should include prior treatment of the area or other cutaneous malignancies, medical conditions rendering a relative (such as collagen vascular disease), or absolute (genodermatoses such as basal cell nevus syndrome or xeroderma pigmentosum) contraindication.
2
Clinical examination: Clinical examination should be performed to choose the correct treatment option for the lesion. In lesions in which boundaries are not well defined, additional scouting skin biopsies (usually shave or punch) are useful methods to gauge lateral extent. The lesion should be palpated and moved to determine if there is significant extension into the subcutaneous fat or if the tumor is fixed to deeper structures. Palpation of the regional lymph node drainage sites should be performed. Also critical is the evaluation of the surface to be treated (flat or curved, regular, or irregular) and measurement of the lesion in the case of macroscopic tumor or the scar in patients after surgery (Fig. 1). Pretreatment and posttreatment photographs should be part of the medical records.
Fig. 1(a) SCC on a flat surface, 40 × 30 × 7 mm and (b) BCC lesion operated on (with affected margins). Treatment of the surgical bed (25 × 10 × 7 mm) based on ultrasound imaging. (c) BCC lesion on the nose, 5 × 4 × 2 mm nose, and eye shields (lead coated with bolus material) used to reduce dose to inner nose structure and transient dose to the eye. SCC = squamous cell carcinoma; BCC = basal cell carcinoma.
Histopathologic classification: It is essential to have a definitive pathology report. The report classifies the tumor in specific terms including the relevant subtypes. Understanding the biologic behavior of subtypes will guide treatment. The goal is to estimate the risk for significant subclinical extension (
BCC and SCC of the skin are usually found while still small and with little potential of metastatic spread. For this reason, patients usually do not require staging, blood work, or imaging tests. In the presence of high-risk features, including tumor thickness of greater than 4 mm, diameter greater than 20 mm, tumor invasion into the lower dermis, perineural invasion, lymphovascular invasion, aggressive histology such as moderate or poor differentiation, or tumor involving high-risk sites such as the scalp, lip, ear, eyelids, and nose, staging may be done. The American Joint Committee on Cancer and TNM (Table 1) system is generally used (
The selection of the appropriate applicator for adequate dose coverage depends on the dimensions of the planning target volume (PTV), and therefore, appropriate imaging, as described in the following sections, may be helpful. During the last decade, advances in noninvasive skin imaging techniques have produced new cutaneous imaging modalities, which vary in resolution, depth of image, and in their ability to provide useful information. MRI and CT of the skin produce transverse images of the full thickness of the skin and the underlying support structures. Although there is no significant detail about skin structure, CT and MR may be helpful for more extensive lesions, particularly when bone involvement is suspected, as an aid for extensive dermatologic surgeries, or in tracking nerves in cases of perineural invasion.
High-frequency conventional ultrasound (US), in the range of 10–50 MHz, provides higher resolution of the skin structure and can give some estimate of tumor depth, length, and width (
). However, US has not been demonstrated to be a reliable predictor either of tumor extent or of tumor clearance and should be considered an investigational tool with skin BT (
Test characteristics of high-resolution ultrasound in the preoperative assessment of margins of basal cell and squamous cell carcinoma in patients undergoing Mohs micrographic surgery.
Fig. 2Nodular lesion imaged with high-resolution B-scan Siemens Ultrasound unit with 18 MHz hand-held transducer. A 2 × 9 cm gel pad was applied over the skin to enhance the air–skin interface.
The two most promising tools for skin cancer imaging, optical coherence tomography and confocal microscopy (CM), use infrared light. Optical coherence tomography provides skin penetration of 1–2 mm with near-cell resolution, whereas CM also provides excellent subcellular resolution although with depth limited to the superficial dermis only. CM may be particularly useful for determination of lateral tumor extent. Light sources for both take advantage of the cutaneous “optical window” between 600 and 1300 nm and rely on changes in the optical properties of skin components to provide endogenous contrast. The two tools are complementary, and although promising, they are not readily available for clinical use (
Surgical and ablative techniques remain the primary management option of small SCC and BCC, especially when occurring on areas of skin allowing uncomplicated excision. Radiotherapy is used primarily in four clinical situations:
1.
Primary treatment of tumor after biopsy.
2.
Adjuvant treatment of excised lesions with close or positive surgical margins.
Radiotherapy is effective in both small (≤20 mm) and large (>20 mm) tumors and therefore is an appropriate alternative to surgery. It is particularly well suited in lesions of the nose, lips, and ears, especially when it is unclear how extensive the surgical defect will be or how complicated the reconstruction will be. In many of these cases, tissue preservation might be better with radiotherapy, thereby enhancing cosmesis and possibly function. If tumor boundaries are in question, additional margins should be used to ensure local control.
In addition, radiotherapy is an alternative for patients who are at high surgical risk, who have significant comorbidities and wish to avoid surgery, and for healthy patients who are simply reluctant about surgery.
Patients with other nonmelanomatous histopathologies including primary cutaneous lymphoma and Kaposi sarcoma have also been treated with BT (HDR or electronic BT) (
Complete response of endemic Kaposi sarcoma lesions with high-dose-rate brachytherapy: treatment method, results, and toxicity using skin surface applicators.
Gross tumor volume (GTV): volume discernible by either imaging or clinical observation.
2.
Clinical target volume (CTV): expansion of the GTV to account for possible tumor extent uncertainty due to microscopic extension and contouring variability.
3.
PTV: expansion of the CTV for geometric uncertainty due to setup variation and organ motion.
In determining adequate radiotherapy treatment margins, minimal surgical recommendations should be considered. Broadland and Zitelli (
) recommend 4 mm for low-risk and 6 mm for high-risk lesions as a minimum margin necessary to achieve 95% or greater tumor clearance by Mohs surgery.
PTV derivation from CTV has been controversial in BT. It seems logical that in an interstitial implant, the PTV equals the CTV, assuming that catheters have been repositioned to their original location before each treatment. Expansion from CTV to PTV to account for the greater setup uncertainty is recommended in cases of superficial lesions using radionuclide based or eBT, custom molds, or flaps applicators (Fig. 3). To ensure adequate dose coverage at the margins, additional catheters should be used at the edges or beyond the PTV (5 to 10.0 mm). An additional setup margin from CTV to PTV of 5 mm is acceptable.
Fig. 3Target delineation with CTV and PTV with 1-cm margin. CTV = clinical target volume; PTV = planning target volume.
For radionuclide-based BT and eBT applicators, an extramargin of approximately 2 mm should be added to account for any misalignment. Once defined, the PTV or CTV should be completely encompassed by the reference isodose, that is, the dose to 100% (D100) of the PTV (superficial implants) or CTV (interstitial implants) equal to the prescription dose. In addition, the penumbra for each applicator should be considered. Note that clinical judgment must be the final determinant in margin delineation as anatomic limitations may require compromise in these standard treatment margins. It is quite common for NMSC patients who are referred to radiation oncology to have lesions in cosmetically sensitive or critical anatomic locations (nasal tip, canthus, and eyelid) where it is not physically possible to allow for margins as suggested previously. Whenever possible, these recommendations should be followed and serve as the desired goal to delineate the PTV when treating with skin BT.
The following is an example (Fig. 4) to illustrate appropriate margins and applicator selection based on a given lesion dimensions and depth:
Fig. 4Lesion of 1 cm showing structures, depth, margins, and dose coverage. CTV = clinical target volume; GTV = gross target volume; PTV = planning target volume.
GTV size = 10 mm diameter; lesion measured depth = 2 mm.
Using a lateral expansion of 5 mm from the GTV, the CTV diameter becomes:
10 + (2 × 5) = 20 mm.
By expanding, the CTV for setup errors by 1.5 mm (lateral direction) will give us a PTV of: 20 + (1.5 × 2) = 23 mm.
In addition, a margin of 1 mm for depth uncertainty should be considered, which will result in a depth of: 2 + 1 = 3 mm.
Applicator selection: based on these dimensions (diameter and depth) and the atlas of dose profiles (provided by the manufacturer and confirmed at time of commissioning), the selection of the 30-mm applicator will be reasonable for use.
The margin should be 5 mm for BCC and 7–10 mm for SCC around the macroscopic lesion when feasible (
). When the surgical bed is treated for possible microscopic disease, at least 10 mm around the scar is usually chosen. Clinical judgment should be used where margins extend to critical structures.
Contraindications
The absolute contraindications for the use of BT in NMSC are invasion of the bone (
), genetic diseases such as ataxia-telangiectasia, xeroderma pigmentosa, or other related diseases of DNA repair, suspected extension in the orbit or deep extension along fascial planes and perineural invasion (
The relative contraindications described are collagen vascular diseases, basal cell nevus syndrome, and other diseases where ionizing radiation is inappropriate.
BT in NMSC is usually limited to older patients (>50 years) decreasing possibility of long-term sequelae.
Dose prescription
As shown in Table 2, there is a wide spectrum of fractionation and protraction schemes. Biological equivalent dose (BED) was calculated for each case using the linear quadratic equation. The weekly fractionation varies significantly and was not taken into account in the BED calculations. For typical NMSC without evidence of significant thickness, the standard prescription depth for surface applicators is 3-mm depth. For larger or thicker lesions, imaging techniques can be used to determine the specific depth prescription. In all cases of surface BT, it is very difficult to achieve adequate dose beyond 4–5 mm without unacceptable skin-surface dose.
Table 2Published protocols for skin cancer treatment
HDR brachytherapy with standardized surface applicators (the Leipzig applicator) as an alternative, radiotherapy treatment for superficial malignant skin lesions.
Rodriguez S. High Dose rate brachytherapy in skin cancers: patient convenience, local control and cosmetical results. 12th International Conference “Optimal Use of Advanced Radiotherapy in Multimodality Oncology”. Roma 2007.
The fundamental principles of BT allow for a hypofractionated approach with the advantages of fewer fractions and short treatment duration.
For surface applicators, which include the Leipzig, Valencia, and eBT applicators, common dose prescriptions are 40 Gy/8 fractions and 42 Gy/6 fractions (
HDR brachytherapy with standardized surface applicators (the Leipzig applicator) as an alternative, radiotherapy treatment for superficial malignant skin lesions.
), achieving a BED target of 60–71.4 Gy using alpha:beta ratio values of 3:10 and the linear quadratic equation. The recommended dose prescription for interstitial BT is 30 Gy/10 fx (BID) (
Rodriguez S. High Dose rate brachytherapy in skin cancers: patient convenience, local control and cosmetical results. 12th International Conference “Optimal Use of Advanced Radiotherapy in Multimodality Oncology”. Roma 2007.
). Increased fractionation is rarely used and only for special indications. For both surface applicators and flaps/custom molds, the treatments are generally delivered every other day.
Planning and postimplant management
Treatment techniques
Superficial lesions
Surface applicators are used for superficial lesions, with PTV of maximum depth of 4–5 mm. The limiting factor of treatment at greater depth is the resulting higher skin-surface dose. Clinical judgment should be used when treating these deeper lesions.
Surface applicators such as the Leipzig, Valencia, custom mold, and eBT applicators are all in direct contact with the skin. Other applicators, such as the Freiburg flap or the H.A.M. applicator, are mounted on an immobilization mask (Fig. 5b) or placed in direct contact with the skin.
Fig. 5Custom mold and Freiburg applicators: (a) custom mold applicator (scar shown in red) and (b) Freiburg flap on a shin lesion pretreatment (left) and with mask/flap mounted (right). (For interpretation of references to color in this figure legend, the reader is referred to the Web version of this article.)
Custom molds are designed to follow the contour of the skin surface and precisely house the catheters at a specified distance (Fig. 5a). Because of the manual workmanship of these applicators, variation in both the separation between catheters and distance between the skin and the custom mold should be monitored. The objective is to position the catheters at a distance of 10 mm (or less) apart with activated dwell points at distances of 2–5 mm from the skin.
Custom molds may be constructed of different materials such as thermoplastic masks and polymethyl methacrylate molds to fit the patient surface in a reproducible manner. These can be used for flat as well as irregular surfaces and can accommodate lesions of all sizes and shapes.
Tape or other methods can also be used to secure the catheters in a reproducible geometry. Transit dose from the afterloader, through the transfer tubes, to the applicator should be minimized by careful design of the mold and placement of the afterloader.
Flaps applicators
Flap applicators are prefabricated custom molds with desirable geometry. They can help minimize the inconsistencies sometimes found in custom molds. The Nucletron Freiburg flap consists of attached 10-mm silicon spheres with catheters, 10 mm apart, embedded in the material at 5 mm from the surface of the sphere. Similar to the custom molds, these applicators can be used for all types of superficial lesions (size and shape). The most common flaps being used clinically are the Freiburg flap (Elekta), the H.A.M. (Mick Radio-Nuclear Instruments), and the Catheter Flap set (Varian Medical Systems). These applicators can be cut to any size to fit the target area.
In some cases with large and curved surfaces, such as the scalp or shin, it is common to use multiple attached pieces of flap to better conform to the surface.
Radionuclide-based applicators
The small, shielded surface applicators are cup-shaped applicators with a single dwell position at the vertex designed to improve dose distribution and limit normal tissue exposure. The applicator is constructed of high Z material, often tungsten. These applicators are limited to flat surfaces and small lesions.
The most common small surface applicators currently used are the Varian and Elekta Leipzig (
) applicators. Examples of these applicators are shown in Fig. 6. They have a fixed geometry (10–45 mm diameter) and short source-to-skin distance (SSD) (13–15 mm). They are divided into two categories: horizontal with the source parallel to the treatment surface and vertical with the source perpendicular to the treatment surface. These applicators include a plastic end cap, which attaches to the applicator and is applied to the skin surface reducing the electron contamination and therefore the skin-surface dose.
Fig. 6(a) Elekta Valencia and (b) Varian Leipzig applicators.
To improve the dose profiles and penumbra of the Leipzig applicators, the Valencia applicator was introduced. The newer design incorporated a flattening filter between the source and the skin surface, with the slight drawback of increased treatment time.
Specific commissioning and quality assurance (QA) are required for these types of applicators. The users should follow the manufacturer's recommendations and published articles addressing this task (
Transit dose from the afterloader, through the transfer tubes, to the applicator should be minimized by careful placement of both the applicator and the afterloader.
Electronic BT applicators
eBT offers an alternative to external beam electrons and HDR radionuclide BT. Because of energy of the eBT devices in the 50–69.9 kV range, treatments can be delivered in an unshielded room. The low radiation exposure allows essential medical staff to remain near the treatment couch during dose delivery, offering the opportunity to provide comfort and encouragement in close proximity to the patient.
There are currently three eBT systems used clinically: Axxent Electronic Brachytherapy System (Xoft Inc. a subsidiary of iCAD inc., San Jose, CA), the Carl Zeiss INTRABEAM System (Carl Zeiss Surgical Gmbh, Oberkochen, Germany), and the Esteya Electronic Brachytherapy System (Elekta Brachytherapy, Veenendal, Netherlands; see Fig. 7).
The Xoft Axxent model S700 brachytherapy source consists of a miniature water-cooled x-ray tube that produces 50 kVp (∼0.3 mA beam current) bremsstrahlung x-rays with a mean energy of 26.7 kV photons (
Fowler JF, Dale RG, Rusch TW. Variation of RBE with dose and dose rate for a miniature electronic brachtherapy source. Poster Presentation. 46th Annual Meeting of the American Association of Physicists in Medicine, Pittsburgh, PA, July 2004.
). The standard surface applicator set includes four circular cones with diameters of 10, 20, 35, and 50 mm with an integrated flattening filter. The source is centered over the flattening filter inside the cone, which ensures the delivery of a uniform dose profile of ±10% at depth of 2 mm (
). The nominal source-to-surface distance is 20 mm, and the averaged dose rate (average over 10 sources) at the applicator surface is approximately 1.3 Gy/min for a 35-mm applicator (
). The cone connects to one end of the applicator source channel, whose other end connects to a Tuohy-Borst adapter that is designed to lock the source in place for treatment. Additional custom-made tungsten-loaded silicone shield (Axxent FlexiShield) cutouts of thickness 1.0 mm can be used to shape the aperture to protect the organ at risk and normal tissue. This cutout has the lead equivalency of 0.45 mm at 50 kVp and provides about a 30-fold reduction in radiation. The treatment times will be adjusted to account for the change in output due to the presence of the cutout. This correction is made by measuring the cutout factor of the open and blocked field and compensating for both the missing scatter and the 1.0-mm gap introduced by the shield (
Just as in radionuclide-based HDR BT, complete contact between the skin-surface and the applicator end cap is crucial to avoid underdosing due to an air gap. The dose falloff in the case of an air gap of 1 mm can be as high as 10%.
Carl Zeiss Meditec Inc. received FDA approval for the INTRABEAM Flat applicator (FLAT) and the Intrabeam Surface applicator (ISA) in June 2013. The FLAT applicators are available in different diameters of 10, 20, 30, 40, 50, and 60 mm. To create a homogenous dose distribution, these applicators have filters of various thicknesses (7.0–23.5 mm) and different source-to-surface distances (9.6–25.6 mm). The ISA is available in sizes of 10, 20, 30, and 40 mm diameter, and it has thinner filters (2.7–5.4 mm) and similar source-to-surface distance (9.6–21.6 mm). The ISA has much higher dose rate due to the thinner filter design. The dosimetric characterization of the surface applicators has recently been published by Schneider (
The Esteya eBT System (Esteya EBS, Elekta AB-Nucletron, Stockholm, Sweden) has been developed specifically for HDR BT treatment of skin lesions. The system, with a miniature 69.5 kV X-ray source, was designed to provide a dose distribution at the skin-surface similar to the Valencia applicator. Available surface applicator sizes are 10, 15, 20, 25, and 30 mm. The nominal source-to-surface distance is 60 mm. The default current is 1.6 mA, which is automatically adjusted to 1.0 mA for fractions smaller than 4 Gy and to 0.5 mA for fractions less than 2 Gy to minimize the effect of current ramp up in the x-ray tube and thus minimize dose delivery inaccuracy. An aluminum flattening filter of 1.6 mm is used to generate a maximum nominal dose rate of 3.3 Gy/min with a flattened dose profile at depth of treatment (typically 3–4 mm). Dosimetric characteristics have been studied by Garcia et al. (
Immobilization devices such as Aquaplast and Vac-Lok are used to position the patient and minimize any possible motion during treatment. A summary of the two eBT system parameters is shown in Table 3.
Table 3Summary of superficial applicators characteristics
The surface cones/applicators are open-ended and are to be used with a plastic cap, just as in the radionuclide small-shielded applicators. The Xoft Axxent system uses a disposable 1-mm polycarbonate end cap, whereas the Esteya system has a mounted cap, as part of the treatment cone. For the radionuclide-based applicators, Varian Oncology Systems has a built-in plastic cap for all their applicators, whereas Elekta provides users with mountable caps. These caps are important and should be used for every treatment for the following reasons:
1.
Reduce the electron contamination generated from the wall of the cone.
2.
Prevent any tissue from protruding inside the cone.
3.
Provide firm contact to flatten, but not compress, the treated area as much as possible.
4.
Provide a complete contact with skin to reproduce the treatment SSD.
Deeper lesions
For lesions with depth greater than 5 mm, the superficial approach should not be used because of an unacceptably high skin-surface dose. Interstitial BT is a better option.
Interstitial is performed with the use of a catheter array of single or multiple planes (Fig. 8) based on the thickness of the lesion. 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. This is illustrated in Fig. 8b.
Fig. 8Interstitial implants: (a) double-plane interstitial implant for an SCC of the neck 150 × 100 × 80 mm and (b) single-plane interstitial implant for an SCC of the thorax lesion (PTV specified to 6 mm depth). SCC = squamous cell carcinoma; PTV = planning target volume.
Implants are generally performed under local anesthesia with a nerve block and sedation if necessary. The number of plastic tubes and length of the implant are selected based on the clinical findings. The catheters are ≤10 mm apart in one or more planes depending of the volume to be covered. Lines, which represent the location of the catheters, can be drawn on the skin for guidance (Fig. 8b). Most skin cancers suitable for interstitial implants can be treated with single plane. If more than one plane is used, separation of 5–7 mm, based on the thickness of the CTV, should be considered. It is important that these catheters are implanted at depth of 2.5–4.5 mm beneath the skin-surface because implants, which are too superficial, may result in late visible telangiectasia, skin necrosis, or delayed healing along the source positions.
The insertion of the proguide needles can be achieved with the use of trocars of different lengths. For implants in difficult areas such as the face where targets are of short length and curved in some instances, hypodermic needles (straight or bent) of appropriate diameter are recommended. Severe curvature of these catheters, which can lead to HDR source obstruction, should be avoided. Possible changes to the target volume due to local anesthesia injected into the dermis and epidermis should be evaluated. To avoid the effect of the temporary swelling on the resulting dosimetry, it is recommended to wait 60–90 min before the acquisition of the treatment planning CT images.
Removal of the implants is done without anesthesia. This method is appropriate for accessible lesions and at depth greater than 5 mm.
Treatment planning
In this section, all the treatment planning steps will be discussed for the different application/applicator types. The treatment plan should be generated by the QMP or trained BT dosimetrist and approved by the AU before treatment delivery. The QMP in BT is an individual who has met all requirements by the regulatory agencies (Nuclear Regulatory Agency [NRC], agreement states, and so forth) and was accepted as an authorized medical physicist in this field. All plans and calculations must be independently checked.
Prescription
A written treatment prescription must be available at time of planning and should contain all parameters necessary for treatment planning. The information must meet the regulatory requirements and should include:
1.
The treatment site, total target dose, dose per fraction, and the fractionation plan (i.e., every day, every other day, weekly, and so forth).
2.
The treatment depth.
3.
The modality to be used (radionuclide-based 192Ir/60Co or eBT [x-ray source]) for the treatment.
4.
The applicator type and size.
5.
Critical organs and dose constraints.
6.
Previous treatment, if any.
Catheter reconstruction
In this section, we assume that CT imaging is the recommended standard for BT reconstruction of catheters and the target area. CTV delineation for skin lesions on the CT images might be difficult in practice due to the limitation of the imaging modality. Other choices such as MRI or US could be used with CT data (fusion) to achieve better results, but caution should be exercised as the accuracy in the skin region becomes difficult. High-resolution US systems with frequency transducers >18 MHz are recommended for cutaneous lesions as they provide better detail of the skin surface. The CT images should be contiguous and no more than 2-mm thick in the axial plane for good target and catheter reconstruction and to account for any catheter curvature. The CT data should extend at least 10 to 20 mm beyond the PTV in all directions.
For custom mold and flaps, the reconstruction of the catheters and their position with respect to the skin-surface should be done with CT imaging. Surface irregularity and any air gap between the custom mold (or flap) and the skin will be taken in consideration. At the time of simulation, the user should use CT wire markers with minimal artifact to reconstruct the catheters and the target as drawn on the patient's surface. These markers will facilitate the identification of the true path of the source, that is, the representation of the dwell points. Similar markers can be used to delineate the PTV on the patient's skin. All critical structures in the area of the target should be reconstructed, and dose constraints should be respected. The three-dimensional target and catheters reconstruction must be verified against the physical custom mold or flap for its accuracy.
Currently, most users are relying on hand calculation or a library plan for the Leipzig, and Valencia applicators. The library plan is simply a phantom generated plan for these applicators. This method does not use CT data. For the dose distribution of these applicators, the user will rely on the atlas of dose profiles provided to them by the manufacturer. These profiles are a representation of the dose distribution in a water phantom and do not take in consideration the heterogeneous medium nor the possible skin curvature, which could alter the dose distribution. With the introduction of sophisticated software, such as Varian Brachyvision Acuros and Collapsed Cone Convolution, the applicators using HDR 192Ir are modeled and plans are available for use. Their high Z material composition and dimensions are taken into account for the dose calculation. Because of the artifacts from the high Z material, accurate positioning of the applicator during simulation may be a challenge. The use of markers on the patient's skin or a plastic applicator, representing the applicator location and orientation, could be a substitute and used for planning. In addition, the lesion should be wired for target reconstruction.
For eBT, similar to small, shielded applicators, it is common practice to use the published atlas of the PDD and profiles for treatment planning purpose. The use of CT data for planning is not common practice and is not available at the present time.
Interstitial implant treatment planning is performed using CT imaging and very similar to the custom molds/flap planning process.
Source dwell points activation
In the case of custom molds, flaps and interstitial implants, the activation of the dwell points, are typically done to cover the extension of the CTV, rounding in excess to the integer because of the 10-mm separation. Catheters in the proximity of the edges of the PTV or CTV should be available for activation to provide an overall good dose distribution. Their absence could lead to hot spots within the target created by distant dwell points used to provide dose at the edges.
Activation is performed according to the different tools provided by the appropriate software. When inverse planning is used, caution should be exercised if significant manual adjustment is performed.
For the small, shielded radionuclide-based applicators, a single dwell position is available for activation. The total length (Varian) or the source to indexer length (Nucletron) are critical parameters and should be verified.
eBT skin applicators use a single dwell point perpendicular to the skin surface. For the Xoft Axxent eBT device, the source-to-skin distance is a critical parameter and varies with the applicator size. The user should pay particular attention while inserting the source in the applicator and ensure that the SSD is correct. The mounting of the source on the Xoft system is the responsibility of the user.
For Esteya users, the SSD remains constant. The manufacturer is responsible for the mounting of the source. A summary of the clinical parameters for all surface applicators can be seen in Table 3.
Optimization
Optimization is achieved through various methods depending on the system being used. Dose points or additional structures, converted from isodose lines, can be used to push the dose at the distal area of the target and reduce dose to critical organs.
When planning large skin lesions, because of the dose/volume effect, special care should be given to avoid high dose regions. Dose should be limited to 125% to the skin surface for flaps and to 140% for custom molds. Higher doses could lead to undesirable results.
For the Leipzig, Valencia, and eBT applicators, a prescription depth of 3–4 mm is generally selected. Other depths, including 2 mm over bone or cartilage or 4–5 mm for deeper lesions, have been used, according to personal reports from experienced users. PDD of various surface applicators normalized at 3mm are shown in Fig. 9. Normalizing the PDD of both the small-shielded radionuclide and the Xoft applicators to a depth of 3 mm implies that the maximum dose at the surface is approximately 125–155%, with an approximate gradient of 10% per mm. Extreme care should be exercised for larger depths as the skin-surface dose would be excessive in such circumstances.
Fig. 9Percent depth dose (PDD): Elekta 30-mm Leipzig applicator (vertical and horizontal), Varian Leipzig 30 mm, 30-mm Esteya applicator, and 35 mm Xoft applicator (Both courtesy of Regina Fulkerson Ph.D.). With the exception of the Esteya PDD, all are indistinguishable.
The prescribed isodose must encompass the PTV. Differences in beam profile and penumbra should be taken into account for appropriate PTV dose coverage when selecting the appropriate applicator. The Leipzig applicators have a nonflat profile in addition to a significant penumbra. The Valencia and electronic applicators produce a very flat distribution and larger useful beam. The dose profiles for the small-shielded applicators are shown in Fig. 10.
Fig. 10Dose profiles: (a) Leipzig (horizontal and vertical) and Valencia applicators. (b) Esteya applicator; (c) Xoft applicator; and (d) full beam profile for the 30-mm Varian Horizontal Leipzig. (Courtesy of Regina Fulkerson Ph.D.).
When treating lesions in close proximity to underlying bone such as those on the shin or scalp, the resulting dose to skin surface and to the target lesion might be lower than expected (
). This decrease is due to a reduction in backscatter dose from bone. This varies with applicator size and depth from surface to bone interface.
Recommended reporting
The following parameters are recommended for data reporting when using skin BT.
1.
The modality used: radionuclide or eBT HDR unit;
2.
The applicator type and size including any additional shielding being used;
3.
Lesion type, size, location, and imaging used for evaluation;
4.
GTV size and margin information for CTV and PTV;
5.
The prescription including the depth, dose per fraction, total dose, and treatment schedule;
6.
Air kerma strength used for the daily fractions and kV and dose rate for eBT;
7.
Output factor for the applicator;
8.
Skin-surface dose;
9.
Dose to critical structures.
Recommendations on commissioning and QA
Institutions must have a commissioning and a QA program in place for skin BT to assure accuracy, efficacy, and safety of the patient treatment, just as they do for other radiotherapy procedures. American Association of Physicists in Medicine (AAPM) Task groups 40, 56, and 152 (
Thomadsen BR, Briggs PJ, DeWerd LA, et al. AAPM protocol for “The 2007 AAPM response to the CRCPD request for recommendations for the CRCPD's model regulations for electronic brachytherapy,” AAPM Report # 152, 2009.
) provide a good summary on this topic and should be referenced for more details. Failure modes and effects analysis for implementing the Valencia and Leipzig applicators has recently been described by Sayler et al. (
For applicators such as the custom mold/flap, the QMP should run an end-to-end test case using a phantom. This exercise would include applicator mounting, scanning with appropriate CT markers for target and catheters, immobilization, planning, and executing the plan on the HDR unit.
Commissioning of custom molds should consider the material used, typically thermoplastic, to guarantee that the shape and catheters configuration are kept constant for the duration of the total treatment. For commissioning of flaps, measurements of sphere diameter, flap thickness, and catheter separation should be performed.
Because the catheter lengths are case specific, special care should be taken with the source indexer length, measuring the total length, labeling catheter, and their orientation for each clinical case. An alternative solution, when possible, is to have all catheters cut at the same length. Consistent contact of the applicator with the patient skin should be monitored and checked with respect to the reference CT-based plan. The setup of these patients with the applicators in place should be reliable and reproducible using a specific fixation method. For interstitial implant, the constancy of the catheter position with respect to the skin should be confirmed for each fraction.
Most current treatment planning systems (TPSs) used for BT dose calculation are based on AAPM TG-43 dosimetric parameters (
). The addition of an equivalent tissue material (bolus) over the custom mold to compensate for the backscatter defect, for 192Ir and 60Co, was evaluated. Their results reveal that no bolus is required to improve the dose distribution. This was due in part to the high gradient from skin to the prescription depth (typically 5 mm). Differences at the prescription depth, between TG-43 and Monte Carlo calculations, were investigated, and their results were negligible with the one exception being the use of a 60Co source for interstitial implantation in which 1 mm of bolus is recommended.
Because the Freiburg flap is composed of small spheres or “pellets,” Vijande et al. (
) studied the scatter defect plus interpellet air gaps effect comparing TG-43 with Monte Carlo for 192Ir. They concluded that deviations at both surface and prescription depths are smaller than 5%.
For all HDR cases, basic BT safety rules should be followed. In addition to the daily QA, required by regulations, the following items should be implemented for the skin BT:
1.
Verification of treatment plan: modality, dose, applicator type and size, location and number of dwell points, and source indexer length or total length.
2.
Verification that all catheters are properly connected.
3.
All catheters should have a weight support to avoid any possible geometric modification due to gravity.
4.
Catheter location and orientation should be done in a manner to facilitate any possible emergency intervention.
5.
An emergency response kit should be available.
6.
Before each treatment, all precautions should be taken to reduce the transient dose.
In the case of the small-shielded radionuclide-based applicators (Leipzig and Valencia), specific commissioning and QA are required and include the following items:
1.
Integrity of the applicators and dimensions should be evaluated and compared to manufacturer specifications.
2.
Output factor must be verified using manufacturer and published recommendations (
Flatness and symmetry of the dose profile must be verified using films or other acceptable devices.
4.
The position within the applicator of the dwell point used for treatment must be accurately identified and compared to published data. This can be performed with radiochromic film or multichamber array (
Reference data of dose distribution and output of radionuclide-based applicator are available in the literature and usually provided by manufacturer. These have been collected using Monte Carlo and validated using experimental measurements. In the case of Nucletron applicators (Valencia and Leipzig applicators), Monte Carlo calculations and experimental validation were used and published (
In the case of eBT, the QMP should perform device/controller-specific functionality and safety interlock tests initially and on major repair of the device. Other tests such as timer accuracy, beam stability, and reproducibility should be performed as described in AAPM task group 152 (
Thomadsen BR, Briggs PJ, DeWerd LA, et al. AAPM protocol for “The 2007 AAPM response to the CRCPD request for recommendations for the CRCPD's model regulations for electronic brachytherapy,” AAPM Report # 152, 2009.
Thomadsen BR, Briggs PJ, DeWerd LA, et al. AAPM protocol for “The 2007 AAPM response to the CRCPD request for recommendations for the CRCPD's model regulations for electronic brachytherapy,” AAPM Report # 152, 2009.
Electronic BT commissioning should also include examination of dose calculation methodology.
For eBT surface applicators, the dose output at the surface is greatly altered due to the integrated flattening filter and therefore the QMP will determine the applicator-specific dose rate at the treatment surface by measuring dose rate. The measurement of the air kerma rate at the exit window of the surface applicator is performed using a small-volume parallel plate ionization chamber, which is then converted to “dose to water” via correction factors proposed in AAPM TG 61 (
For Xoft Axxent eBT, the location of the source inside each surface applicator may vary. Because of the inverse square effect, a small deviation in the source placement inside the plastic source catheter might result in larger differences in dose rate. This error is reduced by acquiring dose rate measurements for the new source with each surface applicator. In addition, source calibration and the determination of the air kerma strength are performed before each patient treatment fraction.
In the case of the Esteya applicator, the source is at a fixed position, and the commissioning and QA are focused on output, flatness, PDD, leakage, linearity and reproducibility. The system includes a QA device that must be used to test the dosimetry of the unit at the beginning of each treatment day. This system is composed of a set of diodes at different positions to guarantee the constancy of output, flatness, and PDD. The QA tool must be also commissioned against other methods such as radiochromic films and ionization chamber. Recently, an Esteya commissioning and periodic test has been proposed by Candela-Juan et al. (
The QMP should describe the frequency of the QA checks and the expected operational criteria setup at the time of acceptance and commissioning tests. The quarterly QA will include device/facility-specific tests, safety interlocks, and source-specific tests including calibration or output measurements at the surface of the applicator.
On the day of treatment, the device/facility interlock and the applicator integrity must be checked.
The institution should have a periodic QA program. The skin BT program should be included in the annual audit program and radiation safety in service.
Recommendations for clinical practice
When using surface applicators, the surface to be treated should be as flat as possible and able to support direct applicator contact.
For users with a variety of surface applicators, a safety measure should be implemented in their daily QA to ensure the use of the appropriate applicator for each patient and each treatment area at the time of treatment planning and delivery. Because of the significant differences in the output factor, the use of the wrong applicator could lead to an undesirable outcome including a possible medical event.
The positioning of each applicator, before each fraction, must be accurate and verified by the AU while providing direct supervision. Tattoos or marks on the patient's skin or mask can be used as a reference for daily applicator positioning. Appropriate placement and angling of the applicator is critical.
A very useful method for applicators setup is the use of templates, as the case of the templates La Fe for the Esteya applicators as described in Pons-Llanas et al. (
) (Fig. 11). 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. Once the applicator is selected, its outer contour can be drawn on the patient skin to facilitate the setup on each fraction.
Fig. 11Patient planning and simulation using La Fe template from Pons-Llanas et al.
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.
During planning, the source indexer length for Nucletron users or total length for Varian users should be verified by a second member of the planning team. Catheter identification, orientation, and labeling should also be performed.
Additional shielding might occasionally be necessary over the eyes, inside the lip, or in the nasal cavity. The dose from the backscatter component must be considered as shown by Lliso et al. (
) should be taken in consideration. Applicator orientation and shielding can be used to reduce the exposure. Newer design for some applicator and specifically the Valencia applicator has rectified the leakage issue.
In surface and interstitial HDR, the implant can be covered with lead to reduce the dose to radiosensitive organs. To avoid the backscatter overdose, few millimeters of bolus can be added (
Thomadsen BR, Briggs PJ, DeWerd LA, et al. AAPM protocol for “The 2007 AAPM response to the CRCPD request for recommendations for the CRCPD's model regulations for electronic brachytherapy,” AAPM Report # 152, 2009.
) include the independent verification of the treatment plan. For skin BT, some practical procedures can be established:
1.
In the case of custom molds, flaps, and interstitial cases, the method is similar to other BT procedures. One typical approach is to use the TPS imported data of positions/times with independent TG-43-based software (
). The implant geometry and orientation should also be verified by a member of the BT team not involved in the treatment planning portion.
2.
For radionuclide-based applicators, users might have access to a library plan for each applicator on the TPS that can be used. When using this method, the air kerma strength, the prescription dose, starting date, and patient information are updated for each case. The resulting treatment time is compared with the manual calculation.
3.
For all superficial applicators, an independent check can also be performed using external look-up tables.
Pretreatment and posttreatment photographs of the treatment area should be part of the patient medical record.
On the regulatory side, BT systems, both eBT and radionuclide based, must be registered within the appropriate agencies (agreement state or NRC). The controller registration requires a documented radiation protection program including shielding requirements, facility and room survey, and operating and emergency procedures. Institutions are responsible in meeting state or federal requirements when using these devices.
In addition, patients with pacemakers implants or implantable cardioverter defibrillators undergoing skin BT should be monitored in a similar fashion as recommended for external beam treatment by the manufacturer. Although in BT there is no electromagnetic field, the pacemaker or implantable cardioverter defibrillator dose remains a factor and should be kept using the manufacturer's recommendations.
Evolving practice areas where guidelines are not established
Given the relative lack of prospective data for BT used for treatment of nonmelanoma skin cancer, several areas of controversy warrant discussion. Ideal margins for BT when treating nonmelanoma skin cancer, especially in difficult anatomic locations, remain to be defined. As stated previously, we have recommended margins of 5 mm for BCC and 7–10 mm for SCC based on the surgical data. However, this may not be feasible for locations such as the nasal tip or eye canthi. Also undefined is the role of imaging for treatment planning techniques including depth prescription. As stated previously, we recommended an empirical 3-mm depth prescription for typical lesions. For lesions that clinically may appear to extend deeper, we would consider US evaluation to confirm the depth or choose another modality for treatment.
Conclusion
Radionuclide and electronic HDR BT systems are increasingly used and popular for nonmelanoma skin cancer. As in all BT treatments, because the dose per fraction is relatively high, special attention to applicator selection, dose prescription, organs at risk, catheter location, and high dose regions is critical. Practitioners are encouraged to use these recommendations to formulate treatments.
References
Rogers H.W.
Wenstock M.A.
Harris A.R.
et al.
Incidence estimate of nonmelanoma skin cancer in the United States, 2006.
The indications for and results of HDR afterloading therapy in diseases of the skin and mucosa with standardized surface applicators (the Leipzig® Applicator).
Test characteristics of high-resolution ultrasound in the preoperative assessment of margins of basal cell and squamous cell carcinoma in patients undergoing Mohs micrographic surgery.
Complete response of endemic Kaposi sarcoma lesions with high-dose-rate brachytherapy: treatment method, results, and toxicity using skin surface applicators.
HDR brachytherapy with standardized surface applicators (the Leipzig applicator) as an alternative, radiotherapy treatment for superficial malignant skin lesions.
Rodriguez S. High Dose rate brachytherapy in skin cancers: patient convenience, local control and cosmetical results. 12th International Conference “Optimal Use of Advanced Radiotherapy in Multimodality Oncology”. Roma 2007.
Fowler JF, Dale RG, Rusch TW. Variation of RBE with dose and dose rate for a miniature electronic brachtherapy source. Poster Presentation. 46th Annual Meeting of the American Association of Physicists in Medicine, Pittsburgh, PA, July 2004.
Thomadsen BR, Briggs PJ, DeWerd LA, et al. AAPM protocol for “The 2007 AAPM response to the CRCPD request for recommendations for the CRCPD's model regulations for electronic brachytherapy,” AAPM Report # 152, 2009.
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