Internal Mammary Node Irradiation Research Articles

Internal mammary lymphadenopathy in breast cancer: a narrative review and update.

While the axillary nodal basin is the most common lymphatic drainage pathway of the breast, the internal mammary (IM) lymph node chain plays a significant role in breast cancer staging and treatment. It has been identified as sentinel nodal drainage in approximately 13-37% of patients. Despite this, the data is still limited with regard to diagnosis and management when there is suspicion or confirmation of IM lymph node (IMLN) involvement by metastatic breast cancer. The objective of this publication is to provide a comprehensive assessment of the current body of literature surrounding the diagnosis, management and prognostic value of IMLNs in breast cancer treatment. Review of the literature published regarding IMLN diagnosis, significance, and management was completed in PubMed. Additional focus was placed on reviewing articles published within the past 10 years as foundation for an update regarding the current practice and future directions in this space. Improved imaging techniques, with positron emission tomography-computed tomography and magnetic resonance imaging, have led to increase in the identification of IM lymphadenopathy, yielding surgical staging of the IM nodes nearly obsolete. While IM nodal metastases may play a role in overall survival (OS), it has not been demonstrated to be an independent risk factor for increased locoregional recurrence. IM nodal irradiation (IMNI) therapy has been a mainstay in the treatment of IM disease in the context of breast cancer. IMNI has demonstrated improvement in OS and risk of distant recurrence. Wide variations in radiation practices for patients with IM lymphadenopathy exist internationally, highlighting the lack of clear data driven consensus guidelines. Herein, we provide an updated assessment of the current diagnosis, clinical significance, and management of IM lymphadenopathy for breast cancer patients.

Internal Mammary Node Irradiation Debate: Case Closed? Not Yet, and Maybe Never.

The IMN debate is still open and may never be closed for reasons outlined in this Comments and Controversies piece.

Quality assurance in a phase III, multicenter, randomized trial of POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a planning benchmark case

PurposeTo report the planning benchmark case results of the POTENTIAL trial—a multicenter, randomized, phase 3 trial—to evaluate the value of internal mammary nodal (IMN) irradiation for patients with high-risk breast cancer.MethodsAll participating institutions were provided the outlines of one benchmark case, and they generated radiation therapy plans per protocol. The plans were evaluated by a quality assurance team, after which the institutions resubmitted their revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed in the first and final submission.ResultsThe plans from 26 institutions were analyzed. Some major deviations were found in the first submission. The protocol compliance rates of dose coverage for the planning target volume of chest wall, supraclavicular fossa plus axilla, and IMN region (PTVim) were all significantly improved in the final submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8%, respectively. For OARs, the compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. In the first and final submission, the mean values of PTVim V100% were 79.9% vs. 92.7%; the mean values of heart Dmean were 11.5 Gy vs. 9.7 Gy for hypofractionated radiation therapy and 11.5 Gy vs. 11.0 Gy for conventional fractionated radiation therapy, respectively.ConclusionThe major deviations were corrected and protocol compliance was significantly improved after revision, which highlighted the importance of planning benchmark case to guarantee the planning quality for multicenter trials.

Treatment of Internal Mammary Nodes is Associated With Improved Overall Survival in Breast Cancer: A Meta-Analysis.

The role of internal mammary nodal irradiation (IMNI) as a component of regional nodal radiotherapy is a controversial issue in breast radiation oncology with conflicting results presented in recent landmark trials. We thus created a meta-analysis of available data to better ascertain the potential benefit of IMNI. We hypothesize that with the increased power available within a meta-analysis, IMNI will prove to improve overall survival (OS) in breast cancer. Literature search was conducted for prospective studies comparing IMNI to no IMNI. Primary endpoint was OS and secondary endpoints included local recurrence, regional recurrence, disease-free survival (DFS), breast cancer mortality (BCM), distant metastasis-free survival (DMFS), grade 2+ skin toxicity, cardiac events, and pneumonitis events. Subgroup analyses were performed for tumor location (medial/central vs. lateral), and nodal status (pN+ vs. pN0). Fixed-effect model was used if there was no heterogeneity, random-effects model otherwise. Four studies with a total of 5258 patients (IMNI: n=2592; control: n=2666) were included in the study. Pooled results showed IMNI significantly improved OS for all-comers (hazard ratio [HR]=0.89; 95% CI 0.81-0.97; P =0.008), as well as subgroups of pN+ with medial/central tumor location (HR=0.84; 95% CI 0.73-0.96; P =0.01) and pN+ with lateral tumor location (HR=0.87; 95% CI 0.77-0.99; P =0.04). There was no significant difference in OS for subgroups of pN0 and medial/central tumor location. There was no difference in local recurrence, but regional recurrence was significantly improved ( P =0.04). Endpoints of DFS (HR 0.91, 95% CI 0.84-0.99 P =0.03), BCM (HR 0.87, 95% CI 0.77-0.98, P =0.03), and DMFS (HR=0.87; 95% CI, 0.78-0.98; P =0.02) were all improved with IMNI. Grade 2+ skin toxicity, cardiac events and pneumonitis events were not significantly different between patient in the IMNI and no IMNI groups. Inclusion of IMN irradiation improves OS, DFS, BCM, and DMFS in breast cancer. Largest effect on OS was noted in the subgroup of patients with pN+ and medial/central tumor location.

Quality Assurance in a Phase III, Multicenter, Randomized Trial of POstmastectomy radioThErapy in Node posiTive Breast Cancer with or without Internal mAmmary nodaL Irradiation (POTENTIAL): A Planning Dummy Run

To report the planning dummy run results of the POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL) trial-a multicenter, randomized, phase 3 trial-to evaluate postmastectomy radiotherapy, with or without internal mammary nodal irradiation, for patients with high-risk breast cancer. All participating institutions were provided the contours of the dummy run case, and they generated radiotherapy (RT) plans per protocol guidelines. The plans were reviewed and feedback were provided by the quality assurance team, after which the institutions resubmitted revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed both in the primary and final submission. Theplans from 26 institutions were included in the analysis. A number of major deviations were found in the primary submission, such as less strict constraint on organs at risk (OARs) V5Gy, and no application of chest wall skin flash. The protocol compliance rates of the dose coverage for the planning target volume of the chest wall (PTVcw), PTV of supra/infraclavicular fossa plus axilla levels I, II, III (PTVsc+ax), and PTV of the IMN region (PTVim) were all significantly improved in the final submission compared with those in the primary submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8, respectively. For OARs, the protocol compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. All major deviations were corrected and protocol compliance was significantly improved and of high level in the final submission. Moreover, the variations were reduced. Therefore, a planning dummy run was essential to guarantee good RT plan quality and inter-institutional consistency for multicenter trials.

Dose-Volume Predictors for Radiation Esophagitis in Breast Cancer Patients Undergoing Hypofractionated Regional Nodal Radiotherapy

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.

Reducing Racial Disparities in Breast Cancer Treatment

Racial disparities in breast cancer screening, treatment, and outcomes are well established. A recent multi-institutional paper showed a higher mean heart dose (MHD) in Black women and other minorities compared to White women who underwent left-sided breast or chest wall irradiation. We evaluated the MHD of women treated in our institution and investigated whether institution-wide measures can mitigate disparities. We identified 509 consecutively treated female patients from 2012 to 2021 who received left-sided breast or chest wall irradiation (with or without regional nodal irradiation). Medical records were queried to report cardiac dosimetry across various racial groups. Details regarding the use of active breathing control (ABC), breast size, internal mammary nodal irradiation, and whether the patient's treatment plan met the departmental boarding pass requirement and was prospectively presented at departmental peer review were noted. MHD were noted in absolute values and 2-Gy equivalent doses (EQD2). Kruskal-Wallis test was used to analyze differences in MHD between racial groups. Univariate and multivariable Cox regression analyses were performed to determine association of MHD with other factors. MHD was similar across racial groups; 1.38 Gy (1.12, 2.02) in Black women, 1.35 Gy (1.02, 1.97) in White women, and 1.39 Gy (1.07, 2.01) in others with an EQD2 of 0.71, 0.70 and 0.72 (P = 0.6). Rates of the use of hypofractionation, a cavity boost, regional nodal irradiation, internal mammary nodal irradiation, meeting departmental boarding pass requirement, and peer review of treatment plan before starting treatment were similar across all racial groups. The use of ABC was 83% in White women, 75% in Black women and 62% in other races (P = 0.005). The difference in ABC use was attributed to a higher rate of volumetric modulated arc therapy treatment in other races (33%). Median breast size was 1904 cc in Black women, 1504 cc in White women, and 1331 cc in other racial groups (P = 0.001). On univariate and multivariate analysis, MHD differed with IMN treatment, boost and use of ABC but remained similar across racial groups and varying breast size. Despite anatomical differences such as breast size, achieving similar cardiac dose is feasible across racial groups by uniformly utilizing ABC for left sided breast or chest wall irradiation, applying standardized boarding pass constraints and peer review of all cases. Further studies to identify factors that may lead to differences in the rates of cardiac morbidity among racial groups are warranted.

Analysis of Institutional DIBH Coaching Program for Surface Guided-DIBH Patients

Our institute has implemented a surface guided-DIBH (SG-DIBH) coaching program which involves consultation, pre-treatment (CT-sim) and treatment. We would like to analyze the effectiveness of the program. A total of 72 left breast cancer patients between 1st Apr 2022 to 9th Dec 2022 were registered for radiation treatment. During consultation, oncologist selected suitable patients based on the following criteria: a) age of 18-70; b) left breast cancer, right breast cancer with internal mammary nodes irradiation or dextrocardia; c) no lung/cardiac disease history & d) volunteer for SG-DIBH technique. The eligible patients were then trained by the coaching therapist using a teaching video and practiced at home. During CT simulation, patients were assessed according to the DIBH evaluation form. The evaluation components included patient's compliancy and understanding, the differences of lateral skin marking (free breathing, FB vs DIBH), duration of breath hold and reproducibility. Patients who passed the evaluation were scanned under both FB and DIBH for SG-DIBH treatment. IMRT-FFF 6 to 7 fields were planned. During SG-DIBH treatment, first 3 fractions and weekly CBCT were taken. Patients were encouraged to continue DIBH practice at home throughout whole course of the treatment and they were given 3 identical survey forms (5 questions) at the beginning, middle and end of treatment. The measure for the success of this coaching program would be number of breath-holds, duration of treatment time, treatment accuracy (CBCT matching) and survey results. There were 48 patients who were eligible for DIBH coaching program, however, only 24 patients had passed the coaching evaluation and 20 patients were treated with SG-DIBH technique successfully. The mean of number of breath-hold and treatment time was 7 times and 7.9 minutes. Total of 123 CBCT images were studied. The setup errors were (0.242±0.180) cm, (0.152±0.137) cm, (0.202±0.165) cm, (0.684±0.640) degrees, (0.816±0.767) degrees, (0.912±0.707) degrees in lateral, longitudinal, vertical, pitch, roll and yaw directions. According to the survey analysis, the number of times to practice at home decreased as the treatment went by. An improvement was seen in patients' self-evaluation in mastering DIBH technique with proper coaching program (from 60% to 90%). Patients' anxiety in performing DIBH were alleviated greatly towards the end of the treatment (from 47% to 15%). 100% of the patients were willing to go for DIBH treatment if given a second chance and additional suggestions claimed that professional clinical teams and coaching program were important for their DIBH treatment journey. A comprehensive DIBH coaching program can effectively identify SG-DIBH patient's suitability. Patient compliancy, treatment accuracy and treatment experience can be enhanced with good coaching program. The involvement of clinical team from consultation to pre-treatment and treatment stage is essential for a successful SG-DIBH treatment.

Patterns and Longitudinal Changes in The Practice of Breast Cancer Radiotherapy in Korea: Korean Radiation Oncology Group 22-01

To analyze contemporary practice patterns in breast cancer radiotherapy (RT) and to assess longitudinal changes therein over 5 years in Korea. A nationwide survey was conducted among board-certified radiation oncologists in Korea by the Division for Breast Cancer of the Korean Radiation Oncology Group in March 2022. The survey consisted of 44 questions related to six domains: hypofractionated (HypoFx) whole breast RT, accelerated partial breast RT (APBI), regional nodal irradiation (RNI), RT for ductal carcinoma in situ (DCIS), postmastectomy RT (PMRT), and tumor bed boost. In total, 70 radiation oncologists from 61 of 101 (60%) institutions participated in the survey. HypoFx RT was used by 62 respondents (89%), which has significantly increased from 36% in 2017. The HypoFx RT was commonly administered at 40-42.5 Gy in 15-16 fractions. APBI was used by 12 respondents (17%), which has increased from 5% in 2017. The use of RNI did not change significantly: ≥ pN2 (6%), ≥ pN1 (33%), and ≥ pN1 with pathological risk factors (61%). However, the indications for use of internal mammary lymph node (IMN) irradiation have expanded. In particular, the rates of routine treatment of IMN (11% from 6% in 2017) and treatment in cases of ≥ pN2 (27% from 14% in 2017) have doubled; however, the rate of treatment for only IMN involvement, identified on imaging, has decreased to 31% from 47% in 2017. With regard to DCIS, the use of hypoFx RT increased to 75% from 25%, and the rate of omission on of RT after breast-conserving surgery decreased to 38% from 48% in 2017. The use of hypoFx RT for PMRT also increased to 36% from 8% in 2017. The adoption of HypoFx RT after breast-conserving surgery in invasive breast cancer and DCIS has increased significantly, whereas that for PMRT has increased moderately, compared to 2017. Further studies are required to determine the optimal use of RNI.

PO-1264 Risk stratification for internal mammary lymph node irradiation based on dynamic MRI vessel imaging

PO-1264 Risk stratification for internal mammary lymph node irradiation based on dynamic MRI vessel imaging

Internal Mammary Node Irradiation for Breast Cancer in the Era of Precision Medicine

Internal Mammary Node Irradiation for Breast Cancer in the Era of Precision Medicine

Dose-Volume Predictors for Radiation Esophagitis in Patients With Breast Cancer Undergoing Hypofractionated Regional Nodal Radiation Therapy

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. 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. In total, 298 patients were included between May 8, 2020, and January5,2022 (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). 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.

Abstract P2-14-06: Prospective, multicenter, clinical validation study of the repeatability and accuracy of internal mammary sentinel lymph node biopsy with modified injection technique (CBCSG026/CBCSG027)

Abstract Background: As a first-echelon nodal drainage site of breast cancer, the status of axillary lymph nodes (ALN) and internal mammary lymph nodes (IMLN) is both valuable for regional staging and treatment choice. The internal mammary sentinel lymph node biopsy (IM-SLNB) may provide minimally invasive staging, and guide individual IMLN radiation. Modified technique (periareolar intraparenchymal, high volume and ultrasound guidance) got a high internal mammary sentinel lymph nodes (IM-SLN) visualization rate of 71.1% in single center, and the prospective multicenter study was designed to verify its repeatability (CBCSG026, NCT03541278). High visualization rate and low false negative rate are prerequisites for the widespread of IM-SLNB. The question arises as to whether IM-SLN detected with the modified technique should be considered as “true” IM-SLN. The prospective, multicenter, clinical validation study of IM-SLNB followed by internal mammary lymph node dissection (IM-LND) was designed to verify the accuracy of IM-SLNB in patients with ALN positive breast cancer (CBCSG027, NCT03024463). Methods: While CBCSG026 trial enrolled patients with both axillary negative and positive breast cancer, CBCSG027 trial only enrolled axillary positive patients receiving mastectomy (either biopsy proving cN+ disease or cN0 with positive axillary SLN). The 1st to 3rd intercostal IM-LND was performed immediately after IM-SLNB to verify its accuracy in the CBCSG027 trial. Result: From May 2018 to June 2022, 600 and 264 patients were enrolled in the CBCSG026 and CBCSG027 trial from seven centers in China, respectively. Among the 600 recruited patients in the CBCSG026, the IM-SLN visualization rate was 65.0% (390/600), which was significantly related to patient’s age, body mass index, radiotracer intensity and interval time between injection and IM-SLN identification (all P&amp;lt; 0.05). The IM-SLNB successful rate was 97.4% (380/390), and the complication was 6.9%. The median number of IM-SLN was 1. The overall IM-SLN metastases rate was 18.9% (72/380), with 33.0% (65/195) and 3.8% (7/185) in ALN positive and negative patients, respectively. Multivariate analysis showed that the tumor size (P=0.028), the tumor location (P&amp;lt; 0.001) and the number of positive ALNs (P&amp;lt; 0.001) were independent predictors of IM-SLN metastasis. Those variables were included in a novel nomogram (Table 1), which was significantly better than the probability based on the number of metastatic ALNs alone according to the current guidelines (area under the curve: 0.860 vs. 0.804, P&amp;lt; 0.001). Of the 264 patients enrolled in the CBCSG027 trial, 185 patients (70.1%) had IM-SLN visualization (included 107 with cN+ disease and 78 with positive axillary SLN). The median number of IM-SLN and IM-nSLN was 2 (1~4) and 3 (1~9), respectively. The positive rate of IMLN and IM-SLN was 37.8% (70/185) and 36.8% (68/185), respectively, yielding the false negative rate of IM-SLNB 2.9% (2/70), the accuracy of 98.9% (183/185) and the sensitivity of 97.1% (68/70). The false negative rate of patients with cN+ disease and patients with positive axillary SLN was 4.8% (2/42) and 0, respectively. The positive IM-SLNs were the only positive IMLNs identified in 51.4% (36/70) patients. IM-SLNB can change the pN stages of 37.2% (68/183) patients. IMLN irradiation could be avoided in 72.7% (80/110) patients with axillary pN1 and 46.7% (35/75) with pN2/N3 disease in the study. Conclusions: The modified technique of radiotracer injection (periareolar intraparenchymal, high volume, and ultrasound guidance) can significantly improve the detection rate of IM-SLN with very low false-negative rate with the prospective, multicenter validation results, providing minimally invasive staging and guiding individual IMLN radiation. When there is no IM-SLN visualization, the nomogram can predict the risk of IMLN metastasis and guide IMLN radiation. The nomogram which can predict the risk of IMLN metastasis The nomogram which can predict the risk of IMLN metastasis Citation Format: Yong-Sheng Wang, Qing Lu, Shi-Guang Zhu, Wen-He Zhao, Guang-Lun Yang, Yuan-Xi Huang, Hong Zhong, Xiao Sun, Pengfei Qiu. Prospective, multicenter, clinical validation study of the repeatability and accuracy of internal mammary sentinel lymph node biopsy with modified injection technique (CBCSG026/CBCSG027) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-14-06.

The optimal regional irradiation volume for breast cancer patients: A comprehensive systematic review and network meta-analysis of published studies.

Currently, the optimal adjuvant regional nodal irradiation (RNI) volume for breast cancer (BC) remained controversial. We aimed to define the optimal RNI treatment volume for BC by using a comprehensive network meta-analysis (NMA) of published studies. PubMed, Embase, Medline, and Cochrane Central Register of Controlled Trials were searched from database inception to 30 May 2022. Studies assessing different adjuvant RNI volumes for BC were eligible for inclusion. The primary outcome was overall survival (OS), and secondary outcome was disease-free survival (DFS) and distant-metastasis-free survival (DMFS). A total of 29,640 BC patients from twenty studies were included. The pooled hazard ratio demonstrated that internal mammary node irradiation (IMNI) in BC patients significantly improved OS giving HR (hazard ratio) of 0.87 (95%CI: 0.83-0.91, p<0.001), DFS with HR of 0.78 (95%CI: 0.68-0.90, p<0.01), and DMFS with HR of 0.87 (95%CI: 0.79-0.97, p<0.01) when compared to controls. Sub-group analysis indicated that RNI with IMNI significantly improved OS (HR 0.87, 95%CI: 0.81-0.93, p<0.01), DFS (HR 0.65, 95%CI: 0.56-0.77, p<0.01), and DMFS (HR 0.90, 95%CI: 0.82-0.98, p=0.02) when compared to RNI without IMNI. NMA showed that CW/WB (chest wall/whole breast) + RNI with IMNI significantly improved DFS (HR 0.93, 95%CI: 0.86-1.00) and DMFS (HR 0.90, 95%CI: 0.81-0.99), but not for OS (HR 0.93, 95%CI: 0.84-1.03) when compared to CW/WB alone. Based on the analysis of the treatment ranking, CW/WB+RNI with IMNI appeared as the best treatment approach for BC patients. Our pooled results demonstrated that RNI with IMNI yielded a significant survival advantage for BC patients. NMA showed that CW/WB+RNI with IMNI was the optimal radiation volume for BC patients.

Patterns and Longitudinal Changes in the Practice of Breast Cancer Radiotherapy in Korea: Korean Radiation Oncology Group 22-01.

We aimed to analyze contemporary practice patterns in breast cancer radiotherapy (RT) and assess longitudinal changes over five years in Korea. In 2022, a nationwide survey was conducted among board-certified radiation oncologists. The survey consisted of 44 questions related to six domains: hypofractionated (HypoFx) whole breast RT, accelerated partial breast RT (APBI), regional nodal irradiation (RNI), RT for ductal carcinoma in situ (DCIS), postmastectomy RT (PMRT), and tumor bed boost. Seventy radiation oncologists from 61 (out of 101; 60%) institutions participated in the survey. HypoFx RT was used by 62 respondents (89%), a significant increase from 36% in 2017. HypoFx RT is commonly administered at 40-42.5 Gy in 15-16 fractions. APBI was used by 12 respondents (17%), an increase from 5% in 2017. The use of RNI did not change significantly: ≥ pN2 (6%), ≥ pN1 (33%), and ≥ pN1 with pathological risk factors (61%). However, indications for internal mammary lymph node (IMN) irradiation have expanded. In particular, the rates of routine treatment of IMN (11% from 6% in 2017) and treatment in cases of ≥ pN2 (27% from 14% in 2017) have doubled; however, the rate of treatment for only IMN involvement, identified on imaging, has decreased from 47% in 2017 to 31%. For DCIS, the use of HypoFx RT increased from 25% in 2017 to 75%, and the rate of RT omissions after breast-conserving surgery (BCS) decreased from 48% in 2017 to 38%. The use of HypoFx RT for PMRT increased from 8% in 2017 to 36%. The adoption of HypoFx RT after BCS for invasive breast cancer and DCIS has increased significantly, whereas the use of HypoFx PMRT has increased moderately since 2017. However, further studies are required to determine the optimal use of RNI.

IMNI PRECISION trial protocol: a phase II, open-label, non-inferior randomized controlled trial of tailoring omission of internal mammary node irradiation for early-stage breast cancer

BackgroundSince the publication of MA-20 and EORTC-22922 trials, chest wall (CW)/ whole breast (WB) irradiation + comprehensive regional nodal irradiation (RNI) with internal mammary node irradiation (IMNI) has been the standard adjuvant treatment for early-stage breast cancer (BC). However, one size does not fit all BC, and the risk of recurrence significantly varies among this patient population. In addition, whether all BC patients presented with one to three positive lymph nodes (pN1) could benefit from IMNI remains controversial. Thus, the optimal adjuvant RNI volume for early-stage BC with T1-2N1 remains undetermined.MethodsThe IMNI PRECISION trial is a single institute, open-labeled, non-inferior, randomized controlled trial. A total of 214 clinically “high risk” BC patients which is characterized as having at least two of the five clinically adverse factors (age ≤ 40, three positive LN, T2 stage, grade 3 and Ki-67 index ≥ 14%), but genomic score “low risk” (the genomic score ≤ 44) N1 breast cancers are randomly assigned to omitting IMNI group (experimental group) or with IMNI (control group) with a 1:1 ratio. The primary endpoint of this trial is event-free survival, and secondary endpoints include overall survival and locoregional recurrence-free survival.DiscussionThe IMNI PRECISION design allows promising clinical-genomic model to stratify the individualized risk of developing recurrence and guides the optimal RNI treatment for early-stage (pT1-2N1) BC patients. We anticipate that our results would provide high-level evidence to tailor IMNI according to individualized recurrence risk of BC.Trial registrationClinicalTrials.gov Identifier NCT04517266. Date of registration: August 18, 2020. Status: Recruiting.

Treatment of Internal Mammary Nodes Associated with Improved Overall Survival in Breast Cancer: A Meta-Analysis

<h3>Purpose/Objective(s)</h3> The role of internal mammary nodal irradiation (IMNI) as a component of regional nodal radiotherapy is a controversial issue in breast radiation oncology with conflicting results presented in recent landmark trials. We thus created a meta-analysis of available data to better ascertain the potential benefit of IMNI. We hypothesize that with the increased power available within a meta-analysis, IMNI will prove to improve overall survival in breast cancer. <h3>Materials/Methods</h3> Four studies (DBCG-IMN 2015, Hennequin <i>et al</i> 2013, KROG 2022, and Stemmer <i>et al</i> 2003) with a total of 5,258 patients (IMNI = 2698, No IMNI = 2560) were meta-analyzed with a primary end point of overall survival (OS). Secondary endpoints were disease free survival (DFS), breast cancer mortality (BCM), and distant metastasis free survival (DMFS). Subgroup analyses were performed for medial/central tumor location, and pN+ versus pN0 status. Fixed-effect model was used if there was no heterogeneity, random-effects model otherwise. <h3>Results</h3> Pooled results showed IMNI significantly improved OS for all comers (HR 0.87, 95% CI 0.79-0.97, <i>p</i>=0.01), as well as subgroups of pN+ with medial/central tumor location (HR 0.80, 95% CI 0.68-0.94, <i>p</i>=0.005) and pN+ with lateral tumor location (HR 0.86, 95% CI 0.745-0.995, <i>p</i>=0.04). There was no significant difference in OS for subgroups of pN0 and medial/central tumor location. Secondary endpoints of DFS (HR 0.90, 95% CI 0.82-0.99, <i>p</i>=0.03), BCM (HR 0.83, 95% CI 0.73-0.96, <i>p</i>=0.01), and DMFS (HR 0.88, 95% CI 0.78-0.99, <i>p</i>=0.04) were all similarly improved with IMNI. <h3>Conclusion</h3> Inclusion of IMNI to regional nodes improves OS in breast cancer, with the strongest effect noted in pN+ patients with medial/central tumor location.

Dosimetry and Toxicity Outcomes in Patients Treated with Hypofractionated Regional Nodal Irradiation for Breast Cancer: What is the Best Dose-Volume Limit to Minimize Risks of Radiation Pneumonitis?

Although published data have supported the use of hypofractionated regional nodal irradiation (HF-RNI) for breast cancer, limited dosimetric data exist to evaluate predictors of lung toxicity. The ongoing RT CHARM trial limits the percentage of ipsilateral lung volume that receives ≥18 Gy to 35 to 40%. We assessed dosimetry, toxicity, and disease outcomes in patients with breast cancer treated with HF-RNI with a particular focus on pneumonitis. We retrospectively reviewed all patients with breast cancer treated with HF-RNI (40-43 Gy in 15-16 fractions) after either lumpectomy or mastectomy at The University of Pittsburgh Medical Center from September 2018 to December 2021 to collect dosimetric and outcomes data. All post-radiation therapy chest computed tomography (CT) scans were manually reviewed for evidence of acute (≤6 months postradiation) or chronic (>6 months postradiation) pneumonitis. One-hundred-ninety-one patients qualified with a median follow-up of 20.3 months (range, 5.1-42.2). Acute grade 1 (G1) pneumonitis was observed in 6.8% of the overall cohort (13 of 191 patients) and 39.4% of the patients (13 of 33) who received a chest CT ≤6 months postradiation therapy. Only 1 patient developed acute G2 pneumonitis. Chronic G1 pneumonitis was observed in 29.8% of the overall cohort (57 of 191 patients) and 77% of patients (57 of 74 patients) who received a chest CT >6 months postradiation therapy. No patients developed acute G3+ or chronic G2+ pneumonitis. Rates of symptomatic pneumonitis were low in this cohort of patients treated with HF-RNI, even with integration of HER2/neu-directed therapy, chemotherapy, hormone therapy, and internal mammary nodal irradiation. Lung V20Gy <26% appeared safe in this cohort to limit symptomatic pneumonitis, though this is not meant to represent the safe upper limit. Given the low event rate of symptomatic pneumonitis, data from larger cohorts will be needed to assess dosimetric predictors and the safe upper limit of lung dose.

Acute Toxicological Outcomes of Postmastectomy Radiotherapy in Node Positive Breast Cancer with or without Internal Mammary Nodal Irradiation: Preliminary Results of POTANTIAL Trial

<h3>Purpose/Objective(s)</h3> 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. <h3>Materials/Methods</h3> 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. <h3>Results</h3> 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). <h3>Conclusion</h3> IMNI caused acceptable dermatitis, esophagitis and pneumonitis in breast cancer after mastectomy. Higher risk of myelosuppression, mainly lymphopenia, was found in IMNI arm.

Quality Assurance in the Dummy Run of a Multicenter Randomized Trial of POstmastectomy radioThErapy in Node-posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL)

<h3>Purpose/Objective(s)</h3> To present the results of the dummy run of POTENTIAL (Clinical trials.gov identifier NCT04320979), a multicenter phase III randomized study, investigating the compliance to the protocol guidelines of participating institutes and evaluating the effect of quality control programs in improving interinstitutional consistency. <h3>Materials/Methods</h3> Prior to protocol activation, all the participating institutes were asked to make a treatment plan for a breast patient with Internal mammary nodal (IMN) irradiation according to the protocol of the trial. CT images and outlines of the target volumes and the organs at risk (OAR) are provided by sponsor in Dicom-RT. The plan quality was evaluated by trail QA committee based on dose distribution, dose volume histogram (DVH) and field parameters, etc. After evaluation, recommendations for improvement of the plan quality would be forwarded to participants if a plan revision was required. Thereafter, dose verifications were completed to ensure the accuracy of treatment delivery. <h3>Results</h3> A number of deviations from trail protocol were observed by plan review. The average D95% of the CW and the IMN target volume were approximately 10% lower than prescribed dose for the conventional fractionation group (50 Gy in 25 fractions) and 3% for the hypofractionation group (43.5 Gy in 15 fractions). After revision, the dose coverage of the targets was significantly improved. The average D95% of the CW and the IMN target volume reached higher than 49 Gy and 43 Gy for the conventional fractionation group and the hypofractionation group, respectively. The revised plans also provided better OAR dose sparing. <h3>Conclusion</h3> The QA program in the dummy run had a positive effect in improving interinstitutional consistency, since the deviations from trail protocol were significantly decreased by plan review and revision.