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Radiation esophagitis (RE) is often overlooked in breast cancer radiotherapy. This study aimed to assess the incidence and dose-volume predictors of RE in breast cancer patients undergoing hypofractionated regional nodal irradiation (RNI). Eligible patients were included who received intensity-modulated radiotherapy (RT) at the chest wall, the supraclavicular/infraclavicular fossa, level II axilla, and/or the internal mammary chain after mastectomy. The prescribed dose was 43.5 Gy in 15 fractions. The dose constraint for the esophagus was maximum dose <48 Gy. 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 the Common Toxicity Criteria for Adverse Events v3.0. 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 (Dmean), maximum dose (Dmax), and the relative and absolute volumes receiving at least 5-45 Gy by 5 Gy increments (RV5–RV45 and AV5–AV45) were evaluated. Univariable and multivariable logistics 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. In total, 298 patients were included between May 8, 2020 and January 5, 2022 (minimum post-RT follow-up: 6 months). A total of 153 (51.3%) patients had left-sided breast cancer and 145 (48.7%) patients received internal mammary nodal irradiation (IMNI). 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. All RE cases resolved within 1 month after RT, and the median duration of RE was 3 weeks (range, 1-5). Based on univariable analyses, tumor laterality (p <.001), IMNI (p =.056) and esophageal Dmean, Dmax, RV10-RV40, and AV10-AV40 were risk factors of ≥grade 2 RE. Esophageal RV10-RV40 and AV35-AV40 were significantly associated with the risk of ≥grade 2 RE after adjusting for tumor laterality and IMNI. Based on multivariable analyses, 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). RE is common in breast cancer patients undergoing hypofractionated RNI. With the same esophageal contouring standard, maintaining the upper esophageal V25 at <20% and V35 at <0.27 mL may decrease the risk of RE and improve the quality of life of patients. [ABSTRACT FROM AUTHOR]

To report acute toxicological outcomes of an ongoing prospective, multicenter, phase III, randomized controlled trial (NCT04320979) designed to evaluate the safety and efficacy of internal mammary node irradiation (IMNI) after mastectomy for high-risk node-positive breast cancer. Eligible patients were randomly assigned (1:1) to receive IMNI (IMNI arm) or not (no IMNI arm). The prescribed dose was either 50 Gy in 25 fractions (conventional fractionated radiotherapy, CFRT) or 43.5 Gy in 15 fractions (hypofractionated radiotherapy, HFRT) Acute toxicities were evaluated weekly during radiotherapy (RT) and at 1 week, 2 weeks, 3 months, 6 months after RT according to Common Toxicity Criteria for Adverse Events v3.0. Clinically significant toxicities were defined as ³ grade 3 dermatitis, esophagitis, myelosuppression and ³ grade 2 pneumonitis. The mean dose, maximum dose, and V10–V50 of ipsilateral lung and neighboring esophagus were evaluated. Chi-square test was performed to compare the differences between IMNI and no IMNI arms. Between May 8, 2020, and June 8, 2021, 219 patients treated in 14 centers were analyzed with minimum follow-up of 6 months. There were 114 (52.1%) and 105 (47.9%) patients in no IMNI and IMNI arm. Chest wall ± IMN was irradiated with intensity-modulated RT (IMRT) in 196 (89.5%) patients and electrons in 23 (10.5%) patients. Supra/infraclavicular ± axillary nodal regions were irradiated with IMRT technique in all patients. There were 147 (67.1%) patients treated with HFRT and 72 (32.9%) patients treated with CFRT. Among patients treated with HFRT and CFRT, the differences were significant in mean lung dose (13.1 Gy vs 13.4 Gy, p=.048 and 14.4 Gy vs 15.2 Gy, p=.009), V10 of lung (37.0% vs 37.9%, p=.024 and 39.0% vs 41.0%, p=.011), but not significant in mean esophagus dose (14.7 Gy vs 15.3 Gy, p=.447 and 16.9 Gy vs 18.8 Gy, p=.257), V10 of esophagus (58.0% vs 62.1%, p=.260 and 59.0% vs 77.4%, p=.059) between no IMNI and IMNI arm. There were no statistically significant differences in ³ grade 3 dermatitis (1.8% vs 1.0%, p = 1.000), ³ grade 3 esophagitis (0.9% vs 0.0%, p =1.000), or ³ grade 2 pneumonitis (3.8% vs 2.0%, p=.684) between no IMNI and IMNI arm. 108 (49.3%) patients had ≥ grade 3 myelosuppression, including 107 (48.9%) lymphopenia, 6 (2.8%) leucopenia, and no thrombocytopenia. The incidence of ≥ grade 3 myelosuppression were significantly higher in IMNI arm than no IMNI arm (56.2% vs 42.1%, p=.037). IMNI caused acceptable dermatitis, esophagitis and pneumonitis in breast cancer after mastectomy. Higher risk of myelosuppression, mainly lymphopenia, was found in IMNI arm. [ABSTRACT FROM AUTHOR]

Postmastectomy radiotherapy in Node-positive breast cancer with or without Internal mammary nodal irradiation (POTENTIAL) study is an ongoing study investigates the role of IMN irradiation in breast cancer patients. This study reported the result of the dosimetric quality assurance regarding individual case review of target coverage and doses to heart and lungs. Real-time central reviews were performed for the first ten enrolled patients in each center regarding contouring and planning. The target coverage, including planning target volume of all targets and IMN (PTVall, PTVim), clinical target volume of IMN (CTVim), and doses to heart and lungs were evaluated. Among the 117 patients who were enrolled at 14 centers, 62 (53.0%) patients were randomly assigned to the IMN irradiation group (IMNI) and 55 (47.0%) patients to no IMN group (no IMNI group). Sixty (51.3%) patients received HFRT at dose of 43.5 Gy/15f/2.9 Gy, and 57 (48.7%) patients received CFRT at dose of 50 Gy/25f/2 Gy. A total of 108 (92.3%) patients were irradiated with intensity-modulated radiotherapy (IMRT) technique to the supra/infraclavicular nodal region (SNR) and chest wall (CW) +/- IMN. In 9 (7.6%) patients, the CW +/-IMN were irradiated by electrons, and the SNR was irradiated with IMRT technique. The D95 and D90 of PTVall reached the prescribed dose in 36.8% and 81.2% of the patients, respectively. In the IMN group who were irradiated with IMRT technique, the D95 and D90 of PTVim reached the prescribed dose in 29.8% and 78.9% of the patients, respectively. When the IMN was irradiated with electrons, the mean D95 and D90 of CTVim was 31.1 Gy and 37.1 Gy, significantly lower than that of patients treated with IMRT (P = 0.008). In the no IMNI group, the mean D95 of PTVim was 12.6 Gy and 20.2 Gy for patients treated with HFRT and CFRT, respectively, which was both significantly lower than that of the IMNI group (P < 0.001). For patients treated with HFRT, the Dmean and V5 of the heart was significantly higher in IMNI group compared to those in no IMNI group (5.2 vs 3.4 Gy, p = 0.001; 26.2% vs 14.4%, p< 0.001). The differences were significant in Dmean (12.9 vs 11.3 Gy, p = 0.001), V20 (26.0% vs 22.4%, p = 0.002), and V5 (50.2% vs 46.6%, p= 0.009) of the ipsilateral lung, but not in V5 (6.2% vs 4.8%, p = 0.367) of contralateral lung, between IMN and no IMN group. For patients treated with CFRT, there were no significant differences in Dmean (5.4 vs 4.8 Gy, p = 0.366) and V5 (32.1% vs 26.7%, p = 0.169) of the heart between IMNI and no IMNI group. There were significant differences in Dmean (15.1 vs 14.0 Gy, p = 0.004), V20 (28.7% vs 26.0%, p =0.002), and V5 (56.9% vs 52.5%, p =0.001) of the ipsilateral lung, and V5 (12.7% vs 5.5%, p < 0.001) of contralateral lung between IMN and no IMN group. Individual case review of POTENTIAL study showed that the target coverage was acceptable, and doses to the heart and lung increased in IMNI group compared to no IMNI group. [ABSTRACT FROM AUTHOR]

To assess the incidence and risk factors of radiation-induced hypothyroidism (RHT) after adjuvant hypofractionated radiotherapy (RT) in patients with breast cancer, and identify the dose constraint for the thyroid gland. The trends of RHT over time were also evaluated to determine the optimal timing of screening for RHT in breast cancer patients treated with hypofractionated RT. Consecutive eligible breast cancer patients who were treated with hypofractionated RT were prospectively evaluated. Thyroid function tests were performed before and at regular times following RT (every 3-4 months during the first two years, then every six months until five years). 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. The incidence of RHT was calculated from the end of RT using the Kaplan–Meier method, and the differences between groups were compared with the log-rank test. Multivariate analysis was performed using Cox logistic regression analysis. A multivariate Cox proportional hazards regression model with penalized spline (P-spline) was used to examine the relationship between thyroid mean dose (Dmean) and RHT. A two-sided test of P < 0.05 was considered statistically significant. A total of 500 patients treated between 2017 and 2020 were analyzed. All patients underwent chest wall/breast ± regional nodal irradiation with a prescription dose of 43.5Gy in 15 fractions. 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. The 2-year cumulative incidence of RHT was 26.0%. Patients with SCRT had a significantly increased 2-year cumulative incidence of RHT compared with patients without SCRT (31.5% and 11.4%, p<0.001). The median time to the onset of RHT was 9.3 months (range, 1.0-42.4) after RT. The peak incidence of RHT occurred around 6-12 months after RT. Multivariate analysis revealed that elevated baseline TSH and increased thyroid Dmean as a continuous variable were independent risk factors for developing RHT. After adjusted for baseline TSH, there was a nonlinear relationship between Dmean and the risk of RHT. Dmean > 21 Gy was identified as the threshold value for predicting RHT (HR=2.2, p<0.001). Dmean > 21 Gy compared with Dmean ≤ 21 Gy was associated with a significantly higher incidence of RHT at two years after RT (17.0% vs. 32.2%, P<0.001). The incidence of RHT was high in breast cancer patients. Thyroid function test should be started no later than six months following RT. We recommend that the Dmean of the thyroid should be kept lower than 21Gy for hypofractionated RT. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): In an era of increasingly use of axilla irradiation in high-risk breast cancer patients after breast-conserving surgery and sentinel lymph node (LN) biopsy, the optimal clinical target volume (CTV) for level I axilla (Ax-L1) LN is uncertain. We mapped the location of pretreatment LN metastases in the Ax-L1 of newly diagnosed breast cancer patients and propose modification of the CTV borders as defined by the Radiation Therapy Oncology Group (RTOG) breast cancer atlas. Further, we assessed the differences in dosimetric parameters of modified Ax-L1 planning target volume (PTV) and surrounding organs at risk (OAR) between whole breast irradiation with standard "high tangential" simplified IMRT (HT-sIMRT WBI) and whole breast plus Ax-L1 irradiation with VMAT (VMAT WBI+ Ax-L1).Materials/methods: We identified 76 newly diagnosed breast cancer patients with 1-4 positive LNs after curative-intent surgery and axillary lymph node dissection treated between 2016 and 2018. All patients had a pretreatment diagnostic computed tomography (CT) chest scan demonstrating involved Ax-L1 LNs. The locations of 116 involved Ax-L1 LNs were mapped onto simulation CT images of a standard patient and the appropriateness of RTOG atlas was assessed. A modified Ax-L1 CTV with better coverage for involved Ax-L1 LNs was proposed, and PTV was generated for plans. Standard "high tangential" sIMRT plans for WBI and VMAT plans for WBI+ Ax-L1 on each side (left side and right side) were designed with a prescription dose of 50 Gy in 25 fractions, and dosimetric parameters were compared.Results: For the RTOG atlas, the mapped LNs were 70.7% (82/116) inside, 13.8% (16/116) marginal and 15.5% (18/116) outside the CTV borders. The RTOG atlas missed 29.3% of LNs: 50.0% (17/34) in the anterior, 23.5% (8/34) in the caudal, 14.7% (5/34) in the cranial, 11.8% (4/34) in the medial direction. Modification by extending 1 cm caudal and 0.5 cm anterior to the CTV borders of the RTOG atlas allowed the modified Ax-L1 CTV to encompass 90.5% (105/116) of LNs. For HT-sIMRT WBI and VMAT WBI+ Ax-L1 plans, the mean V50 of modified Ax-L1 PTV was 69.5% and 97.8%; the mean dose, V20 and V5 of ipsilateral lung were 8.9 Gy, 16.4%, 32.5% and 10.5 Gy, 20.8%, 33.8%; the mean heart dose in left-sided plans was 4.1 Gy and 3.0 Gy; the mean dose and V5 of liver in the right-sided plans were 1.5 Gy, 3.6% and 2.8 Gy, 10.3%, respectively.Conclusion: According to the distribution of Ax-L1 LNs, the RTOG atlas might be insufficient for their coverage. We propose a modified Ax-L1 CTV with expansion of RTOG Ax-L1 CTV borders, most notably in the caudal and anterior directions. Standard "high tangential" sIMRT WBI plans failed to deliver a therapeutic dose adequately to the modified Ax-L1 PTV. VMAT plans intended for whole breast plus Ax-L1 irradiation provided adequate dose to Ax-L1 PTV without increasing the doses to OARs. [ABSTRACT FROM AUTHOR]