Prospective study of once-daily accelerated partial breast irradiation using 3-dimensional conformal external beam radiotherapy for Japanese women: 12-year outcomes, toxicity, and cosmesis

Prospective study of once-daily accelerated partial breast irradiation using 3-dimensional conformal external beam radiotherapy for Japanese women: 12-year outcomes, toxicity, and cosmesis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prospective study of once-daily accelerated partial breast irradiation using 3-dimensional conformal external beam radiotherapy for Japanese women: 12-year outcomes, toxicity, and cosmesis Kana Takahashi, Yoshikazu Kagami, Ryoichi Yoshimura, Madoka Morota, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4652213/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Dec, 2024 Read the published version in Breast Cancer → Version 1 posted 5 You are reading this latest preprint version Abstract Background To analyze in a prospective study the long-term safety and efficacy of 3-dimensional conformal radiotherapy (3D-CRT) to deliver accelerated partial breast irradiation (APBI) for Japanese women with early breast cancer. Methods Breast cancer patients with pathological tumor size ≤ 3 cm, age ≥ 20 years, lumpectomy with at least a 5 mm margin, and ≤ 3 positive axillary nodes were eligible. APBI was delivered by 3D-CRT at a dose of 38.5 Gy in 10 fractions over 10 days. The primary endpoints were the frequency and severity of acute and late radiation toxicities, and secondary endpoints were local control, survival, and cosmesis. The sample size was determined based on the incidence of ≥ grade 3 acute and late radiation toxicities, which required 71 enrollments. Results Between 2008 and 2010, 73 patients enrolled in this trial. Twelve patients (16%) had 1–3 lymph node metastases. At a median follow-up of 12.6 years (range: 2.7–13.9 years), there were no cases of grade ≥ 3 acute or late toxicity. There were 4 ipsilateral breast tumor recurrence (IBTR) events: 12-year IBTR incidence was 4.4%. The difference in the incidence of IBTR between node-negative and node-positive patients was marginal (1.9% vs. 16.7%, p = 0.055). The majority of patients (95.8%) had excellent/good cosmesis. Conclusions APBI delivered with 3D-CRT is a feasible treatment option for Asian females, but it was indicated that node-positive status might increase IBTR risk. APBI Once-daily 3D-CRT Breast cancer Japanese women Introduction Accelerated partial breast irradiation (APBI) has increasingly been offered as an alternative to conventional external beam whole breast irradiation (WBI) following lumpectomy in selected early-stage breast cancer patients [ 1 ]. Different treatment techniques and dose fractionations have been utilized in APBI [ 2 ]. The majority of trials have indicated similar treatment outcomes with APBI in carefully selected patients. However, determining the most effective schedule that achieves the optimal balance between patient preference, local control, toxicity, and cosmesis remains an issue. APBI is rarely used in Japan. One reason for this is the difficulty in target identification caused by oncoplastic surgery, which is generally adopted in Japan. Secondary: APBI is often unsuitable for Asian females because they generally have smaller breast sizes than Western females. In 2008, we conducted a study (umin0000003405) to examine the use of once-daily APBI with 3-dimensional conformal radiation therapy (3D-CRT). We carried out this trial to test the safety and efficacy of APBI delivered with 3D-CRT, even for Japanese females. We present 12-year outcomes in terms of local control, treatment-related toxicities, and cosmesis. Materials and methods Patient selection Eligibility criteria were as follows: pathological tumor size ≤ 3 cm; invasive ductal carcinoma and special types including medullary, papillary, mucinous, invasive lobular, or apocrine histologies (other than squamous cell carcinoma) of the breast as well as ductal carcinoma in situ; unifocal lesion; age ≥ 20 years; lumpectomy with negative surgical margins (defined as at least a 5 mm margin); lumpectomy cavity identifiable on planning computer tomography (CT) with titanium clips; and ≤ 3 positive axillary nodes (proved by sentinel lymph node biopsy and/or axillary dissection). Exclusion criteria included the following: prior history of radiotherapy for ipsilateral breast; neoadjuvant chemotherapy or hormonal therapy; bilateral breast cancer; concomitant malignancies; systemic lupus erythematosis, scleroderma, dermatomyositis; pregnancy or lactation. This prospective study was approved by the Institutional Review Board of the National Cancer Center on October 22, 2007 (reference number: 19–042), and all enrolled patients gave their written informed consents before being registered in the study. Simulation and treatment planning Treatment planning and delivery were performed with the patient in the supine position. Patients were first imaged (3-mm CT slice thickness) with both arms raised over the head. The normal breast volume was defined by applying radiopaque wires to define the volume that would have been treated by classic whole-breast tangents. The lumpectomy cavity, ipsilateral and contralateral breasts, bilateral lungs and heart were delineated on each CT slice. The clinical target volume (CTV) was defined as an expansion of the lumpectomy cavity including surgical clips with 1 cm in all directions minus chest wall and 2 mm thick tissue under the skin. An isotropic 1 cm margin was added to the CTV to obtain the planning target volume (PTV). For evaluating the dose of the PTV, PTV_EVAL was generated from the PTV, excluding the lung, chest wall and 2 mm thick tissue under the skin. For each patient, treatment was delivered by 3D-CRT using 2–4 coplanar or noncoplanar fields with 4 or 6 MV photons. Intensity modulated radiation therapy was not allowed. A total of 38.5 Gy in 10 fractions were prescribed to the ICRU point (located centrally in the PTV on the beam axes at their intersection). Single fraction per day, each 3.85 Gy, were given in 10 consecutive working days. The dose-volume constraints were based on National Surgical Adjuvant Breast and Bowel Project (NSABP) B39/Radiation Therapy Oncology Group (RTOG) 0413 protocols, but we changed the constraint of PTV_EVAL as in Table 1, because it was easy to satisfy the original dose limitation of PTV_EVAL and higher part of the PTV_EVAL dose could be appropriately evaluated with D90 PTV_EVAL (Table 1). Dose-fractionation design We adopted a dose-fractionation of 38.5 Gy in 10 fractions based on NSABP B-39/RTOG 0413 APBI regimen. Although NSABP B-39/RTOG 0413 delivered twice-daily APBI, we chose once-daily APBI because of patient convenience and the limited number of treatment machines. Using the linear quadratic model and assuming an α/β ratio of 4 for breast tumor kill, this prescription was equivalent to 50 Gy in a standard 2-Gy fractionation. Sample size The primary endpoints of this study were the frequency and severity of acute and late radiation toxicities. The incidence of ≥ grade 3 acute and late radiation toxicities when treated with external WBI was considered to be around 3% [ 3 ]. Because APBI had the advantage of reduced treatment time and cost compared to WBI, we assumed a threshold incidence of ≥ grade 3 radiation toxicities in APBI of 10% and an expected incidence of 3%. With the type one error rate of 5% and 80% power, 71 patients must be accumulated in this APBI trial. Secondary endpoints were local control, survival, and cosmetic results. Follow-up and statistical analysis Patients were seen first 1 month after the last fraction of APBI, then every 6 months for the first 5 years, and then on an annual basis by the treating radiation oncologist. Annual bilateral mammography or ultrasound was mandatory. Ipsilateral breast tumor recurrence (IBTR) was defined as any histologically confirmed cancer tissue in the treated breast. The follow-up CT scan was not mandatory, so the asymptomatic radiation pneumonitis was detected only by the follow-up chest radiography performed at least annually. Acute and late radiation toxicities were evaluated and graded according to the Common Terminology Criteria for Adverse Events, version 4 [ 4 ]. The values of acute toxicities presented are the patient’s worst toxicity occurring until 3 months after completion of the APBI. Late toxicity was graded by worst toxicity from 4th month after completion of the APBI to the last follow-up visit. Cosmetic outcome was physician-assessed prospectively at the last follow-up according to the Harvard Scale [ 5 ]. All time intervals were calculated from the starting date of APBI. Time until IBTR was censored on lost follow-up and on death. The cumulative incidence of IBTR, disease free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Groups were compared using the log-rank test. For all statistical tests a significance level of 0.05 was used. Results Patient- and treatment-related characteristics Between January 2008 and January 2010, 73 patients enrolled in this trial. The patient- and treatment-related characteristics for all eligible patients are shown in Table 2. All patients completed the prescribed course of external beam radiotherapy. Median age was 60 years (range: 32–79 years). In 12 patients (16%), 1–3 lymph nodes metastases were present and all the patients underwent axillary lymph nodes dissection removing at least 8 nodes. Following the American Society of Radiation Oncology (ASTRO) Consensus Panel (CP) groups, almost half (49%) of patients were classified as 'suitable', with 'cautionary' and 'unsuitable' accounting for 27% and 23% respectively [ 6 , 7 ]. The median follow-up was 12.6 years (range: 2.7–13.9 years). For 2 patients, late toxicities and cosmetics were not assessed; one patient refused to be followed up by visit and the other patient moved immediately after the APBI, but both of them had been monitored for relapse regularly by telephone. Dosimetric analysis A total of 73 treatment plans from all the enrolled patients were evaluable for dosimetric analysis. Table 3 lists the results. Due to the smallness of breast volume, V50 ipsi_breast (the volume of the ipsilateral breast covered by 50% of the prescribed dose) tended to be much higher than the values of the established constraints. Treatment-related toxicities and cosmetic results Table 4 lists the acute and late toxicities as well as the cosmetic results. There were no grade 3 or 4 toxicities. A single case of grade 2 radiation pneumonitis was observed 4 months after completion of the APBI, which improved without using steroid. V30ipsi_lung of the case was 14.5% which was below the allowed value of 15%. The most frequent late toxicities observed were skin pigmentation (66.2%) and induration/ fibrosis (64.8%). Grade 2 late toxicity was limited to 1 patient (dry skin). The parameters of the patients were within the set dose-volume constraints. On the basis of the Harvard Scale for cosmetic outcomes, the majority of patients (95.8%) had excellent/good cosmetic outcomes. Three patients had a fair cosmetic outcome (4.2%) and no patients had a poor outcome. Treatment efficacy Twelve-year outcomes are presented in Table 5. Four patients (5.5%) developed IBTR 2.9, 7.9, 11.4 and 13 years after APBI. The first two IBTR occurred as isolated cutaneous relapse in the irradiated field and were found on inspection. One patient underwent mastectomy of ipsilateral breast as a salvage treatment. The other patient has received chemotherapy as a salvage treatment because the cutaneous erythema had invaded from ipsilateral breast to the medial part of contralateral breast, and the histological subtype of this new cancer was ER-, PR- and HER2+, while the first cancer was ER+, PR + and HER2-. The latter two IBTR occurred in different quadrants of the breast from the first cancer and both of them underwent mastectomy. The 10- and 12-year cumulative incidence of IBTR was 2.8% and 4.4%. There were 1 regional nodal failure at 1 year after APBI (12-year cumulative incidence: 1.4%) and 3 distant failure at 4.1, 4.8 and 10.8 years after APBI (12-year cumulative incidence: 4.3%). In 4 patients, contralateral breast cancer occurred (12-year cumulative incidence: 5.6%). During the follow-up, 3 died from recurrence of the breast cancer and 4 died of causes other than the breast cancer: 1 of the four died from contralateral breast cancer. Of the 4 patients with IBTR, only one with distant metastasis died. The 10-year point estimate for DFS and OS was 93.1% and 97.2%, and the 12-year point estimate for DFS and OS was 91.5% and 94.3%, respectively. Two of the four IBTR were detected in the ‘unsuitable’ patients and the other two in the ‘cautionary’ group, and no significant difference was detected in the 12-year point estimate of IBTR, regional nodal failure, distant failure, DFS and OS between the ASTRO CP groups (Table 5). The decisive factors on ‘unsuitable’ group in 2 of the 4 IBTR cases were not age but positive axillary nodes. The difference in the rates of IBTR between node-negative and node-positive patients was marginal (12-year cumulative incidence of IBTR: 1.9% vs. 16.7%, p = 0.055 log-rank, p = 0.016 Gehan-Breslow-Wilcoxon). No significant difference were found in the 12-year point estimate for DFS and OS between the ASTRO CP groups, between age ≥ 50 and age < 50 or between node-negative and node-positive patients. Discussion To date, four groups published their 10-year results of APBI with EBRT (Table 6) [ 8 – 14 ]. Although many long-term results of APBI with brachytherapy have been reported, there are few reports of APBI with EBRT exceeding 10 years of follow-up. This prospective study targeting to Japanese breast cancer patients showed comparable results to other APBI series with regard to long-term local tumor control, toxicity, and cosmetic results. The eligibility criteria of our study included patients of young age and patients with positive axillary nodes. They were unsuitable characteristics according to present inclusion criteria for APBI: the ASTRO CP guidelines on the off-protocol use of APBI listed < 50 year-old patients in the ‘cautionary’ or ‘unsuitable’ and node-positive patients in the ‘unsuitable’ category [ 6 , 7 ]. In our trial, 17 patients (23.3%) were below the age of 50, but no significant difference was detected in the 12-year point estimate of IBTR, regional nodal failure, distant failure, DFS and OS between ≥ 50 and < 50 year-old patients. On the other hand, the rate of IBTR were marginally higher in the patients with positive lymph nodes than those with negative lymph nodes. As with ASTRO CP, the guidelines developed by other groups also do not recommend young or node-positive patients to be treated using APBI, except in a clinical trial [ 15 , 16 ]. In NSABP B-39/RTOG 0413, 38% were under the age of 50, and pre- and post-menopausal subgroups did not identify significant differences between the IBTR of APBI and WBI. Up to three axillary lymph nodes could be positive in the study, with DCIS or pN0 accounting for 90% in both groups. Subgroup analyses of IBTR for DCIS, N0, and N1 showed no significant differences in IBTR between APBI and WBI [ 9 ]. However, limited research has been completed to determine the ideal age criteria for patients undergoing APBI, and only limited data remains available on patients with node-positive disease treated with APBI despite node-positive patients being included in some trials [ 9 , 17 , 18 ]. Our findings might support references that suggest APBI is a feasible treatment option for young breast cancer patients, and off-protocol patients should be node-negative. Although NSABP B-39/RTOG 0413 delivered twice-daily APBI, we chose once-daily APBI for patient convenience and the limited number of treatment machines. Hoopes et al. reported that 70% of women prefer once-daily radiation over 10 days vs. twice-daily radiation over 5 days [ 19 ]. Because NSABP B-39/RTOG 0413 included all APBI modalities (twice-daily EBRT or brachytherapy) as one group, it was unclear whether acute and late toxicities differed between patients receiving different APBI methods [ 9 ]. The RAPID trial, which used the same twice-daily APBI regimen (38.5 Gy in 10 fractions over 5 treatment days), showed that acute toxicity was less with twice-daily APBI, while grade ≥ 2 late toxicity was increased with twice-daily APBI (32% vs. 13%). The increased 7-year fair/poor cosmesis (36% vs. 19%) with APBI was likely caused by the twice-daily fractionation. Following the RAPID results, the recently published ASTRO guidelines do not recommend twice-daily APBI with EBRT with respect to toxicity and cosmesis [ 20 ]. Consistent with the RAPID study, the IRMA trial, which randomly assigned over 3300 patients to receive twice-daily APBI of 38.5 Gy in 10 fractions or WBI, showed that twice-daily APBI had higher rates of late soft tissue toxicity (2.8% vs. 1%), bone toxicity (1.1% vs. 0%), and adverse cosmesis [ 21 ]. The randomized trial by Boutrus et al. [ 22 ] compared once-daily APBI vs. twice-daily APBI schemes with EBRT (38.5 Gy in 10 fractions) on 113 patients. The once-daily APBI arm had similar local control and acute toxicities, and there was a statistically significant decrease in late skin toxicity (3.8% vs. 11.7%). The 2-year fair/poor cosmesis was lower for once-daily APBI fractionation than for twice-daily APBI fractionation (7.5% vs. 26.7%). The long-term results of our study support the favorable results of once-daily APBI with EBRT. Ipsilateral breast volume of this study was obviously smaller compared to those of other APBI trials (Table 6). Generally, small breasts are considered unsuitable for APBI because the PTV tend to be close to the risk organ including skin, chest wall and lung, resulting excessive exposure of normal tissue. In the cases of APBI with small breasts, the ratio of the PTV to the ipsilateral breast volume would be inescapably larger than the cases of large breasts. Hepel et al. [ 23 ] reported that PTV_EVAL/total breast volume was found to be correlated with both grade 2–4 fibrosis and fair/poor cosmesis; the mean PTV_EVAL/total breast volume was 19% for all patients, 18% for patients with excellent/good cosmesis, and 24% for patients with fair/poor cosmesis. Shaitelman et al. [ 24 ] found a small cavity-to-skin distance was associated with an increased risk of grade ≥ 2 induration, a marginally increased risk of grade ≥ 2 volume reduction, and poor or fair cosmesis. APBI delivered with multicatheter brachytherapy permit better dose distribution with favorable dose concentration and without excessive exposure of normal tissue even in the small breasts. The 5-year results of a multi-institutional prospective study of APBI with multicatheter brachytherapy for Japanese patients were published [ 25 ]. There were no reports of Grade 4 late toxicity, local recurrence, or breast cancer-related deaths. The overall score for cosmetic outcome was 74% Excellent/Good. Although the optimal method of APBI for small breasts is still unclear, our study demonstrated that APBI with 3DCRT is a feasible option for Asian females with small breasts in terms of toxicity and cosmetics. The major limitation of this study is that the Harvard Scale was scored only by physicians, and cosmesis was not assessed by patients themselves. If there might be discrepancies in the cosmetic assessments between the physicians and patients, then the cosmetic outcomes of this study should be interpreted with caution. However, the strengths of our study include that the median follow-up length of 12 years was sufficiently long to take into account the latency of radiation toxicities, and this is the first report of a long follow-up period of ≥ 10 years of once-daily APBI with EBRT from Asian countries. Conclusions The 12-year local tumor control, toxicity, and cosmesis of once-daily APBI delivered with 3D-CRT for Japanese females were satisfactory and compatible with the long-term outcomes of other ABPI trials. This prospective study demonstrated that once-daily APBI delivered with 3D-CRT is a feasible treatment option alternative to WBI for early-stage breast cancer patients, even in Asian countries, but also indicated that node-positive status might increase IBTR risk. Declarations Acknowledgments None. Funding None. CrediT authorship contribution statement Conceptualization: Yoshikazu Kagami; Methodology: Yoshikazu Kagami; Project administration: Yoshikazu Kagami; Formal analysis and investigation: Kana Takahashi, Yoshikazu Kagami, Ryoichi Yoshimura, Madoka Morota, Naoya Murakami, Tomoya Kaneda, Kae Okuma; Visualization: Kana Takahashi; Writing - original draft preparation: Kana Takahashi, Jun Itami; Writing - review and editing: Kana Takahashi, Yoshikazu Kagami, Ryoichi Yoshimura, Madoka Morota, Naoya Murakami, Satoshi Nakamura, Hiroyuki Okamoto, Ayaka Nagao, Madoka Sakuramachi, Tairo Kashihara, Tomoya Kaneda, Koji Inaba, Kae Okuma, Yuko Nakayama, Jun Itami, Hiroshi Igaki. Compliance with ethical standards Disclosure of potential conflicts of interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Research involving human participants and/or animals: All procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all participants included in the study. References Gradishar WJ, Moran MS, Abraham J, Abramson V, Aft R, Agnese D, et al. NCCN Guidelines® Insights: Breast Cancer, Version 4.2023. J Natl Compr Canc Netw. 2023;21:594–608. 10.6004/jnccn.2023.0031 . Goldberg M, Whelan TJ. Accelerated Partial Breast Irradiation (APBI): Where Are We Now? Curr Breast Cancer Rep. 2020;12:275–84. 10.1007/s12609-020-00384-x . Vicini F, Winter K, Wong J, Pass H, Rabinovitch R, Chafe S, et al. 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Predictors of long-term toxicity using three-dimensional conformal external beam radiotherapy to deliver accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2011;81:788–94. 10.1016/j.ijrobp.2010.06.062 . Yoshida K, Nose T, Otani Y, Asahi S, Tsukiyama I, Dokiya T, et al. A Japanese prospective multi-institutional feasibility study on accelerated partial breast irradiation using multicatheter interstitial brachytherapy: clinical results with a median follow-up of 60 months. Breast Cancer. 2022;29:636–44. 10.1007/s12282-022-01339-z . Tables Tables 1 to 6 are available in the Supplementary Files section. 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Takahashi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYBACCTB5gCGBHybC2EBYC1ANUIskTCXxWgwOEOswyfazxx/8OGOXZ3y7+eEHhl82DMyzCVgjzZOX2NhzI7nY7M4xYwnGvjQGxjkE7JNjyDFs4PnAnLjtRg4bA2PPYQbGGQkEtPC/MWz886E+cfMMYrVIS+QYNvPcOJy4QQKoheEHEVokZ7wxnC1z5njijBtpxhKJDWk8BP0icT7H4OObY9WJ/TOSH3748MdGzpBQiKGCxDYGHsMZpOhgYPjDwCAvQZqWUTAKRsEoGP4AALn6SZd9IxZFAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-5648-1884","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":true,"prefix":"","firstName":"Kana","middleName":"","lastName":"Takahashi","suffix":""},{"id":323607963,"identity":"491f4a7b-8091-4a6a-9f61-488bd4d0f6db","order_by":1,"name":"Yoshikazu Kagami","email":"","orcid":"","institution":"Showa University: Showa Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yoshikazu","middleName":"","lastName":"Kagami","suffix":""},{"id":323607964,"identity":"b0488818-26f1-4ba8-915c-12217a150060","order_by":2,"name":"Ryoichi Yoshimura","email":"","orcid":"","institution":"Tokyo Medical and Dental University: Tokyo Ika Shika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Ryoichi","middleName":"","lastName":"Yoshimura","suffix":""},{"id":323607965,"identity":"b519f94d-434a-40ba-b5aa-6aeecad134e4","order_by":3,"name":"Madoka Morota","email":"","orcid":"","institution":"Showa University Koto Toyosu Hospital: Showa Daigaku Koto Toyosu Byoin","correspondingAuthor":false,"prefix":"","firstName":"Madoka","middleName":"","lastName":"Morota","suffix":""},{"id":323607966,"identity":"c635d3f0-ad52-4e62-9bfd-3a06331f9692","order_by":4,"name":"Naoya Murakami","email":"","orcid":"","institution":"Juntendo University School of Medicine Graduate School of Medicine: Juntendo Daigaku Igakubu Daigakuin Igaku Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Naoya","middleName":"","lastName":"Murakami","suffix":""},{"id":323607967,"identity":"69cffa86-3888-4ade-8448-173af7f4fae8","order_by":5,"name":"Satoshi Nakamura","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Nakamura","suffix":""},{"id":323607968,"identity":"4e1910f2-9f94-4e2b-8253-2c2bc3aec516","order_by":6,"name":"Hiroyuki Okamoto","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Okamoto","suffix":""},{"id":323607969,"identity":"bb76cd5f-d18a-4aa8-820a-ddcb8c86994f","order_by":7,"name":"Ayaka Nagao","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Ayaka","middleName":"","lastName":"Nagao","suffix":""},{"id":323607970,"identity":"05da0e04-c631-4ca8-98fb-5bdcfe7caa29","order_by":8,"name":"Madoka Sakuramachi","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Madoka","middleName":"","lastName":"Sakuramachi","suffix":""},{"id":323607971,"identity":"ce4ffb84-ce73-4137-a091-fa690c504793","order_by":9,"name":"Tairo Kashihara","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Tairo","middleName":"","lastName":"Kashihara","suffix":""},{"id":323607972,"identity":"98262f08-6e6c-4ca1-a003-53d3e0ede214","order_by":10,"name":"Tomoya Kaneda","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Tomoya","middleName":"","lastName":"Kaneda","suffix":""},{"id":323607973,"identity":"c3ecd34c-461b-4148-a11e-2b21c79878e8","order_by":11,"name":"Koji Inaba","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Koji","middleName":"","lastName":"Inaba","suffix":""},{"id":323607974,"identity":"ae365517-4aa1-4356-b5c5-e108331886a1","order_by":12,"name":"Kae Okuma","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Kae","middleName":"","lastName":"Okuma","suffix":""},{"id":323607975,"identity":"49b7ac6e-e507-435b-9fac-5517f49862c2","order_by":13,"name":"Yuko Nakayama","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Yuko","middleName":"","lastName":"Nakayama","suffix":""},{"id":323607976,"identity":"ce33b5ba-680c-4845-886e-568590c53677","order_by":14,"name":"Jun Itami","email":"","orcid":"","institution":"Shin-Matsudo Central General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Itami","suffix":""},{"id":323607977,"identity":"b75e3bea-9752-44de-911e-c16d42e24bce","order_by":15,"name":"Hiroshi Igaki","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Igaki","suffix":""}],"badges":[],"createdAt":"2024-06-28 05:31:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4652213/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4652213/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12282-024-01650-x","type":"published","date":"2024-12-04T15:58:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70965333,"identity":"66e3731d-a53d-4592-98b6-413bd2004ea2","added_by":"auto","created_at":"2024-12-09 16:19:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":471270,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4652213/v1/d873ebd7-5fb3-48ef-a11f-197b3f9c7565.pdf"},{"id":61442430,"identity":"adf429d2-29e7-4077-8788-571bcdce21bb","added_by":"auto","created_at":"2024-07-30 20:39:06","extension":"jpeg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1267116,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4652213/v1/ddc8f09745ed95b88e5ca9c0.jpeg"},{"id":61442654,"identity":"4587f1bd-8226-4f45-b2d6-23d303f93a06","added_by":"auto","created_at":"2024-07-30 20:47:06","extension":"jpeg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":861206,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4652213/v1/a6480f9cda5c420dfd8a7446.jpeg"},{"id":61442432,"identity":"7ba594e6-586e-47dd-93d6-e0e7fce69295","added_by":"auto","created_at":"2024-07-30 20:39:06","extension":"jpeg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":1183645,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4652213/v1/a7e3cb29f378025b6e871316.jpeg"},{"id":61442433,"identity":"4aaaeb11-52b9-416f-9dfb-62e97994673a","added_by":"auto","created_at":"2024-07-30 20:39:06","extension":"jpeg","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":874336,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4652213/v1/153546fde0f3cb1ffddb4050.jpeg"},{"id":61442434,"identity":"fc8a1336-3aea-4ef0-acd9-7e379a5b6ba5","added_by":"auto","created_at":"2024-07-30 20:39:06","extension":"jpeg","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":521030,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage7.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4652213/v1/13fa884837d559d52c9d20f9.jpeg"},{"id":61442429,"identity":"23067eff-2db1-4b7f-bbfe-de7eafbabe64","added_by":"auto","created_at":"2024-07-30 20:39:06","extension":"jpeg","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":521812,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage8.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4652213/v1/309621a625b3b4528c2ad9f8.jpeg"}],"financialInterests":"","formattedTitle":"Prospective study of once-daily accelerated partial breast irradiation using 3-dimensional conformal external beam radiotherapy for Japanese women: 12-year outcomes, toxicity, and cosmesis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAccelerated partial breast irradiation (APBI) has increasingly been offered as an alternative to conventional external beam whole breast irradiation (WBI) following lumpectomy in selected early-stage breast cancer patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Different treatment techniques and dose fractionations have been utilized in APBI [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The majority of trials have indicated similar treatment outcomes with APBI in carefully selected patients. However, determining the most effective schedule that achieves the optimal balance between patient preference, local control, toxicity, and cosmesis remains an issue.\u003c/p\u003e \u003cp\u003eAPBI is rarely used in Japan. One reason for this is the difficulty in target identification caused by oncoplastic surgery, which is generally adopted in Japan. Secondary: APBI is often unsuitable for Asian females because they generally have smaller breast sizes than Western females.\u003c/p\u003e \u003cp\u003eIn 2008, we conducted a study (umin0000003405) to examine the use of once-daily APBI with 3-dimensional conformal radiation therapy (3D-CRT). We carried out this trial to test the safety and efficacy of APBI delivered with 3D-CRT, even for Japanese females. We present 12-year outcomes in terms of local control, treatment-related toxicities, and cosmesis.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient selection\u003c/h2\u003e \u003cp\u003eEligibility criteria were as follows: pathological tumor size\u0026thinsp;\u0026le;\u0026thinsp;3 cm; invasive ductal carcinoma and special types including medullary, papillary, mucinous, invasive lobular, or apocrine histologies (other than squamous cell carcinoma) of the breast as well as ductal carcinoma in situ; unifocal lesion; age\u0026thinsp;\u0026ge;\u0026thinsp;20 years; lumpectomy with negative surgical margins (defined as at least a 5 mm margin); lumpectomy cavity identifiable on planning computer tomography (CT) with titanium clips; and \u0026le;\u0026thinsp;3 positive axillary nodes (proved by sentinel lymph node biopsy and/or axillary dissection). Exclusion criteria included the following: prior history of radiotherapy for ipsilateral breast; neoadjuvant chemotherapy or hormonal therapy; bilateral breast cancer; concomitant malignancies; systemic lupus erythematosis, scleroderma, dermatomyositis; pregnancy or lactation.\u003c/p\u003e \u003cp\u003eThis prospective study was approved by the Institutional Review Board of the National Cancer Center on October 22, 2007 (reference number: 19\u0026ndash;042), and all enrolled patients gave their written informed consents before being registered in the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSimulation and treatment planning\u003c/h2\u003e \u003cp\u003eTreatment planning and delivery were performed with the patient in the supine position. Patients were first imaged (3-mm CT slice thickness) with both arms raised over the head. The normal breast volume was defined by applying radiopaque wires to define the volume that would have been treated by classic whole-breast tangents. The lumpectomy cavity, ipsilateral and contralateral breasts, bilateral lungs and heart were delineated on each CT slice. The clinical target volume (CTV) was defined as an expansion of the lumpectomy cavity including surgical clips with 1 cm in all directions minus chest wall and 2 mm thick tissue under the skin. An isotropic 1 cm margin was added to the CTV to obtain the planning target volume (PTV). For evaluating the dose of the PTV, PTV_EVAL was generated from the PTV, excluding the lung, chest wall and 2 mm thick tissue under the skin.\u003c/p\u003e \u003cp\u003eFor each patient, treatment was delivered by 3D-CRT using 2\u0026ndash;4 coplanar or noncoplanar fields with 4 or 6 MV photons. Intensity modulated radiation therapy was not allowed. A total of 38.5 Gy in 10 fractions were prescribed to the ICRU point (located centrally in the PTV on the beam axes at their intersection). Single fraction per day, each 3.85 Gy, were given in 10 consecutive working days. The dose-volume constraints were based on National Surgical Adjuvant Breast and Bowel Project (NSABP) B39/Radiation Therapy Oncology Group (RTOG) 0413 protocols, but we changed the constraint of PTV_EVAL as in Table\u0026nbsp;1, because it was easy to satisfy the original dose limitation of PTV_EVAL and higher part of the PTV_EVAL dose could be appropriately evaluated with D90\u003csub\u003ePTV_EVAL\u003c/sub\u003e (Table\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDose-fractionation design\u003c/h2\u003e \u003cp\u003eWe adopted a dose-fractionation of 38.5 Gy in 10 fractions based on NSABP B-39/RTOG 0413 APBI regimen. Although NSABP B-39/RTOG 0413 delivered twice-daily APBI, we chose once-daily APBI because of patient convenience and the limited number of treatment machines. Using the linear quadratic model and assuming an α/β ratio of 4 for breast tumor kill, this prescription was equivalent to 50 Gy in a standard 2-Gy fractionation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eThe primary endpoints of this study were the frequency and severity of acute and late radiation toxicities. The incidence of \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;grade 3 acute and late radiation toxicities when treated with external WBI was considered to be around 3% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Because APBI had the advantage of reduced treatment time and cost compared to WBI, we assumed a threshold incidence of \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;grade 3 radiation toxicities in APBI of 10% and an expected incidence of 3%. With the type one error rate of 5% and 80% power, 71 patients must be accumulated in this APBI trial. Secondary endpoints were local control, survival, and cosmetic results.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up and statistical analysis\u003c/h2\u003e \u003cp\u003ePatients were seen first 1 month after the last fraction of APBI, then every 6 months for the first 5 years, and then on an annual basis by the treating radiation oncologist. Annual bilateral mammography or ultrasound was mandatory. Ipsilateral breast tumor recurrence (IBTR) was defined as any histologically confirmed cancer tissue in the treated breast. The follow-up CT scan was not mandatory, so the asymptomatic radiation pneumonitis was detected only by the follow-up chest radiography performed at least annually.\u003c/p\u003e \u003cp\u003eAcute and late radiation toxicities were evaluated and graded according to the Common Terminology Criteria for Adverse Events, version 4 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The values of acute toxicities presented are the patient\u0026rsquo;s worst toxicity occurring until 3 months after completion of the APBI. Late toxicity was graded by worst toxicity from 4th month after completion of the APBI to the last follow-up visit. Cosmetic outcome was physician-assessed prospectively at the last follow-up according to the Harvard Scale [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAll time intervals were calculated from the starting date of APBI. Time until IBTR was censored on lost follow-up and on death. The cumulative incidence of IBTR, disease free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Groups were compared using the log-rank test. For all statistical tests a significance level of 0.05 was used.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient- and treatment-related characteristics\u003c/h2\u003e \u003cp\u003eBetween January 2008 and January 2010, 73 patients enrolled in this trial. The patient- and treatment-related characteristics for all eligible patients are shown in Table\u0026nbsp;2. All patients completed the prescribed course of external beam radiotherapy. Median age was 60 years (range: 32\u0026ndash;79 years). In 12 patients (16%), 1\u0026ndash;3 lymph nodes metastases were present and all the patients underwent axillary lymph nodes dissection removing at least 8 nodes. Following the American Society of Radiation Oncology (ASTRO) Consensus Panel (CP) groups, almost half (49%) of patients were classified as 'suitable', with 'cautionary' and 'unsuitable' accounting for 27% and 23% respectively [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The median follow-up was 12.6 years (range: 2.7\u0026ndash;13.9 years). For 2 patients, late toxicities and cosmetics were not assessed; one patient refused to be followed up by visit and the other patient moved immediately after the APBI, but both of them had been monitored for relapse regularly by telephone.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eDosimetric analysis\u003c/h2\u003e \u003cp\u003eA total of 73 treatment plans from all the enrolled patients were evaluable for dosimetric analysis. Table\u0026nbsp;3 lists the results. Due to the smallness of breast volume, V50\u003csub\u003eipsi_breast\u003c/sub\u003e (the volume of the ipsilateral breast covered by 50% of the prescribed dose) tended to be much higher than the values of the established constraints.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eTreatment-related toxicities and cosmetic results\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;4 lists the acute and late toxicities as well as the cosmetic results. There were no grade 3 or 4 toxicities. A single case of grade 2 radiation pneumonitis was observed 4 months after completion of the APBI, which improved without using steroid. V30ipsi_lung of the case was 14.5% which was below the allowed value of 15%. The most frequent late toxicities observed were skin pigmentation (66.2%) and induration/ fibrosis (64.8%). Grade 2 late toxicity was limited to 1 patient (dry skin). The parameters of the patients were within the set dose-volume constraints.\u003c/p\u003e \u003cp\u003eOn the basis of the Harvard Scale for cosmetic outcomes, the majority of patients (95.8%) had excellent/good cosmetic outcomes. Three patients had a fair cosmetic outcome (4.2%) and no patients had a poor outcome.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eTreatment efficacy\u003c/h2\u003e \u003cp\u003eTwelve-year outcomes are presented in Table\u0026nbsp;5. Four patients (5.5%) developed IBTR 2.9, 7.9, 11.4 and 13 years after APBI. The first two IBTR occurred as isolated cutaneous relapse in the irradiated field and were found on inspection. One patient underwent mastectomy of ipsilateral breast as a salvage treatment. The other patient has received chemotherapy as a salvage treatment because the cutaneous erythema had invaded from ipsilateral breast to the medial part of contralateral breast, and the histological subtype of this new cancer was ER-, PR- and HER2+, while the first cancer was ER+, PR\u0026thinsp;+\u0026thinsp;and HER2-. The latter two IBTR occurred in different quadrants of the breast from the first cancer and both of them underwent mastectomy. The 10- and 12-year cumulative incidence of IBTR was 2.8% and 4.4%.\u003c/p\u003e \u003cp\u003eThere were 1 regional nodal failure at 1 year after APBI (12-year cumulative incidence: 1.4%) and 3 distant failure at 4.1, 4.8 and 10.8 years after APBI (12-year cumulative incidence: 4.3%). In 4 patients, contralateral breast cancer occurred (12-year cumulative incidence: 5.6%). During the follow-up, 3 died from recurrence of the breast cancer and 4 died of causes other than the breast cancer: 1 of the four died from contralateral breast cancer. Of the 4 patients with IBTR, only one with distant metastasis died. The 10-year point estimate for DFS and OS was 93.1% and 97.2%, and the 12-year point estimate for DFS and OS was 91.5% and 94.3%, respectively.\u003c/p\u003e \u003cp\u003eTwo of the four IBTR were detected in the \u0026lsquo;unsuitable\u0026rsquo; patients and the other two in the \u0026lsquo;cautionary\u0026rsquo; group, and no significant difference was detected in the 12-year point estimate of IBTR, regional nodal failure, distant failure, DFS and OS between the ASTRO CP groups (Table\u0026nbsp;5). The decisive factors on \u0026lsquo;unsuitable\u0026rsquo; group in 2 of the 4 IBTR cases were not age but positive axillary nodes. The difference in the rates of IBTR between node-negative and node-positive patients was marginal (12-year cumulative incidence of IBTR: 1.9% vs. 16.7%, p\u0026thinsp;=\u0026thinsp;0.055 log-rank, p\u0026thinsp;=\u0026thinsp;0.016 Gehan-Breslow-Wilcoxon). No significant difference were found in the 12-year point estimate for DFS and OS between the ASTRO CP groups, between age\u0026thinsp;\u0026ge;\u0026thinsp;50 and age\u0026thinsp;\u0026lt;\u0026thinsp;50 or between node-negative and node-positive patients.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo date, four groups published their 10-year results of APBI with EBRT (Table\u0026nbsp;6) [\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Although many long-term results of APBI with brachytherapy have been reported, there are few reports of APBI with EBRT exceeding 10 years of follow-up. This prospective study targeting to Japanese breast cancer patients showed comparable results to other APBI series with regard to long-term local tumor control, toxicity, and cosmetic results.\u003c/p\u003e \u003cp\u003eThe eligibility criteria of our study included patients of young age and patients with positive axillary nodes. They were unsuitable characteristics according to present inclusion criteria for APBI: the ASTRO CP guidelines on the off-protocol use of APBI listed\u0026thinsp;\u0026lt;\u0026thinsp;50 year-old patients in the \u0026lsquo;cautionary\u0026rsquo; or \u0026lsquo;unsuitable\u0026rsquo; and node-positive patients in the \u0026lsquo;unsuitable\u0026rsquo; category [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In our trial, 17 patients (23.3%) were below the age of 50, but no significant difference was detected in the 12-year point estimate of IBTR, regional nodal failure, distant failure, DFS and OS between \u0026ge;\u0026thinsp;50 and \u0026lt;\u0026thinsp;50 year-old patients. On the other hand, the rate of IBTR were marginally higher in the patients with positive lymph nodes than those with negative lymph nodes. As with ASTRO CP, the guidelines developed by other groups also do not recommend young or node-positive patients to be treated using APBI, except in a clinical trial [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In NSABP B-39/RTOG 0413, 38% were under the age of 50, and pre- and post-menopausal subgroups did not identify significant differences between the IBTR of APBI and WBI. Up to three axillary lymph nodes could be positive in the study, with DCIS or pN0 accounting for 90% in both groups. Subgroup analyses of IBTR for DCIS, N0, and N1 showed no significant differences in IBTR between APBI and WBI [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, limited research has been completed to determine the ideal age criteria for patients undergoing APBI, and only limited data remains available on patients with node-positive disease treated with APBI despite node-positive patients being included in some trials [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Our findings might support references that suggest APBI is a feasible treatment option for young breast cancer patients, and off-protocol patients should be node-negative.\u003c/p\u003e \u003cp\u003eAlthough NSABP B-39/RTOG 0413 delivered twice-daily APBI, we chose once-daily APBI for patient convenience and the limited number of treatment machines. Hoopes et al. reported that 70% of women prefer once-daily radiation over 10 days vs. twice-daily radiation over 5 days [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Because NSABP B-39/RTOG 0413 included all APBI modalities (twice-daily EBRT or brachytherapy) as one group, it was unclear whether acute and late toxicities differed between patients receiving different APBI methods [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The RAPID trial, which used the same twice-daily APBI regimen (38.5 Gy in 10 fractions over 5 treatment days), showed that acute toxicity was less with twice-daily APBI, while grade\u0026thinsp;\u0026ge;\u0026thinsp;2 late toxicity was increased with twice-daily APBI (32% vs. 13%). The increased 7-year fair/poor cosmesis (36% vs. 19%) with APBI was likely caused by the twice-daily fractionation. Following the RAPID results, the recently published ASTRO guidelines do not recommend twice-daily APBI with EBRT with respect to toxicity and cosmesis [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Consistent with the RAPID study, the IRMA trial, which randomly assigned over 3300 patients to receive twice-daily APBI of 38.5 Gy in 10 fractions or WBI, showed that twice-daily APBI had higher rates of late soft tissue toxicity (2.8% vs. 1%), bone toxicity (1.1% vs. 0%), and adverse cosmesis [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The randomized trial by Boutrus et al. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] compared once-daily APBI vs. twice-daily APBI schemes with EBRT (38.5 Gy in 10 fractions) on 113 patients. The once-daily APBI arm had similar local control and acute toxicities, and there was a statistically significant decrease in late skin toxicity (3.8% vs. 11.7%). The 2-year fair/poor cosmesis was lower for once-daily APBI fractionation than for twice-daily APBI fractionation (7.5% vs. 26.7%). The long-term results of our study support the favorable results of once-daily APBI with EBRT.\u003c/p\u003e \u003cp\u003eIpsilateral breast volume of this study was obviously smaller compared to those of other APBI trials (Table\u0026nbsp;6). Generally, small breasts are considered unsuitable for APBI because the PTV tend to be close to the risk organ including skin, chest wall and lung, resulting excessive exposure of normal tissue. In the cases of APBI with small breasts, the ratio of the PTV to the ipsilateral breast volume would be inescapably larger than the cases of large breasts. Hepel et al. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] reported that PTV_EVAL/total breast volume was found to be correlated with both grade 2\u0026ndash;4 fibrosis and fair/poor cosmesis; the mean PTV_EVAL/total breast volume was 19% for all patients, 18% for patients with excellent/good cosmesis, and 24% for patients with fair/poor cosmesis. Shaitelman et al. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] found a small cavity-to-skin distance was associated with an increased risk of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 induration, a marginally increased risk of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 volume reduction, and poor or fair cosmesis.\u003c/p\u003e \u003cp\u003eAPBI delivered with multicatheter brachytherapy permit better dose distribution with favorable dose concentration and without excessive exposure of normal tissue even in the small breasts. The 5-year results of a multi-institutional prospective study of APBI with multicatheter brachytherapy for Japanese patients were published [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. There were no reports of Grade 4 late toxicity, local recurrence, or breast cancer-related deaths. The overall score for cosmetic outcome was 74% Excellent/Good. Although the optimal method of APBI for small breasts is still unclear, our study demonstrated that APBI with 3DCRT is a feasible option for Asian females with small breasts in terms of toxicity and cosmetics.\u003c/p\u003e \u003cp\u003eThe major limitation of this study is that the Harvard Scale was scored only by physicians, and cosmesis was not assessed by patients themselves. If there might be discrepancies in the cosmetic assessments between the physicians and patients, then the cosmetic outcomes of this study should be interpreted with caution. However, the strengths of our study include that the median follow-up length of 12 years was sufficiently long to take into account the latency of radiation toxicities, and this is the first report of a long follow-up period of \u0026ge;\u0026thinsp;10 years of once-daily APBI with EBRT from Asian countries.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe 12-year local tumor control, toxicity, and cosmesis of once-daily APBI delivered with 3D-CRT for Japanese females were satisfactory and compatible with the long-term outcomes of other ABPI trials. This prospective study demonstrated that once-daily APBI delivered with 3D-CRT is a feasible treatment option alternative to WBI for early-stage breast cancer patients, even in Asian countries, but also indicated that node-positive status might increase IBTR risk.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCrediT authorship contribution statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: Yoshikazu Kagami; Methodology: Yoshikazu Kagami; Project administration: Yoshikazu Kagami; Formal analysis and investigation: Kana Takahashi, Yoshikazu Kagami, Ryoichi Yoshimura, Madoka Morota, Naoya Murakami, Tomoya Kaneda, Kae Okuma; Visualization: Kana Takahashi; Writing - original draft preparation: Kana Takahashi, Jun Itami; Writing - review and editing: Kana Takahashi, Yoshikazu Kagami, Ryoichi Yoshimura, Madoka Morota, Naoya Murakami, Satoshi Nakamura, Hiroyuki Okamoto, Ayaka Nagao, Madoka Sakuramachi, Tairo Kashihara, Tomoya Kaneda, Koji Inaba, Kae Okuma, Yuko Nakayama, Jun Itami, Hiroshi Igaki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with ethical standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of potential conflicts of interest:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch involving human participants and/or animals:\u0026nbsp;\u003c/strong\u003eAll procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent:\u0026nbsp;\u003c/strong\u003eInformed consent was obtained from all participants included in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGradishar WJ, Moran MS, Abraham J, Abramson V, Aft R, Agnese D, et al. 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Breast Cancer. 2022;29:636\u0026ndash;44. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12282-022-01339-z\u003c/span\u003e\u003cspan address=\"10.1007/s12282-022-01339-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 6 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"breast-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brca","sideBox":"Learn more about [Breast Cancer](http://link.springer.com/journal/12282)","snPcode":"12282","submissionUrl":"https://www.editorialmanager.com/brca/default2.aspx","title":"Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"APBI, Once-daily, 3D-CRT, Breast cancer, Japanese women","lastPublishedDoi":"10.21203/rs.3.rs-4652213/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4652213/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTo analyze in a prospective study the long-term safety and efficacy of 3-dimensional conformal radiotherapy (3D-CRT) to deliver accelerated partial breast irradiation (APBI) for Japanese women with early breast cancer.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eBreast cancer patients with pathological tumor size\u0026thinsp;\u0026le;\u0026thinsp;3 cm, age\u0026thinsp;\u0026ge;\u0026thinsp;20 years, lumpectomy with at least a 5 mm margin, and \u0026le;\u0026thinsp;3 positive axillary nodes were eligible. APBI was delivered by 3D-CRT at a dose of 38.5 Gy in 10 fractions over 10 days. The primary endpoints were the frequency and severity of acute and late radiation toxicities, and secondary endpoints were local control, survival, and cosmesis. The sample size was determined based on the incidence of \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;grade 3 acute and late radiation toxicities, which required 71 enrollments.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBetween 2008 and 2010, 73 patients enrolled in this trial. Twelve patients (16%) had 1\u0026ndash;3 lymph node metastases. At a median follow-up of 12.6 years (range: 2.7\u0026ndash;13.9 years), there were no cases of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 acute or late toxicity. There were 4 ipsilateral breast tumor recurrence (IBTR) events: 12-year IBTR incidence was 4.4%. The difference in the incidence of IBTR between node-negative and node-positive patients was marginal (1.9% vs. 16.7%, p\u0026thinsp;=\u0026thinsp;0.055). The majority of patients (95.8%) had excellent/good cosmesis.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eAPBI delivered with 3D-CRT is a feasible treatment option for Asian females, but it was indicated that node-positive status might increase IBTR risk.\u003c/p\u003e","manuscriptTitle":"Prospective study of once-daily accelerated partial breast irradiation using 3-dimensional conformal external beam radiotherapy for Japanese women: 12-year outcomes, toxicity, and cosmesis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-30 20:39:01","doi":"10.21203/rs.3.rs-4652213/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revision","date":"2024-07-23T19:22:32+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-07-07T04:33:15+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-07T03:00:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-28T05:55:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer","date":"2024-06-28T01:30:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"breast-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brca","sideBox":"Learn more about [Breast Cancer](http://link.springer.com/journal/12282)","snPcode":"12282","submissionUrl":"https://www.editorialmanager.com/brca/default2.aspx","title":"Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"fd26627b-7d9d-4af9-aa01-d4b82fd4a607","owner":[],"postedDate":"July 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-09T16:12:26+00:00","versionOfRecord":{"articleIdentity":"rs-4652213","link":"https://doi.org/10.1007/s12282-024-01650-x","journal":{"identity":"breast-cancer","isVorOnly":false,"title":"Breast Cancer"},"publishedOn":"2024-12-04 15:58:00","publishedOnDateReadable":"December 4th, 2024"},"versionCreatedAt":"2024-07-30 20:39:01","video":"","vorDoi":"10.1007/s12282-024-01650-x","vorDoiUrl":"https://doi.org/10.1007/s12282-024-01650-x","workflowStages":[]},"version":"v1","identity":"rs-4652213","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4652213","identity":"rs-4652213","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}