A pilot study of wider use of accelerated partial Breast irradiation: Intraoperative margin-directed re-excision combined with sole high-dose-rate interstitial brachytherapy

Accelerated partial breast irradiation (APBI) is generally limited to patients at extremely low risk of local recurrence. The significance of the risk factors, however, depends on the extent of surgery, radiation, and systemic therapy. In Japan, wide
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  Breast Cancer Vol. 13 No. 3 July 2006 Original Article A Pilot Study of Wider Use of Accelerated Partial Breast Irradiation: Intraoperative Margin directed Re excision Combined with Sole High dose rate Interstitial Brachytherapy Takayuki Nose .1, Yoshihurni Komoike .2, Ken Yoshida .3, Masahiko Koizumi .4, Kazuyoshi Motomura .2, Tsutomu Kasugai .5, Hideo Inaji .2, Kinji Nishiyama .4, Hiroki Koyama .2, Takuyo Kozuka *~ Kotaro Gomi .1, Masahiko Oguchi* , Yutaka Takahashi ,1, Iori Sumida*~, and Takashi Yamashita*l ~Department of Radiation Oncology, Cancer Institute Hospital, 2Department of Breast Surgery, Osaka Medical Center, 3Department of Radiology, Osaka National Hospital, 4Department of Radiation Oncology, Osaka Medical Center, SDepartment of Pathology, Osaka Medical Center, Japan. Background: Accelerated partial breast irradiation (APBI) is generally limited to patients at extreme- ly low risk of local recurrence. The significance of the risk factors, however, depends on the extent of surgery, radiation, and systemic therapy. In Japan, wide excision is generally supplemented by intraopera- tive margin-directed re-excision if the frozen section examination yields positive results. This approach combined with conventional radiotherapy achieved an excellent 10-year local control rate of 93%, and young age and ductal carcinoma in situ were not risk factors for local recurrence. To reduce the treatment duration, high-dose-rate interstitial brachytherapy (HDRIB) was employed. The first APBI phase I / II tri- al in Japan was conducted to determine if wider indications for early breast cancer patients were appropri- ate. Methods: The subjects comprised 20 patients including those with extensive intraductal component (n = 7), ductal carcinoma in situ (n = 2), positive final margins (n = 3), and of younger age (~45 years; n = 5). Breast-conserving surgery using an intraoperative re-excision approach was followed by intraoperative implantation of applicators. Sole HDRIB of a 3642 Gy in 67 fractions was delivered postoperatively over 3- 4 days. Tumors were staged as follows: cT1 (n = 12), cT2 (n = 8), cN0 (n = 20). Systemic therapy was used in 16 patients (80%). The median follow-up period was 52 months (range, 2686 months). Results: Te five-year crude local, distant control, and Kaplan-Meier cause-specific survival rates were 95%, 95%, and 89%, respectively. Fat necrosis developed in 1 patient. Conclusions: Sole HDRIB with intraoperative margin-directed re-excision was feasible under wider indications compared to other contemporary APBI series, and achieved acceptable and similar results to these series in terms of the local control rate and complications. Breast Cancer 13:289-299, 2006. Key words: Breast cancer, Accelerated partial breast irradiation (APBI), Brachytherapy, Intraoperative re-excision, Frozen section examination In the urban centers of Japan, where public transportation is readily available, most women reach a radiotherapy center within 1 hour. Radio- therapy for breast conserving therapy (BCT) last- ing 5-7 weeks does not represent a physical con- cern, even for the elderly patients. However, for a Reprint requests to Takayuki Nose, Department of Radiation Oncology, Cancer Institute Hospital, 3-10-6, Ariake, Koto-Ku, Tokyo 135-8550, Japan. E-mail: akayuki.nose@ifcr.or.jp Received August 18, 2005; accepted March 27, 2006 subset of women who are busy at work or caring for infants, prolonged treatment represents an obstacle to undergo BCT. We initiated a phase I/H study of accelerated partial breast irradiation (APBI) using sole high-dose-rate interstitial bra- chytherapy (HDRIB) in 1998. Early studies utiliz- ing APBI demonstrated frequent local recurren- ces 13). The indications for APBI have thus been limited to low-risk patients, resulting in excellent local controP -'). However, implant procedures are loaded separately after assessing the final histol- ogy, and more importantly, young patients who 289  Nose T et al APBI with Brachytherapy would benefit most from APBI have been exclu- ded 8~. The significance of risk factors, however, depends on the extent of surgery, radiation dose, and use of systemic therapyr'~~ In the current study, to achieve wider indications for APBI, wide excision was supplemented by intraoperative mar- gin-directed re-excision, the HDRIB dose was set as equivalent to the boosted dose, and systemic therapy was applied to 80% of patients. The cur- rent report presents the techniques, feasibility, and complications associated with sole HDRIB combined with an intraoperative re-excision appr- oach. This is the first report on APBI applied to Japanese breast cancer patients. Methods and Materials Eligibility Criteria Study protocols were approved by the review board of Osaka Medical Center (OMC). Criteria for inclusion were as follows: 1) invasive or non- invasive ductal or lobular carcinoma 2) age >20 years old 3) clinical NO 4) tumor < 3 cm in maxi- mum diameter. Between May 1998 and May 2003, a total of 20 early breast carcinoma patients entered the trial after providing signed informed consent. Patient characteristics are presented in Table 1. Patient Age and Background for Participation The mean and median age of the patients was 50 and 51 years, respectively, with 5 patients 45 years old or younger and only i patient more than 70 years old. The distribution of the patients' age resembled that for Japanese breast cancer pati- ents in generaP 1). The registered backgrounds for participation were as follows: busy job (n = 13); caring for infants (n = 2) and elderly mother (n-- 1); living in a remote location (n = 2); severe art- hritis of the knee (n = 1); and frequent angina pec- toffs with left breast carcinoma (n-- 1). Participa- tion was thus related to temporal concerns (busy for job or caring for family members) in 80% of patients, distance in 10%, and physical concerns in only 10%. Wide Excision Intraoperative Pathological Examination and Intraoperative Margin- directed Re-excision At wide excision, the palpable tumor was exci- sed with a 1.5-2 cm margin of additional tissue Table 1. Patient Characteristics No. of patients 20 Age median 50 range 32-72 <45 5 >70 1 Menopausal status pre- 12 post- 8 cT- 1 12 2 8 cN- 0 20 Follow-up (months) median 52 range 2686 Background temporal 16 distance 2 physical 2 TNM Classification of malignant tumours UICC 6th ed. was used for staging. (Fig la, b). Three small specimens were sampled from the nipple-, lateral- (caudal-), and medial- (cranial-) sides of the wide excision cavity wall and submitted to the pathology service. Level I/II axillary dissection was then performed. Sentinel node sampling was not indicated for the current study cohort. Results from the frozen section exa- mination were reported within 15 minutes. If any of the specimens were positive, an additional 1.5 cm of tissue was excised in the same direction and examined again. This process was repeated until negative margins were confirmed. Detailed per- manent histological features were reported within about 10 days. Intraoperative margin-directed re- excision was performed in 11 patients, with 1 re- excision in 9 patients and 2 re-excisions in 2 patients. Nipple-, lateral- (cranial-), and medial- (caudal-) margins were marked with titanium clips. At the tumor center, 2 clips were placed side- by-side on the pectoralis major muscle (Fig lb). A provisional 'target' was defined as a wide excision cavity with a 2-3 cm margin. To facilitate re-app- roximation of the cavity wall, the mammary gland and surrounding adipose tissue were separated 2- 3 cm laterally both from the skin flap above, and from the fascia of the pectoralis major muscle ben- eath, allowing sufficient mobilization of the gland 290  Breast Cancer Vol. 13 No. 3 July 2006 Fig la. A cross section of a breast. The mammary gland (slashed area) contains a cancer lesion (black area). Fig le. A cross section of the wide excision cavity. Two cavi- ties (gray zones) were created, (1) between the skin flap and the mammary gland flap (white arrow), and (2) between the mammary gland flap and the pectoralis major muscle (white arrowhead). Two-headed black arrow indicates planned dis- tance between planned surface plane and planned deep plane. Fig ld. Implantation of the deep plane. A metal needle was introduced to the cavity between the gland flap and the pec- toralis muscle. Fig lb. A wide excision specimen (arrow) and a re-excision specimen (arrowhead) were removed. The lumpectomy cavity was marked with 5 clips for (1) nipple side, (2) lateral (caudal) side, (3) medial (cranial) side, (4) the srcinal tumor center using 2 clips. flap (Fig lc). Consequently, 2 cavities were creat- ed, one between the gland flap and skin flap; and one between the gland flap and pectoralis fascia. Implantation Implantation of applicators was undertaken by a radiation oncologist. A 2-plane implant was uti- lized for 19 patients, and a single plane implant for 1 patient. The deep plane was planned between the gland flap and pectoralis fascia, while the sur- face plane was planned 2-3 mm beneath the anteri- or surface of the gland flap. Inter-plane separation was measured on the cut margin of the gland flap (0.9-1.7 cm, Fig lc). Following the Paris System, inter-applicator separation was designated as 1.15 x inter-plane separation (median, 1.5 cm; range, 1.0-2.0 cm). Applicator locations and numbers were planned to encompass the provisional target. The median number of applicators was 11 (range, 6-18). The deep plane was implanted starting with the first applicator passing over the central clips indicating the srcinal tumor center. Under digital guidance, a metal needle was introduced into the cavity (Fig ld). From the opposite side, another needle was introduced into the same cavity (Fig le). A plastic applicator replaced the metal nee- dles (Fig If). Planned applicators were implanted parallel to the first applicator with the planned sep- aration (Fig lg). After the deep plane applicators were implanted, surgeons re-approximated the cavity wall (Fig lh, i). Re-approximation was con- sidered important for cosmesis and by arranging the margin as a zigzag or quasi-line (Figs lh, 2), the target volume could be smaller than the provi- 291  Nose T et al APBI with Brachytherapy Fig le. Implantation of the deep plane. Another metal needle was introduced to the same cavity from the opposite side. A plastic applicator with thin guides at both ends replaced the metal needles. Fig lh. Completion of re-approximation of the mammary gland. The direction of re-approximation was arranged as par- allel as possible to the applicators. The 3 clips on the wide excision cavity wall and the 2 clips indicating the srcinal tumor center formed a quasi-line. Fig lf. Completion of the deep plane. Fig li. A cross section (cutting the quasi-line of the 5 clips) for completion of re-approximation of the mammary gland. Fig lg. Completion of the deep plane viewed from brachy- therapist's view. Three applicators were partially visible thr- ough the wide excision cavity. Fig lj. Implantation of the surface plane. A metal needle was introduced into the gland flap 2-3 mm beneath the surface. sional volume (Fig 3). The direction of re-approxi- mation was roughly parallel to the applicators, to allow efficient target coverage (Fig lh, 3). A radia- tion oncologist then undertook surface plane imp- lantation. A metal needle, later replaced by a plas- tic applicator, was kept 2-3 mm beneath the sur- face of the gland flap by palpation and visual guid- ance (Fig lj, k, 1, m). Re-approximated walls often came partially loose because of needle interfer- ence, but were covered with additional sutures or by shifting nearby adipose tissue. Subcutaneous tissue was re-approximated, and the skin incision 9  Breast Cancer Vol. 13 No. 3 July 2006 Fig lk. Implantation of the surface plane. The metal needle passed the gland flap and pierced out to the opposite-side skin. Fig in. Completion of implantation procedure. The subcuta- neous tissue was sutured (arrow) and the skin incision closed. The sutured subcutaneous tissue pressed the gland flap, 2 cavities and the deep plane applicators onto the pectoralis muscles. Fig 11. Implantation of the surface plane. A plastic applicator replaced the metal needle. Fig 2. A radiograph showing a zigzag line formed by 5 clips, 3 on re-approximated margins (circles); and 2 indicating the srcinal tumor center (arrows). Only the deep plane applica- tors were loaded with dummy markers. Note the zigzag is roughly parallel to the applicators. Fig lm. Completion of implantation of applicators (circles). A cross section viewed from the applicator axis. was dressed using surgical tapes (Fig ln). Both ends of the applicators were fixed on skin using metal buttons. Dose Specification A median of 5 days after implantation, a simula- tion was performed. Dummy sources were loaded in the applicators, and isocentric radiographs were taken to reconstruct the implant geometry. From 2000, computed tomography (CT) was added for Fig 3. A schema showing provisional target (white arrow: large and shaded circle) and ultimate CTV (black arrow: small and white ellipse). Three metal clips on the cavity wall moved from the srcinal margins to the re-approximated margins (small arrows). 12 patients, allowing superimposition of radiogr- aph-based planning on CT images. The ultimate clinical target volume (CTV) was designated as the volume around the line formed by the clips, with a 2-to 3-cm margin (Fig 3), but CTV was tri- 293
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