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Purpose: To evaluate the prognostic value of peripheral lymphocyte count (PLC) in the breast cancer patients after breast-conserving surgery (BCS) with radiotherapy (RT)., Methods and Materials: This post hoc analysis was performed using data of 628 patients from a phase III, randomized controlled trial comparing hypofractionated RT (HFRT) with conventional fractionated RT (CFRT) after BCS. PLCs were obtained before, during, and after RT until the 1-year follow-up. The optimal cut-off PLCs were determined using the maxstat package in R. Survival rates were estimated using the Kaplan-Meier method and compared with the log-rank test., Results: A total of 275 (46.1 %) patients developed lymphopenia during RT, among them, 17 (2.8 %) had grade 3 lymphopenia and no one developed grade 4 lymphopenia. With a median follow-up of 110.8 months, patients with pre-RT PLCs of < 1.77 × 10 9 /L had a significantly lower 10-year breast cancer-specific survival (BCSS) rate (P = 0.013) and overall survival (OS) rate (P = 0.026). Patients with a nadir PLC of < 1.35 × 10 9 /L had a significantly poorer 10-year OS rate (P = 0.048). Multivariate analysis showed that a pre-RT PLC of < 1.77 × 10 9 /L was an independent factor influencing BCSS and OS, while the effect of the nadir PLC did not remain significant. Neither PLC nor lymphopenia recovery at post-RT 1, 3, and 6 months and 1 year was associated with survival., Conclusions: Radiation-induced lymphopenia in patients with breast cancer after BCS tends to be mild. The lower pre-RT PLC predicted poorer survival., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Our objective was to assess the incidence and dose-volume predictors of radiation esophagitis (RE) in patients with breast cancer undergoing hypofractionated regional nodal irradiation., Methods and Materials: Eligible patients who received intensity modulated radiation therapy (RT) at the chest wall, the supraclavicular/infraclavicular fossa, level II axilla, and/or the internal mammary chain after mastectomy were included. The prescribed dose was 43.5 Gy in 15 fractions. RE was evaluated weekly during RT and at 1 and 2 weeks, followed by 3 and 6 months after RT, and was graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. The esophagus was contoured from the lower border level of the cricoid cartilage to the lower margin of the aortic arch. Esophageal total volume, mean dose, maximum dose, and the relative volumes (RV) and absolute volumes (AV) receiving at least 5 to 45 Gy by 5-Gy increments (RV5-RV45 and AV5-AV45) were evaluated. Univariable and multivariable logistic regression analyses were performed to determine risk factors for RE, and receiver operating characteristic curves were obtained to identify the thresholds of esophageal dosimetric parameters., Results: In total, 298 patients were included between May 8, 2020, and January 5, 2022 (minimum post-RT follow-up: 6 months). Grade 2 and 3 RE incidence was 40.9% (122/298) and 0.3% (1/298), respectively. No grade 4 or 5 RE was observed. Esophageal RV20-RV40 and AV35-AV40 were significantly associated with the risk of grade ≥2 RE after adjusting for tumor laterality and internal mammary nodal irradiation. RV25 and AV35 were optimum dose-volume predictors for grade ≥2 RE at thresholds 20% for RV25 (35.9% vs 60.9%; P = .04) and 0.27 mL for AV35 (31.0% vs 54.6%; P = .04)., Conclusions: RE is common in patients with breast cancer undergoing hypofractionated regional nodal irradiation. Maintaining the upper esophageal V25 at <20% and V35 at <0.27 mL may decrease the risk of RE., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To map supraclavicular fossa-involved lymph nodes (SCF-LNs) in patients with nonmetastatic breast cancer, evaluate the coverage of widely adopted atlases, and propose modified borders for individualized regional irradiation., Methods and Materials: M0 patients with biopsy-proven SCF-LNs who were SCF treatment-naïve were included. The SCF was spatially divided into subregions, with each node mapped on the original images. The geographic misses after the borders of multiple atlases were evaluated and factors affecting SCF-LNs' spread pattern were analyzed., Results: From 1998 to 2022, 209 patients with 1242 SCF-LNs were eligible. Patients had a median of 4 nodes. At least 537 nodes (43.2%) in 147 patients (70.3%) were lateral to the sternocleidomastoid muscle (SCM), and 403 nodes (32.4%) in 127 patients (60.8%) were dorsal to the anterior scalene muscle (ASM). In the 88 patients with ≤3 SCF-LNs, at least 66 nodes (39.1%) in 40 patients (45.5%) were lateral to the SCM, and 34 nodes (20.1%) in 29 patients (33.0%) were dorsal to the ASM. These nodes were not covered by the Radiation Therapy Oncology Group (RTOG) atlas and partly within the Radiotherapy Comparative Effectiveness atlas. One hundred four patients (49.8%) had 432 SCF-LNs (34.8%) beyond the upper border of the European Society for Radiotherapy and Oncology (ESTRO) atlas. In multivariate regression, nodal sizes were associated with wider spread in the primary group. Being triple-negative (TN) subtype was associated with less spread in the recurrent group. Situation-based clinical target volumes (CTVs) were theorized, in which for a sequential spread, the posterior border could be the posterior scalene muscle or even be more constringent; otherwise, it should touch the anterior trapezius surface., Conclusions: SCF-LNs tend to spread laterally and dorsally beyond the RTOG borders, even in M0 stages with ≤3 SCF-LNs. The ESTRO upper border does not guarantee coverage with multiple SCF-LNs. Nodal burden and non-TN types are predictive of wider dissemination. A situation-based CTV is possibly feasible. Deciphering the SCF-LN spread route is needed., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: To investigate the dosimetric advantages of the voluntary deep inspiration breath-hold technique assisted by optical surface monitoring system for whole breast irradiation in left breast cancer after breast-conserving surgery and verify the reproducibility and acceptability of this technique. Methods: Twenty patients with left breast cancer receiving whole breast irradiation after breast-conserving surgery were enrolled in this prospective phase II study. Computed tomography simulation was performed during both free breathing and voluntary deep inspiration breath-hold for all patients. Whole breast irradiation plans were designed, and the volumes and doses of the heart, left anterior descending coronary artery, and lung were compared between free breathing and voluntary deep inspiration breath-hold. Cone beam computed tomography was performed for the first 3 treatments, then weekly during voluntary deep inspiration breath-hold treatment to evaluate the accuracy of the optical surface monitoring system technique. The acceptance of this technique was evaluated with in-house questionnaires completed by patients and radiotherapists. Results: The median age was 45 (27-63) years. All patients received hypofractionated whole breast irradiation using intensity-modulated radiation therapy up to a total dose of 43.5 Gy/2.9 Gy/15f. Seventeen of the 20 patients received concomitant tumor bed boost to a total dose of 49.5 Gy/3.3 Gy/15f. Voluntary deep inspiration breath-hold showed a significant decrease in the heart mean dose (262 ± 163 cGy vs 515 ± 216 cGy, P  < .001) and left anterior descending coronary artery (1191 ± 827 cGy vs 1794 ± 833 cGy, P  < .001). The median delivery time of radiotherapy was 4 (1.5-11) min. The median deep breathing cycles were 4 (2-9) times. The average score for acceptance of voluntary deep inspiration breath-hold by patients and radiotherapists was 8.7 ± 0.9 (out of 12) and 10.6 ± 3.2 (out of 15), respectively, indicating good acceptance by both. Conclusions: The voluntary deep inspiration breath-hold technique for whole breast irradiation after breast-conserving surgery in patients with left breast cancer significantly reduces the cardiopulmonary dose. Optical surface monitoring system-assisted voluntary deep inspiration breath-hold is reproducible and feasible and showed good acceptance by both patients and radiotherapists.

Purpose: Our objective was to assess the incidence and risk factors of radiation-induced hypothyroidism (RHT) after adjuvant hypofractionated radiation therapy (RT) in patients with breast cancer., Methods and Materials: Eligible patients with breast cancer who were treated with hypofractionated RT were prospectively evaluated. Thyroid function tests were performed before and at regular times after RT. RHT was defined as twice elevated serum thyroid-stimulating hormone (TSH) with decreased or normal free thyroxin after RT. The patient, tumor, and treatment factors were evaluated for possible associations with the risk of RHT., Results: Five hundred patients were analyzed. All patients underwent chest wall/breast with or without regional nodal irradiation. Among them, 369 (73.8%) patients received supraclavicular nodal radiation (SCRT). Eighty-two (16.4%) patients had elevated TSH before RT. At a median follow-up of 21.9 months, 131 (26.2%) patients developed RHT, and 59 (11.8%) patients received thyroid hormone-replacement therapy. Patients with SCRT had a significantly increased 2-year cumulative incidence of RHT compared with patients without SCRT (31.5% and 11.4%, P<.001). The peak incidence of RHT occurred around 6 to 12 months after RT. Multivariate analysis revealed that elevated baseline TSH and increased thyroid mean dose (Dmean) were independent risk factors for developing RHT. After adjusted for baseline TSH, there was a nonlinear relationship between thyroid Dmean and the risk of RHT. Dmean >21 Gy was the threshold value for predicting RHT (hazard ratio, 2.2; P<.001)., Conclusions: The incidence of RHT was high in patients with breast cancer. Thyroid function test should be started no later than 6 months after RT. We recommend that the Dmean of the thyroid should be kept lower than 21 Gy for hypofractionated RT., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To assess the influence of age as a continuous variable on the prognosis of pT1-2N1 breast cancer and examine its decision-making value for postmastectomy radiotherapy (PMRT)., Methods: We retrospectively evaluated 5438 patients with pT1-2N1 breast cancer after mastectomy in 11 hospitals. A multivariable Cox proportional hazards regression model with penalized splines was used to examine the relationship between age and oncologic outcomes., Results: The median follow-up was 67.0 months. After adjustments for confounding characteristics, nonsignificant downward trend in locoregional recurrence (LRR) risk was observed with increasing age (P-non-linear association = 0.640; P-linear association = 0.078). A significant non-linear association was found between age and disease-free survival (DFS) and overall survival (OS) (P-non-linear association <0.05; P-linear association >0.05, respectively). The DFS and OS exhibited U-shaped relationships, with the hazard ratios (HRs), reaching a nadir at 50 years old. A decreased risk of LRR with PMRT vs. no PMRT (HR = 0.304, 95% CI: 0.204-0.454) was maintained in all ages. The HR of PMRT vs. no PMRT for DFS and OS gradually increased with age. In patients ≤50 years old, PMRT was independently associated with favorable LRR, DFS, and OS, all P < 0.05). In patients >50 years old, PMRT was independently associated with reduced LRR (P = 0.004), but had no effect on DFS or OS., Conclusions: Age was an independent prognostic factor for pT1-2N1 breast cancer; PMRT provided survival benefits for patients ≤50 years old, but not for patients >50 years old., Competing Interests: Declaration of competing interest All listed authors declare that they have no conflict of interests., (Copyright © 2022. Published by Elsevier Ltd.)

Purpose: To investigate the appropriate timing of radiotherapy (RT) after mastectomy and adjuvant chemotherapy for women with high-risk breast cancer., Patients and Methods: Post hoc analyses of 584 patients with stage II and III breast cancer from a randomised controlled clinical trial were performed. All patients underwent mastectomy followed by sequential chemotherapy and RT. The optimal cut-off values for the surgery-RT interval (SRI) and the chemotherapy-RT interval (CRI) for overall survival (OS) were determined using the hazard ratio for continuous predictors. The locoregional recurrence (LRR), distant metastasis (DM), disease-free survival (DFS), and OS rates were estimated using the Kaplan-Meier method. Multivariate analyses were performed using Cox proportional hazards regression., Results: Median follow-up time was 83.5 months. Median SRI and CRI were 168 and 27 days, respectively. An SRI of &gt;210 days was independently associated with higher DM (HR 2.65, 95% CI: 1.49-4.71; HR 2.78, 95% CI 1.51-5.26), lower OS (HR 2.44, 95% CI: 1.28-4.54; HR 2.50, 95% CI: 1.41-4.35), and lower DFS (HR 2.57, 95% CI: 1.45-4.57; HR 2.70, 95% CI: 1.45-5.00) than SRI of &lt;180 or 180-210 days. Furthermore, a CRI of more than 42 days was independently associated with higher DM (HR 1.89, 95% CI: 1.17-3.06; HR 1.96, 95% CI: 1.19-3.22), lower OS (HR 2.44, 95% CI: 1.41-4.35; HR 1.92, 95% CI: 1.10-3.33), and lower DFS (HR 1.84, 95% CI: 1.14-2.96; HR 1.82, 95% CI: 1.12-2.94) than a CRI of &lt;28 or 28-42 days. However, SRI and CRI had no significant effect on LRR., Conclusions: Based on the present findings, the timing of the initiation of RT both after mastectomy and after the completion of adjuvant chemotherapy is crucial for patients with high-risk breast cancer., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Various randomized trials have demonstrated that postmastectomy radiotherapy (RT) to the chest wall and comprehensive regional nodal areas improves survival in patients with axillary node-positive breast cancer. Controversy exists as to whether the internal mammary node (IMN) region is an essential component of regional nodal irradiation. Available data on the survival benefit of IMN irradiation (IMNI) are conflicting. The patient populations enrolled in previous studies were heterogeneous and most studies were conducted before modern systemic treatment and three-dimensional (3D) radiotherapy (RT) techniques were introduced. This study aims to assess the efficacy and safety of IMNI in the context of modern systemic treatment and computed tomography (CT)-based RT planning techniques., Methods: POTENTIAL is a prospective, multicenter, open-label, parallel, phase III, randomized controlled trial investigating whether IMNI improves disease-free survival (DFS) in high-risk breast cancer with positive axillary nodes (pN+) after mastectomy. A total of 1800 patients will be randomly assigned in a 1:1 ratio to receive IMNI or not. All patients are required to receive ≥ six cycles of anthracycline and/or taxane-based chemotherapy. Randomization will be stratified by institution, tumor location (medial/central vs. other quadrants), the number of positive axillary nodes (1-3 vs. 4-9 vs. ≥10), and neoadjuvant chemotherapy (yes vs. no). Treatment will be delivered with CT-based 3D RT techniques, including 3D conformal RT, intensity-modulated RT, or volumetric modulated arc therapy. The prescribed dose is 50 Gy in 25 fractions or 43.5 Gy in 15 fractions. Tiered RT quality assurance is required. After RT, patients will be followed up at regular intervals. Oncological and toxilogical outcomes, especially cardiac toxicities, will be assessed., Discussion: This trial design is intended to overcome the limitations of previous prospective studies by recruiting patients with pN+ breast cancer, using DFS as the primary endpoint, and prospectively assessing cardiac toxicities and requiring RT quality assurance. The results of this study will provide high-level evidence for elective IMNI in patients with breast cancer after mastectomy., Trial Registration: ClinicalTrails.gov , NCT04320979 . Registered 25 Match 2020, https://clinicaltrials.gov/ct2/show/NCT04320979., (© 2021. The Author(s).)

Background: The phase 3 NCT00793962 trial demonstrated that postmastectomy hypofractionated radiation therapy (HFRT) was noninferior to conventional fractionated radiation therapy (CFRT) in patients with high-risk breast cancer. This study assessed the cost-effectiveness of postmastectomy HFRT vs CFRT based on the NCT00793962 trial., Methods: A Markov model was adopted to synthesize the medical costs and health benefits of patients with high-risk breast cancer based on data from the NCT00793962 trial. Main outcomes were discounted lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). We employed a time-dependent horizon from Chinese, French and USA payer perspectives. Model robustness was evaluated with one-way and probabilistic sensitivity analyses., Results: Patients receiving CFRT versus HFRT gained an incremental 0.0163 QALYs, 0.0118 QALYs and 0.0028 QALYs; meanwhile an incremental cost of $2351.92, $4978.34 and $8812.70 from Chinese, French and USA payer perspectives, respectively. Thus CFRT versus HFRT yielded an ICER of $144,281.47, $420,636.10 and $3,187,955.76 per QALY from Chinese, French and USA payer perspectives, respectively. HFRT could maintain a trend of >50% probabilities of cost-effectiveness below a willingness-to-pay (WTP) of $178,882.00 in China, while HFRT was dominant relative to CFRT, regardless of the WTP values in France and the USA. Sensitivity analyses indicated that the ICERs were most sensitive to the parameters of overall survival after radiotherapy., Conclusions: Postmastectomy HFRT could be used as a cost-effective substitute for CFRT in patients with high-risk breast cancer and should be considered in appropriately selected patients., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: To compare the survival outcomes between breast-conserving surgery (BCS) and modified radical mastectomy (MRM), and to investigate the role of radiotherapy (RT) in patients with pT1-2N1M0 breast cancer., Methods: A total of 4262 women with T1-2N1M0 breast cancer treated at two institutions were retrospectively reviewed. A total of 3858 patients underwent MRM, and 832 (21.6%) of them received postoperative RT (MRM + RT). A total of 404 patients received BCS plus postoperative RT (BCS + RT). All patients received axillary lymph node dissection, while 3.8% of them had upfront sentinel node biopsy. The association of survival outcomes with different surgical modalities (BCS vs. MRM) and the role of RT were evaluated using multivariable proportional hazards regression and confirmed by the propensity score-matching (PSM) method., Results: At a median follow-up of 71 months (range of 6-230 months), the 5-year overall survival (OS) rates of the BCS and MRM groups were 96.5 and 92.7%, respectively (P = .001), and the corresponding 5-year disease-free-survival (DFS) and locoregional recurrence (LRR) rates were 92.9 and 84.0%, and 2.0 and 7.0% (P = .001), respectively (P < .001). Multivariate analysis revealed that RT was an independent prognostic factor for improved OS (P = .001) and DFS (P = .009), and decreased LRR (P < .001). However, surgery procedure was not independently associated with either OS (P = .495), DFS (P = .204), or LRR (P = .996), which was confirmed by PSM analysis., Conclusion: Postoperative radiotherapy rather than the surgery procedures was associated with superior survival outcomes in patients with T1-2N1M0 breast cancer.

Purpose: No randomized trials have compared hypofractionated radiotherapy (HFRT) with conventional fractionated radiotherapy (CFRT) after breast-conserving surgery in the Asian population. This study aimed to determine whether a 3.5-week schedule of HFRT is noninferior to a standard 6-week schedule of CFRT in China., Patients and Methods: Patients from 4 Chinese institutions who had undergone breast-conserving surgery and had T1-2N0-3 invasive breast cancers participated this study. Patients were randomly assigned (1:1) using a computer-generated central randomization schedule, without stratification, to receive whole-breast irradiation with or without nodal irradiation, followed by tumor-bed boost, either at a dose of 50 Gy in 25 fractions over 5 weeks with a boost of 10 Gy in five fractions over 1 week (CFRT) or 43.5 Gy in 15 fractions over 3 weeks with a boost of 8.7 Gy in three daily fractions (HFRT). The primary endpoint was 5-year local recurrence (LR), and a 5% margin of 5-year LR was used to establish noninferiority., Results: Between August 2010 and November 2015, 734 patients were assigned to the HFRT (n = 368) or CFRT (n = 366) group. At a median follow-up of 73.5 months (interquartile range, 60.5-91.4 months), the 5-year cumulative incidence of LR was 1.2% in the HFRT group and 2.0% in the CFRT group (hazard ratio, 0.62; 95% CI, 0.20 to 1.88; P = .017 for noninferiority). There were no significant differences in acute and late toxicities, except that the HFRT group had less grade 2-3 acute skin toxicity than the CFRT group ( P = .019)., Conclusion: CFRT and HFRT with a tumor-bed boost may have similar low LR and toxicity.

Background: To our knowledge, no randomised study has compared postmastectomy hypofractionated radiotherapy with conventional fractionated radiotherapy in patients with breast cancer. This study aimed to determine whether a 3-week schedule of postmastectomy hypofractionated radiotherapy is as efficacious and safe as a 5-week schedule of conventional fractionated radiotherapy., Methods: This randomised, non-inferiority, open-label, phase 3 study was done in a single academic hospital in China. Patients aged 18-75 years who had undergone mastectomy and had at least four positive axillary lymph nodes or primary tumour stage T3-4 disease were eligible to participate. Patients were randomly assigned (1:1) according to a computer-generated central randomisation schedule, without stratification, to receive chest wall and nodal irradiation at a dose of 50 Gy in 25 fractions over 5 weeks (conventional fractionated radiotherapy) or 43·5 Gy in 15 fractions over 3 weeks (hypofractionated radiotherapy). The modified intention-to-treat population (including all eligible patients who underwent randomisation but excluding those who were considered ineligible or withdrew consent after randomisation) was used in primary and safety analyses. The primary endpoint was 5-year locoregional recurrence, and a 5% margin was used to establish non-inferiority (equivalent to a hazard ratio <1·883). This trial is registered at ClinicalTrials.gov, number NCT00793962., Findings: Between June 12, 2008, and June 16, 2016, 820 patients were enrolled and randomly assigned to the conventional fractionated radiotherapy group (n=414) or hypofractionated radiotherapy group (n=406). 409 participants in the conventional fractionated radiotherapy group and 401 participants in the hypofractionated radiotherapy group were included in the modified intention-to-treat analyses. At a median follow-up of 58·5 months (IQR 39·2-81·8), 60 (7%) patients had developed locoregional recurrence (31 patients in the hypofractionated radiotherapy group and 29 in the conventional fractionated radiotherapy group); the 5-year cumulative incidence of locoregional recurrence was 8·3% (90% CI 5·8-10·7) in the hypofractionated radiotherapy group and 8·1% (90% CI 5·4-10·6) in the conventional fractionated radiotherapy group (absolute difference 0·2%, 90% CI -3·0 to 2·6; hazard ratio 1·10, 90% CI 0·72 to 1·69; p<0·0001 for non-inferiority). There were no significant differences between the groups in acute and late toxicities, except that fewer patients in the hypofractionated radiotherapy group had grade 3 acute skin toxicity than in the conventional fractionated radiotherapy group (14 [3%] of 401 patients vs 32 [8%] of 409 patients; p<0·0001)., Interpretation: Postmastectomy hypofractionated radiotherapy was non-inferior to and had similar toxicities to conventional fractionated radiotherapy in patients with high-risk breast cancer. Hypofractionated radiotherapy could provide more convenient treatment and allow providers to treat more patients., Funding: National Key Projects of Research and Development of China; the Chinese Academy of Medical Science Innovation Fund for Medical Sciences; and Beijing Marathon of Hope, Cancer Foundation of China., (Copyright © 2019 Elsevier Ltd. All rights reserved.)