Two-year outcomes from the HyPORT-BC study: hypofractionated radiotherapy for Japanese breast cancer patients after surgery

Two-year outcomes from the HyPORT-BC study: hypofractionated radiotherapy for Japanese breast cancer patients after surgery | 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 Two-year outcomes from the HyPORT-BC study: hypofractionated radiotherapy for Japanese breast cancer patients after surgery Masaki Nakamura, Kenji Makita, Takeshi Fujisawa, Yuzheng Zhou, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8987514/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background International guidelines now prefer hypofractionated radiotherapy for breast cancer, yet prospective data for Japanese patients remain limited. In our prospective observational study of hypofractionated radiotherapy for Japanese breast cancer patients (HyPORT-BC), acute adverse events were found to be within an acceptable range. Herein, we report the 2-year follow-up data. Methods Between January and December 2023, 123 Japanese patients were enrolled: 81 received moderately hypofractionated radiotherapy (42.5 Gy/16 fractions) including the supraclavicular lymph node region (Cohort M), and 42 received ultra-hypofractionated radiotherapy (26 Gy/5 fractions) for the conserved breast (Cohort U). For endpoints, overall survival (OS), relapse-free survival (RFS), ipsilateral breast relapse-free survival (IBRS), locoregional relapse-free survival (LRFS), late adverse events (CTCAE v5.0), and cosmetic deterioration were evaluated. Results At a median follow-up of 28.8 months for Cohort M and 25.2 months for Cohort U, the 2-year OS, RFS, IBRS, and LRFS were 96.2%, 91.3%, 100%, and 95.0% for Cohort M, and 97.0%, 94.5%, 97.0%, and 97.0% for Cohort U, respectively. Grade ≥ 2 late AEs occurred in 9.1% of patients at 24 months in Cohort M; no Grade ≥ 2 late AEs were observed in Cohort U. Regarding cosmetic outcomes, the proportion of patients who showed any worsening from baseline was 12.5% in Cohort M and 20.0% in Cohort U. Conclusion Both moderately hypofractionated and ultra-hypofractionated radiotherapy demonstrated favorable 2-year efficacy and safety with acceptable cosmetic preservation in Japanese patients. Breast cancer radiotherapy adverse event ultra cosmetic Figures Figure 1 Figure 2 Figure 3 Introduction Several recent clinical trials of hypofractionated radiotherapy have published results, marking a groundbreaking advancement in breast cancer radiation treatment [ 1 – 4 ]. The latest St. Gallen guidelines state that ultra-hypofractionated radiotherapy (uHFRT) for whole-breast irradiation and moderately hypofractionated radiotherapy (mHFRT) for regional nodal irradiation are the preferred treatments, and conventional fractionation is no longer recommended [ 5 ]. In consideration of international guideline recommendations, our institution no longer utilizes conventional fractionation; instead, we apply mHFRT for all patients receiving postoperative breast cancer irradiation. Furthermore, uHFRT is indicated only when the following two criteria are met: 1) patients have undergone breast-conserving surgery and have no lymph node metastases or only one macro metastasis in the axillary lymph node, with axillary dissection omitted; and 2) patients are over 70 years of age or face a heavy burden from frequent hospital visits. However, there are limited prospective data on hypofractionated radiotherapy for Japanese patients in such situations, and Japanese breast cancer guidelines have not made definitive recommendations regarding either mHFRT for the lymph node area or uHFRT for the conserved breast [ 6 ]. Therefore, we conducted a single-center prospective observational study (HyPORT-BC) to evaluate the safety of hypofractionated radiotherapy in postoperative Japanese breast cancer patients and previously reported the primary endpoint of acute adverse event (AE) incidence [ 7 ]. This report presents the secondary endpoints, including efficacy, late adverse events, and cosmetic outcomes. Patients and Methods Patient eligibility criteria, which were reported previously [ 7 ], are summarized briefly below. Patients aged ≥ 20 years and scheduled for mHFRT involving the supraclavicular lymph node region (Cohort M) or uHFRT for the conserved breast (Cohort U) as postoperative treatment for breast cancer were included. Patients with a history of ipsilateral thoracic or supraclavicular radiation therapy or those enrolled in other clinical trials that did not allow duplicate enrollment were excluded. This study was conducted in accordance with the principles of the 1964 Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Review Board of the National Cancer Center (reference number: 2022 − 323), and informed consent was obtained from all participants. Treatment methods, which were reported previously [ 7 ], are briefly summarized below. Radiotherapy planning for Cohort M was performed using RayStation (RaySearch Laboratories AB (publ), Stockholm, Sweden) with atlas-based segmentation and in-house software. Radiotherapy planning for Cohort U was performed using RayAutoBreast, an automated tangential breast treatment planning module in RayStation. If hotspots were present, the field-in-field method was used to limit the maximum dose constraint to no more than 107% of the prescribed dose. For both radiotherapy plans, the dose distribution was visually confirmed by a board-certified radiation oncologist. Irradiation of 42.5 Gy/16 fractions (Cohort M) or 26 Gy/5 fractions (Cohort U) was delivered via 6 MV or 10 MV X-ray beam energy, and boost irradiation of 10 Gy/5 fractions via electrons or photons was performed in cases of close (< 5 mm) or positive margins after breast-conserving surgery. Radiotherapy was delivered 5 days per week. Systemic therapies permitted for concurrent use with radiotherapy were hormone therapy, pembrolizumab, pertuzumab, and trastuzumab; no cytotoxic chemotherapy was permitted. The primary endpoint of the study was the proportion of Grade ≥ 2 acute AEs within 90 days in evaluable patients. Secondary endpoints included: (i) overall survival (OS), relapse-free survival (RFS), ipsilateral breast relapse-free survival (IBRS), and locoregional relapse-free survival (LRFS); (ii) 2-year proportion of late AEs; and (iii) 2-year proportion of breast cosmetic deterioration based on the 4-point scoring system [ 8 ]. OS was defined as the time from the start of radiotherapy to death from any cause, with surviving patients censored at the date of the last follow-up. RFS, IBRS, and LRFS were defined as the time from the start of radiotherapy to the first documented overall disease recurrence (or death), ipsilateral breast tumor recurrence (or death), and locoregional recurrence (or death), respectively. For these endpoints, patients surviving without the recurrence of interest were censored at the date of the last follow-up. Late AEs evaluated included breast or chest pain, bone fracture, dry skin, breast shrinkage, skin hyperpigmentation, skin hypopigmentation, telangiectasia, skin induration, skin infection, lymphedema, brachial plexopathy, pneumonitis, pulmonary fibrosis, cardiac ischemia, pericardial effusion, pericarditis, heart failure, and others. Other toxicity was limited to that related to radiotherapy. Toxicities were evaluated by radiation oncologists using CTCAE v5.0. Breast cosmetics were evaluated by the radiation oncologist during the examination. The primary endpoint was evaluated as the incidence rate of acute AEs, excluding dropouts. For the survival time (time-to-event) endpoints among the secondary endpoints, survival curves were estimated using the Kaplan-Meier method. For subgroup comparisons, the log-rank test was used for survival time endpoints, and hazard ratios were estimated by Cox proportion hazards model. For endpoints involving proportions, Fisher's exact test was performed. All statistical analyses were conducted using R software (version 4.3.1; The R Foundation, Vienna, Austria). All tests were 2-sided, with a significance threshold set at P < .05. Results Patients Between January 2023 and December 2023, 123 patients (81 in Cohort M and 42 in Cohort U) were enrolled in the HyPORT-BC study. All included patients were Japanese. The demographic, clinical, and treatment characteristics at baseline are shown in our previous report ( Table 1 ). Table 1 Patient characteristics Age, years Cohort M (n = 81) Cohort U (n = 42) Median (Range) 57(34–82) 74 (32–89) BMI Median (Range) 22.2(16.4–37.5) 22.9 (17.2–36.4) Primary laterality left 44 (54%) 18 (43%) right 37 (46%) 24 (57%) Histology DCIS 1 (1%) 4 (10%) IDC 70 (86%) 34 (81%) ILC 8 (10%) 1 (2%) others 2 (3%) 3 (7%) ER status Positive 57 (70%) 37 (88%) PR status Positive 59 (73%) 32 (76%) HER2 status Positive 18 (22%) 2 (5%) Lymphvascular invasion Present 23 (28%) 4 (10%) Tumor grade 1 13 (16%) 17 (40% 2 37 (46%) 23 (55%) 3 29 (36%) 0 (0%) Unknown 2 (2%) 2 (5%) Breast surgery Conserving 16 (20%) 42 (100%) Mastectomy 65 (80%) 0 (0%) Axillary surgery Sentinel node biopsy 23 (28%) 34 (81%) Axillary dissection 58 (72%) 1 (2%) No 0 (0%) 7 (17%) Neoadjuvant chemotherapy Yes 40 (49%) 2 (5%) Adjuvant chemotherapy Yes 71 (88%) 4 (10%) Hormonal therapy Yes 61 (53%) 32 (76%) Anti-HER2 therapy Yes 18 (22%) 1 (2%) CDK4/6 inhibitor Yes 23 (28%) 0 (0%) Immune checkpoint inhibitor Yes 6 (7%) 0 (0%) PARP inhibitor Yes 3 (4%) 0 (0%) Boost irradiation Yes 2 (2%) 6 (14%) Radiation field Axillary 16 (20%) 2 (5%) Internal mammary 10 (12%) 0 (0%) Supraclavicular 81 (100%) 0 (0%) Ipsilateral lung V20, % Median (Range) 15.7(1.6–27.9) 4.6 (0–20.0) Mean heart dose, cGy Median (Range) 54 (16–287) 25 (12–65) Clinical outcomes of Cohort M The median follow-up duration for Cohort M patients was 28.8 months (95%CI: 27.2–30.3), calculated using the reverse Kaplan–Meier method. By the time of the last follow-up, five deaths were observed. The causes of death were primary breast cancer for four patients and another cancer for one patient. There were nine recurrences (one local only, one regional only, one local + regional + distant, and six distant only recurrences) during the follow-up period. Kaplan–Meier estimates for 2-year OS, RFS, and LRFS are 96.2% (88.8–98.8%), 91.3% (82.6–95.8%), and 95.0% (87.2–98.1%), respectively (Fig. 1 ). Among the 16 patients who underwent breast-conserving surgery, no ipsilateral breast recurrence or death were observed (2-year IBRS was 100%). Observed AEs are shown in Table 2 . Grade 3 AEs included heart failure and lymphedema, both occurring in the same patient. This patient had left breast cancer and a history of heart disease (mitral regurgitation) and had received anti-HER2 therapy. Although the internal mammary lymph nodes were within the radiation field, the mean heart dose was low at 85 cGy; thus, heart failure was unlikely to be attributed to the radiotherapy. The most common Grade 2 AE was lymphedema, occurring in seven patients. All eight patients with Grade 2 or higher lymphedema had undergone axillary lymph node dissection. Lymphedema incidence was higher in the 19 patients with a BMI of 25 or higher, but no significant difference was observed (3/19 vs. 5/62, p = 0.38). No patients of brachial plexus injury were observed. Other AEs included Grade 1 breast edema and Grade 2 hematoma. Any Grade 2 AEs were observed in 7.4%, 8.6%, 7.6%, and 9.1% of patients at the 6-, 12-, 18-, and 24-month follow-ups, respectively. Table 2 Observed adverse events Cohort M Cohort U 6M (n = 81) 12M (n = 81) 18M (n = 79) 24M (n = 77) 6M (n = 40) 12M (n = 39) 18M (n = 38) 24M (n = 37) Breast/chest wall pain G1 12 8 5 4 8 5 3 2 G2 0 0 0 0 0 0 0 0 Fracture G1 1 0 0 0 0 0 0 0 G2 0 1 0 0 0 0 0 0 Dry skin G1 29 36 25 15 9 11 8 6 G2 1 0 0 0 0 0 0 0 Breast shrinkage G1 0 1 0 2 2 2 2 3 G2 0 0 0 0 0 0 0 0 Skin hyperpigmentation G1 46 40 19 12 14 14 2 0 G2 0 0 0 0 0 0 0 0 Skin hypopigmentation G1 2 3 1 2 0 0 0 0 G2 0 0 0 0 0 0 0 0 Telangiectasia G1 2 4 3 3 1 0 0 0 G2 0 0 0 0 0 0 0 0 Skin induration G1 7 6 8 10 13 9 6 5 G2 2 2 1 0 0 0 0 0 Skin infection G1 1 0 0 0 0 0 0 0 G2 0 0 0 0 0 0 0 0 Lymphedema G1 8 12 11 6 0 0 0 0 G2 1 3 3 5 0 0 0 0 G3 0 0 0 1 0 0 0 0 Brachial plexopathy G1 0 0 0 0 0 0 0 0 G2 0 0 0 0 0 0 0 0 Pneumonitis G1 4 4 5 4 1 1 0 0 G2 1 1 0 0 0 0 0 0 Pulmonary fibrosis G1 0 0 0 0 0 0 0 0 G2 0 0 0 0 0 0 0 0 Cardiac ischemia G1 0 0 0 0 0 0 0 0 G2 0 0 0 0 0 0 0 0 Pericardial effusion G1 0 0 0 0 0 0 0 0 G2 0 0 0 0 0 0 0 0 Pericarditis G1 0 0 0 0 0 0 0 0 G2 0 0 0 0 0 0 0 0 Heart failure G1 0 0 0 0 0 0 0 0 G2 1 0 0 0 0 0 0 0 G3 0 0 0 1 0 0 0 0 On evaluation using a 4-point scale for the 16 patients who underwent breast-conserving surgery, excellent or good breast appearance was seen at baseline, 6, 12, 18, and 24 months after enrollment in 15 (93.8%), 14 (87.5%), 14 (87.5%), 14 (87.5%) and 14 (87.5%) patients, respectively. Figure 2 A shows the temporal changes in cosmetic outcomes. At the final follow-up point within 24 months after irradiation, the proportion of patients who showed any worsening from baseline was 12.5% (95% CI: 1.6–38.3%). In both cases where cosmetic outcomes deteriorated, the patient’s BMI was 25 or higher, and no boost irradiation had been administered. Clinical outcomes of Cohort U The median follow-up duration for Cohort U patients was 25.2 months (95%CI: 23.7–28.6), calculated using the reverse Kaplan–Meier method. By the time of the last follow-up, one patient died of another disease. There was one brain recurrence during the follow-up period. Kaplan–Meier estimates for 2-year OS, RFS, IBRS, and LRFS were 97.0% (80.4–99.6%), 94.5% (79.8–98.6%), 97.0% (80.4–99.6%), and 97.0% (80.4–99.6%), respectively (Fig. 3 ). Observed adverse events are shown in Table 2 . No Grade 2 or higher late adverse events were observed. Grade 1 induration was observed in 13 patients at 6 months, but the proportion decreased over time to nine patients at 12 months, six patients at 18 months, and five patients at 24 months. Breast shrinkage was observed in only four patients, all of Grade 1 severity, during follow-up. The only other adverse event observed was Grade 1 breast edema. On evaluation using a 4-point scale, excellent or good breast appearance was seen at baseline, 6, 12, 18, and 24 months after enrollment in 39 (93%), 38 (95%), 39 (100%), 37 (97%) and 36 (97%) patients, respectively. Figure 2 B shows the temporal changes in cosmetic outcomes. At the final follow-up point within 24 months after irradiation, the proportion of patients who showed any worsening from baseline was 20.0% (95% CI: 9.1–35.6%). Among the eight patients with worsened cosmetic outcome, boost irradiation was administered in only one patient, and no significant association was observed (1/8 vs. 5/32, p = 1.00). Discussion In this prospective observational study (HyPORT-BC), we evaluated the efficacy, late adverse events, and cosmetic outcomes of hypofractionated radiotherapy in Japanese patients with postoperative breast cancer as secondary endpoints. Our findings demonstrate that both mHFRT for regional nodal irradiation and uHFRT for breast irradiation provided excellent locoregional control with acceptable rates of late toxicity and favorable cosmetic outcomes. To the best of our knowledge, this is one of the few prospective studies specifically addressing the treatment outcomes of these hypofractionated radiotherapy regimens within the Japanese population, adhering to the latest international consensus. In Cohort M, we observed two events of local recurrence and two regional recurrence events. The 2-year OS, RFS, and LRFS rates were 96.2%, 91.3%, and 95.0%, respectively. Regarding data for Asian populations, there are results from a Phase III trial conducted in China [ 2 ] and a prospective observational study including Japanese patients [ 9 ], reporting 5-year OS, RFS, and locoregional recurrence rates of 84%, 74%, and 8.3%, and 90.9%, 81.0%, and 3.7%, respectively. Although 2-year data for OS, DFS, and locoregional recurrence were not explicitly stated in either study, the results estimated from their survival curves appear comparable to our findings. Grade 2 or higher AEs remained below 10% at all time points, with lymphedema being the most frequent (one patient of G3 and seven patients of G2). In the pooled analysis of the UK START trials [ 10 ], the reported 5-year prevalence of moderate-to-marked lymphedema following mHFRT ranged from 2.8% to 13.9%. Furthermore, Wang et al. [ 2 ] reported a 1% incidence of Grade 3 lymphedema. In our cohort, all patients who developed lymphedema had undergone axillary lymph node dissection. This is consistent with previous reports suggesting that the surgical technique and other clinical factors have a more substantial impact on the risk of lymphedema than the dose-fractionation schedule [ 11 ]. In Cohort U, only one death from other causes and one patient of distant metastasis were observed, with no instances of locoregional recurrence. No late AEs of Grade 2 or higher were reported. In the FAST-Forward trial [ 4 ], a pivotal study of uHFRT, the 26 Gy group reported a mortality rate of 6.6%, local recurrence of 1.5%, regional recurrence of 0.7%, and distant recurrence of 5.5%; thus, our results are comparable. Regarding Japanese data on mHFRT for whole-breast irradiation, JCOG0906 [ 12 ] showed 5-year OS, PFS, and IB-RFS rates of 98.7%, 95.4%, and 98.0%, respectively, with Grade 2 or higher late adverse events occurring in 9.5%. Considering these findings, it can be considered that there is no evidence of increased recurrence or toxicity risk associated with uHFRT for older Japanese patients, at least within the short-term follow-up period of 2 years. Regarding cosmesis, some degree of cosmetic deterioration was observed in 12.5% of patients in Cohort M and 20% in Cohort U. The FAST-Forward trial [ 4 ] reported a 10.8% rate of cosmetic deterioration at 2 years based on photographic assessment. The JCOG0906 trial [ 12 ] observed cosmetic deterioration in 36.1% and 26.7% of patients at 1 and 3 years, respectively, after mHFRT. While we adopted a sequential boost of 10 Gy in 5 fractions, no correlation was found between the boost irradiation and cosmetic deterioration. However, a sequential boost extends the overall treatment period, potentially diminishing the primary advantage of hypofractionation, which is its shorter duration. Several clinical trials [ 13 – 16 ] evaluating the use of simultaneous integrated boost radiation therapy are underway, and its clinical implementation may be considered in the future. There are several limitations to this study. First, although it was a prospective study, the number of patients was relatively small and most of the patients included in Cohort U were elderly. This is due to the limited indications for uHFRT at our institution; therefore, these results cannot be generalized across all age groups. Second, the 2-year follow-up period is relatively short for evaluating very late radiation-induced toxicities and long-term recurrence. However, since many late adverse events such as lymphedema and induration manifest within 2 years after irradiation, the 2-year assessment in this study can adequately predict the long-term safety profile of this schedule[ 17 , 18 ]. On the other hand, it should be noted that tissue fibrosis and the associated deterioration in cosmetic appearance have been reported to gradually progress and stabilize beyond the second year, continuing toward the fifth year. Therefore, continued follow-up at the 5-year mark is essential to determine the final level of late toxicity in this cohort. In conclusion, hypofractionated radiotherapy, including mHFRT for regional nodes and uHFRT for the conserved breast, is safe and effective for Japanese breast cancer patients during the 2-year follow-up period. These findings provide prospective evidence to support the harmonization of Japanese clinical practice with international guidelines, suggesting that these hypofractionated regimens are viable and safe alternatives to conventional fractionation for the majority of patients in this population. Declarations Conflict of interest MN reports research grant from Illumina, personal fees from AstraZeneca, Sumitomo Heavy Industries, and Illumina outside the submitted work. All remaining authors declare no conflicts of interest in the writing of this article. Acknowledgments We would like to thank Steve Bogart for developing SankeyMATIC, which was used to generate the flow diagrams in this paper. Author contributions MN: Conceptualization, Data curation, Formal analysis, Project administration, Visualization, Writing- Original draft preparation, Writing review & editing. KM: Investigation, Resources, Writing- Original draft preparation.TF: Investigation, Resources, Writing- Original draft preparation. YZ: Investigation, Resources, Writing- Original draft preparation. HH: Investigation, Resources, Writing- Original draft preparation. AM: Investigation, Resources, Writing- Original draft preparation. MW: Formal analysis, Writing- Original draft preparation. AN: Data curation, Writing- Original draft preparation. SZ: Supervision, Writing review & editing. References Haviland JS, Owen JR, Dewar JA, Agrawal RK, Barrett J, Barrett-Lee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013;14:1086–94. https://doi.org/10.1016/S1470-2045(13)70386-3 . Wang SL, Fang H, Song YW, Wang WH, Hu C, Liu YP, et al. Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer: a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol. 2019;20:352–60. https://doi.org/10.1016/S1470-2045(18)30813-1 . Brunt AM, Haviland JS, Sydenham M, Agrawal RK, Algurafi H, Alhasso A, et al. Ten-Year Results of FAST: A Randomized Controlled Trial of 5-Fraction Whole-Breast Radiotherapy for Early Breast Cancer. J Clin Oncol. 2020;38:3261–72. https://doi.org/10.1200/JCO.19.02750 . Murray Brunt A, Haviland JS, Wheatley DA, Sydenham MA, Alhasso A, Bloomfield DJ, et al. Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial. Lancet. 2020;395:1613–26. https://doi.org/10.1016/S0140-6736(20)30932-6 . Burstein HJ, Curigliano G, Gnant M, Loibl S, Regan MM, Loi S, et al. Tailoring treatment to cancer risk and patient preference: the 2025 St Gallen International Breast Cancer Consensus Statement on individualizing therapy for patients with early breast cancer. Ann Oncol. 2025;36:1433–46. https://doi.org/10.1016/j.annonc.2025.09.007 . Yoshimura M, Yamauchi C, Sanuki N, Hamamoto Y, Hirata K, Kawamori J, et al. The Japanese breast cancer society clinical practice guidelines for radiation treatment of breast cancer, 2022 edition. Breast Cancer. 2024;31:347–57. https://doi.org/10.1007/s12282-024-01568-4 . Nakamura M, Fujisawa T, Oyoshi H, Zhou Y, Fukushi K, Hirata H, et al. Acute toxicity of hypofractionated radiotherapy for Japanese breast cancer patients after surgery: a single center prospective observational study (HyPORT-BC). Breast Cancer. 2024;31:1176–81. https://doi.org/10.1007/s12282-024-01626-x . Winchester DP, Cox JD. Standards for breast-conservation treatment. CA Cancer J Clin. 1992;42:134–62. https://doi.org/10.3322/canjclin.42.3.134 . Okonogi N, Kono S, Karasawa K, Banu PA, Xu X, Erawati D, et al. Significance of Hypofractionated Radiotherapy in Postoperative Irradiation for Breast Cancer: An Asian Multi-institutional Prospective Study. Clin Oncol (R Coll Radiol). 2023;35:463–71. https://doi.org/10.1016/j.clon.2023.04.007 . Haviland JS, Mannino M, Griffin C, Porta N, Sydenham M, Bliss JM, et al. Late normal tissue effects in the arm and shoulder following lymphatic radiotherapy: Results from the UK START (Standardisation of Breast Radiotherapy) trials. Radiother Oncol. 2018;126:155–62. https://doi.org/10.1016/j.radonc.2017.10.033 . Naoum GE, Taghian AG, Regional Lymph Node Radiation Is Not the Main Risk Factor for Breast Cancer Related Lymphedema. Stop Chasing Radiation Doses, Fractionation or Techniques-Focus on Axillary Surgery De-escalation or Prevention. Int J Radiat Oncol Biol Phys. 2023;117:461–4. https://doi.org/10.1016/j.ijrobp.2023.04.020 . Nozaki M, Kagami Y, Machida R, Nakamura K, Ito Y, Nishimura Y, et al. Final analysis of a Multicenter Single-Arm Confirmatory Trial of hypofractionated whole breast irradiation after breast-conserving surgery in Japan: JCOG0906. Jpn J Clin Oncol. 2021;51:865–72. https://doi.org/10.1093/jjco/hyab024 . Chakraborty S, Chatterjee S, Hyport Adjuvant Author G. HYPORT adjuvant acute toxicity and patient dosimetry quality assurance results - Interim analysis. Radiother Oncol. 2022;174:59–68. https://doi.org/10.1016/j.radonc.2022.07.003 . Vicini FA, Winter K, Freedman GM, Arthur DW, Hayman JA, Rosenstein BS, et al. NRG RTOG 1005: A Phase III Trial of Hypo Fractionated Whole Breast Irradiation with Concurrent Boost vs. Conventional Whole Breast Irradiation Plus Sequential Boost Following Lumpectomy for High Risk Early-Stage Breast Cancer. Int J Radiat Oncol Biol Phys. 2022;114:S1–S. Coles CE, Haviland JS, Kirby AM, Griffin CL, Sydenham MA, Titley JC, et al. Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trial. Lancet. 2023;401:2124–37. https://doi.org/10.1016/S0140-6736(23)00619-0 . Laughlin BS, Corbin KS, Toesca DAS, Thorpe CS, Golafshar MA, Pockaj B, et al. Physician- and Patient-Reported Outcomes of the MC1635 Phase 3 Trial of Ultrahypofractionated Versus Moderately Hypofractionated Adjuvant Radiation Therapy After Breast-Conserving Surgery. Int J Radiat Oncol Biol Phys. 2024;118:1049–59. https://doi.org/10.1016/j.ijrobp.2023.10.018 . Norman SA, Localio AR, Potashnik SL, Simoes Torpey HA, Kallan MJ, Weber AL, et al. Lymphedema in breast cancer survivors: incidence, degree, time course, treatment, and symptoms. J Clin Oncol. 2009;27:390–7. https://doi.org/10.1200/JCO.2008.17.9291 . Mukesh MB, Barnett G, Cumming J, Wilkinson JS, Moody AM, Wilson C, et al. Association of breast tumour bed seroma with post-operative complications and late normal tissue toxicity: results from the Cambridge Breast IMRT trial. Eur J Surg Oncol. 2012;38:918–24. https://doi.org/10.1016/j.ejso.2012.05.008 . 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8987514","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":599609551,"identity":"f3adfa81-e479-4ae6-872d-26edd073989b","order_by":0,"name":"Masaki Nakamura","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYPCCBAZ+VAEeIrRINgCpAyRpMTiAogUP0G0//vBzQU2avPHx5sefPzDckedvYL/4gEHmDk4tZmdyjKVnHMsx3HbmmJnEAYZnhjMO8BQbMPA8w63lQA6DNA9bBeO2GwlmQIcdTgAqT5Ng4DmMW8v5549/8/yrsN88//nnD8RpARouzduWk7hBgsdAAqKF/RgBLW/MrHn70pJnnMkpkzhjcNhwxmEeZoMEfH45n/74Ns+3ZNv+9uObP1RUHJbnb29/+OBjD+4QQwMGQMzMY8CQ2HOAWC1gwP6AgeEHaVpGwSgYBaNgWAMAwmJYcRlYj+QAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-4431-8892","institution":"National Cancer Center-Hospital East: Kokuritsu Gan Center Higashi Byoin","correspondingAuthor":true,"prefix":"","firstName":"Masaki","middleName":"","lastName":"Nakamura","suffix":""},{"id":599609552,"identity":"a5007a82-eb23-4db9-89df-3d83acf4e69f","order_by":1,"name":"Kenji Makita","email":"","orcid":"","institution":"National Cancer Center-Hospital East: Kokuritsu Gan Center Higashi Byoin","correspondingAuthor":false,"prefix":"","firstName":"Kenji","middleName":"","lastName":"Makita","suffix":""},{"id":599609553,"identity":"9ba9e678-f730-4fbc-aaf7-c5b754483c75","order_by":2,"name":"Takeshi Fujisawa","email":"","orcid":"","institution":"National Cancer Center-Hospital East: Kokuritsu Gan Center Higashi Byoin","correspondingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Fujisawa","suffix":""},{"id":599609554,"identity":"201c5338-fcd5-4c5f-9e0d-e91ba1f1575c","order_by":3,"name":"Yuzheng Zhou","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Yuzheng","middleName":"","lastName":"Zhou","suffix":""},{"id":599609555,"identity":"a25eb1a9-b78f-4328-9adf-21c89679d82b","order_by":4,"name":"Hidenari Hirata","email":"","orcid":"","institution":"National Cancer Center-Hospital East: Kokuritsu Gan Center Higashi Byoin","correspondingAuthor":false,"prefix":"","firstName":"Hidenari","middleName":"","lastName":"Hirata","suffix":""},{"id":599609556,"identity":"247cad8b-132a-40d5-8845-b3515e5f095a","order_by":5,"name":"Atsushi Motegi","email":"","orcid":"","institution":"National Cancer Center-Hospital East: Kokuritsu Gan Center Higashi Byoin","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Motegi","suffix":""},{"id":599609557,"identity":"a5b0c248-c28a-4824-81d0-81d47f608057","order_by":6,"name":"Masashi Wakabayashi","email":"","orcid":"","institution":"National Cancer Center-Hospital East: Kokuritsu Gan Center Higashi Byoin","correspondingAuthor":false,"prefix":"","firstName":"Masashi","middleName":"","lastName":"Wakabayashi","suffix":""},{"id":599609558,"identity":"72cf5052-4c2d-4dd7-8682-959ae842e73e","order_by":7,"name":"Azusa Nakamura","email":"","orcid":"","institution":"National Cancer Center-Hospital East: Kokuritsu Gan Center Higashi Byoin","correspondingAuthor":false,"prefix":"","firstName":"Azusa","middleName":"","lastName":"Nakamura","suffix":""},{"id":599609559,"identity":"b0029836-e0fe-4262-b3ba-00c394194678","order_by":8,"name":"Sadamoto Zenda","email":"","orcid":"","institution":"National Cancer Center-Hospital East: Kokuritsu Gan Center Higashi Byoin","correspondingAuthor":false,"prefix":"","firstName":"Sadamoto","middleName":"","lastName":"Zenda","suffix":""}],"badges":[],"createdAt":"2026-02-27 11:36:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8987514/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8987514/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104179192,"identity":"f778eecb-843e-4560-aef6-24fc56cd74c5","added_by":"auto","created_at":"2026-03-08 17:03:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1129690,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival (A), relapse-free survival (B), locoregional relapse-free survival (C), and ipsilateral breast relapse-free survival (D) in Cohort M.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-8987514/v1/37ee1877b13f70178bfe6e10.png"},{"id":104403679,"identity":"fe818d67-f75b-4591-8f32-73bcf944562f","added_by":"auto","created_at":"2026-03-11 12:18:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":975390,"visible":true,"origin":"","legend":"\u003cp\u003eTemporal changes in cosmeticoutcomes of (A) Cohort M and (B) Cohort U.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-8987514/v1/f8bdb3660a19c4d9614315a8.png"},{"id":104404186,"identity":"8bca2612-01d2-43cd-8814-ff00995bf668","added_by":"auto","created_at":"2026-03-11 12:19:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1103484,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival (A), relapse-free survival (B), locoregional relapse-free survival (C), and ipsilateral breast relapse-free survival (D) in Cohort U.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-8987514/v1/b8d3eeed3cec3c629a54528c.png"},{"id":105563670,"identity":"aef75106-fd8b-4182-ad3c-7ef78d9efe40","added_by":"auto","created_at":"2026-03-27 12:47:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4120542,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8987514/v1/51b0f639-5d3b-4c26-8438-f1187706bf3b.pdf"}],"financialInterests":"","formattedTitle":"Two-year outcomes from the HyPORT-BC study: hypofractionated radiotherapy for Japanese breast cancer patients after surgery","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSeveral recent clinical trials of hypofractionated radiotherapy have published results, marking a groundbreaking advancement in breast cancer radiation treatment [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The latest St. Gallen guidelines state that ultra-hypofractionated radiotherapy (uHFRT) for whole-breast irradiation and moderately hypofractionated radiotherapy (mHFRT) for regional nodal irradiation are the preferred treatments, and conventional fractionation is no longer recommended [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e In consideration of international guideline recommendations, our institution no longer utilizes conventional fractionation; instead, we apply mHFRT for all patients receiving postoperative breast cancer irradiation. Furthermore, uHFRT is indicated only when the following two criteria are met: 1) patients have undergone breast-conserving surgery and have no lymph node metastases or only one macro metastasis in the axillary lymph node, with axillary dissection omitted; and 2) patients are over 70 years of age or face a heavy burden from frequent hospital visits.\u003c/p\u003e \u003cp\u003eHowever, there are limited prospective data on hypofractionated radiotherapy for Japanese patients in such situations, and Japanese breast cancer guidelines have not made definitive recommendations regarding either mHFRT for the lymph node area or uHFRT for the conserved breast [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Therefore, we conducted a single-center prospective observational study (HyPORT-BC) to evaluate the safety of hypofractionated radiotherapy in postoperative Japanese breast cancer patients and previously reported the primary endpoint of acute adverse event (AE) incidence [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This report presents the secondary endpoints, including efficacy, late adverse events, and cosmetic outcomes.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003ePatient eligibility criteria, which were reported previously [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], are summarized briefly below. Patients aged\u0026thinsp;\u0026ge;\u0026thinsp;20 years and scheduled for mHFRT involving the supraclavicular lymph node region (Cohort M) or uHFRT for the conserved breast (Cohort U) as postoperative treatment for breast cancer were included. Patients with a history of ipsilateral thoracic or supraclavicular radiation therapy or those enrolled in other clinical trials that did not allow duplicate enrollment were excluded. This study was conducted in accordance with the principles of the 1964 Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Review Board of the National Cancer Center (reference number: 2022\u0026thinsp;\u0026minus;\u0026thinsp;323), and informed consent was obtained from all participants.\u003c/p\u003e \u003cp\u003eTreatment methods, which were reported previously [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], are briefly summarized below. Radiotherapy planning for Cohort M was performed using RayStation (RaySearch Laboratories AB (publ), Stockholm, Sweden) with atlas-based segmentation and in-house software. Radiotherapy planning for Cohort U was performed using RayAutoBreast, an automated tangential breast treatment planning module in RayStation. If hotspots were present, the field-in-field method was used to limit the maximum dose constraint to no more than 107% of the prescribed dose. For both radiotherapy plans, the dose distribution was visually confirmed by a board-certified radiation oncologist. Irradiation of 42.5 Gy/16 fractions (Cohort M) or 26 Gy/5 fractions (Cohort U) was delivered via 6 MV or 10 MV X-ray beam energy, and boost irradiation of 10 Gy/5 fractions via electrons or photons was performed in cases of close (\u0026lt;\u0026thinsp;5 mm) or positive margins after breast-conserving surgery. Radiotherapy was delivered 5 days per week. Systemic therapies permitted for concurrent use with radiotherapy were hormone therapy, pembrolizumab, pertuzumab, and trastuzumab; no cytotoxic chemotherapy was permitted.\u003c/p\u003e \u003cp\u003eThe primary endpoint of the study was the proportion of Grade\u0026thinsp;\u0026ge;\u0026thinsp;2 acute AEs within 90 days in evaluable patients. Secondary endpoints included: (i) overall survival (OS), relapse-free survival (RFS), ipsilateral breast relapse-free survival (IBRS), and locoregional relapse-free survival (LRFS); (ii) 2-year proportion of late AEs; and (iii) 2-year proportion of breast cosmetic deterioration based on the 4-point scoring system [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. OS was defined as the time from the start of radiotherapy to death from any cause, with surviving patients censored at the date of the last follow-up. RFS, IBRS, and LRFS were defined as the time from the start of radiotherapy to the first documented overall disease recurrence (or death), ipsilateral breast tumor recurrence (or death), and locoregional recurrence (or death), respectively. For these endpoints, patients surviving without the recurrence of interest were censored at the date of the last follow-up. Late AEs evaluated included breast or chest pain, bone fracture, dry skin, breast shrinkage, skin hyperpigmentation, skin hypopigmentation, telangiectasia, skin induration, skin infection, lymphedema, brachial plexopathy, pneumonitis, pulmonary fibrosis, cardiac ischemia, pericardial effusion, pericarditis, heart failure, and others. Other toxicity was limited to that related to radiotherapy. Toxicities were evaluated by radiation oncologists using CTCAE v5.0. Breast cosmetics were evaluated by the radiation oncologist during the examination.\u003c/p\u003e \u003cp\u003eThe primary endpoint was evaluated as the incidence rate of acute AEs, excluding dropouts. For the survival time (time-to-event) endpoints among the secondary endpoints, survival curves were estimated using the Kaplan-Meier method. For subgroup comparisons, the log-rank test was used for survival time endpoints, and hazard ratios were estimated by Cox proportion hazards model. For endpoints involving proportions, Fisher's exact test was performed. All statistical analyses were conducted using R software (version 4.3.1; The R Foundation, Vienna, Austria). All tests were 2-sided, with a significance threshold set at P \u0026lt; .05.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eBetween January 2023 and December 2023, 123 patients (81 in Cohort M and 42 in Cohort U) were enrolled in the HyPORT-BC study. All included patients were Japanese. The demographic, clinical, and treatment characteristics at baseline are shown in our previous report \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort M (n\u0026thinsp;=\u0026thinsp;81)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCohort U (n\u0026thinsp;=\u0026thinsp;42)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian (Range)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57(34\u0026ndash;82)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e74 (32\u0026ndash;89)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian (Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.2(16.4\u0026ndash;37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.9 (17.2\u0026ndash;36.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary laterality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eleft\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (43%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eright\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 (57%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDCIS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (10%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIDC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70 (86%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (81%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eILC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eothers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57 (70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37 (88%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (73%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (76%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER2 status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphvascular invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePresent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (10%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (40%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (55%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eConserving\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMastectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 (80%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAxillary surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSentinel node biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (81%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAxillary dissection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58 (72%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (17%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeoadjuvant chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (49%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdjuvant chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71 (88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (10%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHormonal therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (76%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-HER2 therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCDK4/6 inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmune checkpoint inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePARP inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBoost irradiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (14%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation field\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAxillary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInternal mammary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSupraclavicular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIpsilateral lung V20, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian (Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.7(1.6\u0026ndash;27.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.6 (0\u0026ndash;20.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean heart dose, cGy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian (Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (16\u0026ndash;287)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (12\u0026ndash;65)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eClinical outcomes of Cohort M\u003c/h3\u003e\n\u003cp\u003eThe median follow-up duration for Cohort M patients was 28.8 months (95%CI: 27.2\u0026ndash;30.3), calculated using the reverse Kaplan\u0026ndash;Meier method. By the time of the last follow-up, five deaths were observed. The causes of death were primary breast cancer for four patients and another cancer for one patient. There were nine recurrences (one local only, one regional only, one local\u0026thinsp;+\u0026thinsp;regional\u0026thinsp;+\u0026thinsp;distant, and six distant only recurrences) during the follow-up period. Kaplan\u0026ndash;Meier estimates for 2-year OS, RFS, and LRFS are 96.2% (88.8\u0026ndash;98.8%), 91.3% (82.6\u0026ndash;95.8%), and 95.0% (87.2\u0026ndash;98.1%), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among the 16 patients who underwent breast-conserving surgery, no ipsilateral breast recurrence or death were observed (2-year IBRS was 100%).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eObserved AEs are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Grade 3 AEs included heart failure and lymphedema, both occurring in the same patient. This patient had left breast cancer and a history of heart disease (mitral regurgitation) and had received anti-HER2 therapy. Although the internal mammary lymph nodes were within the radiation field, the mean heart dose was low at 85 cGy; thus, heart failure was unlikely to be attributed to the radiotherapy. The most common Grade 2 AE was lymphedema, occurring in seven patients. All eight patients with Grade 2 or higher lymphedema had undergone axillary lymph node dissection. Lymphedema incidence was higher in the 19 patients with a BMI of 25 or higher, but no significant difference was observed (3/19 vs. 5/62, p\u0026thinsp;=\u0026thinsp;0.38). No patients of brachial plexus injury were observed. Other AEs included Grade 1 breast edema and Grade 2 hematoma. Any Grade 2 AEs were observed in 7.4%, 8.6%, 7.6%, and 9.1% of patients at the 6-, 12-, 18-, and 24-month follow-ups, respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eObserved adverse events\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eCohort M\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c11\" namest=\"c8\"\u003e \u003cp\u003eCohort U\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6M (n\u0026thinsp;=\u0026thinsp;81)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12M (n\u0026thinsp;=\u0026thinsp;81)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18M (n\u0026thinsp;=\u0026thinsp;79)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24M (n\u0026thinsp;=\u0026thinsp;77)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6M (n\u0026thinsp;=\u0026thinsp;40)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12M (n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e18M (n\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003e24M (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast/chest wall pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFracture\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDry skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast shrinkage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin hyperpigmentation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin hypopigmentation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTelangiectasia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin induration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphedema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrachial\u0026nbsp;plexopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePulmonary fibrosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac ischemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePericardial effusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePericarditis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOn evaluation using a 4-point scale for the 16 patients who underwent breast-conserving surgery, excellent or good breast appearance was seen at baseline, 6, 12, 18, and 24 months after enrollment in 15 (93.8%), 14 (87.5%), 14 (87.5%), 14 (87.5%) and 14 (87.5%) patients, respectively. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA shows the temporal changes in cosmetic outcomes. At the final follow-up point within 24 months after irradiation, the proportion of patients who showed any worsening from baseline was 12.5% (95% CI: 1.6\u0026ndash;38.3%). In both cases where cosmetic outcomes deteriorated, the patient\u0026rsquo;s BMI was 25 or higher, and no boost irradiation had been administered.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eClinical outcomes of Cohort U\u003c/h3\u003e\n\u003cp\u003eThe median follow-up duration for Cohort U patients was 25.2 months (95%CI: 23.7\u0026ndash;28.6), calculated using the reverse Kaplan\u0026ndash;Meier method. By the time of the last follow-up, one patient died of another disease. There was one brain recurrence during the follow-up period. Kaplan\u0026ndash;Meier estimates for 2-year OS, RFS, IBRS, and LRFS were 97.0% (80.4\u0026ndash;99.6%), 94.5% (79.8\u0026ndash;98.6%), 97.0% (80.4\u0026ndash;99.6%), and 97.0% (80.4\u0026ndash;99.6%), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eObserved adverse events are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. No Grade 2 or higher late adverse events were observed. Grade 1 induration was observed in 13 patients at 6 months, but the proportion decreased over time to nine patients at 12 months, six patients at 18 months, and five patients at 24 months. Breast shrinkage was observed in only four patients, all of Grade 1 severity, during follow-up. The only other adverse event observed was Grade 1 breast edema.\u003c/p\u003e \u003cp\u003eOn evaluation using a 4-point scale, excellent or good breast appearance was seen at baseline, 6, 12, 18, and 24 months after enrollment in 39 (93%), 38 (95%), 39 (100%), 37 (97%) and 36 (97%) patients, respectively. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB shows the temporal changes in cosmetic outcomes. At the final follow-up point within 24 months after irradiation, the proportion of patients who showed any worsening from baseline was 20.0% (95% CI: 9.1\u0026ndash;35.6%). Among the eight patients with worsened cosmetic outcome, boost irradiation was administered in only one patient, and no significant association was observed (1/8 vs. 5/32, p\u0026thinsp;=\u0026thinsp;1.00).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this prospective observational study (HyPORT-BC), we evaluated the efficacy, late adverse events, and cosmetic outcomes of hypofractionated radiotherapy in Japanese patients with postoperative breast cancer as secondary endpoints. Our findings demonstrate that both mHFRT for regional nodal irradiation and uHFRT for breast irradiation provided excellent locoregional control with acceptable rates of late toxicity and favorable cosmetic outcomes. To the best of our knowledge, this is one of the few prospective studies specifically addressing the treatment outcomes of these hypofractionated radiotherapy regimens within the Japanese population, adhering to the latest international consensus.\u003c/p\u003e \u003cp\u003eIn Cohort M, we observed two events of local recurrence and two regional recurrence events. The 2-year OS, RFS, and LRFS rates were 96.2%, 91.3%, and 95.0%, respectively. Regarding data for Asian populations, there are results from a Phase III trial conducted in China [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and a prospective observational study including Japanese patients [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], reporting 5-year OS, RFS, and locoregional recurrence rates of 84%, 74%, and 8.3%, and 90.9%, 81.0%, and 3.7%, respectively. Although 2-year data for OS, DFS, and locoregional recurrence were not explicitly stated in either study, the results estimated from their survival curves appear comparable to our findings. Grade 2 or higher AEs remained below 10% at all time points, with lymphedema being the most frequent (one patient of G3 and seven patients of G2). In the pooled analysis of the UK START trials [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], the reported 5-year prevalence of moderate-to-marked lymphedema following mHFRT ranged from 2.8% to 13.9%. Furthermore, Wang et al. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] reported a 1% incidence of Grade 3 lymphedema. In our cohort, all patients who developed lymphedema had undergone axillary lymph node dissection. This is consistent with previous reports suggesting that the surgical technique and other clinical factors have a more substantial impact on the risk of lymphedema than the dose-fractionation schedule [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn Cohort U, only one death from other causes and one patient of distant metastasis were observed, with no instances of locoregional recurrence. No late AEs of Grade 2 or higher were reported. In the FAST-Forward trial [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], a pivotal study of uHFRT, the 26 Gy group reported a mortality rate of 6.6%, local recurrence of 1.5%, regional recurrence of 0.7%, and distant recurrence of 5.5%; thus, our results are comparable. Regarding Japanese data on mHFRT for whole-breast irradiation, JCOG0906 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] showed 5-year OS, PFS, and IB-RFS rates of 98.7%, 95.4%, and 98.0%, respectively, with Grade 2 or higher late adverse events occurring in 9.5%. Considering these findings, it can be considered that there is no evidence of increased recurrence or toxicity risk associated with uHFRT for older Japanese patients, at least within the short-term follow-up period of 2 years.\u003c/p\u003e \u003cp\u003eRegarding cosmesis, some degree of cosmetic deterioration was observed in 12.5% of patients in Cohort M and 20% in Cohort U. The FAST-Forward trial [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] reported a 10.8% rate of cosmetic deterioration at 2 years based on photographic assessment. The JCOG0906 trial [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] observed cosmetic deterioration in 36.1% and 26.7% of patients at 1 and 3 years, respectively, after mHFRT. While we adopted a sequential boost of 10 Gy in 5 fractions, no correlation was found between the boost irradiation and cosmetic deterioration. However, a sequential boost extends the overall treatment period, potentially diminishing the primary advantage of hypofractionation, which is its shorter duration. Several clinical trials [\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] evaluating the use of simultaneous integrated boost radiation therapy are underway, and its clinical implementation may be considered in the future.\u003c/p\u003e \u003cp\u003eThere are several limitations to this study. First, although it was a prospective study, the number of patients was relatively small and most of the patients included in Cohort U were elderly. This is due to the limited indications for uHFRT at our institution; therefore, these results cannot be generalized across all age groups. Second, the 2-year follow-up period is relatively short for evaluating very late radiation-induced toxicities and long-term recurrence. However, since many late adverse events such as lymphedema and induration manifest within 2 years after irradiation, the 2-year assessment in this study can adequately predict the long-term safety profile of this schedule[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. On the other hand, it should be noted that tissue fibrosis and the associated deterioration in cosmetic appearance have been reported to gradually progress and stabilize beyond the second year, continuing toward the fifth year. Therefore, continued follow-up at the 5-year mark is essential to determine the final level of late toxicity in this cohort.\u003c/p\u003e \u003cp\u003e In conclusion, hypofractionated radiotherapy, including mHFRT for regional nodes and uHFRT for the conserved breast, is safe and effective for Japanese breast cancer patients during the 2-year follow-up period. These findings provide prospective evidence to support the harmonization of Japanese clinical practice with international guidelines, suggesting that these hypofractionated regimens are viable and safe alternatives to conventional fractionation for the majority of patients in this population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMN reports research grant from Illumina, personal fees from AstraZeneca, Sumitomo Heavy Industries, and Illumina outside the submitted work. All remaining authors declare no conflicts of interest in the writing of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Steve Bogart for developing SankeyMATIC, which was used to generate the flow diagrams in this paper.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMN: Conceptualization, Data curation, Formal analysis, Project administration, Visualization, Writing- Original draft preparation, Writing review \u0026amp; editing. KM: Investigation, Resources, Writing- Original draft preparation.TF: Investigation, Resources, Writing- Original draft preparation. YZ: Investigation, Resources, Writing- Original draft preparation. HH: Investigation, Resources, Writing- Original draft preparation. AM: Investigation, Resources, Writing- Original draft preparation. MW: Formal analysis, Writing- Original draft preparation. AN: Data curation, Writing- Original draft preparation. SZ: Supervision, Writing review \u0026amp; editing.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHaviland JS, Owen JR, Dewar JA, Agrawal RK, Barrett J, Barrett-Lee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013;14:1086\u0026ndash;94. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S1470-2045(13)70386-3\u003c/span\u003e\u003cspan address=\"10.1016/S1470-2045(13)70386-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang SL, Fang H, Song YW, Wang WH, Hu C, Liu YP, et al. Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer: a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol. 2019;20:352\u0026ndash;60. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S1470-2045(18)30813-1\u003c/span\u003e\u003cspan address=\"10.1016/S1470-2045(18)30813-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrunt AM, Haviland JS, Sydenham M, Agrawal RK, Algurafi H, Alhasso A, et al. Ten-Year Results of FAST: A Randomized Controlled Trial of 5-Fraction Whole-Breast Radiotherapy for Early Breast Cancer. J Clin Oncol. 2020;38:3261\u0026ndash;72. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1200/JCO.19.02750\u003c/span\u003e\u003cspan address=\"10.1200/JCO.19.02750\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurray Brunt A, Haviland JS, Wheatley DA, Sydenham MA, Alhasso A, Bloomfield DJ, et al. Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial. Lancet. 2020;395:1613\u0026ndash;26. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0140-6736(20)30932-6\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(20)30932-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurstein HJ, Curigliano G, Gnant M, Loibl S, Regan MM, Loi S, et al. Tailoring treatment to cancer risk and patient preference: the 2025 St Gallen International Breast Cancer Consensus Statement on individualizing therapy for patients with early breast cancer. Ann Oncol. 2025;36:1433\u0026ndash;46. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.annonc.2025.09.007\u003c/span\u003e\u003cspan address=\"10.1016/j.annonc.2025.09.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshimura M, Yamauchi C, Sanuki N, Hamamoto Y, Hirata K, Kawamori J, et al. The Japanese breast cancer society clinical practice guidelines for radiation treatment of breast cancer, 2022 edition. Breast Cancer. 2024;31:347\u0026ndash;57. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s12282-024-01568-4\u003c/span\u003e\u003cspan address=\"10.1007/s12282-024-01568-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakamura M, Fujisawa T, Oyoshi H, Zhou Y, Fukushi K, Hirata H, et al. Acute toxicity of hypofractionated radiotherapy for Japanese breast cancer patients after surgery: a single center prospective observational study (HyPORT-BC). Breast Cancer. 2024;31:1176\u0026ndash;81. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s12282-024-01626-x\u003c/span\u003e\u003cspan address=\"10.1007/s12282-024-01626-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWinchester DP, Cox JD. Standards for breast-conservation treatment. CA Cancer J Clin. 1992;42:134\u0026ndash;62. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3322/canjclin.42.3.134\u003c/span\u003e\u003cspan address=\"10.3322/canjclin.42.3.134\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOkonogi N, Kono S, Karasawa K, Banu PA, Xu X, Erawati D, et al. Significance of Hypofractionated Radiotherapy in Postoperative Irradiation for Breast Cancer: An Asian Multi-institutional Prospective Study. Clin Oncol (R Coll Radiol). 2023;35:463\u0026ndash;71. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.clon.2023.04.007\u003c/span\u003e\u003cspan address=\"10.1016/j.clon.2023.04.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaviland JS, Mannino M, Griffin C, Porta N, Sydenham M, Bliss JM, et al. Late normal tissue effects in the arm and shoulder following lymphatic radiotherapy: Results from the UK START (Standardisation of Breast Radiotherapy) trials. Radiother Oncol. 2018;126:155\u0026ndash;62. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.radonc.2017.10.033\u003c/span\u003e\u003cspan address=\"10.1016/j.radonc.2017.10.033\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNaoum GE, Taghian AG, Regional Lymph Node Radiation Is Not the Main Risk Factor for Breast Cancer Related Lymphedema. Stop Chasing Radiation Doses, Fractionation or Techniques-Focus on Axillary Surgery De-escalation or Prevention. Int J Radiat Oncol Biol Phys. 2023;117:461\u0026ndash;4. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ijrobp.2023.04.020\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2023.04.020\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNozaki M, Kagami Y, Machida R, Nakamura K, Ito Y, Nishimura Y, et al. Final analysis of a Multicenter Single-Arm Confirmatory Trial of hypofractionated whole breast irradiation after breast-conserving surgery in Japan: JCOG0906. Jpn J Clin Oncol. 2021;51:865\u0026ndash;72. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/jjco/hyab024\u003c/span\u003e\u003cspan address=\"10.1093/jjco/hyab024\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChakraborty S, Chatterjee S, Hyport Adjuvant Author G. HYPORT adjuvant acute toxicity and patient dosimetry quality assurance results - Interim analysis. Radiother Oncol. 2022;174:59\u0026ndash;68. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.radonc.2022.07.003\u003c/span\u003e\u003cspan address=\"10.1016/j.radonc.2022.07.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVicini FA, Winter K, Freedman GM, Arthur DW, Hayman JA, Rosenstein BS, et al. NRG RTOG 1005: A Phase III Trial of Hypo Fractionated Whole Breast Irradiation with Concurrent Boost vs. Conventional Whole Breast Irradiation Plus Sequential Boost Following Lumpectomy for High Risk Early-Stage Breast Cancer. Int J Radiat Oncol Biol Phys. 2022;114:S1\u0026ndash;S.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColes CE, Haviland JS, Kirby AM, Griffin CL, Sydenham MA, Titley JC, et al. Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trial. Lancet. 2023;401:2124\u0026ndash;37. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0140-6736(23)00619-0\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(23)00619-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLaughlin BS, Corbin KS, Toesca DAS, Thorpe CS, Golafshar MA, Pockaj B, et al. Physician- and Patient-Reported Outcomes of the MC1635 Phase 3 Trial of Ultrahypofractionated Versus Moderately Hypofractionated Adjuvant Radiation Therapy After Breast-Conserving Surgery. Int J Radiat Oncol Biol Phys. 2024;118:1049\u0026ndash;59. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ijrobp.2023.10.018\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2023.10.018\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNorman SA, Localio AR, Potashnik SL, Simoes Torpey HA, Kallan MJ, Weber AL, et al. Lymphedema in breast cancer survivors: incidence, degree, time course, treatment, and symptoms. J Clin Oncol. 2009;27:390\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1200/JCO.2008.17.9291\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2008.17.9291\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMukesh MB, Barnett G, Cumming J, Wilkinson JS, Moody AM, Wilson C, et al. Association of breast tumour bed seroma with post-operative complications and late normal tissue toxicity: results from the Cambridge Breast IMRT trial. Eur J Surg Oncol. 2012;38:918\u0026ndash;24. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ejso.2012.05.008\u003c/span\u003e\u003cspan address=\"10.1016/j.ejso.2012.05.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Breast cancer, radiotherapy, adverse event, ultra, cosmetic","lastPublishedDoi":"10.21203/rs.3.rs-8987514/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8987514/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003e International guidelines now prefer hypofractionated radiotherapy for breast cancer, yet prospective data for Japanese patients remain limited. In our prospective observational study of hypofractionated radiotherapy for Japanese breast cancer patients (HyPORT-BC), acute adverse events were found to be within an acceptable range. Herein, we report the 2-year follow-up data.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eBetween January and December 2023, 123 Japanese patients were enrolled: 81 received moderately hypofractionated radiotherapy (42.5 Gy/16 fractions) including the supraclavicular lymph node region (Cohort M), and 42 received ultra-hypofractionated radiotherapy (26 Gy/5 fractions) for the conserved breast (Cohort U). For endpoints, overall survival (OS), relapse-free survival (RFS), ipsilateral breast relapse-free survival (IBRS), locoregional relapse-free survival (LRFS), late adverse events (CTCAE v5.0), and cosmetic deterioration were evaluated.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAt a median follow-up of 28.8 months for Cohort M and 25.2 months for Cohort U, the 2-year OS, RFS, IBRS, and LRFS were 96.2%, 91.3%, 100%, and 95.0% for Cohort M, and 97.0%, 94.5%, 97.0%, and 97.0% for Cohort U, respectively. Grade\u0026thinsp;\u0026ge;\u0026thinsp;2 late AEs occurred in 9.1% of patients at 24 months in Cohort M; no Grade\u0026thinsp;\u0026ge;\u0026thinsp;2 late AEs were observed in Cohort U. Regarding cosmetic outcomes, the proportion of patients who showed any worsening from baseline was 12.5% in Cohort M and 20.0% in Cohort U.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eBoth moderately hypofractionated and ultra-hypofractionated radiotherapy demonstrated favorable 2-year efficacy and safety with acceptable cosmetic preservation in Japanese patients.\u003c/p\u003e","manuscriptTitle":"Two-year outcomes from the HyPORT-BC study: hypofractionated radiotherapy for Japanese breast cancer patients after surgery","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-08 17:02:57","doi":"10.21203/rs.3.rs-8987514/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9ed85c72-5f2b-4f1d-b016-404fb85f579e","owner":[],"postedDate":"March 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-22T03:33:39+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-08 17:02:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8987514","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8987514","identity":"rs-8987514","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}