Accepted Manuscript A novel approach of INTRABEAM intraoperative radiotherapy for nipple-sparing mastectomy with breast reconstruction Lingxiao Pan , Wenbo Zheng , Xigang Ye , Lun Chen , Yaohua Ke , Minghui Wan , Wei Tang , Jin Gao , Xiaoshen Zhang PII:
S1526-8209(14)00083-4
DOI:
10.1016/j.clbc.2014.04.002
Reference:
CLBC 272
To appear in:
Clinical Breast Cancer
Received Date: 25 December 2013 Revised Date:
31 March 2014
Accepted Date: 23 April 2014
Please cite this article as: Pan L, Zheng W, Ye X, Chen L, Ke Y, Wan M, Tang W, Gao J, Zhang X, A novel approach of INTRABEAM intraoperative radiotherapy for nipple-sparing mastectomy with breast reconstruction, Clinical Breast Cancer (2014), doi: 10.1016/j.clbc.2014.04.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT A novel approach of INTRABEAM intraoperative radiotherapy for nipplesparing mastectomy with breast reconstruction
Lingxiao Pan1, Wenbo Zheng1, Xigang Ye1, Lun Chen1, Yaohua Ke2, Minghui
1
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Wan3, Wei Tang1, Jin Gao 1, Xiaoshen Zhang1
Department of breast surgery, the first affiliated hospital of Guangzhou Medical
University, Guangzhou, People’s Republic of China
Metabolic bone disease and genetic research unit, department of osteoporosis and
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2
bone diseases, Shanghai Jiao Tong University, affiliated sixth people’s hospital,
3
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Shanghai, People’s Republic of China
Department of radiation oncology, the first affiliated hospital of Guangzhou Medical
University, Guangzhou, People’s Republic of China
A
running
title:
INTRABEAM
nipple-sparing
mastectomy
with
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reconstruction
for
Correspondence and reprint requests to: Dr Wenbo Zheng, MD, Department of breast
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surgery, the first affiliated hospital of Guangzhou Medical University, No. 151, Yanjiang West Road, Guangzhou, P.R.China (e-mail: [email protected])
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Number of Words in abstract: 251 Number of Words in manuscript: 3295
All authors have no conflicts of interest.
1
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Abstract This study aims to broaden the application of Intrabeam® intraoperative radiotherapy in nipple-sparing mastectomy with breast reconstruction for breast
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cancer. A single dose of 16 Gy was carried out in seven patients receiving intraoperative radiotherapy. The median radiation time was 13 min 14 sec. No acute radiation injury with symptoms was observed and the short-term
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outcomes were good.
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Background: Despite the advancement and increasing use of breast-conserving surgery, mastectomies, including nipple-sparing mastectomy (NSM), are still carried out in a portion of breast cancer patients. However, the role of NSM is still controversial, mainly owing to the oncologic safety of the NAC. Intrabeam® (Carl
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Zeiss, Germany) is the most widely used mobile intraoperative radiotherapy (IORT) device to date. This pilot study aims to broaden the application of Intrabeam® system for breast cancer, investigating the feasibility of Intrabeam® IORT in NSM with
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breast reconstruction. Patients and Methods: From December 2012 to June 2013,
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seven female patients with breast cancer were enrolled in the study. NSM with or without axillary dissection was performed first. After confirming negative retroareolar frozen section and no poor local bleeding of the NAC, Intrabeam® IORT was carried out, with a single dose of 16 Gy, followed by breast reconstruction. The complications and short-term outcomes were assessed. Results: The median radiation time was 13 min 14 sec in the seven cases. One patient complained of mild pain in the radiation field on the skin in the first 2 weeks. All seven patients were followed for a median 2
ACCEPTED MANUSCRIPT time of 7 months. No acute radiation injury with symptoms (heart, lung, or hematological system), NAC necrosis, local recurrence, or metastasis was observed. Although every patient had reduction in NAC sensitivity, the contours of the breasts
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(including the NAC) were satisfactory. Conclusions: Intrabeam® IORT may be a feasible and convenient approach for NSM with breast reconstruction in patients with
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breast cancer.
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Keywords: Breast cancer, intraoperative radiotherapy, nipple sparing, mastectomy,
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breast reconstruction
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ACCEPTED MANUSCRIPT Introduction Nowadays, mastectomy is usually performed to treat breast cancer patients with medium or large size tumors, multicentric tumors, recurrent foci after conservative
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treatment, and patients who reject or have no other indications for breast-conserving surgery. Standard mastectomy technique requires removal of the nipple-areola complex (NAC). Long1 has mentioned that “…The loss of the nipple may be as or
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more psychologically significant than the loss of the breast mound itself”. Albeit it is
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possible to create a NAC, a second-stage procedure of plastic surgery, sometimes with additional revisions, is usually needed2,3. Most importantly, whether autologous cartilage, skin flap, or artificial material is used in NAC reconstruction3-6, the appearance is not natural, and loss of NAC sensation is inevitable. Both may affect
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the patient’s psychological adjustment1,7.
In recent years, there has been increasing interest in the technique of nipple sparing mastectomy (NSM)8–18. Its role is still controversial, based upon its oncologic safety.
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Serial histological sections have revealed that involvement of the NAC in mastectomy
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specimens varied from 0–58%, mostly less than 20%19–25. What’s more, there has been no prospective, multicenter, randomized controlled trial evaluating any differences in local recurrence rates (LRRs) between NSM and standard mastectomy to date. Some current studies8–18 have demonstrated inconsistent LRRs following NSM for primary breast cancer, in the range of 0–28.4% (most were less than 5%). Currently, to reduce the recurrence risk in the remaining breast tissue, breast irradiation is applied after breast-conserving surgery, which preserves the NAC. Thus, 4
ACCEPTED MANUSCRIPT it might be assumed that irradiation of the NAC may also play some roles in reducing the LRR following NSM for breast cancer. However, there is little evidence in the literature in regard to that to the best of our knowledge. Benediktsson et al.12
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investigated the effect of postoperative radiotherapy on NSM combined with immediate breast reconstruction, and concluded that the LRRs in the groups with and without radiotherapy were 8.5% and 28.4% (P = 0.025), respectively. Additionally,
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Petit et al.26 first reported the results of the electron beam intraoperative radiotherapy
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(ELIOT) study in the last decade. ELIOT combined NSM with intraoperative therapy (IORT), which delivered a single fractional dose of radiation with a linear accelerator directly to the NAC during the operation. With a median follow-up time of 20 months (range, 1–69 months), ELIOT revealed that 14 out of 830 cases (1.7%) suffered local
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recurrences, but none were observed in the NAC27. The operational principle of Novac-7 (Hitesys SPA, Aprilia, Italy), a device used in ELIOT, involved positioning the collimator of linear accelerator to contact over the entire NAC 26. So the
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radioactive ray is transmitted from the surface to the fundus of the NAC.
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Another innovative IORT device, a mobile X-ray system (Intrabeam®; Carl Zeiss, Oberkochen, Germany), is in use worldwide28. A homogeneous dose distribution is obtained on the surface of its spherical applicator. The applicator is fixed to the end of the system’s articulated arm, which is flexible with six degrees of freedom. Owing to this different design from Novac-7’s, the spherical applicator of Intrabeam® can be placed beneath the NAC easily. Taking advantages of (1) a single high-dose of IORT, which may reduce the risk of proliferation of residual tumor cells in the NAC before 5
ACCEPTED MANUSCRIPT delayed administrations of chemotherapy or radiotherapy theoretically, and (2) a dose fall-off from the fundus towards the surface of the NAC, which may mimic the direction of tumor infiltration from macroscopic tumor to the NAC in most cases, we
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have explored a novel approach to expand the applications of Intrabeam®. The shortterm results of safety and feasibility of Intrabeam® IORT in NSM with breast
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reconstruction for breast cancer patients are presented here.
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Patients and Methods
The current study complied with the Declaration of Helsinki and was approved by the Ethics Committee of the first affiliated hospital of Guangzhou Medical University with the informed consent from each study subject. This interdisciplinary approach,
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NSM with Intrabeam® IORT and breast reconstruction, was carried out by a team of breast surgeons, radiation oncologists, and technicians. Patient selection
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From December 2012 to June 2013, patients undergoing NSM combined with
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IORT and breast reconstruction were continuously enrolled in the study. All of them were admitted to the breast surgery department of the first affiliated hospital of Guangzhou Medical University. Inclusion criteria were: breast carcinoma (including ductal/lobular carcinoma in situ); multifocal and multicentric tumors; unifocal or unicentric tumor unsuitable for breast-conserving surgery; diffuse suspicious or malignant-appearing
microcalcifications;
primary
tumor
or
suspicious
microcalcifications located at least 1 cm away from the areola margin; refusing 6
ACCEPTED MANUSCRIPT breast-conserving surgery. Exclusion criteria included: pregnant women; Paget’s disease; bloody discharge or nipple retraction; and positive intraoperative retroareolar frozen section.
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Surgical technique (1) Sentinel lymph node biopsy with methylene blue was performed through a 2- to 3-cm axillary incision. (2) A short arc periareolar incision with lateral radial extension
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or lateral fusiform incision, ending at the anterior axillary line, was drawn for NSM
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(Figure 1). This surgical approach provided excellent access not only to the breast tissue in all four quadrants, but also for procedures such as axillary exploration if necessary, IORT to the NAC, and breast reconstruction. Subcutaneous dissection of the breast, with a thick flap for the NAC and a thin flap for the remaining breast tissue,
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was done by the use of electrocautery. To better preserve the blood supply of the NAC, sharp dissection with a scalpel or scissors was then carried out beneath the NAC and the adjacent area to ensure a 3- to 5-mm-thick glandular layer26. A biopsy specimen
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was taken from the top layer of the tissue beneath the NAC obtained by sharp
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dissection and sent for intraoperative frozen section analysis. If the intraoperative frozen section was positive for tumor in one or more sentinel lymph nodes, axillary dissection was undertaken. (3) Before IORT, the possibility of successfully preserving the NAC was evaluated. The NAC would be removed in case of identification of malignant cells beneath the NAC at frozen section, or expectation of high risk of necrosis postoperatively according to the color and blood supply of the NAC. (4) Intrabeam® IORT to the NAC was performed in the operating room. (5) After IORT, 7
ACCEPTED MANUSCRIPT breast reconstruction was then performed with a silicone gel-filled breast implant or an expander, which was placed in a complete muscular pocket by undermining the pectoralis major and the serratus anterior. The silicone gel-filled breast implant and
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the expander were indicated for patients with negative and positive sentinel lymph nodes, respectively. In patients with positive sentinel lymph nodes, delayed breast reconstruction with a silicone gel-filled breast implant would be arranged after
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completion of postchemotherapy radiation therapy. CT treatment planning was
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utilized in all cases with postoperative radiotherapy. The radiation areas included chest wall, infraclavicular and supraclavicular areas ± internal mammary nodes. All dose schedules were given five days per week, with 2 Gy per fraction to a total dose of 50-60 Gy.
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Intrabeam® IORT Technique
Intrabeam® (Carl Zeiss) is a mobile IORT device, which has a balanced floor stand and a flexible articulated arm (Figure 2). An electron beam drift tube (3.2 mm in
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diameter) is fixed at the end of the arm29. A spherical applicator with a cone-shaped
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shank at the bottom (Figure 2) is placed upside down to sheath the tube during the IORT. Soft X-rays with low energy (50 kV) are emitted after electron beam hitting the gold target at the tip of tube and modulated by a spherical applicator to give a uniform dose in a spherical field29,30. Various diameters, in the range of 1.5–5.0 cm, of the applicators are available. According to the size of the NAC, an appropriate applicator was fixed to the end of the articulated arm and was placed beneath the NAC. The flap of the NAC was 8
ACCEPTED MANUSCRIPT attached to the spherical applicator surface. To achieve a uniform dose to the NAC, traction by suturing at the edge of the areola was sometimes necessary, holding the pliable flap to the applicator surface. A piece of round shielding material (tungsten-
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filled polyurethane) was cut into an appropriate shape, and covered the exposed surface of the applicator to shield the chest wall (Figure 3), ensuring that the dose was confined to the NAC (including the remaining glandular tissue beneath it) and the
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adjacent flap. A total single dose of 16 Gy at the surface of the applicator was
and the size of the applicator.
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employed in this study. The irradiation time differed according to the prescribed dose
Parameters of IORT are summarized in Table 1. Figure 4 shows the depth-dose curve of Intrabeam® treatment in a case with a 2.5-cm-size applicator.
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Outcomes
Outpatient follow-up was scheduled every 1–2 months in the first year. The shortterm outcomes were assessed, including complications, acute radiation injury,
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sensitivity of the NAC, the contour of the breasts, relapse-free survival, metastasis-
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free survival, and overall survival. Complications were recorded on a specialized checklist: the skin of the NAC, delayed wound healing, wound infection, hematoma, and seroma. The criteria of acute radiation injury (within 3 months) were based on the Radiation Therapy Oncology Group (RTOG version 2.0). The patient-generated subjective assessment of the NAC sensitivity was scored by applying a piece of printing paper to touch the NACs bilaterally27. The contour of the breasts was scored by a mean value generated from the patient and the surgeon, according to the 9
ACCEPTED MANUSCRIPT symmetry of breasts, and any discoloration, radiodystrophy, or necrosis of the treated NAC. Scores were divided into “poor” (0–3), “medium” (4–6), and “good” (7–10).
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Results Seven female patients underwent Intrabeam® IORT at the time of NSM followed by breast reconstruction. All of them had unilateral breast cancer, and none of them
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received prophylactic mastectomy. No case was excluded because of positive
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intraoperative retroareolar frozen section or poor local bleeding of the NAC that needed to be removed intraoperatively. All seven patients were followed with a median follow-up of 7 months (range, 4–10 months). The median patient age was 48 years (range, 35–59 years). Sentinel lymph node biopsy was undertaken successfully
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in all seven cases, with concordance between frozen and paraffin wax sections. Most of the tumor sizes (5 cases) were between 2 and 5 cm, another two were larger than 5 cm. Zero, 1–3, and more than 3 positive lymph nodes were found in four, two, and
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one case, respectively. The histopathologic types included: invasive ductal carcinoma
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(four cases), invasive lobular carcinoma (two cases), and mucinous adenocarcinoma (one case). Four patients underwent immediate breast reconstruction with a silicone gel-filled breast implant, another three patients underwent breast reconstruction with an expander.
After removing the drainage tube, no severe hematomas or seromas occurred that needed needle aspiration or incision. No wound infection needing intravenous antibiotics was observed after operation. Only one patient complained of mild pain in 10
ACCEPTED MANUSCRIPT the irradiation field on the skin, which relieved spontaneously within 2 weeks. Adjuvant therapies were carried out on schedule for the seven patients postoperatively. There was no acute heart failure, or acute radiation injury in lung (≥ Grade 1) or
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hematological system (leucopenia, neutropenia, or thrombocytopenia, ≥ Grade 2) at the follow-up visit.
Six out of seven cases showed mild congestion or insufficiency of blood supply to
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the NAC in the first 4 weeks. All of them resolved gradually, with some superficial
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sloughing. Till the last visit, three cases had slight pigmentation of the NAC, but no total or partial necrosis of the NAC had appeared in any seven cases. In all seven cases, partial or total decrease of the NAC sensitivity was noted on the third postoperative day, with “poor” and “medium” sensitivity scores for five cases and two
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cases, respectively. Most improved over time, with three cases rated “poor” and four cases rated “medium” at the last visit. With a median follow-up of 7 months, relapsefree survival, metastasis-free survival, and overall survival were all 100%. No implant
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or expander was removed for infection or capsular contracture during the early
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follow-up. The assessments of the contour of the breasts manifested as three cases rated “medium” and four cases rated “good” (Figure 5).
Discussion
The advantage of NSM is preserving a natural-appearing NAC and some NAC sensation. Existing data8–25 have focused on the involvement of the NAC, LRR after NSM, or ameliorating the surgical techniques to reduce the complications after NSM. 11
ACCEPTED MANUSCRIPT However, agreement has not been reached about the criteria of indications and contraindications of NSM, standard incision, the thickness of remaining glandular tissue beneath the areola, and the effectiveness of intraoperative frozen section
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assessment of retroareolar tissue. In addition, whole-breast or accelerated partialbreast irradiation is necessary for breast-conserving surgery, which preserves the NAC31. It is worth considering the effect of radiotherapy on NSM. Limited studies12,27
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have evaluated the oncologic risks of NSM with postoperative radiotherapy or IORT.
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Getting inspiration from them, this pilot study shed new light on broadening the applications of Intrabeam® IORT for breast cancer.
Intrabeam® is the most widely used mobile IORT device so far. The initial experience using Intrabeam® IORT for breast cancer was outlined in a pilot study
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called “TARGIT” (Targeted intra-operative radiotherapy)32. The data (Phase III) from TARGIT29 for breast-conserving surgery showed that the radiotherapy complication (RTOG grade 3 or 4) rate was lower in the IORT group (n=1 113) than that in the
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external beam radiotherapy group (n=1 119) (P = 0.002), and there was no significant
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difference in local recurrence between the two groups at 4 years. Another singleinstitution study33 pointed out that Intrabeam® IORT was well tolerated with low morbidity in breast-conserving surgery. These results may partially support the assumption that Intrabeam® system has a small high physical dose region which would increase acute tumor effects while reducing damage to the healthy tissue and long-term toxic effects30. Furthermore, Herskind et al.34 concluded that the relative biologic effectiveness was higher close to the applicator surface and lower at greater 12
ACCEPTED MANUSCRIPT distances from the applicator, compared with conventional fractionation. On the basis of the in vitro experimental data from Belletti et al.35, the stimulatory effects of proliferation, migration, and invasion of breast cancer cell lines were almost
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completely abrogated in the wound fluids from Intrabeam® IORT-treated patients. In addition, Punglia et al.36 found that starting radiotherapy as soon as possible could minimize the LRR in older women with breast cancer. If so, IORT may have an
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additional advantage, compared with fractionated postoperative radiotherapy.
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The choice of a single dose of 16 Gy for Intrabeam® IORT in this pilot study was based upon the followings: (1) Intrabeam® IORT had a steep dose fall-off with increasing distance from the applicator surface in soft tissue30. For example, an average dose of 13.52 Gy (range, 11.29–16.65 Gy), measured between applicator
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surface and breast tissue, would attenuate to an average dose of 2.22 Gy (range, 0.88– 4.69 Gy) and 0.29 Gy (range, 0.03–0.67 Gy) with 1–2 cm and 5–10 cm away from the applicator, respectively37. In our study, most of the distances from target tissue to the
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applicator surface were less than 1 cm, except for large and elongated nipples. Thus,
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the received dose to the NAC was high with a single dose of 16 Gy. The possibility of radiation injury to the normal tissues would be low, especially using a piece of shielding material. (2) Delivering a single dose of 20 Gy to the remaining breast tissue demonstrated good safety and tolerability in breast-conserving surgery with Intrabeam® IORT29,33. Moreover, Deneve et al.33 emphasized that maintaining a distance of at least 1 cm between the applicator and the nearest skin margin in breastconserving surgery was important for avoiding skin-related toxicity. Since most of the 13
ACCEPTED MANUSCRIPT target distances were less than 1 cm in our study, it was reasonable to choose a dose of less than 20 Gy. (3) Using the Novac-7 system, the feasibility of delivering a total dose of 16 Gy from the outside of the NAC had been preliminarily verified in NSM
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with IORT27. It is noteworthy that the applicator of Intrabeam® was placed inside of the skin envelope in our study, and the operational principles of Intrabeam® system and Novac-7 system are not the same. Therefore, any different effects of the same
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irradiation doses delivered by these two devices should be taken into consideration.
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Our preliminary results reveal very low risks of complications in NSM with Intrabeam® IORT, such as hematoma or seroma needing interventions, wound infection needing intravenous antibiotics, pain in the radiation field, or some major toxicities cause by radiation. Intrabeam® IORT would not delay the start time of
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adjuvant therapies. The procedure of Intrabeam® IORT, including the preparation, only took about half an hour. Because the X-rays generated from the Intrabeam ® device were transmitted from the fundus to the surface of the NAC, the glandular
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tissue beneath the NAC would receive a larger dose than the surface of the NAC.
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Owing to the spherical dose distribution of Intrabeam®38, we ensured the attachment of the NAC flap to the spherical applicator surface to achieve a uniform receiving dose.
The incidences of mild congestion, insufficiency of blood supply, and superficial sloughing of the NAC were high in our study. The ELIOT studies showed that 2 of 25 patients had superficial skin areolar slough26 and the average value of NAC discoloration was 8 (10 being optimum)27. They also demonstrated one case (4.0%) of 14
ACCEPTED MANUSCRIPT total necrosis of the NAC necessitating subsequent removal26. Total or partial necrosis were observed in 90 of the 1,001 NSM cases (9.0%) and the NAC was removed in 50 cases (5.0%)27. In our study, no total or partial necrosis of the NAC has been observed
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in the seven cases. Preserving the sensitivity of the NAC after NSM with IORT remains an unsolved problem both in our study and in the ELIOT study. One study26 showed that in 25
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cases, partial normalization of sensitivity was observed in seven cases (28.0%) after
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2–8 months, and in one case (4.0%) a very well-conserved sensitivity completely disappeared 3 months after the surgery. Another27 concluded that the average score of sensitivity of the areola and the periareolar area was 2 (10 being optimal), and only 15% of the patients recovered some kind of sensitivity a year after the operation. Similarly,
noticed in our study.
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the phenomenon of gradual improvement in sensitivity after an operation was also
In our study, no implant or expander was removed and no local recurrence or
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metastasis occurred during the early follow-up. In the three cases with “medium” in
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the assessment of the contour of the breasts, two were still of insufficient filling of the expanders till the last visit, another one was of a large sagging contralateral breast that affected the symmetry. The single dose of 16 Gy currently used to the NAC in our study is still under evaluation. The followings will be taken into account in a future study with a larger sample size and a longer follow-up: short-term and long-term side effects associated with Intrabeam® IORT; tailoring the radiation dose (dose reduction probably) to 15
ACCEPTED MANUSCRIPT reduce the NAC complications (especially for the loss of sensitivity) without decreasing the relapse-free survival, metastasis-free survival, or overall survival; determining the appropriate thickness of remaining glandular tissue beneath the NAC;
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finding the relationships between the total dose and the size of the NAC or the thickness of the target tissue (from the bottom of remaining glandular tissue to the areola skin and the tip of nipple); choosing an appropriate spherical applicator
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individually for a better proportion of the attachment of the NAC flap to the applicator;
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and formulating the indications for Intrabeam® IORT in NSM with breast reconstruction for breast cancer patients.
Conclusion
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Our initial experience suggested that Intrabeam® IORT might be a feasible and convenient approach for NSM with breast reconstruction. This is likely to have a
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contraindicated.
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bright future for the breast cancer patients in whom breast-conserving surgery is
Clinical Practice Points
The role of nipple sparing mastectomy (NSM) is still controversial, mainly owing to the oncologic safety of the nipple-areola complex (NAC). Irradiation of the NAC may play some roles in reducing the local recurrence rate following NSM for breast cancer. But there is little evidence in the literature in regard to that to the best of our knowledge. 16
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Intrabeam® (Carl Zeiss, Germany) is the most widely used mobile intraoperative radiotherapy (IORT) device to date. However, the current reported application of Intrabeam in breast cancer is restricted to breast-conserving surgery. In the current study, Intrabeam® IORT was carried out in NSM with breast
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reconstruction. With a single dose of 16 Gy, the median radiation time was 13 min 14 sec in the seven cases. No acute radiation injury with symptoms (heart,
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lung, or hematological system), NAC necrosis, local recurrence, or metastasis
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was observed in the short term follow-up. Although every patient had reduction in NAC sensitivity, the contours of the breasts (including the NAC) were satisfactory.
We believe these findings are likely to have a bright future for the breast cancer
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patients in whom breast-conserving surgery is contraindicated, and they would be of great interest to breast surgeons.
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Acknowledgments
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The authors would like to thank Dr. Daoli Liu for assistance with reviewing and validating the data of intraoperative radiotherapy.
Disclosure
All authors have no conflicts of interest.
References 17
ACCEPTED MANUSCRIPT 1.
Long L. The use of nipple-sparing mastectomy in patients with breast cancer. Clin J Oncol Nurs 2013; 17:68-72.
2.
Costa MP, Ferreira MC. Aesthetic quality of the nipple-areola complex in breast
3.
RI PT
reconstruction with a new local graft technique. Aesthetic Plast Surg 2009; 33:774-9. Fitoussi AD, Pollet AG, Couturaud B, et al. Nipple and areola reconstruction by tattooing, "F" and "Z" flaps. Ann Chir Plast Esthet 2008; 53:348-57.
Yanaga H. Nipple-areola reconstruction with a dermal-fat flap: technical improvement from
SC
4.
5.
M AN U
rolled auricular cartilage to artificial bone. Plast Reconstr Surg 2003; 112:1863-9. Heitland A, Markowicz M, Koellensperger E, et al. Long-term nipple shrinkage following augmentation by an autologous rib cartilage transplant in free DIEP-flaps. J Plast Reconstr Aesthet Surg 2006; 59:1063-7.
Mohamed SA, Parodi PC. A modified technique for nipple-areola complex reconstruction.
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6.
Indian J Plast Surg 2011; 44:76-80. 7.
Wellisch DK, Schain WS, Noone RB, et al. The psychological contribution of nipple addition
Petit JY, Veronesi U, Orecchia R, et al. Risk factors associated with recurrence after nipple-
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8.
EP
in breast reconstruction. Plast Reconstr Surg 1987; 80:699-704.
sparing mastectomy for invasive and intraepithelial neoplasia. Ann Oncol 2012; 23:2053-8. 9.
de Alcantara Filho P, Capko D, Barry JM, et al. Nipple-sparing mastectomy for breast cancer and risk-reducing surgery: the Memorial Sloan-Kettering Cancer Center experience. Ann Surg Oncol 2011; 18:3117-22.
10. Gerber B, Krause A, Dieterich M, et al. The oncological safety of skin sparing mastectomy with conservation of the nipple-areola complex and autologous reconstruction: an extended 18
ACCEPTED MANUSCRIPT follow-up study. Ann Surg 2009; 249:461-8. 11. Garwood ER, Moore D, Ewing C, et al. Total skin-sparing mastectomy: complications and local recurrence rates in 2 cohorts of patients. Ann Surg 2009; 249:26-32.
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12. Benediktsson KP, Perbeck L. Survival in breast cancer after nipple-sparing subcutaneous mastectomy and immediate reconstruction with implants: a prospective trial with 13 years median follow-up in 216 patients. Eur J Surg Oncol 2008; 34:143-8.
SC
13. Petit JY, Veronesi U, Rey P, et al. Nipple-sparing mastectomy: risk of nipple-areolar
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recurrences in a series of 579 cases. Breast Cancer Res Treat 2009; 114:97-101. 14. Jensen JA, Orringer JS, Giuliano AE. Nipple-sparing mastectomy in 99 patients with a mean follow-up of 5 years. Ann Surg Oncol 2011; 18:1665-70.
15. Harness JK, Vetter TS, Salibian AH. Areola and nipple-areola-sparing mastectomy for breast
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cancer treatment and risk reduction: report of an initial experience in a community hospital setting. Ann Surg Oncol 2011; 18:917-22.
16. Kim HJ, Park EH, Lim WS, et al. Nipple areola skin-sparing mastectomy with immediate
EP
transverse rectus abdominis musculocutaneous flap reconstruction is an oncologically safe
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procedure: a single center study. Ann Surg 2010; 251:493-8. 17. Voltura AM, Tsangaris TN, Rosson GD, et al. Nipple-sparing mastectomy: critical assessment of 51 procedures and implications for selection criteria. Ann Surg Oncol 2008; 15:3396-401. 18. Paepke S, Schmid R, Fleckner S, et al. Subcutaneous mastectomy with conservation of the nipple-areola skin: broadening the indications. Ann Surg 2009; 250:288-92. 19. Menon RS, van Geel AN. Cancer of the breast with nipple involvement. Br J Cancer 1989; 59:81-4. 19
ACCEPTED MANUSCRIPT 20. Verma GR, Kumar A, Joshi K. Nipple involvement in peripheral breast carcinoma: a prospective study. Indian J Cancer 1997; 34:1-5. 21. Laronga C, Kemp B, Johnston D, et al. The incidence of occult nipple-areola complex
RI PT
involvement in breast cancer patients receiving a skin-sparing mastectomy. Ann Surg Oncol 1999; 6:609-13.
22. Pirozzi PR, Rossetti C, Carelli I, et al. Clinical and morphological factors predictive of occult
SC
involvement of the nipple-areola complex in mastectomy specimens. Eur J Obstet Gynecol
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Reprod Biol 2010; 148:177-81.
23. Simmons RM, Brennan M, Christos P, et al. Analysis of nipple/areolar involvement with mastectomy: can the areola be preserved? Ann Surg Oncol 2002; 9:165-8. 24. Brachtel EF, Rusby JE, Michaelson JS, et al. Occult nipple involvement in breast cancer:
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clinicopathologic findings in 316 consecutive mastectomy specimens. J Clin Oncol 2009; 27:4948-54.
25. Vyas JJ, Chinoy RF, Vaidya JS. Prediction of nipple and areola involvement in breast cancer.
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Eur J Surg Oncol 1998; 24:15-6.
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26. Petit JY, Veronesi U, Orecchia R, et al. The nipple-sparing mastectomy: early results of a feasibility study of a new application of perioperative radiotherapy (ELIOT) in the treatment of breast cancer when mastectomy is indicated. Tumori 2003; 89:288-91. 27. Petit JY, Veronesi U, Orecchia R, et al. Nipple sparing mastectomy with nipple areola intraoperative radiotherapy: one thousand and one cases of a five years experience at the European institute of oncology of Milan (EIO). Breast Cancer Res Treat 2009; 117:333-8. 28. Njeh CF, Saunders MW, Langton CM. Accelerated Partial Breast Irradiation (APBI): A 20
ACCEPTED MANUSCRIPT review of available techniques. Radiat Oncol 2010; 5:90. 29. Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective,
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randomised, non-inferiority phase 3 trial. Lancet 2010; 376:91-102. 30. Vaidya JS, Tobias JS, Baum M, et al. Intraoperative radiotherapy for breast cancer. Lancet Oncol 2004; 5:165-73.
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31. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated Partial Breast Irradiation Consensus
Biol Phys 2009; 74:987-1001.
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Statement From the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol
32. Vaidya JS, Baum M, Tobias JS, et al. Targeted intra-operative radiotherapy (Targit): an innovative method of treatment for early breast cancer. Ann Oncol 2001; 12:1075-80.
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33. Deneve JL, Hoefer RA Jr, Harris EE, et al. Accelerated partial breast irradiation: A Review and Description of an Early North American Surgical Experience With the Intrabeam Delivery System. Cancer Control 2012; 19:295-308.
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34. Herskind C, Griebel J, Kraus-Tiefenbacher U, et al. Sphere of equivalence--a novel target
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volume concept for intraoperative radiotherapy using low-energy X rays. Int J Radiat Oncol Biol Phys 2008; 72:1575-81. 35. Belletti B, Vaidya JS, D'Andrea S, et al. Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding. Clin Cancer Res 2008; 14:1325-32. 36. Punglia RS, Saito AM, Neville BA, et al. Impact of interval from breast conserving surgery to radiotherapy on local recurrence in older women with breast cancer: retrospective cohort 21
ACCEPTED MANUSCRIPT analysis. BMJ 2010; 340:c845. 37. Avanzo M, Rink A, Dassie A, et al. In vivo dosimetry with radiochromic films in low-voltage intraoperative radiotherapy of the breast. Med Phys 2012; 39:2359-68.
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brachytherapy. Int J Radiat Oncol Biol Phys 2009; 74:1298-305.
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38. Schneider F, Fuchs H, Lorenz F, et al. A novel device for intravaginal electronic
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Figure legends:
Figure 1 Incision for nipple-sparing mastectomy
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Figure 2 (a) Intrabeam® device. (b) Spherical applicators with cone-shaped shanks (with permission from Carl Zeiss, Oberkochen, Germany)
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Figure 3 Protection of the chest wall by a piece of shielding material
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(tungsten-filled polyurethane)
Figure 4 The depth-dose curve of Intrabeam® treatment in a case with a 2.5cm-size applicator
Figure 5 The contour of the breasts (two months after operation)
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ACCEPTED MANUSCRIPT Table 1 Parameters of Intrabeam® intraoperative radiotherapy for seven patients undergoing nipple sparing mastectomy with breast reconstruction Variable
N
beneath the areola 5
4-5 mm
2
＞ 2.5 cm, ≤ 3.0 cm ＞ 3.0 cm, ≤ 4.0 cm ＞ 4.0 cm, ≤ 4.5 cm
2.0 cm 2.5 cm
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Applicator diameter
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Diameter of the nipple-areola complex
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3-4 mm
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Thickness of remaining glandular tissue
1
5
1
1 6 16 Gy
Median radiation time
13 min 14 sec
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Radiation dose at the applicator surface
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S1526-8209(14)00083-4
DOI:
10.1016/j.clbc.2014.04.002
Reference:
CLBC 272
To appear in:
Clinical Breast Cancer
Received Date: 25 December 2013 Revised Date:
31 March 2014
Accepted Date: 23 April 2014
Please cite this article as: Pan L, Zheng W, Ye X, Chen L, Ke Y, Wan M, Tang W, Gao J, Zhang X, A novel approach of INTRABEAM intraoperative radiotherapy for nipple-sparing mastectomy with breast reconstruction, Clinical Breast Cancer (2014), doi: 10.1016/j.clbc.2014.04.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT A novel approach of INTRABEAM intraoperative radiotherapy for nipplesparing mastectomy with breast reconstruction
Lingxiao Pan1, Wenbo Zheng1, Xigang Ye1, Lun Chen1, Yaohua Ke2, Minghui
1
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Wan3, Wei Tang1, Jin Gao 1, Xiaoshen Zhang1
Department of breast surgery, the first affiliated hospital of Guangzhou Medical
University, Guangzhou, People’s Republic of China
Metabolic bone disease and genetic research unit, department of osteoporosis and
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2
bone diseases, Shanghai Jiao Tong University, affiliated sixth people’s hospital,
3
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Shanghai, People’s Republic of China
Department of radiation oncology, the first affiliated hospital of Guangzhou Medical
University, Guangzhou, People’s Republic of China
A
running
title:
INTRABEAM
nipple-sparing
mastectomy
with
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reconstruction
for
Correspondence and reprint requests to: Dr Wenbo Zheng, MD, Department of breast
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surgery, the first affiliated hospital of Guangzhou Medical University, No. 151, Yanjiang West Road, Guangzhou, P.R.China (e-mail: [email protected])
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Number of Words in abstract: 251 Number of Words in manuscript: 3295
All authors have no conflicts of interest.
1
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Abstract This study aims to broaden the application of Intrabeam® intraoperative radiotherapy in nipple-sparing mastectomy with breast reconstruction for breast
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cancer. A single dose of 16 Gy was carried out in seven patients receiving intraoperative radiotherapy. The median radiation time was 13 min 14 sec. No acute radiation injury with symptoms was observed and the short-term
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outcomes were good.
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Background: Despite the advancement and increasing use of breast-conserving surgery, mastectomies, including nipple-sparing mastectomy (NSM), are still carried out in a portion of breast cancer patients. However, the role of NSM is still controversial, mainly owing to the oncologic safety of the NAC. Intrabeam® (Carl
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Zeiss, Germany) is the most widely used mobile intraoperative radiotherapy (IORT) device to date. This pilot study aims to broaden the application of Intrabeam® system for breast cancer, investigating the feasibility of Intrabeam® IORT in NSM with
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breast reconstruction. Patients and Methods: From December 2012 to June 2013,
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seven female patients with breast cancer were enrolled in the study. NSM with or without axillary dissection was performed first. After confirming negative retroareolar frozen section and no poor local bleeding of the NAC, Intrabeam® IORT was carried out, with a single dose of 16 Gy, followed by breast reconstruction. The complications and short-term outcomes were assessed. Results: The median radiation time was 13 min 14 sec in the seven cases. One patient complained of mild pain in the radiation field on the skin in the first 2 weeks. All seven patients were followed for a median 2
ACCEPTED MANUSCRIPT time of 7 months. No acute radiation injury with symptoms (heart, lung, or hematological system), NAC necrosis, local recurrence, or metastasis was observed. Although every patient had reduction in NAC sensitivity, the contours of the breasts
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(including the NAC) were satisfactory. Conclusions: Intrabeam® IORT may be a feasible and convenient approach for NSM with breast reconstruction in patients with
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breast cancer.
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Keywords: Breast cancer, intraoperative radiotherapy, nipple sparing, mastectomy,
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breast reconstruction
3
ACCEPTED MANUSCRIPT Introduction Nowadays, mastectomy is usually performed to treat breast cancer patients with medium or large size tumors, multicentric tumors, recurrent foci after conservative
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treatment, and patients who reject or have no other indications for breast-conserving surgery. Standard mastectomy technique requires removal of the nipple-areola complex (NAC). Long1 has mentioned that “…The loss of the nipple may be as or
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more psychologically significant than the loss of the breast mound itself”. Albeit it is
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possible to create a NAC, a second-stage procedure of plastic surgery, sometimes with additional revisions, is usually needed2,3. Most importantly, whether autologous cartilage, skin flap, or artificial material is used in NAC reconstruction3-6, the appearance is not natural, and loss of NAC sensation is inevitable. Both may affect
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the patient’s psychological adjustment1,7.
In recent years, there has been increasing interest in the technique of nipple sparing mastectomy (NSM)8–18. Its role is still controversial, based upon its oncologic safety.
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Serial histological sections have revealed that involvement of the NAC in mastectomy
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specimens varied from 0–58%, mostly less than 20%19–25. What’s more, there has been no prospective, multicenter, randomized controlled trial evaluating any differences in local recurrence rates (LRRs) between NSM and standard mastectomy to date. Some current studies8–18 have demonstrated inconsistent LRRs following NSM for primary breast cancer, in the range of 0–28.4% (most were less than 5%). Currently, to reduce the recurrence risk in the remaining breast tissue, breast irradiation is applied after breast-conserving surgery, which preserves the NAC. Thus, 4
ACCEPTED MANUSCRIPT it might be assumed that irradiation of the NAC may also play some roles in reducing the LRR following NSM for breast cancer. However, there is little evidence in the literature in regard to that to the best of our knowledge. Benediktsson et al.12
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investigated the effect of postoperative radiotherapy on NSM combined with immediate breast reconstruction, and concluded that the LRRs in the groups with and without radiotherapy were 8.5% and 28.4% (P = 0.025), respectively. Additionally,
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Petit et al.26 first reported the results of the electron beam intraoperative radiotherapy
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(ELIOT) study in the last decade. ELIOT combined NSM with intraoperative therapy (IORT), which delivered a single fractional dose of radiation with a linear accelerator directly to the NAC during the operation. With a median follow-up time of 20 months (range, 1–69 months), ELIOT revealed that 14 out of 830 cases (1.7%) suffered local
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recurrences, but none were observed in the NAC27. The operational principle of Novac-7 (Hitesys SPA, Aprilia, Italy), a device used in ELIOT, involved positioning the collimator of linear accelerator to contact over the entire NAC 26. So the
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radioactive ray is transmitted from the surface to the fundus of the NAC.
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Another innovative IORT device, a mobile X-ray system (Intrabeam®; Carl Zeiss, Oberkochen, Germany), is in use worldwide28. A homogeneous dose distribution is obtained on the surface of its spherical applicator. The applicator is fixed to the end of the system’s articulated arm, which is flexible with six degrees of freedom. Owing to this different design from Novac-7’s, the spherical applicator of Intrabeam® can be placed beneath the NAC easily. Taking advantages of (1) a single high-dose of IORT, which may reduce the risk of proliferation of residual tumor cells in the NAC before 5
ACCEPTED MANUSCRIPT delayed administrations of chemotherapy or radiotherapy theoretically, and (2) a dose fall-off from the fundus towards the surface of the NAC, which may mimic the direction of tumor infiltration from macroscopic tumor to the NAC in most cases, we
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have explored a novel approach to expand the applications of Intrabeam®. The shortterm results of safety and feasibility of Intrabeam® IORT in NSM with breast
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reconstruction for breast cancer patients are presented here.
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Patients and Methods
The current study complied with the Declaration of Helsinki and was approved by the Ethics Committee of the first affiliated hospital of Guangzhou Medical University with the informed consent from each study subject. This interdisciplinary approach,
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NSM with Intrabeam® IORT and breast reconstruction, was carried out by a team of breast surgeons, radiation oncologists, and technicians. Patient selection
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From December 2012 to June 2013, patients undergoing NSM combined with
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IORT and breast reconstruction were continuously enrolled in the study. All of them were admitted to the breast surgery department of the first affiliated hospital of Guangzhou Medical University. Inclusion criteria were: breast carcinoma (including ductal/lobular carcinoma in situ); multifocal and multicentric tumors; unifocal or unicentric tumor unsuitable for breast-conserving surgery; diffuse suspicious or malignant-appearing
microcalcifications;
primary
tumor
or
suspicious
microcalcifications located at least 1 cm away from the areola margin; refusing 6
ACCEPTED MANUSCRIPT breast-conserving surgery. Exclusion criteria included: pregnant women; Paget’s disease; bloody discharge or nipple retraction; and positive intraoperative retroareolar frozen section.
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Surgical technique (1) Sentinel lymph node biopsy with methylene blue was performed through a 2- to 3-cm axillary incision. (2) A short arc periareolar incision with lateral radial extension
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or lateral fusiform incision, ending at the anterior axillary line, was drawn for NSM
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(Figure 1). This surgical approach provided excellent access not only to the breast tissue in all four quadrants, but also for procedures such as axillary exploration if necessary, IORT to the NAC, and breast reconstruction. Subcutaneous dissection of the breast, with a thick flap for the NAC and a thin flap for the remaining breast tissue,
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was done by the use of electrocautery. To better preserve the blood supply of the NAC, sharp dissection with a scalpel or scissors was then carried out beneath the NAC and the adjacent area to ensure a 3- to 5-mm-thick glandular layer26. A biopsy specimen
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was taken from the top layer of the tissue beneath the NAC obtained by sharp
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dissection and sent for intraoperative frozen section analysis. If the intraoperative frozen section was positive for tumor in one or more sentinel lymph nodes, axillary dissection was undertaken. (3) Before IORT, the possibility of successfully preserving the NAC was evaluated. The NAC would be removed in case of identification of malignant cells beneath the NAC at frozen section, or expectation of high risk of necrosis postoperatively according to the color and blood supply of the NAC. (4) Intrabeam® IORT to the NAC was performed in the operating room. (5) After IORT, 7
ACCEPTED MANUSCRIPT breast reconstruction was then performed with a silicone gel-filled breast implant or an expander, which was placed in a complete muscular pocket by undermining the pectoralis major and the serratus anterior. The silicone gel-filled breast implant and
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the expander were indicated for patients with negative and positive sentinel lymph nodes, respectively. In patients with positive sentinel lymph nodes, delayed breast reconstruction with a silicone gel-filled breast implant would be arranged after
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completion of postchemotherapy radiation therapy. CT treatment planning was
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utilized in all cases with postoperative radiotherapy. The radiation areas included chest wall, infraclavicular and supraclavicular areas ± internal mammary nodes. All dose schedules were given five days per week, with 2 Gy per fraction to a total dose of 50-60 Gy.
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Intrabeam® IORT Technique
Intrabeam® (Carl Zeiss) is a mobile IORT device, which has a balanced floor stand and a flexible articulated arm (Figure 2). An electron beam drift tube (3.2 mm in
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diameter) is fixed at the end of the arm29. A spherical applicator with a cone-shaped
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shank at the bottom (Figure 2) is placed upside down to sheath the tube during the IORT. Soft X-rays with low energy (50 kV) are emitted after electron beam hitting the gold target at the tip of tube and modulated by a spherical applicator to give a uniform dose in a spherical field29,30. Various diameters, in the range of 1.5–5.0 cm, of the applicators are available. According to the size of the NAC, an appropriate applicator was fixed to the end of the articulated arm and was placed beneath the NAC. The flap of the NAC was 8
ACCEPTED MANUSCRIPT attached to the spherical applicator surface. To achieve a uniform dose to the NAC, traction by suturing at the edge of the areola was sometimes necessary, holding the pliable flap to the applicator surface. A piece of round shielding material (tungsten-
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filled polyurethane) was cut into an appropriate shape, and covered the exposed surface of the applicator to shield the chest wall (Figure 3), ensuring that the dose was confined to the NAC (including the remaining glandular tissue beneath it) and the
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adjacent flap. A total single dose of 16 Gy at the surface of the applicator was
and the size of the applicator.
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employed in this study. The irradiation time differed according to the prescribed dose
Parameters of IORT are summarized in Table 1. Figure 4 shows the depth-dose curve of Intrabeam® treatment in a case with a 2.5-cm-size applicator.
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Outcomes
Outpatient follow-up was scheduled every 1–2 months in the first year. The shortterm outcomes were assessed, including complications, acute radiation injury,
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sensitivity of the NAC, the contour of the breasts, relapse-free survival, metastasis-
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free survival, and overall survival. Complications were recorded on a specialized checklist: the skin of the NAC, delayed wound healing, wound infection, hematoma, and seroma. The criteria of acute radiation injury (within 3 months) were based on the Radiation Therapy Oncology Group (RTOG version 2.0). The patient-generated subjective assessment of the NAC sensitivity was scored by applying a piece of printing paper to touch the NACs bilaterally27. The contour of the breasts was scored by a mean value generated from the patient and the surgeon, according to the 9
ACCEPTED MANUSCRIPT symmetry of breasts, and any discoloration, radiodystrophy, or necrosis of the treated NAC. Scores were divided into “poor” (0–3), “medium” (4–6), and “good” (7–10).
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Results Seven female patients underwent Intrabeam® IORT at the time of NSM followed by breast reconstruction. All of them had unilateral breast cancer, and none of them
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received prophylactic mastectomy. No case was excluded because of positive
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intraoperative retroareolar frozen section or poor local bleeding of the NAC that needed to be removed intraoperatively. All seven patients were followed with a median follow-up of 7 months (range, 4–10 months). The median patient age was 48 years (range, 35–59 years). Sentinel lymph node biopsy was undertaken successfully
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in all seven cases, with concordance between frozen and paraffin wax sections. Most of the tumor sizes (5 cases) were between 2 and 5 cm, another two were larger than 5 cm. Zero, 1–3, and more than 3 positive lymph nodes were found in four, two, and
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one case, respectively. The histopathologic types included: invasive ductal carcinoma
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(four cases), invasive lobular carcinoma (two cases), and mucinous adenocarcinoma (one case). Four patients underwent immediate breast reconstruction with a silicone gel-filled breast implant, another three patients underwent breast reconstruction with an expander.
After removing the drainage tube, no severe hematomas or seromas occurred that needed needle aspiration or incision. No wound infection needing intravenous antibiotics was observed after operation. Only one patient complained of mild pain in 10
ACCEPTED MANUSCRIPT the irradiation field on the skin, which relieved spontaneously within 2 weeks. Adjuvant therapies were carried out on schedule for the seven patients postoperatively. There was no acute heart failure, or acute radiation injury in lung (≥ Grade 1) or
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hematological system (leucopenia, neutropenia, or thrombocytopenia, ≥ Grade 2) at the follow-up visit.
Six out of seven cases showed mild congestion or insufficiency of blood supply to
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the NAC in the first 4 weeks. All of them resolved gradually, with some superficial
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sloughing. Till the last visit, three cases had slight pigmentation of the NAC, but no total or partial necrosis of the NAC had appeared in any seven cases. In all seven cases, partial or total decrease of the NAC sensitivity was noted on the third postoperative day, with “poor” and “medium” sensitivity scores for five cases and two
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cases, respectively. Most improved over time, with three cases rated “poor” and four cases rated “medium” at the last visit. With a median follow-up of 7 months, relapsefree survival, metastasis-free survival, and overall survival were all 100%. No implant
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or expander was removed for infection or capsular contracture during the early
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follow-up. The assessments of the contour of the breasts manifested as three cases rated “medium” and four cases rated “good” (Figure 5).
Discussion
The advantage of NSM is preserving a natural-appearing NAC and some NAC sensation. Existing data8–25 have focused on the involvement of the NAC, LRR after NSM, or ameliorating the surgical techniques to reduce the complications after NSM. 11
ACCEPTED MANUSCRIPT However, agreement has not been reached about the criteria of indications and contraindications of NSM, standard incision, the thickness of remaining glandular tissue beneath the areola, and the effectiveness of intraoperative frozen section
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assessment of retroareolar tissue. In addition, whole-breast or accelerated partialbreast irradiation is necessary for breast-conserving surgery, which preserves the NAC31. It is worth considering the effect of radiotherapy on NSM. Limited studies12,27
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have evaluated the oncologic risks of NSM with postoperative radiotherapy or IORT.
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Getting inspiration from them, this pilot study shed new light on broadening the applications of Intrabeam® IORT for breast cancer.
Intrabeam® is the most widely used mobile IORT device so far. The initial experience using Intrabeam® IORT for breast cancer was outlined in a pilot study
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called “TARGIT” (Targeted intra-operative radiotherapy)32. The data (Phase III) from TARGIT29 for breast-conserving surgery showed that the radiotherapy complication (RTOG grade 3 or 4) rate was lower in the IORT group (n=1 113) than that in the
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external beam radiotherapy group (n=1 119) (P = 0.002), and there was no significant
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difference in local recurrence between the two groups at 4 years. Another singleinstitution study33 pointed out that Intrabeam® IORT was well tolerated with low morbidity in breast-conserving surgery. These results may partially support the assumption that Intrabeam® system has a small high physical dose region which would increase acute tumor effects while reducing damage to the healthy tissue and long-term toxic effects30. Furthermore, Herskind et al.34 concluded that the relative biologic effectiveness was higher close to the applicator surface and lower at greater 12
ACCEPTED MANUSCRIPT distances from the applicator, compared with conventional fractionation. On the basis of the in vitro experimental data from Belletti et al.35, the stimulatory effects of proliferation, migration, and invasion of breast cancer cell lines were almost
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completely abrogated in the wound fluids from Intrabeam® IORT-treated patients. In addition, Punglia et al.36 found that starting radiotherapy as soon as possible could minimize the LRR in older women with breast cancer. If so, IORT may have an
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additional advantage, compared with fractionated postoperative radiotherapy.
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The choice of a single dose of 16 Gy for Intrabeam® IORT in this pilot study was based upon the followings: (1) Intrabeam® IORT had a steep dose fall-off with increasing distance from the applicator surface in soft tissue30. For example, an average dose of 13.52 Gy (range, 11.29–16.65 Gy), measured between applicator
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surface and breast tissue, would attenuate to an average dose of 2.22 Gy (range, 0.88– 4.69 Gy) and 0.29 Gy (range, 0.03–0.67 Gy) with 1–2 cm and 5–10 cm away from the applicator, respectively37. In our study, most of the distances from target tissue to the
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applicator surface were less than 1 cm, except for large and elongated nipples. Thus,
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the received dose to the NAC was high with a single dose of 16 Gy. The possibility of radiation injury to the normal tissues would be low, especially using a piece of shielding material. (2) Delivering a single dose of 20 Gy to the remaining breast tissue demonstrated good safety and tolerability in breast-conserving surgery with Intrabeam® IORT29,33. Moreover, Deneve et al.33 emphasized that maintaining a distance of at least 1 cm between the applicator and the nearest skin margin in breastconserving surgery was important for avoiding skin-related toxicity. Since most of the 13
ACCEPTED MANUSCRIPT target distances were less than 1 cm in our study, it was reasonable to choose a dose of less than 20 Gy. (3) Using the Novac-7 system, the feasibility of delivering a total dose of 16 Gy from the outside of the NAC had been preliminarily verified in NSM
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with IORT27. It is noteworthy that the applicator of Intrabeam® was placed inside of the skin envelope in our study, and the operational principles of Intrabeam® system and Novac-7 system are not the same. Therefore, any different effects of the same
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irradiation doses delivered by these two devices should be taken into consideration.
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Our preliminary results reveal very low risks of complications in NSM with Intrabeam® IORT, such as hematoma or seroma needing interventions, wound infection needing intravenous antibiotics, pain in the radiation field, or some major toxicities cause by radiation. Intrabeam® IORT would not delay the start time of
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adjuvant therapies. The procedure of Intrabeam® IORT, including the preparation, only took about half an hour. Because the X-rays generated from the Intrabeam ® device were transmitted from the fundus to the surface of the NAC, the glandular
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tissue beneath the NAC would receive a larger dose than the surface of the NAC.
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Owing to the spherical dose distribution of Intrabeam®38, we ensured the attachment of the NAC flap to the spherical applicator surface to achieve a uniform receiving dose.
The incidences of mild congestion, insufficiency of blood supply, and superficial sloughing of the NAC were high in our study. The ELIOT studies showed that 2 of 25 patients had superficial skin areolar slough26 and the average value of NAC discoloration was 8 (10 being optimum)27. They also demonstrated one case (4.0%) of 14
ACCEPTED MANUSCRIPT total necrosis of the NAC necessitating subsequent removal26. Total or partial necrosis were observed in 90 of the 1,001 NSM cases (9.0%) and the NAC was removed in 50 cases (5.0%)27. In our study, no total or partial necrosis of the NAC has been observed
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in the seven cases. Preserving the sensitivity of the NAC after NSM with IORT remains an unsolved problem both in our study and in the ELIOT study. One study26 showed that in 25
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cases, partial normalization of sensitivity was observed in seven cases (28.0%) after
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2–8 months, and in one case (4.0%) a very well-conserved sensitivity completely disappeared 3 months after the surgery. Another27 concluded that the average score of sensitivity of the areola and the periareolar area was 2 (10 being optimal), and only 15% of the patients recovered some kind of sensitivity a year after the operation. Similarly,
noticed in our study.
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the phenomenon of gradual improvement in sensitivity after an operation was also
In our study, no implant or expander was removed and no local recurrence or
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metastasis occurred during the early follow-up. In the three cases with “medium” in
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the assessment of the contour of the breasts, two were still of insufficient filling of the expanders till the last visit, another one was of a large sagging contralateral breast that affected the symmetry. The single dose of 16 Gy currently used to the NAC in our study is still under evaluation. The followings will be taken into account in a future study with a larger sample size and a longer follow-up: short-term and long-term side effects associated with Intrabeam® IORT; tailoring the radiation dose (dose reduction probably) to 15
ACCEPTED MANUSCRIPT reduce the NAC complications (especially for the loss of sensitivity) without decreasing the relapse-free survival, metastasis-free survival, or overall survival; determining the appropriate thickness of remaining glandular tissue beneath the NAC;
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finding the relationships between the total dose and the size of the NAC or the thickness of the target tissue (from the bottom of remaining glandular tissue to the areola skin and the tip of nipple); choosing an appropriate spherical applicator
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individually for a better proportion of the attachment of the NAC flap to the applicator;
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and formulating the indications for Intrabeam® IORT in NSM with breast reconstruction for breast cancer patients.
Conclusion
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Our initial experience suggested that Intrabeam® IORT might be a feasible and convenient approach for NSM with breast reconstruction. This is likely to have a
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contraindicated.
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bright future for the breast cancer patients in whom breast-conserving surgery is
Clinical Practice Points
The role of nipple sparing mastectomy (NSM) is still controversial, mainly owing to the oncologic safety of the nipple-areola complex (NAC). Irradiation of the NAC may play some roles in reducing the local recurrence rate following NSM for breast cancer. But there is little evidence in the literature in regard to that to the best of our knowledge. 16
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Intrabeam® (Carl Zeiss, Germany) is the most widely used mobile intraoperative radiotherapy (IORT) device to date. However, the current reported application of Intrabeam in breast cancer is restricted to breast-conserving surgery. In the current study, Intrabeam® IORT was carried out in NSM with breast
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reconstruction. With a single dose of 16 Gy, the median radiation time was 13 min 14 sec in the seven cases. No acute radiation injury with symptoms (heart,
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lung, or hematological system), NAC necrosis, local recurrence, or metastasis
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was observed in the short term follow-up. Although every patient had reduction in NAC sensitivity, the contours of the breasts (including the NAC) were satisfactory.
We believe these findings are likely to have a bright future for the breast cancer
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patients in whom breast-conserving surgery is contraindicated, and they would be of great interest to breast surgeons.
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Acknowledgments
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The authors would like to thank Dr. Daoli Liu for assistance with reviewing and validating the data of intraoperative radiotherapy.
Disclosure
All authors have no conflicts of interest.
References 17
ACCEPTED MANUSCRIPT 1.
Long L. The use of nipple-sparing mastectomy in patients with breast cancer. Clin J Oncol Nurs 2013; 17:68-72.
2.
Costa MP, Ferreira MC. Aesthetic quality of the nipple-areola complex in breast
3.
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reconstruction with a new local graft technique. Aesthetic Plast Surg 2009; 33:774-9. Fitoussi AD, Pollet AG, Couturaud B, et al. Nipple and areola reconstruction by tattooing, "F" and "Z" flaps. Ann Chir Plast Esthet 2008; 53:348-57.
Yanaga H. Nipple-areola reconstruction with a dermal-fat flap: technical improvement from
SC
4.
5.
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rolled auricular cartilage to artificial bone. Plast Reconstr Surg 2003; 112:1863-9. Heitland A, Markowicz M, Koellensperger E, et al. Long-term nipple shrinkage following augmentation by an autologous rib cartilage transplant in free DIEP-flaps. J Plast Reconstr Aesthet Surg 2006; 59:1063-7.
Mohamed SA, Parodi PC. A modified technique for nipple-areola complex reconstruction.
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6.
Indian J Plast Surg 2011; 44:76-80. 7.
Wellisch DK, Schain WS, Noone RB, et al. The psychological contribution of nipple addition
Petit JY, Veronesi U, Orecchia R, et al. Risk factors associated with recurrence after nipple-
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8.
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in breast reconstruction. Plast Reconstr Surg 1987; 80:699-704.
sparing mastectomy for invasive and intraepithelial neoplasia. Ann Oncol 2012; 23:2053-8. 9.
de Alcantara Filho P, Capko D, Barry JM, et al. Nipple-sparing mastectomy for breast cancer and risk-reducing surgery: the Memorial Sloan-Kettering Cancer Center experience. Ann Surg Oncol 2011; 18:3117-22.
10. Gerber B, Krause A, Dieterich M, et al. The oncological safety of skin sparing mastectomy with conservation of the nipple-areola complex and autologous reconstruction: an extended 18
ACCEPTED MANUSCRIPT follow-up study. Ann Surg 2009; 249:461-8. 11. Garwood ER, Moore D, Ewing C, et al. Total skin-sparing mastectomy: complications and local recurrence rates in 2 cohorts of patients. Ann Surg 2009; 249:26-32.
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12. Benediktsson KP, Perbeck L. Survival in breast cancer after nipple-sparing subcutaneous mastectomy and immediate reconstruction with implants: a prospective trial with 13 years median follow-up in 216 patients. Eur J Surg Oncol 2008; 34:143-8.
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13. Petit JY, Veronesi U, Rey P, et al. Nipple-sparing mastectomy: risk of nipple-areolar
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recurrences in a series of 579 cases. Breast Cancer Res Treat 2009; 114:97-101. 14. Jensen JA, Orringer JS, Giuliano AE. Nipple-sparing mastectomy in 99 patients with a mean follow-up of 5 years. Ann Surg Oncol 2011; 18:1665-70.
15. Harness JK, Vetter TS, Salibian AH. Areola and nipple-areola-sparing mastectomy for breast
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cancer treatment and risk reduction: report of an initial experience in a community hospital setting. Ann Surg Oncol 2011; 18:917-22.
16. Kim HJ, Park EH, Lim WS, et al. Nipple areola skin-sparing mastectomy with immediate
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transverse rectus abdominis musculocutaneous flap reconstruction is an oncologically safe
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procedure: a single center study. Ann Surg 2010; 251:493-8. 17. Voltura AM, Tsangaris TN, Rosson GD, et al. Nipple-sparing mastectomy: critical assessment of 51 procedures and implications for selection criteria. Ann Surg Oncol 2008; 15:3396-401. 18. Paepke S, Schmid R, Fleckner S, et al. Subcutaneous mastectomy with conservation of the nipple-areola skin: broadening the indications. Ann Surg 2009; 250:288-92. 19. Menon RS, van Geel AN. Cancer of the breast with nipple involvement. Br J Cancer 1989; 59:81-4. 19
ACCEPTED MANUSCRIPT 20. Verma GR, Kumar A, Joshi K. Nipple involvement in peripheral breast carcinoma: a prospective study. Indian J Cancer 1997; 34:1-5. 21. Laronga C, Kemp B, Johnston D, et al. The incidence of occult nipple-areola complex
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involvement in breast cancer patients receiving a skin-sparing mastectomy. Ann Surg Oncol 1999; 6:609-13.
22. Pirozzi PR, Rossetti C, Carelli I, et al. Clinical and morphological factors predictive of occult
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involvement of the nipple-areola complex in mastectomy specimens. Eur J Obstet Gynecol
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Reprod Biol 2010; 148:177-81.
23. Simmons RM, Brennan M, Christos P, et al. Analysis of nipple/areolar involvement with mastectomy: can the areola be preserved? Ann Surg Oncol 2002; 9:165-8. 24. Brachtel EF, Rusby JE, Michaelson JS, et al. Occult nipple involvement in breast cancer:
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clinicopathologic findings in 316 consecutive mastectomy specimens. J Clin Oncol 2009; 27:4948-54.
25. Vyas JJ, Chinoy RF, Vaidya JS. Prediction of nipple and areola involvement in breast cancer.
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Eur J Surg Oncol 1998; 24:15-6.
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26. Petit JY, Veronesi U, Orecchia R, et al. The nipple-sparing mastectomy: early results of a feasibility study of a new application of perioperative radiotherapy (ELIOT) in the treatment of breast cancer when mastectomy is indicated. Tumori 2003; 89:288-91. 27. Petit JY, Veronesi U, Orecchia R, et al. Nipple sparing mastectomy with nipple areola intraoperative radiotherapy: one thousand and one cases of a five years experience at the European institute of oncology of Milan (EIO). Breast Cancer Res Treat 2009; 117:333-8. 28. Njeh CF, Saunders MW, Langton CM. Accelerated Partial Breast Irradiation (APBI): A 20
ACCEPTED MANUSCRIPT review of available techniques. Radiat Oncol 2010; 5:90. 29. Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective,
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randomised, non-inferiority phase 3 trial. Lancet 2010; 376:91-102. 30. Vaidya JS, Tobias JS, Baum M, et al. Intraoperative radiotherapy for breast cancer. Lancet Oncol 2004; 5:165-73.
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31. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated Partial Breast Irradiation Consensus
Biol Phys 2009; 74:987-1001.
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Statement From the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol
32. Vaidya JS, Baum M, Tobias JS, et al. Targeted intra-operative radiotherapy (Targit): an innovative method of treatment for early breast cancer. Ann Oncol 2001; 12:1075-80.
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33. Deneve JL, Hoefer RA Jr, Harris EE, et al. Accelerated partial breast irradiation: A Review and Description of an Early North American Surgical Experience With the Intrabeam Delivery System. Cancer Control 2012; 19:295-308.
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34. Herskind C, Griebel J, Kraus-Tiefenbacher U, et al. Sphere of equivalence--a novel target
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volume concept for intraoperative radiotherapy using low-energy X rays. Int J Radiat Oncol Biol Phys 2008; 72:1575-81. 35. Belletti B, Vaidya JS, D'Andrea S, et al. Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding. Clin Cancer Res 2008; 14:1325-32. 36. Punglia RS, Saito AM, Neville BA, et al. Impact of interval from breast conserving surgery to radiotherapy on local recurrence in older women with breast cancer: retrospective cohort 21
ACCEPTED MANUSCRIPT analysis. BMJ 2010; 340:c845. 37. Avanzo M, Rink A, Dassie A, et al. In vivo dosimetry with radiochromic films in low-voltage intraoperative radiotherapy of the breast. Med Phys 2012; 39:2359-68.
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brachytherapy. Int J Radiat Oncol Biol Phys 2009; 74:1298-305.
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38. Schneider F, Fuchs H, Lorenz F, et al. A novel device for intravaginal electronic
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Figure legends:
Figure 1 Incision for nipple-sparing mastectomy
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Figure 2 (a) Intrabeam® device. (b) Spherical applicators with cone-shaped shanks (with permission from Carl Zeiss, Oberkochen, Germany)
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Figure 3 Protection of the chest wall by a piece of shielding material
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(tungsten-filled polyurethane)
Figure 4 The depth-dose curve of Intrabeam® treatment in a case with a 2.5cm-size applicator
Figure 5 The contour of the breasts (two months after operation)
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ACCEPTED MANUSCRIPT Table 1 Parameters of Intrabeam® intraoperative radiotherapy for seven patients undergoing nipple sparing mastectomy with breast reconstruction Variable
N
beneath the areola 5
4-5 mm
2
＞ 2.5 cm, ≤ 3.0 cm ＞ 3.0 cm, ≤ 4.0 cm ＞ 4.0 cm, ≤ 4.5 cm
2.0 cm 2.5 cm
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Applicator diameter
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Diameter of the nipple-areola complex
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3-4 mm
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Thickness of remaining glandular tissue
1
5
1
1 6 16 Gy
Median radiation time
13 min 14 sec
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Radiation dose at the applicator surface
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SC
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SC
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