Brachytherapy

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Review Article

American Brachytherapy Society consensus report for accelerated partial breast irradiation using interstitial multicatheter brachytherapy Jaroslaw T. Hepel1,2,*, Douglas Arthur3, Simona Shaitelman4, Csaba Polg
ar5, Dorin Todor3, Imran Zoberi6, Mitchell Kamrava7, Tibor Major5, Catheryn Yashar8, David E. Wazer1,2 1

Department of Radiation Oncology, Rhode Island Hospital, Brown University, Providence, RI 2 Department of Radiation Oncology, Tufts Medical Center, Tufts University, Boston, MA 3 Department of Radiation Oncology, Virginia Commonwealth University School of Medicine, Richmond, VA 4 Department of Radiation Oncology, MD Anderson Cancer Center, Houston, TX 5 Department of Radiation Oncology, National Institute of Oncology, Budapest, Hungary 6 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 7 Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA 8 Department of Radiation Oncology, University of California San Diego, La Jolla, CA

ABSTRACT

PURPOSE: To develop a consensus report for the quality practice of accelerated partial breast irradiation (APBI) using interstitial multicatheter brachytherapy (IMB). METHODS AND MATERIALS: The American Brachytherapy Society Board appointed an expert panel with clinical and research experience with breast brachytherapy to provide guidance for the current practice of IMB. This report is based on a comprehensive literature review with emphasis on randomized data and expertise of the panel. RESULTS: Randomized trials have demonstrated equivalent efficacy of APBI using IMB compared with whole breast irradiation for select patients with early-stage breast cancer. Several techniques for placement of interstitial catheters are described, and importance of threedimensional planning with appropriate optimization is reviewed. Optimal target definition is outlined. Commonly used dosing schemas include 50 Gy delivered in pulses of 0.6e0.8 Gy/h using pulsed-dose-rate technique and 34 Gy in 10 fractions, 32 Gy in eight fractions, or 30 Gy in seven fractions using high-dose-rate technique. Potential toxicities and strategies for toxicity avoidance are described in detail. Dosimetric constraints include limiting whole breast volume that receives $50% of prescription dose to !60%, skin dose to #100% of prescription dose (#60e70% preferred), chest wall dose to #125% of prescription dose, Dose Homogeneity Index to O0.75 (O0.85 preferred), V150 ! 45 cc, and V200 ! 14 cc. Using an optimal implant technique coupled with optimal planning and appropriate dose constraints, a low rate of toxicity and a good-toexcellent cosmetic outcome of $90% is expected. CONCLUSIONS: IMB is an effective technique to deliver APBI for appropriately selected women with early-stage breast cancer. This consensus report has been created to assist clinicians in the appropriate practice of APBI using IMB. Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Keywords:

Interstitial multicatheter brachytherapy; Accelerated partial breast irradiation; Breast brachytherapy; Breast cancer

Introduction

Received 31 January 2017; received in revised form 11 May 2017; accepted 28 May 2017. * Corresponding author. Department of Radiation Oncology, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903. Tel.: þ1-401-4448311; fax: þ1-401-444-5335. E-mail address: [email protected] (J.T. Hepel).

The concept of accelerated partial breast irradiation (APBI) is firmly rooted in pathologic data and patterns of failure showing that residual disease and clinical recurrences are largely confined to the tissues surrounding the lumpectomy cavity for patients with early-stage breast cancer (1e8). The interstitial multicatheter brachytherapy (IMB) technique was one of the early

1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2017.05.012

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Table 1 Studies evaluating APBI using interstitial multicatheter brachytherapy Study

Study design

Number of patients

Median followup

IBTRa %

GEC-ESTRO (10) NIO, Hungary (11) William Beaumont Hospital (12) RTOG 9517 (13) PROMIS (14) Germany/Austria (15) NIO, Hungary (16) Harvard University (17) Orebro Medical Centre, Sweden (18) London Regional CC, Canada (19) Tufts University (20) Ochsner Clinic (21) Washington University (22) Tata Memorial Hospital, India (23) University of Perugia, Italy (24) University of Nice-Sophia, France (25) Florence Hospital., Italy (26) University of Wisconsin (27)

Randomized Randomized Matched pair Multi-institutional case series Multi-institutional case series Multi-institutional case series Case series Case series Case series Case series Case series Case series Case series Case series Case series Case series Case series Case series

1118 258 199 99 1356 274 45 50 50 33 32 304 202 140 100 70 115 247

6.6 years 10 years 11 years 12 years 7 years 5 years 11 years 11 years 7 years 7 years 7 years 6 years 5 years 5 years 5 years 5 years 4 years 4 years

University of Kansas (28) Soonchunhyang University, Korea (29) VCU (30)

Case series Case series Case series

24 48 44

4 years 4 years 3.5 years

1.4 5.9 (10 years) 5 (12 years) 5.2 (10 years) 7.6 (10 years) 2.3 9.3 (12 years) 15 (12 years) 4 (7 years) 16.2 6.1 2 3 3 2.3 2.4 6 (crude rate) 2.2 (low risk) 6.4 (high risk) 0 4.6 0

APBI 5 accelerated partial breast irradiation; GEC-ESTRO 5 Groupe Europ
een de Curieth
erapie and the European Society for Radiotherapy and Oncology; NIO 5 National Institute of Oncology; RTOG 5 Radiation Therapy Oncology Group; PROMIS 5 Pooled Registry of Multicatheter Interstitial Sites; VCU 5 Virginia Commonwealth University. a IBTR: ipsilateral breast tumor recurrence (5-year actuarial rate if not otherwise specified in parentheses).

approaches to explore the concept of APBI, and thus this technique has accumulated the most robust clinical data with the longest followup. The IMB technique, compared with other APBI techniques, is also the most versatile one allowing for conformal dose distribution across a variety of breast and tumor bed volumes and geometries (9). The IMB technique can be technically challenging. However, with appropriate knowledge and skill, IMB can result in a convenient and effective treatment, both in regards to tumor control and cosmetic outcomes. The American Brachytherapy Society (ABS) Board, therefore, presents this consensus report to assist clinicians in using the IMB technique.

Methods and materials In 2016, The ABS Board of Directors appointed a group of practitioners with clinical and research experience with breast brachytherapy to provide guidance for the present practice of IMB. Consensus report development was initiated with a systemic literature review. A PubMed search performed using search terms interstitial, breast, and brachytherapy yielded 340 publications. This included reports on two randomized trials (10, 11), 1 case-controlled trial (12), and 18 nonrandomized studies (13e30). These are listed in Table 1. Recommendations were based on published literature with emphasis on randomized data when applicable and clinical experience of the expert panel. This final report was reviewed and approved by the ABS Board of Directors.

Summary of clinical outcomes Early in the development of the IMB technique, it was commonly employed to deliver boost irradiation to the tumor bed as part of whole breast radiation therapy. IMB to deliver APBI and the concept of APBI itself was initially investigated in the United States at William Beaumont Hospital and the Ochsner Clinic and in Europe at the National Institute of Oncology (NIO) in Hungary (31e33). Patients were largely required to be O 40 years old, with invasive ductal carcinoma, surgical margins $ 2 mm, and axillary lymph node dissection of Levels I and II with 0e1 lymph nodes positive, no extensive intraductal component, and no residual microcalcifications on postlumpectomy mammogram. One of the first publications to compare IMB to whole breast irradiation (WBI) was a matched-pair analysis from William Beaumont Hospital. This study evaluated 199 patients receiving IMB and an equal number receiving WBI. At 12 years, no significant difference was noted in the rates of local recurrence (12). The first randomized trial comparing APBI to WBI was conducted by the NIO, in which 258 women with early-stage breast cancer were randomized to WBI or partial breast irradiation (with 69% of patients treated with IMB and 31% with electrons). Fiveyear and 10-year clinical outcomes were comparable, and no difference in local recurrence was noted (12, 34). Most recently, the Groupe Europ
een de Curieth
erapie and the European Society for Radiotherapy and Oncology (GEC-ESTRO) conducted a randomized trial of 1184 patients.

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After a median followup of 6.6 years, the 5-year incidence of local recurrence after IMB was 1.44%, noninferior to the local recurrence seen with WBI (10). Neither of the two randomized trials comparing IMB to WBI demonstrated inferior cosmetic outcome or worse toxicity with IMB. Indeed, 81% of patients treated with IMB in the NIO Phase III trial had good-to-excellent cosmesis, compared with 63% of patients in the WBI group (34). Similarly, patients treated in the GEC-ESTRO Phase III trial demonstrated a trend of lower rates of Grade 2e3 late effects to the skin compared with those patients treated with WBI. The incidence of Grade 2e3 late subcutaneous side effects and severe fibrosis was similar in both groups (10).

Patient selection The ABS published updated guidelines for appropriate patient selection for APBI in 2013 (35). Most clinical data for APBI, using IMB as well as other techniques, have largely consisted of treatment of older patients with earlystage disease without high-risk features. This is reflected in the current guidelines. The following criteria are recommended by the ABS: age $ 50 years, invasive breast cancer (any histology) or ductal carcinoma in situ, size # 3 cm, lymph node negative, lymphovascular space invasion absent, and resection margins negative (no ink on tumor). The GEC-ESTRO, American Society for Radiation Oncology, and American Society of Breast Surgeons have also proposed patient selection guidelines defining a similar patient population although with several notable differences (36e38). As data from randomized trials mature, particularly from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B39/Radiation Therapy Oncology Group (RTOG) 0413 which enrolled a subset of patients who were young or had high-risk features, we will gain a better understanding of which patients are and which patients are not appropriate candidates for APBI. Until these data are available, the guidelines set forth by the ABS are an appropriate guide.

Implant technique considerations The basic principles of interstitial catheter insertion are similar regardless of the technique used. Careful attention to the implant quality is critical, as dose optimization cannot compensate for a poorly placed implant. The implant needs to cover the tumor bed with adequate margin (1e2 cm). The catheters need to be equally and evenly spaced (1e1.5 cm apart) within each implant plane, and the number of and spacing between implant planes as well as the total number of catheters used needs to be optimized for the individual patient’s tumor bed and anatomic geometry. Needle spacing may need to be adjusted for single plane compared with multiplane implants. A preimplant

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virtual plan is helpful in determining the optimal number of catheters and planes, spacing between catheters and planes, and overall implant geometry. In addition, the direction that the catheters should be inserted needs to be considered. One should select an orientation that will allow optimal coverage of the tumor bed, but one should also consider the entry site in relation to the patient’s cosmetic outcome where catheter marks may be less visible as well as the exit sites to maximize the patient’s comfort where the catheters will be coming out of the skin during the duration of the patient’s subsequent brachytherapy. Several specific techniques have been described to guide catheter placement including freehand and template-based approaches using either intraoperative, open-cavity placement, or postoperative image guidance. Sedation for the implant procedure can be performed with general anesthesia or local anesthesia with or without conscious sedation. The intraoperative technique by virtue of the setting is always performed under general anesthesia. For postoperative placement of catheters, either approach can be used. The optimal solution is based on the resources available and experience of the brachytherapy team. Insertion techniques are described briefly. Freehand, intraoperative insertion technique The advantage of an open-cavity technique is that one can see the cavity that needs to be implanted as well as the distribution of the catheters without difficulties. With this technique, it is helpful for the surgeon to place clips to define the borders of the lumpectomy cavity as this will greatly assist with contouring and planning. An additional consideration for catheter insertion with this technique is to consider a catheter insertion orientation that will have the least resistance and tension along the catheters once the skin is sutured closed at the end of the case. Before inserting catheters, one should use a ruler and a marking pen to roughly outline the anticipated insertion and exit sites for the implant. Once the spacing has been determined, a hollow beveled needle is inserted through the skin at the respective identified insertion site, pushed along and through the lumpectomy cavity, and then through the skin on the exit side of the implant. A single catheter is then thread through the hollow needle. The catheter should be advanced far enough so that a significant amount is protruding through the end of the hollow needle. The needle can then be pulled out over the catheter. Buttons are often used on both the insertion and exit sites to minimize friction against the skin and to help stabilize the catheter. This process is then repeated for each subsequent catheter insertion. Postoperative insertion techniques Postoperative catheter implantation is performed a few weeks after the lumpectomy allowing for initial wound healing as well as for final pathology to be available to

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guide optimal patient selection for APBI. Image guidance before and/or during catheter insertion is necessary for placing the adequate number of catheters in the right geometry relative to the cavity volume. In case of CT or ultrasound (US) guidance, the implantation of catheters is performed in the supine position, whereas in the case of mammography guidance, a prone position is used. Freehand and template-based insertion with US guidance US imaging is an effective method to localize the surgical cavity, define the target volume, and guide the catheter implantation (39). The dimensions of the cavity are defined as the largest hypoechoic region in each cardinal direction. The distance between the superior cavity wall and skin and the depth of the chest wall are also measured. The implant geometry is then designed, and the entry and exit points of the catheters are marked on the skin. Using real-time US guidance, the needles are inserted one by one (Fig. 1). It is recommended to insert the deepest plane first and then to work more superficially. This is because an artifact is

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cast from the catheters making it more difficult to visualize new catheters. The catheters should be visualized both along the length of the catheter to follow its full trajectory through the breast tissue and in the axial plane to assess its in-plane distribution. A template can be used which makes the insertions of the needles easier and ensures even spacing between needles. If a freehand technique is used, the holes in a 10-French round JacksonePratt drain can be used to assist with evenly spacing the catheters (40). The trajectory of needles needs to be carefully considered to both ensure optimal spacing and also to prevent inadvertent pneumothorax as this rare complication has been reported (13). Template-based insertion with CT guidance The entrance and exit sites of the catheters on the skin are always determined using the three-dimensional (3D) rendering of the target volume and patient anatomy. When implantation and imaging are done in the same room, after placement of a few needles (e.g., in the deep plane), a CT scan can be used for an initial evaluation of target coverage.

Fig. 1. Freehand, postop insertion technique using ultrasound guidance. Needles are inserted to cover the lumpectomy cavity using real-time ultrasound imaging (a, b). The needles are then replaced by plastic catheters and fixed in position with buttons (c). CT-based three-dimensional planning depicting the target volume (pink contour) and prescription isodose line (green) (d). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

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Fig. 2. Template-based insertion technique using CT guidance. Three-dimensional rendering of patient in needle’s eye view depicting template and target volume (red) (a). Needles are inserted in the template to cover the target volume (b). The needles are then replaced by plastic catheters and fixed in position with buttons (c). CT-based three-dimensional planning depicting the target volume (red contour) and isodose distribution (d). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Then, the remaining needles are inserted in a standard pattern with 1.0e1.5 cm separation, Fig. 2 (41). If needed another CT scan can be performed and with frequent imaging, optimal catheter placement is ensured. In another technique, two CT image series (preimplant and postimplant) are used for the implantation and planning (42, 43). First, before the implantation, a CT-compatible plastic template is placed around the involved breast taking into account the scar position on the skin and other relevant clinical information about the tumor location. Geometrical parameters of the template are recorded, and its position is marked on the skin. A preimplant CT imaging is performed, the cavity is outlined in axial slices, and the target volume is created. Then, using 3D rendering, the patient is rotated in the needle’s eye view, and the target volume is projected on the rendered template. By visual inspection, the holes covering the target volumes are identified, and their coordinates are recorded. On the implant day, the template is placed around the breast in the same position using the skin marks and template parameters. Then, using the predefined coordinates, the needles are inserted into the

breast. Postimplant CT imaging is acquired to verify the quality of the implant and for treatment planning. Template-based insertion with mammography guidance In case of mammography guidance, the implantation is done in the prone position. An advantage of this technique is that the breast tissue pulls away from the chest wall, pectoral muscles, and ribs, and this makes the deep plane implantation safe and easy. With the patient lying on a stereotactic core needle breast biopsy table with a template and built-in mammography equipment, the catheters can be placed accurately in relation to the target volume (8). To help with cavity localization, a contrast medium is injected into the lumpectomy cavity by US guidance. After taking a mammographic image, the cavity defined by the contrast media and the superimposed holes of the templates are clearly identified. The template coordinates of the needles covering the target volume can then be easily chosen. Implanting a deep plane near the pectoralis fascia can be difficult to achieve. Using a prone position, the breast hangs by

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gravity, and the template can be pushed up against the chest wall. In this way, an adequate deep plane implant can be achieved. CT imaging for treatment planning is then performed. CT imaging and treatment delivery are generally performed in the supine position.

Target volume definition The target definition for partial breast irradiation has been debated repeatedly and varies depending on whether the treatment is delivered preoperative, postoperative and, for uncertain reasons, is often modified to fit the dosimetric limitations of the radiotherapy treatment method or device employed. However, despite these variances, the clinical target volume (CTV) most often used for APBI, and specifically for interstitial brachytherapy, has been the normal breast tissue within 1e2 cm from the lumpectomy cavity edge limited by breast tissue extent. Many pathologic studies support this definition (1e8); the reported single and multi-institutional experiences have applied this definition; and the large Phase III trials exploring APBI have used this definition with variable specifics as discussed below (44e46). Generally for the IMB technique, no additional margin expansion is used to define the planning target volume (PTV), that is, PTV 5 CTV. In the United States, the goal of covering a uniform target of normal breast tissue surrounding the lumpectomy cavity of 1e2 cm has been applied. This is limited by breast tissue extent, that is, the chest wall and 0.5 cm from the skin surface. Large clinical experience of intracavitary brachytherapy using a margin of 1 cm around the lumpectomy has shown a low rate of local failure (47, 48). Initial data suggested that the tissue surrounding an intracavitary balloon implant is stretched thereby resulting in 1.5 cm of tissue treated in the relaxed state (49). As a result, the NSABP B-39/RTOG 0413 Phase III randomized trial required a 1.5 cm margin for the IMB technique. However, more contemporary analysis shows that the 1 cm margin used with intracavitary brachytherapy corresponds to essentially the same 1 cm margin in the relaxed state, thus suggesting that a smaller margin may be appropriate (50). Some practitioners also vary the margin based on perceived risk of microscopic disease extension. Through a uniform expansion, physicians are assured that a minimum of 1.5 cm of normal breast tissue is treated beyond the lumpectomy cavity. However, in the case of wide surgical margins, there is the potential expense of treating unnecessary additional normal tissue without added benefit. To avoid the potential overtreatment, the European community has followed a more elegant approach as outlined within the GEC-ESTRO multicenter trial (51). The goal within this trial was to assure that a full 2 cm of normal tissue beyond known disease extent was addressed with surgery, radiation, or in combination. With this approach, a 0.5 cm surgical margin would require an

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additional 1.5 cm margin treated with brachytherapy in that direction, whereas with a 1.5 cm surgical margin, only an additional 0.5 cm is targeted with brachytherapy. For surgical margins O1.5 cm, a minimum margin of 0.5 cm was used for brachytherapy. This approach assures that 2 cm of surrounding breast tissue is addressed, and this logically reduces the amount of breast tissue treated based on the extent of surgery. Cooperation between surgeon, pathologist, and radiation oncologist is crucial with this approach.

Treatment planning considerations Before discussing dose optimization, one needs to stress the importance of optimal number, placement, and spacing of catheters. If an implant results in suboptimal PTV coverage, extra catheters should be placed (typically free hand) to achieve a better implant geometry rather than trying to use dose optimization. Dose optimization cannot compensate for a poorly placed implant. It is good practice to acquire an evaluation CT before the implant, outline the lumpectomy cavity, and construct the PTV. A physiciane physicist consultation will determine, at this time, the number of catheters, optimal orientation, and spacing. A virtual implant can be constructed on the evaluation CT data set to help visualize the implant dosimetry. Once an appropriate implant is placed, a treatment planning CT with the patient in a supine position is acquired. The CT should start at or above the mandible and extend several centimeter below the inframammary fold (including the entire lung). A slice thickness of 3 mm or less is recommended. Although marker wires are not required, they can help with catheter delineation and with establishing the most distal dwell position. Catheters should be numbered or uniquely labeled by other means, so that each individual catheter can be identified. Catheters, PTVs, and organs at risk (breast, skin, chest wall, and ribs) should be delineated and contoured. Although there are many ways of creating a dose distribution, among them, manual and geometrical optimization, we strongly recommend volume or doseevolume histogramebased optimization. In this process, dwell positions are defined as part of the optimization. Each of the structures will be subjected to doseevolume constraints. An avoidance structure created to surround the PTV is helpful. This avoidance structure is used to limit the prescription dose and hot spots from extending outside of the PTV into the normal tissue and thus driving the dose conformity to PTV and implicitly minimizing dose to the adjacent organs at risk. Accurate structures and appropriate dose constraints will produce optimal plans, Figs. 1d and 2d. If one needs to manually adjust an already optimized plan, it is very likely that either the optimizer is not performing adequately (might be too sensitive and easily captured by local minima) or the set of constraints does not adequately or completely reflect the goals for the plan. Plans should be

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Table 2 The most common dose fractionation schedules in HDR interstitial multicatheter brachytherapy for APBI BEDa (Gy)

EQD2b (Gy)

BED (Gy)

a/b 5 2 Gy

EQD2 (Gy)

BED (Gy)

a/b 5 4 Gy

EQD2 (Gy)

a/b 5 10 Gy

Author/trial

Fractionation

Total dose (Gy)

RTOG 95-17 (13) NSABP B39/RTOG 04e13 (45) GEC-ESTRO (10) GEC-ESTRO (10) NIO Hungary (16)

10  3.4 Gy

34.0

91.8

45.9

62.9

41.9

45.6

38.0

8  4 Gy 7  4.3 Gy 7  5.2 Gy

32.0 30.1 36.4

96.0 94.8 131.0

48.0 47.4 65.5

64.0 62.5 83.7

42.7 41.6 55.8

44.8 43.0 55.3

37.3 35.9 46.1

HDR 5 high-dose-rate; APBI 5 accelerated partial breast irradiation; BED 5 biologic equivalent dose; EQD2 5 equivalent dose at 2 Gy/fx; RTOG 5 Radiation Therapy Oncology Group; NSABP 5 National Surgical Adjuvant Breast and Bowel Project; GEC-ESTRO 5 Groupe Europ
een de Curieth
erapie and the European Society for Radiotherapy and Oncology; NIO 5 National Institute of Oncology. a Biologically effective dose. b Equivalent dose given in 2-Gy fractions.

evaluated to ensure optimal PTV coverage and normal tissue dose constraints, particularly the skin. In addition, the volume of hot spots and the overall homogeneity of the implant defined by the Dose Homogeneity Index (DHI) should be evaluated. Prescription dose and fractionation The treatment volume for IMB APBI is confined to the tissues surrounding the lumpectomy cavity, thereby it is possible to use larger fractional doses and a shorter overall treatment schedule compared with conventional WBI. Dose can be delivered using either low-dose-rate (LDR) or highdose-rate sources. In addition, a pulsed-dose-rate (PDR) technique has been used. Historically, LDR treatment was performed using a total dose of 45e50 Gy at 30e60 cGy/h over 3.5e6 days (32, 52, 53). However, LDR sources are rarely used for IMB treatment today because of the inability to perform 3D dose optimization with these sources. PDR is a technique whereby an iridium-192 source via remote afterloader is used to simulate an LDR source by delivering small doses or pulses of radiation every hour over several days. PDR treatments have been more commonly employed in Europe. A dose of 50 Gy delivered in pulses of 0.6e0.8 Gy/h (one pulse per hour, 24 h/day) is typically prescribed (10, 16, 19). This dose schedule was used in the GEC-ESTRO randomized trial where 19% of patients in the APBI arm were treated using the PDR technique. High-dose-rate treatment delivery is by far the most commonly used method for IMB APBI. Various treatment schedules exist which are listed in Table 2. Biologic equivalent dose and equivalent dose at 2 Gy/fx using the lineare quadratic formula and an a/b ratio of four for breast cancer are also shown for each schedule (54). In RTOG 9517 and NSABP B-39/RTOG 0413, a dose schedule of 34 Gy in 10 fractions delivered twice daily over a week was used (13, 45). In the GEC-ESTRO randomized trial, a dose schedule 32 Gy in eight fractions or 30.1 Gy in seven fractions was employed. Both schedules were delivered using twice daily fractionation (10).

Dose constraints and toxicity avoidance Over the decades, because the inception of the interstitial technique, we have gained a much more robust understanding of the parameters important for avoiding treatment-related toxicities. These toxicities can be broadly grouped into five categories: implant-related infection, skin toxicity, subcutaneous tissue toxicity, chest wall or ribs toxicity, and internal organ toxicity. All of these can affect the patients’ cosmetic outcome and/or their quality of life. Recommended dosee volume constraints are summarized in Table 3. Infection Infectious complications can increase the risk of both late skin and subcutaneous toxicities and have been associated with compromise in overall cosmetic outcome (55e 57). Sterile technique for catheter placement and meticulous attention to wound care throughout the duration of the implant is essential. Using a trained nurse for daily wound/catheter care is very helpful. Prophylactic antibiotic can be considered (58). With these measures, an implantrelated infection rate of !5% is expected (14, 59). Skin toxicity Late skin toxicities include catheter marks, telangiectasia, and skin fibrosis. RTOG 95-17 reported on toxicity Table 3 Recommended planning dose constraints for interstitial multicatheter APBI Variable

Recommended constraint

Breast volume

!60% of the breast should receive $50% of prescription dose #100% of prescription dose (#60e70% preferred) #125% of prescription dose O0.75 (O0.85 preferred)

Skin dose (measured at skin surface) Chest wall DHI Hot spots V150 V200

!45 cc !14 cc

APBI 5 accelerated partial breast irradiation; DHI 5 Dose Homogeneity Index.

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related to early experience using IMB (53). No skin dose constraints were required on this trial resulting in a high rate of mild to moderate toxicity, catheter marks (54%), skin fibrosis (45%), and telangiectasia (45%). Catheter marks are related to skin injury at the catheter entry site from both trauma and high-radiation point doses. These can be minimized by ensuring that source dwell positions are placed distal to the entry site during treatment planning. In addition, daily setup verification is crucial to ensure that catheter movement has not occurred. Skin fibrosis and telangiectasia are related to the overall skin dose. To minimize these late toxicities, the recommended maximum skin dose should be !100% of the prescription dose. Polgar et al. (16) reported outcomes using a stricter skin dose constraints of !60% of prescription. With this approach, the rates of Grade 2 and 3 skin toxicities were 4% and 0%, respectively. In the GEC-ESTRO randomized APBI trial, any skin Grade 2e3 skin toxicity was equivalent between IMB and WBI, but the rate of any skin pigmentation was higher with WBI; 5.7% versus 10.0%, respectively ( p ! 0.01) (10). Subcutaneous tissue toxicity Late subcutaneous tissues toxicities consist of fibrosis and fat necrosis. Early multi-institutional analysis by Wazer et al. (55) identified that hot spots within the implant were associated with fibrosis, fat necrosis, and overall cosmetic outcome. Specifically, the overall heterogeneity of the implant as represented by the DHI and the volume of high-dose regions as represented by the V150 and V200 correlated with these adverse outcomes. Patients who developed fat necrosis have a mean V150 of 69 cc compared with 44 cc for those without fat necrosis, p 5 0.02. Likewise, the mean V200 was 22 cc and 13 cc for patients with and without fat necrosis, respectively, p 5 0.01. DHI was 0.73 for patients who developed Grade 2 or greater subcutaneous fibrosis compared with 0.77 for those with Grade 0e1 fibrosis, p 5 0.02. A more recent analysis from Washington University showed that acute infection, chemotherapy use, number of catheters, V100, V150, V200, and integrated reference air kerma are all significantly correlated with fat necrosis on univariate analysis (56). On multivariate analysis, only V150 remained significant. Furthermore, analysis revealed that fat necrosis was detrimental to several quality of life domains (60). To minimize late subcutaneous toxicity, a DHI of O0.75, V150 ! 45 cc, and V200 ! 14 cc are recommended. In the GEC-ESTRO randomized APBI trial, the rate of Grade 2e3 subcutaneous toxicity was 11.4% for APBI and was not different for patients who received WBI (10). Chest wall/rib toxicity and internal organ toxicity Chest wall pain or even rib fracture can develop following breast radiotherapy. These toxicities have generally not been

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reported using IMB (10e12, 16, 53, 55). However, a chest wall dose constraint of #125% of the prescription dose is reasonable and commonly employed. The advantages of brachytherapy in general and the IMB technique specifically are the rapid fall off of dose outside the implant volume. As such, the dose to internal organs including the heart and lung are generally minimal. Low-dose heart exposure, however, should be evaluated as this can be associated with late cardiac effects. Cosmetic outcome Achieving an optimal overall cosmetic outcome is complex and involves the interplay of patient, surgical (resection), implant, and other treatment-related variables. Avoidance of infection, and skin and subcutaneous toxicity is crucial as all have been correlated with suboptimal cosmetic outcomes (14, 31, 53, 55, 58, 59, 61e64). Implant technique and use of planning dose optimization are important in meeting DHI, V150, and V200 dose constraints. Older studies which used two-dimensional planning without dose optimization have reported lower rates of good-to-excellent cosmetic outcomes (53). Use of LDR brachytherapy implants has also been shown to result in suboptimal cosmetic outcome likely owing to the inability to perform dose optimization for these implants (30). In addition, the volume of the implant appears to matter, and this should be kept as low as practically achievable (29, 55e57, 65). For larger volume implants, keeping the hot spots low is particularly important. Lastly, the use of chemotherapy in several studies has been associated with a deleterious effect on cosmetic outcome (30, 55, 56). Using optimal implant technique, plan optimization, and appropriate dose constraints, the expected rate of good-to-excellent cosmetic outcome is in excess of 90% (12, 55, 56, 58). In the GEC-ESTRO randomized APBI trial, the rate of good-to-excellent cosmetic outcome with IMB was 92%, which was not different from patient treated with WBI who had a 91% rate ( p 5 0.62) (66). However, the rate of excellent cosmetic outcome was higher in patients treated with IMB APBI, 43.6% versus 30.9%, respectively ( p ! 0.0001) (67).

Conclusion IMB is an effective technique to deliver APBI resulting in a low rate of tumor recurrence for appropriately selected women with early-stage breast cancer and a high rate of good-to-excellent cosmetic outcomes. This consensus report can help guide practitioners on the appropriate use of this technique. References [1] Faverly D, Holland R, Burgers L. An original stereomicroscopic analysis of the mammary glandular tree. Virchows Arch A Pathol Anat Histopathol 1992;421:115e119.

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