Locoregional Recurrence in Adenoid Cystic Carcinoma of the Breast: A Retrospective, Multicenter Study (KROG 22-14).

Purpose: This study aims to evaluate the treatment approaches and locoregional patterns for Adenoid cystic carcinoma (ACC) in the breast, which is an uncommon malignant tumor with limited clinical data. Materials and Methods: A total of 93 patients diagnosed with primary ACC in the breast between 1992 and 2022 were collected from multi-institutions. All patients underwent surgical resection, including breast-conserving surgery (BCS) or total mastectomy (TM). The recurrence patterns and locoregional recurrence-free survival (LRFS) were assessed. Results: Seventy-five patients (80.7%) underwent BCS, and 71 of them (94.7%) received post-operative radiation therapy (PORT). Eighteen patients (19.3%) underwent TM, with 5 of them (27.8%) also receiving PORT. With a median follow-up of 50 months, the LRFS rate was 84.2% at 5 years. Local recurrence (LR) was observed in 5 patients (5.4%) and 4 cases (80%) of the LR occurred in the tumor bed. Three of LR (3/75, 4.0%) had a history of BCS and PORT, meanwhile, two of LR (2/18, 11.1%) had a history of mastectomy. Regional recurrence occurred in 2 patients (2.2%), and both cases had a history of PORT with (n=1) and without (n=1) irradiation of the regional lymph nodes. Partial breast irradiation (p=0.35), BCS (p=0.96) and PORT in BCS group (p=0.33) had no significant association with LRFS. Conclusion: BCS followed by PORT was the predominant treatment approach for ACC of the breast and local recurrence mostly occurred in the tumor bed. The findings of this study suggest that partial breast irradiation might be considered for PORT in primary breast ACC.

Palliative Radiotherapy for Symptomatic Primary Tumors in Patients With Locally Advanced Breast Cancer.

Breast cancer remains a significant health concern for women, with a significant number of women facing unresectable, symptomatic, and advanced disease that severely affects their quality of life. Palliative radiotherapy (RT) is a well-established modality for managing such cases and alleviating symptoms. Recent advancements in systemic therapies and the resulting increase in long-term survival rates have not only heightened the need for retreatment in certain patients, but have also emphasized the importance of achieving durable local control. Additionally, inconsistencies in RT referral timing and variations in disease severity and extent contribute to diverse RT objectives and expected outcomes. The optimal dose fractionation for RT remains underexplored. Furthermore, a deeper understanding of breast radiobiology, along with the introduction of ultra- and moderately hypofractionated regimens and the widespread adoption of conformal techniques such as intensity-modulated RT, has diversified the approaches in RT dose and target volume. This review aimed to provides a comprehensive summary of the current evidence on the efficacy, outcomes, and toxicity profiles of palliative RT for symptomatic breast cancer. It highlights the need for more optimized regimens and further research to address the evolving treatment landscape and differing expectations of patients and physicians regarding RT.

Risk of radionecrosis in HER2-positive breast cancer with brain metastasis receiving trastuzumab emtansine (T-DM1) and brain stereotactic radiosurgery.

OBJECTIVES: To investigate the potential relationship between trastuzumab emtansine (T-DM1) treatment and radionecrosis induced by brain stereotactic radiosurgery (SRS) in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. MATERIALS AND METHODS: Patients with HER2-positive breast cancer who were diagnosed with brain metastasis and received both SRS and HER2-targeted agents between 2012 and 2022 were retrospectively analyzed. Patients who received T-DM1 within 1 year (either before or after) of SRS were considered as 'T-DM1 exposure (+)'. T-DM1 exposure (-) group had other HER2-targeted agents or received T-DM1 more than 1 year before or after SRS. Symptomatic radionecrosis was defined as Common Terminology Criteria for Adverse Events grade 2 or greater. RESULTS: A total of 103 patients with 535 treatment sessions were included from seven tertiary medical centers in Korea and Italy. The median follow-up duration was 15.5 months (range 1.1-101.9). By per-patient analysis, T-DM1 exposure (+) group had an increased risk of overall radionecrosis after multivariate analysis (HR 2.71, p = 0.020). Additionally, T-DM1 exposure (+) group was associated with a higher risk of symptomatic radionecrosis compared to T-DM1 exposure (-) patients (HR 4.34, p = 0.030). In per-treatment analysis, T-DM1 exposure (+) was linked to higher incidences of overall (HR 3.13, p = 0.036) and symptomatic radionecrosis (HR 10.4, p = 0.013) after multivariate analysis. A higher prevalence of radionecrosis was observed with T-DM1 exposure (+) and a previous history of whole brain radiotherapy. CONCLUSION: An increased risk of radionecrosis was observed in patients receiving T-DM1 with brain SRS. Further research is needed to better understand the optimal sequence and interval for administering T-DM1 and SRS.

Quantifying radiation-induced breast fibrosis by shear-wave elastography in patients with breast cancer: A 12-months-follow-up data of a prospective study.

Purpose: To assess radiation-induced fibrosis (RIF) using shear-wave elastography (SWE) in patients with breast cancer who received radiotherapy (RT) after breast conserving surgery. Methods: Forty-one patients were enrolled in a prospective study before RT. SWE and B-mode ultrasonography were performed to measure elasticity. For quantitative measurement, the maximum elasticity value was measured in the tumor bed and non-tumor bed of the treated breast, and contralateral breast before RT and at 3, and 12 months after RT. and RIF was recorded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: The mean ± standard deviation elasticity values for the tumor bed, non-tumor bed, and contralateral breast were 71.2 ± 74.9 kPa, 19.4 ± 9.8 kPa and 20.3 ± 10.0 kPa before RT; 28.7 ± 26.3 kPa, 15.1 ± 7.0 kPa, and 14.7 ± 6.3 kPa at 12 months after RT, respectively. The elasticity values for all three measurement areas before and 12 months after RT were significantly different (p < 0.001 for tumor bed, p = 0.002 for non-tumor bed, p = 0.001 for contralateral breast). At 12 months follow-up, the distribution of grades of RIF evaluated by CTCAE grade was grade 0 in 43.9 %, grade 1 in 48.8 %, and grade 2 in 7.3 %. Conclusion: We demonstrated that SWE enables the evaluation of tissue stiffness to provide quantified information for the RIF of breast cancer. Further studies with long-term follow-up should provide more quantitative data.

Practice guidelines for managing extrahepatic biliary tract cancers.

Backgrounds/Aims: Reported incidence of extrahepatic bile duct cancer is higher in Asians than in Western populations. Korea, in particular, is one of the countries with the highest incidence rates of extrahepatic bile duct cancer in the world. Although research and innovative therapeutic modalities for extrahepatic bile duct cancer are emerging, clinical guidelines are currently unavailable in Korea. The Korean Society of Hepato-Biliary-Pancreatic Surgery in collaboration with related societies (Korean Pancreatic and Biliary Surgery Society, Korean Society of Abdominal Radiology, Korean Society of Medical Oncology, Korean Society of Radiation Oncology, Korean Society of Pathologists, and Korean Society of Nuclear Medicine) decided to establish clinical guideline for extrahepatic bile duct cancer in June 2021. Methods: Contents of the guidelines were developed through subgroup meetings for each key question and a preliminary draft was finalized through a Clinical Guidelines Committee workshop. Results: In November 2021, the finalized draft was presented for public scrutiny during a formal hearing. Conclusions: The extrahepatic guideline committee believed that this guideline could be helpful in the treatment of patients.

Pro-inflammatory markers associated with COVID-19-related persistent olfactory dysfunction.

INTRODUCTION: While localized inflammation has been implicated in the pathophysiology of acute coronavirus disease of 2019 (COVID-19) olfactory dysfunction (OD), persistent COVID-19 OD remains poorly understood with limited therapeutics. Our prospective study evaluated olfactory cleft (OC) biomarkers as predictors of persistent OD in mucus sampling. METHODS: COVID-19 subjects with persistent OD >3 months confirmed by psychophysical olfaction tests were compared to COVID-19 subjects with no OD and those with no prior infection. OC mucus samples were evaluated for 13 anti-viral and inflammatory biomarkers. Cohorts were compared using analysis of variance (ANOVA) and Mann-Whitney tests with multi-comparison adjustment. Viral RNA was assessed through RT-PCR using the COVID-19 N2 primer. RESULTS: Thirty-five samples were collected (20 COVID persistent OD, 8 COVID no OD, and 7 non-COVID no OD). Significant differences in IFN-λ1 (p = 0.007) and IFN-γ (p = 0.006) expression in OC mucus were found across all three groups, with the highest cytokine concentrations corresponding to COVID OD. IFN-α2 levels were elevated in COVID OD versus no OD (p = 0.026). Mean IFN-γ levels were the highest in COVID OD, but there were higher levels found in COVID no OD compared to non-COVID no OD (p = 0.008). No difference was seen in IL6. No N2 gene expression was detected in all cohorts. CONCLUSION: IFN pathway cytokines were found elevated in the olfactory microenvironment of COVID-19 persistent OD compared to those with no OD and no prior history of COVID-19 infection.

Risk Factors for Distant Metastasis in Extrahepatic Bile Duct Cancer after Curative Resection (KROG 1814).

PURPOSE: Risk factors predicting distant metastasis (DM) in extrahepatic bile duct cancer (EHBDC) patients treated with curative resection were investigated. MATERIALS AND METHODS: Medical records of 1,418 EHBDC patients undergoing curative resection between Jan 2000 and Dec 2015 from 14 institutions were reviewed. After resection, 924 patients (67.6%) were surveilled without adjuvant therapy, 297 (21.7%) were treated with concurrent chemoradiotherapy (CCRT) and 148 (10.8%) with CCRT followed by chemotherapy. To exclude the treatment effect from innate confounders, patients not treated with adjuvant therapy were evaluated. RESULTS: After a median follow-up of 36.7 months (range, 2.7 to 213.2 months), the 5-year distant metastasis-free survival (DMFS) rate was 57.7%. On multivariate analysis, perihilar or diffuse tumor (hazard ratio [HR], 1.391; p=0.004), poorly differentiated histology (HR, 2.014; p < 0.001), presence of perineural invasion (HR, 1.768; p < 0.001), positive nodal metastasis (HR, 2.670; p < 0.001) and preoperative carbohydrate antigen (CA) 19-9 ≥ 37 U/mL (HR, 1.353; p < 0.001) were significantly associated with inferior DMFS. The DMFS rates significantly differed according to the number of these risk factors. For validation, patients who underwent adjuvant therapy were evaluated. In patients with ≥ 3 factors, additional chemotherapy after CCRT resulted in a superior DMFS compared with CCRT alone (5-year rate, 47.6% vs. 27.7%; p=0.001), but the benefit of additional chemotherapy was not observed in patients with 0-2 risk factors. CONCLUSION: Tumor location, histologic differentiation, perineural invasion, lymph node metastasis, and preoperative CA 19-9 level predicted DM risk in resected EHBDC. These risk factors might help identifying a subset of patients who could benefit from additional chemotherapy after resection.

Assessment of deep learning-based auto-contouring on interobserver consistency in target volume and organs-at-risk delineation for breast cancer: Implications for RTQA program in a multi-institutional study.

PURPOSE: To quantify interobserver variation (IOV) in target volume and organs-at-risk (OAR) contouring across 31 institutions in breast cancer cases and to explore the clinical utility of deep learning (DL)-based auto-contouring in reducing potential IOV. METHODS AND MATERIALS: In phase 1, two breast cancer cases were randomly selected and distributed to multiple institutions for contouring six clinical target volumes (CTVs) and eight OAR. In Phase 2, auto-contour sets were generated using a previously published DL Breast segmentation model and were made available for all participants. The difference in IOV of submitted contours in phases 1 and 2 was investigated quantitatively using the Dice similarity coefficient (DSC) and Hausdorff distance (HD). The qualitative analysis involved using contour heat maps to visualize the extent and location of these variations and the required modification. RESULTS: Over 800 pairwise comparisons were analysed for each structure in each case. Quantitative phase 2 metrics showed significant improvement in the mean DSC (from 0.69 to 0.77) and HD (from 34.9 to 17.9 mm). Quantitative analysis showed increased interobserver agreement in phase 2, specifically for CTV structures (5-19 %), leading to fewer manual adjustments. Underlying IOV differences causes were reported using a questionnaire and hierarchical clustering analysis based on the volume of CTVs. CONCLUSION: DL-based auto-contours improved the contour agreement for OARs and CTVs significantly, both qualitatively and quantitatively, suggesting its potential role in minimizing radiation therapy protocol deviation.

Assessment of Eligibility and Utilization of Accelerated Partial Breast Irradiation in Korean Breast Cancer Patients (KROG 22-15).

PURPOSE: We investigated the proportions of patients eligible for accelerated partial breast irradiation (APBI) among those with pT1-2N0 breast cancer, based on the criteria set by the American Society for Radiation Oncology (ASTRO), the Groupe Européen de Curiethérapie and the European Society for Radiotherapy and Oncology (GEC-ESTRO), the American Brachytherapy Society (ABS), and the American Society of Breast Surgeons (ASBS). Additionally, we analyzed the rate of APBI utilization among eligible patients. MATERIALS AND METHODS: Patients diagnosed with pT1-2N0 breast cancer in 2019 were accrued in four tertiary medical centers in Korea. All patients had undergone breast conserving surgery followed by radiotherapy, either whole breast irradiation or APBI. To determine which guideline best predicts the use of APBI in Korea, the F1 score and Matthews Correlation Coefficient (MCC) were determined for each guideline. RESULTS: A total of 1,251 patients were analyzed, of whom 196 (15.7%) underwent APBI. The percentages of eligible patients identified by the ASTRO, GEC-ESTRO, ABS, and ASBS criteria were 13.7%, 21.0%, 50.5%, and 63.5%, respectively. APBI was used to treat 54.4%, 37.2%, 27.1%, and 23.7% of patients eligible by the ASTRO, GEC-ESTRO, ABS, and ASBS criteria, respectively. The ASTRO guideline exhibited the highest F1 score (0.76) and MCC (0.67), thus showing the best prediction of APBI utilization in Korea. CONCLUSION: The proportion of Korean breast cancer patients who are candidates for APBI is substantial. The actual rate of APBI utilization among eligible patients may suggest there is a room for risk-stratified optimization in offering radiation therapy.

ZIF-8/Graphene Oxide Hybrid Membranes as Breathable and Protective Barriers against Chemical Warfare Agents.

Personal protective equipment against chemical warfare agents and other toxic chemicals must be protective, be breathable, and have a low thermal burden. Selectively permeable membranes are promising candidates for such equipment. In this study, a hybrid membrane consisting of a continuous and thin zeolitic imidazolate framework (ZIF)-8 layer on an oxygen-rich small-flake graphene oxide layer was produced using a simple and scalable synthesis method. The small intrinsic pores of ZIF-8 allow it to selectively separate chemicals via size exclusion while permitting water vapor to permeate out. The ZIF-8/graphene oxide membrane had high selectivity for the penetration of water vapor over nerve agent simulants (ratio of dimethyl methylphosphonate to water vapor transmittance rates of ∼312) with a high water vapor transmittance rate of 3000 g m-2 day-1. This protective barrier layer is a promising material for next-generation protective clothing with enhanced comfort and operability.

Patterns of locoregional recurrences and suggestion of the clinical target volume in resected perihilar extrahepatic cholangiocarcinoma.

Purpose: To evaluate the patterns of locoregional recurrence (LRR) in patients with perihilar extrahepatic cholangiocarcinoma (PEHC) treated with radical resection and to suggest the optimal target volume for elective nodal irradiation. Methods: Medical records of PEHC patients who underwent radical resection between January 2000 and September 2021 at five institutions were reviewed. Patients who were confirmed with LRR in the follow-up imaging study were included. The LRR sites were mapped onto the corresponding sites in template computed tomography images. The margin around the vascular structure was investigated to generate the clinical target volume (CTV) covering the common sites of regional recurrences. Results: A total of 87 LRRs in 46 patients were identified, 29 (33.3%) of which were local recurrences and 58 (66.7%) were regional recurrences. The most common site of local recurrence was the liver resection margin (n = 16), followed by the anastomosis site (n = 8). Regional recurrences were observed most commonly in the para-aortic area (n = 13), followed by in the aortocaval space (n = 11), portal vein area (n = 11), and portocaval area (n = 9). Nodal CTV was generated by adding an individualized margin around the portal vein, aorta, common hepatic artery, celiac artery, and left gastric artery. Conclusions: The LRR patterns in the resected PEHC were evaluated and specific guidelines for nodal CTV delineation were provided, which may help physicians delineating the target volume in postoperative radiotherapy for PEHC. These findings need further validation in a lager cohort.

Safety profile of trastuzumab-emtansine (T-DM1) with concurrent radiation therapy: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: In recent years, the treatment landscape for breast cancer has undergone significant advancements, with the introduction of several new anticancer agents. One such agent is trastuzumab emtansine (T-DM1), an antibody drug conjugate that has shown improved outcomes in both early and advanced breast cancer. However, there is currently a lack of comprehensive evidence regarding the safety profile of combining T-DM1 with radiation therapy (RT). In this study, we aim to provide a summary of the available data on the safety of combining RT with T-DM1 in both early and metastatic breast cancer settings. MATERIALS AND METHODS: This systematic review and meta-analysis project is part of the consensus recommendations by the European Society for Radiotherapy and Oncology (ESTRO) Guidelines Committee on integrating RT with targeted treatments for breast cancer. A thorough literature search was conducted using the PUBMED/MedLine, Embase, and Cochrane databases to identify original studies focusing on the safety profile of combining T-DM1 with RT. RESULTS: After applying eligibility criteria, nine articles were included in the meta-analysis. Pooled data from these studies revealed a high incidence of grade 3 + radionecrosis (17%), while the rates of grade 3 + radiation-related pneumonitis (<1%) and skin toxicity (1%) were found to be very low. CONCLUSION: Although there is some concern regarding a slight increase in pneumonitis when combining T-DM1 with postoperative RT, the safety profile of this combination was deemed acceptable for locoregional treatment in non-metastatic breast cancer. However, caution is advised when irradiating intracranial sites concurrently with T-DM1. There is a pressing need for international consensus guidelines regarding the safety considerations of combining T-DM1 and RT for breast cancer.

A Survey of Practice Patterns for Clinical Nodal Staging Prior to Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND: The importance of clinical staging in breast cancer has increased owing to the wide use of neoadjuvant systemic therapy (NST). This study aimed to investigate the current practice patterns regarding clinical nodal staging in breast cancer in real-world settings. MATERIALS AND METHODS: A web-based survey was administered to board-certified oncologists in Korea, including breast surgical, medical, and radiation oncologists, from January to April 2022. The survey included 19 general questions and 4 case-based questions. RESULTS: In total, 122 oncologists (45 radiation, 44 surgical, and 33 medical oncologists) completed the survey. Among them, 108 (88%) responded that clinical staging before NST was primarily performed by breast surgeons. All the respondents referred to imaging studies during nodal staging. Overall, 64 (52.5%) responders determined the stage strictly based on the radiology reports, whereas 58 (47.5%) made their own decision while noting radiology reports. Of those who made their own decisions, 88% referred to the number or size of the suspicious node. Of the 75 respondents involved in prescribing regimens for neoadjuvant chemotherapy, 58 (77.3%) responded that the reimbursement regulations in the selection of NST regimens affected nodal staging in clinical practice. In the case-based questions, high variability was observed among the clinicians in the same cases. CONCLUSIONS: Diverse assessments by specialists owing to the lack of a clear, harmonized staging system for the clinical nodal staging of breast cancer can lead to diverse practice patterns. Thus, practical, harmonized, and objective methods for clinical nodal staging and for the outcomes of post-NST response are warranted for appropriate treatment decisions and accurate outcome evaluation.

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

PURPOSE: We aimed to analyze contemporary practice patterns in breast cancer radiotherapy (RT) and assess longitudinal changes over five years in Korea. METHODS: 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. RESULTS: 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%. CONCLUSION: 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.

Comparison of initial and sequential salvage brain-directed treatment in patients with 1-4 vs. 5-10 brain metastases from breast cancer (KROG 16-12).

PURPOSE: We aimed to compare the initial and salvage brain-directed treatment and overall survival (OS) between patients with 1-4 brain metastases (BMs) and those with 5-10 from breast cancer (BC). We also organized a decision tree to select the initial whole-brain radiotherapy (WBRT) for these patients. METHODS: Between 2008 and 2014, 471 patients were diagnosed with 1-10 BMs. They were divided into two groups based on the number of BM: 1-4 BMs (n = 337) and 5-10 BMs (n = 134). Median follow-up duration was 14.0 months. RESULTS: Stereotactic radiosurgery (SRS)/fractionated stereotactic radiotherapy (FSRT) was the most common treatment modality (n = 120, 36%) in the 1-4 BMs group. In contrast, 80% (n = 107) of patients with 5-10 BMs were treated with WBRT. The median OS of the entire cohort, 1-4 BMs, and 5-10 BMs was 18.0, 20.9, and 13.9 months, respectively. In the multivariate analysis, the number of BM and WBRT were not associated with OS, whereas triple-negative BC and extracranial metastasis decreased OS. Physicians determined the initial WBRT based on four variables in the following order: number and location of BM, primary tumor control, and performance status. Salvage brain-directed treatment (n = 184), mainly SRS/FSRT (n = 109, 59%), prolonged OS by a median of 14.3 months. CONCLUSION: The initial brain-directed treatment differed notably according to the number of BM, which was chosen based on four clinical factors. In patients with ≤ 10 BMs, the number of BM and WBRT did not affect OS. The major salvage brain-directed treatment modality was SRS/FSRT and increased OS.

Incorporating axillary-lateral thoracic vessel juncture dosimetric variables improves model for predicting lymphedema in patients with breast cancer: A validation analysis.

Background: A relationship between the axillary-lateral thoracic vessel juncture (ALTJ) dose and lymphedema rate has been reported in patients with breast cancer. The purpose of this study was to validate this relationship and explore whether incorporation of the ALTJ dose-distribution parameters improves the prediction model's accuracy. Methods: A total of 1,449 women with breast cancer who were treated with multimodal therapies from two institutions were analyzed. We categorized regional nodal irradiation (RNI) as limited RNI, which excluded level I/II, vs extensive RNI, which included level I/II. The ALTJ was delineated retrospectively, and dosimetric and clinical parameters were analyzed to determine the accuracy of predicting the development of lymphedema. Decision tree and random forest algorithms were used to construct the prediction models of the obtained dataset. We used Harrell's C-index to assess discrimination. Results: The median follow-up time was 77.3 months, and the 5-year lymphedema rate was 6.8 %. According to the decision tree analysis, the lowest lymphedema rate (5-year, 1.2 %) was observed in patients with ≤ six removed lymph nodes and ≤ 66 % ALTJ V35Gy. The highest lymphedema rate was observed in patients with > 15 removed lymph nodes and an ALTJ maximum dose (Dmax) of > 53 Gy (5-year, 71.4 %). Patients with > 15 removed lymph nodes and an ALTJ Dmax ≤ 53 Gy had the second highest rate (5-year, 21.5 %). All other patients had relatively minor differences, with a rate of 9.5 % at 5 years. Random forest analysis revealed that the model's C-index increased from 0.84 to 0.90 if dosimetric parameters were included instead of RNI (P <.001). Conclusion: The prognostic value of ALTJ for lymphedema was externally validated. The estimation of lymphedema risk based on individual dose-distribution parameters of the ALTJ seemed more reliable than that based on the conventional RNI field design.

Development and Validation of a Normal Tissue Complication Probability Model for Lymphedema After Radiation Therapy in Breast Cancer.

PURPOSE: To develop and test a multivariable normal tissue complication probability (NTCP) model predicting lymphedema in patients with breast cancer receiving radiation therapy. METHODS AND MATERIALS: We retrospectively reviewed 1345 patients with breast cancer who received radiation therapy from 2 independent institutions. The patients were divided into a training cohort (institution A, n = 368, all treated with 3-dimensional conformal external beam radiation therapy [RT] with 2 Gy/fraction) and an external validation cohort (institution B, n = 977, treated either with 3-dimensional conformal external beam RT or with volumetric modulated RT and either with 1.8-2.0 Gy/fraction or with 2.67 Gy/fraction). Axillary-lateral thoracic vessel juncture (ALTJ) was delineated. The multivariable model was generated using dosimetric and clinical parameters. The performance of the model was comprehensively validated internally and externally. RESULTS: During a median follow-up of 78.7 months for the entire cohort, 97 patients (7.2%) developed lymphedema. The multivariable model that took into account the number of lymph nodes dissected, as well as the volume of the ALTJ receiving a dose ≥35 Gy equivalent doses in 2-Gy fractions (ALTJ V35), showed good agreement between predicted and observed results for both internal and external validation (Hosmer-Lemeshow P value > .05). The area under the receiver operating characteristic curve (AUC) and negative log-likelihood values for the multivariable NTCP model were 0.89 and 0.19 in internal validation and 0.83 and 0.19 in external validation. In addition, the multivariable model performance was acceptable for hypofractionated regimens (AUC 0.70) and volumetric modulated arc therapy (AUC 0.69). The number of lymph nodes dissected and ALTJ V35 were found to be the most important factors influencing lymphedema after radiation therapy. CONCLUSIONS: We first developed and validated the multivariable NTCP model for the lymphedema incidence in patients with breast cancer after radiation therapy. The multivariable NTCP model showed excellent performance and robustness in predicting lymphedema in both internal and completely independent external validations. The multivariable model for lymphedema prediction was robust and reliable for different treatment modalities and fractionation regimens.