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.

Experience of Implementing Deep Learning-Based Automatic Contouring in Breast Radiation Therapy Planning: Insights From Over 2000 Cases.

PURPOSE: This study evaluated the impact and clinical utility of an auto-contouring system for radiation therapy treatments. METHODS AND MATERIALS: The auto-contouring system was implemented in 2019. We evaluated data from 2428 patients who underwent adjuvant breast radiation therapy before and after the system's introduction. We collected the treatment's finalized contours, which were reviewed and revised by a multidisciplinary team. After implementation, the treatment contours underwent a finalization process that involved manual review and adjustment of the initial auto-contours. For the preimplementation group (n = 369), auto-contours were generated retrospectively. We compared the auto-contours and final contours using the Dice similarity coefficient (DSC) and the 95% Hausdorff distance (HD95). RESULTS: We analyzed 22,215 structures from final and corresponding auto-contours. The final contours were generally larger, encompassing more slices in the superior or inferior directions. Among organs at risk (OAR), the heart, esophagus, spinal cord, and contralateral breast demonstrated significantly increased DSC and decreased HD95 postimplementation (all P < .05), except for the lungs, which presented inaccurate segmentation. Among target volumes, CTVn_L2, L3, L4, and the internal mammary node showed increased DSC and decreased HD95 postimplementation (all P < .05), although the increase was less pronounced than the OAR outcomes. The analysis also covered factors contributing to significant differences, pattern identification, and outlier detection. CONCLUSIONS: In our study, the adoption of an auto-contouring system was associated with an increased reliance on automated settings, underscoring its utility and the potential risk of automation bias. Given these findings, we underscore the importance of considering the integration of stringent risk assessments and quality management strategies as a precautionary measure for the optimal use of such systems.

Feasibility of Intraoperative Radiotherapy Tumor Bed Boost in Patients with Breast Cancer after Neoadjuvant Chemotherapy.

PURPOSE: This study aimed to assess the feasibility and safety of administering intraoperative radiotherapy (IORT) as a boost during breast-conserving surgery (BCS) following neoadjuvant chemotherapy for patients at high risk of breast cancer recurrence. MATERIALS AND METHODS: Patients who underwent neoadjuvant chemotherapy received a single 20-Gy dose of IORT during BCS, followed by external beam radiotherapy 4-6 weeks after surgery. RESULTS: The median follow-up duration was 31.0 months (range, 18.0-59.0 months). Initial tumor sizes had a median of 2.6 cm (range: 0.8-5.3 cm), reducing to 0.3 cm (range: 0-4.0 cm) after neoadjuvant chemotherapy. The most common neoadjuvant chemotherapy regimen was doxorubicin and cyclophosphamide, followed by paclitaxel (n=42, 73.7%). Among 57 patients who received neoadjuvant chemotherapy before BCS and IORT, 2 patients (3.5%) required secondary surgery to achieve negative resection margins due to initially positive margins. Regional lymph node irradiation was performed in 37 (64.9%) patients. There was no grade 3 or higher adverse events, with 4 patients (7.0%) experiencing grade 2 acute radiation dermatitis and 3 (5.3%) having less than grade 2 breast edema. Binary correlation analysis did not reveal statistically significant associations between applicator size or radiation therapy modality and the risk of treatment-related toxicity. Furthermore, chi-square analysis showed that the grade of treatment-related toxicity was not associated with the fractionated regimen (p=0.375). CONCLUSION: Most patients successfully received IORT as a tumor bed boost after neoadjuvant chemotherapy. Thus, IORT may be a safe and feasible option for patients with advanced-stage breast cancer receiving neoadjuvant chemotherapy.

Normal tissue complication probability models of hypothyroidism after radiotherapy for breast cancer.

Purpose: We aimed to develop Lyman-Kutcher-Burman (LKB) and multivariable normal tissue complication probability (NTCP) models to predict the risk of radiation-induced hypothyroidism (RIHT) in breast cancer patients. Materials and methods: A total of 1,063 breast cancer patients who underwent whole breast irradiation between 2009 and 2016 were analyzed. Individual dose-volume histograms were used to generate LKB and multivariable logistic regression models. LKB model was fit using the thyroid radiation dose-volume parameters. A multivariable model was constructed to identify potential dosimetric and clinical parameters associated with RIHT. Internal validation was conducted using bootstrapping techniques, and model performance was evaluated using the area under the curve (AUC) and Hosmer-Lemeshow (HL) goodness-of-fit test. Results: RIHT developed in 4 % of patients with a median follow-up of 77.7 months. LKB and multivariable NTCP models exhibited significant agreement between the predicted and observed results (HL P values > 0.05). The multivariable NTCP model outperformed the LKB model in predicting RIHT (AUC 0.62 vs. 0.54). In the multivariable model, systemic therapy, age, and percentage of thyroid volume receiving ≥ 10 Gy (V10) were significant prognostic factors for RIHT. The cumulative incidence of RIHT was significantly higher in patients who exceeded the cut-off values for all three risk predictors (systemic therapy, age ≥ 40 years, and thyroid V10 ≥ 26 %, P < 0.005). Conclusions: Systemic therapy, age, and V10 of the thyroid were identified as strong risk factors for the development of RIHT. Our NTCP models provide valuable insights to clinicians for predicting and preventing hypothyroidism by identifying high-risk patients.

Large institutional experience of early outcomes and dosimetric findings with postoperative stereotactic partial breast irradiation in breast cancer.

PURPOSE: To analyze the dosimetric and toxicity outcomes of patients treated with postoperative stereotactic partial breast irradiation (S-PBI). METHODS: We identified 799 women who underwent S-PBI at our institution between January 2016 and December 2022. The most commonly used dose-fraction and technique were 30 Gy in 5 fractions (91.7 %) and a robotic stereotactic radiation system with real-time tracking (83.7 %). The primary endpoints were dosimetric parameters and radiation-related toxicities. For comparison, a control group undergoing ultra-hypofractionated whole breast irradiation (UF-WBI, n = 468) at the same institution was selected. RESULTS: A total of 815 breasts from 799 patients, with a median planning target volume (PTV) volume of 89.6 cm3, were treated with S-PBI. Treatment plans showed that the mean and maximum doses received by the PTV were 96.2 % and 104.8 % of the prescription dose, respectively. The volume of the ipsilateral breast that received 50 % of the prescription dose was 32.3 ± 8.9 %. The mean doses for the ipsilateral lung and heart were 2.5 ± 0.9 Gy and 0.65 ± 0.39 Gy, respectively. Acute toxicity occurred in 175 patients (21.5 %), predominantly of grade 1. Overall rate of late toxicity was 4 % with a median follow-up of 31.6 months. Compared to the UF-WBI group, the S-PBI group had comparably low acute toxicity (21.5 % vs. 25.2 %, p = 0.12) but significantly lower dosimetric parameters for all organs-at-risks (all p < 0.05). CONCLUSION: In this large cohort, S-PBI demonstrated favorable dosimetric and toxicity profiles. Considering the reduced radiation exposure to surrounding tissues, external beam PBI with advanced techniques should at least be considered over traditional WBI-based approaches for PBI candidates.

Normal Tissue Complication Probability Modeling of Severe Radiation-Induced Lymphopenia Using Blood Dose for Patients With Hepatocellular Carcinoma.

PURPOSE: This study aimed to develop a normal tissue complication probability (NTCP) model to estimate the risk of severe radiation-induced lymphopenia (SRIL; absolute lymphocyte count [ALC] < 500/µL) by using the blood dose of patients with hepatocellular carcinoma (HCC). METHODS AND MATERIALS: We retrospectively collected data from 75 patients with HCC who received radiation therapy (RT) between 2015 and 2018. The hematological dose framework calculated blood dose-volume histograms (DVHs) using a predefined blood flow model, organ DVHs, the number of treatment fractions, and beam delivery time. A Lyman-Kutcher-Burman model with a generalized equivalent dose was used to establish the NTCP model, reflecting the whole-blood DVHs. Optimization of the Lyman-Kutcher-Burman parameters was conducted by minimizing a negative log-likelihood function. RESULTS: There were 6, 4, 18, 33, and 14 patients in the groups with radiation-induced lymphopenia grades 0, 1, 2, 3, and 4, respectively. The median pre- and post-RT ALC values were 1410/µL (range, 520-3710/µL) and 470/µL (range, 60-1760/µL), respectively. There was a correlation between mean blood dose and ALC depletion (Pearson r = -0.664; P < .001). The average mean blood doses in each radiation-induced lymphopenia group were 2.90 Gy (95% CI, 1.96-3.85 Gy) for grade 0 to 1, 5.29 Gy (95% CI, 4.12-6.45 Gy) for grade 2, 8.81 Gy (95% CI, 7.55-10.07 Gy) for grade 3, and 11.69 Gy (95% CI, 9.82-17.57 Gy) for grade 4. When applying the developed NTCP model to predict SRIL, the area under the receiver operating characteristic curve and Brier score values were 0.89 and 0.12, respectively. CONCLUSIONS: We developed the first NTCP model based on whole-blood DVHs for estimating SRIL after abdominal RT in patients with HCC. Our results showed a strong correlation between blood dose and ALC depletion, suggesting the potential to predict the risk of SRIL occurrence using blood dose.

Radiation dose-event relationship after intraoperative radiotherapy as a boost in patients with breast cancer.

Purpose: Intraoperative radiotherapy (IORT) can be used as a boost in combination with external whole breast irradiation. This study reports the clinical and dosimetric factors associated with IORT-related adverse events (AE). Methods and materials: Between 2014 and 2021, 654 patients underwent IORT. A single fraction of 20 Gy was prescribed to the surface of the tumour cavity using the mobile 50-kV X-ray source. For skin dose measurement, at least four optically stimulated luminescent dosimeter (OSLD) chips were annealed and attached to the skin edge in the superior, inferior, medial, and lateral locations during IORT. Logistic regression analyses were conducted to identify factors associated with IORT-related AE. Results: With a median follow-up period of 42 months, 7 patients experienced local recurrence, resulting in a 4-year local failure-free survival rate of 97.9%. The median skin dose measured by OSLD was 3.85 Gy (range, 0.67-10.89 Gy), and a skin dose of > 6 Gy was observed in 38 patients (2%). The most common AE was seroma (90 patients, 13.8%). We also found that 25 patients (3.9%) experienced fat necrosis during follow-up, and among them, 8 patients underwent biopsy or excision to exclude local recurrence. IORT-related late skin injury occurred in 14 patients, and a skin dose > 6 Gy was significantly associated with IORT-induced skin injury (odds ratio 4.942, 95% confidence interval 1.294-18.871, p = 0.019). Conclusions: IORT was safely administered as a boost to various populations of patients with breast cancer. However, several patients may experience severe skin injuries, and for older patients with diabetes, IORT should be performed with caution.

Targeting AXL Using the AVB-500 Soluble Receptor and through Genetic Knockdown Inhibits Bile Duct Cancer Growth and Metastasis.

Bile duct cancer, or cholangiocarcinoma, is a rare disease with limited treatment options that include surgery and cytotoxic chemotherapy. The high recurrence rate and poor prognosis of this type of cancer highlights the need to identify new and more effective therapeutic targets. In this study, we found that AXL, a receptor tyrosine kinase, is highly expressed in biliary cancer patients and significantly correlated with poor patient outcomes, including metastasis and low survival rates. We also demonstrated that targeting AXL inhibits tumor progression. In vitro studies with bile duct cancer cells (SNU1196 and HUCCT1) showed that genetic knockdown of AXL significantly reduced both tumor cell growth and invasion. In addition, in vivo studies using subcutaneous and orthotopic intrahepatic models demonstrated that genetic inhibition of AXL resulted in tumor-growth delay. To further examine the possible clinical translation of AXL inhibition in the clinic, we tested the efficacy of AVB-500, a soluble AXL receptor, in reducing AXL activation and tumor growth. AVB-500 was effective at inhibiting AXL activation and decreasing the growth and invasion of SNU1196 and HUCCT1 tumors which possess high AXL expression. Most importantly, AVB-500 was highly effective at decreasing tumor dissemination of bile duct tumor cells in the peritoneal cavity. This study strongly supports the idea of using the AXL receptor as a new therapeutic target to treat the growth and progression of biliary cancer.

Selective Inhibition of PI3K Isoforms in Brain Tumors Suppresses Tumor Growth by Increasing Radiosensitivity.

PURPOSE: Glioblastoma (GBM) is a malignant brain tumor with poor prognosis. Radioresistance is a major challenge in the treatment of brain tumors. The development of several types of tumors, including GBM, involves the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Upon activation, this pathway induces radioresistance. In this study, we investigated whether additional use of selective inhibitors of PI3K isoforms would enhance radiosensitivity in GBM. MATERIALS AND METHODS: We evaluated whether radiation combined with PI3K isoform selective inhibitors can suppress radioresistance in GBM. Glioma 261 expressing luciferase (GL261-luc) and LN229 were used to confirm the effect of combination of radiation and PI3K isoform inhibitors in vitro. Cell viability was confirmed by clonogenic assay, and inhibition of PI3K/AKT signaling activation was observed by Western blot. To confirm radiosensitivity, the expression of phospho-γ-H2AX was observed by immunofluorescence. In addition, to identify the effect of a combination of radiation and PI3K-α isoform inhibitor in vivo, an intracranial mouse model was established by implanting GL261-luc. Tumor growth was observed by IVIS imaging, and survival was analyzed using Kaplan-Meier survival curves. RESULTS: Suppression of the PI3K/AKT signaling pathway increased radiosensitivity, and PI3K-α inhibition had similar effects on PI3K-pan inhibition in vitro. The combination of radiotherapy and PI3K-α isoform inhibitor suppressed tumor growth and extended survival in vivo. CONCLUSION: This study verified that PI3K-α isoform inhibition improves radiosensitivity, resulting in tumor growth suppression and extended survival in GBM mice.

Impact of Denoising on Deep-Learning-Based Automatic Segmentation Framework for Breast Cancer Radiotherapy Planning.

Objective: This study aimed to investigate the segmentation accuracy of organs at risk (OARs) when denoised computed tomography (CT) images are used as input data for a deep-learning-based auto-segmentation framework. Methods: We used non-contrast enhanced planning CT scans from 40 patients with breast cancer. The heart, lungs, esophagus, spinal cord, and liver were manually delineated by two experienced radiation oncologists in a double-blind manner. The denoised CT images were used as input data for the AccuContourTM segmentation software to increase the signal difference between structures of interest and unwanted noise in non-contrast CT. The accuracy of the segmentation was assessed using the Dice similarity coefficient (DSC), and the results were compared with those of conventional deep-learning-based auto-segmentation without denoising. Results: The average DSC outcomes were higher than 0.80 for all OARs except for the esophagus. AccuContourTM-based and denoising-based auto-segmentation demonstrated comparable performance for the lungs and spinal cord but showed limited performance for the esophagus. Denoising-based auto-segmentation for the liver was minimal but had statistically significantly better DSC than AccuContourTM-based auto-segmentation (p < 0.05). Conclusions: Denoising-based auto-segmentation demonstrated satisfactory performance in automatic liver segmentation from non-contrast enhanced CT scans. Further external validation studies with larger cohorts are needed to verify the usefulness of denoising-based auto-segmentation.

Intraoperative Radiotherapy for Resectable Pancreatic Cancer Using a Low-Energy X-Ray Source: Postoperative Complications and Early Outcomes.

PURPOSE: We evaluated the safety, feasibility, and early treatment outcomes of intraoperative radiotherapy (IORT) using a low-energy X-ray source. MATERIALS AND METHODS: Patients with resectable pancreatic cancer were enrolled in this single-institution, prospective, single-arm, phase II trial. Patients underwent surgery and IORT with 10 Gy prescribed at a 5-mm depth from the tumor bed using a 50 kV X-ray source (Intrabeam, Carl Zeiss). Six cycles of adjuvant gemcitabine-based chemotherapy were administered 8-12 weeks after surgery. RESULTS: A total of 41 patients were included. Thirty-one patients (75.6%) underwent wide R0 resection, while 5 (12.2%) underwent R1 resection and 5 (12.2%) underwent narrow R0 resection (retroperitoneal margin <1 mm). Grade 3 postoperative complications were reported in only one patient (4.9%) who needed additional surgery due to ulcer perforation. At a median follow-up of 9 months, four patients showed local-only recurrence, nine had distant metastases, and two showed both local and distant recurrence. The 1-year local control rate was 76.4%. CONCLUSION: Our preliminary report suggests that IORT is well-tolerated and feasible in patients with resectable pancreatic cancer. Further follow-up is needed to confirm the clinical benefits of IORT in terms of local control and overall survival. TRIAL REGISTRATION: Trial Registration: Clinical trial registration No. (NCT03273374).

Compact bunker shielding assessment for 1.5 T MR-Linac.

This study evaluated the effect of the 1.5 T magnetic field of the magnetic resonance-guided linear accelerator (MR-Linac) on the radiation leakage doses penetrating the bunker radiation shielding wall. The evaluated 1.5 T MR-Linac Unity system has a bunker of the minimum recommended size. Unlike a conventional Linac, both primary beam transmission and secondary beam leakage were considered independently in the design and defined at the machine boundary away from the isocenter. Moreover, additional shielding was designed considering the numerous ducts between the treatment room and other rooms. The Linac shielding was evaluated by measuring the leakage doses at several locations. The intrinsic vibration and magnetic field were inspected at the proposed isocenter of the system. For verification, leakage doses were measured before and after applying the magnetic field. The intrinsic vibration and magnetic field readings were below the permitted limit. The leakage dose (0.05-12.2 µSv/week) also complied with internationally stipulated limits. The special shielding achieved a five-fold reduction in leakage dose. Applying the magnetic field increased the leakage dose by 0.12 to 4.56 µSv/week in several measurement points, although these values fall within experimental uncertainty. Thus, the effect of the magnetic field on the leakage dose could not be ascertained.

Optimal management of recurrent and metastatic upper tract urothelial carcinoma: Implications of intensity modulated radiation therapy.

BACKGROUND: Upper tract urothelial carcinoma (UTUC) is rare and the treatment for recurrent or metastatic UTUC is unclear. We evaluated the outcomes of salvage and palliative radiotherapy (RT) and prognostic factors in UTUC patients and find implications for salvage and palliative RT. METHODS: Between August 2006 and February 2021, 174 patients (median age, 68 years; range, 37-90) underwent salvage and palliative RT. Disease status at RT included initially diagnosed advanced disease (n = 8, 4.6%), local recurrence only (n = 56, 32.2%), distant metastasis only (n = 59, 33.9%), and local recurrence and distant metastasis (n = 51, 29.3%). The primary tumor location included the renal pelvis (n = 87, 50%), ureter (n = 77, 44.3%), and both (n = 10, 5.7%). Radical nephroureterectomy, chemotherapy, and immunotherapy were used in 135 (77.6%), 101 (58%), and 19 (10.9%) patients, respectively. Survival outcomes and prognostic factors were analysed using Cox and logistic regression analysis. RESULTS: Salvage RT and palliative RT was administered in 73 (42%) and 101 (58%) patients, respectively. The median radiation dose was 45 Gy (range, 15-65). Two-dimensional (2D) or three-dimensional (3D) RT and intensity modulated RT (IMRT) were used in 61 (35.1%) and 113 (64.9%) patients, respectively. The median follow-up was 7.8 months. The median duration of overall survival (OS) was 13.4 months, and the 1-year OS was 53.5%. The median progression-free survival (PFS) was 4.7 months, and the 6-month PFS was 41.9%. The 6-month infield PFS was 84%. In multivariate analysis, RT method (2D/3D vs. IMRT, p = 0.007) and RT response (p = 0.008) were independent prognostic factors for OS, and RT response correlated with PFS (p = 0.015). In subgroup analysis in patients with PD-L1 data, positive PD-L1 correlated with better PFS (p = 0.009). RT response-associated factors were concurrent chemotherapy (p = 0.03) and higher radiation dose (p = 0.034). Of 145 patients, 10 (6.9%) developed grade 3 acute or late toxicity. CONCLUSIONS: Salvage and palliative RT for UTUC are feasible and effective. Patients with RT response using IMRT may have survival benefit from salvage and palliative RT. Positive PD-L1 status might be related to radiosensitivity. High-dose radiation with concurrent chemotherapy may improve RT response.

Validation of a nomogram for predicting the risk of lymphedema following contemporary treatment for breast cancer: a large multi-institutional study (KROG 20-05).

PURPOSE: We previously constructed a nomogram for predicting the risk of arm lymphedema following contemporary breast cancer treatment. This nomogram should be validated in patients with different background characteristics before use. Therefore, we aimed to externally validate the nomogram in a large multi-institutional cohort. METHODS: Overall, 8835 patients who underwent breast cancer surgery during 2007-2017 were identified. Data of variables in the nomogram and arm lymphedema were collected. The nomogram was validated externally using C-index and integrated area under the curve (iAUC) with 1000 bootstrap samples and by calibration plots. RESULTS: Overall, 1377 patients (15.6%) developed lymphedema. The median time from surgery to lymphedema development was 11.4 months. Lymphedema rates at 2, 3, and 5 years were 11.2%, 13.1%, and 15.6%, respectively. Patients with lymphedema had significantly higher body mass index (median, 24.1 kg/m2 vs. 23.4 kg/m2) and a greater number of removed nodes (median, 17 vs. 6) and more frequently underwent taxane-based chemotherapy (85.7% vs. 41.9%), total mastectomy (73.1% vs. 52.1%), conventionally fractionated radiotherapy (71.9% vs. 54.2%), and regional nodal irradiation (70.7% vs 22.4%) than those who did not develop lymphedema (all P < 0.001). The C-index of the nomogram was 0.7887, and iAUC was 0.7628, indicating good predictive accuracy. Calibration plots confirmed that the predicted lymphedema risks were well correlated with the actual lymphedema rates. CONCLUSION: This nomogram, which was developed using factors related to multimodal breast cancer treatment and was validated in a large multi-institutional cohort, can well predict the risk of breast cancer-related lymphedema.

Lymphocyte dynamics during and after chemo-radiation correlate to dose and outcome in stage III NSCLC patients undergoing maintenance immunotherapy.

PURPOSE: We investigated the dynamics of lymphocyte depletion and recovery during and after definitive concurrent chemoradiotherapy (CCRT), dose to which structures is correlated to them, and how they affect the prognosis of stage III non-small cell lung cancer (NSCLC) patients undergoing maintenance immunotherapy. METHODS AND MATERIALS: In this retrospective study, absolute lymphocyte counts (ALC) of 66 patients were obtained before, during, and after CCRT. Persistent lymphopenia was defined as ALC < 500/µL at 3 months after CCRT. The impact of regional dose on lymphocyte depletion and recovery was investigated using voxel-based analysis (VBA). RESULTS: Most patients (n = 65) experienced lymphopenia during CCRT: 39 patients (59.0%) had grade (G) 3+ lymphopenia. Fifty-nine patients (89.3%) recovered from treatment-related lymphopenia at 3 months after CCRT, whereas 7 (10.6%) showed persistent lymphopenia. Patient characteristics associated with persistent lymphopenia were older age and ALC before and during treatment. In multivariable Cox regression analysis, recovery from lymphopenia was identified as a significant prognostic factor for Progression Free Survival (HR 0.35, 95% CI 0.13-0.93, p = 0.034) and Overall Survival (HR 0.24, 95% CI 0.08-0.68, p = 0.007). Voxel-based analysis showed strong correlation of dose to the upper mediastinum with lymphopenia at the end of CCRT, but not at 3 months after CCRT. CONCLUSION: Recovery from lymphopenia is strongly correlated to improved survival of patients undergoing CCRT and adjuvant immunotherapy, and is correlated to lymphocyte counts pre- and post-CCRT. VBA reveals high correlation of dose to large vessels to lymphopenia at the end of CCRT. Therefore, efforts should be made not only for preventing lymphocyte depletion during CCRT but also for helping lymphocyte recovery after CCRT.

Effect of Elective Internal Mammary Node Irradiation on Disease-Free Survival in Women With Node-Positive Breast Cancer: A Randomized Phase 3 Clinical Trial.

IMPORTANCE: The benefit of internal mammary node irradiation (IMNI) for treatment outcomes in node-positive breast cancer is unknown. OBJECTIVE: To investigate whether the inclusion of IMNI in regional nodal irradiation improves disease-free survival (DFS) in women with node-positive breast cancer. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, phase 3 randomized clinical trial was conducted from June 1, 2008, to February 29, 2020, at 13 hospitals in South Korea. Women with pathologically confirmed, node-positive breast cancer after breast-conservation surgery or mastectomy with axillary lymph node dissection were eligible and enrolled between November 19, 2008, and January 14, 2013. Patients with distant metastasis and those who had received neoadjuvant treatment were excluded. Data analyses were performed according to the intention-to-treat principle. INTERVENTIONS: All patients underwent regional nodal irradiation along with breast or chest wall irradiation. They were randomized 1:1 to receive radiotherapy either with IMNI or without IMNI. MAIN OUTCOMES AND MEASURES: The primary end point was the 7-year DFS. Secondary end points included the rates of overall survival, breast cancer-specific survival, and toxic effects. RESULTS: A total of 735 women (mean [SD] age, 49.0 [9.1] years) were included in the analyses, of whom 373 received regional nodal irradiation without IMNI and 362 received regional nodal irradiation with IMNI. Nearly all patients underwent taxane-based adjuvant systemic treatment. The median (IQR) follow-up was 100.4 (89.7-112.1) months. The 7-year DFS rates did not significantly differ between the groups treated without IMNI and with IMNI (81.9% vs 85.3%; hazard ratio [HR], 0.80; 95% CI, 0.57-1.14; log-rank P = .22). However, an ad hoc subgroup analysis showed significantly higher DFS rates with IMNI among patients with mediocentrally located tumors. In this subgroup, the 7-year DFS rates were 81.6% without IMNI vs 91.8% with IMNI (HR, 0.42; 95% CI, 0.22-0.82; log-rank P = .008), and the 7-year breast cancer mortality rates were 10.2% without IMNI vs 4.9% with IMNI (HR, 0.41; 95% CI, 0.17-0.99; log-rank P = .04). No differences were found between the 2 groups in the incidence of adverse effects, including cardiac toxic effects and radiation pneumonitis. CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that including IMNI in regional nodal irradiation did not significantly improve the DFS in patients with node-positive breast cancer. However, patients with medially or centrally located tumors may benefit from the use of IMNI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04803266.

Postmastectomy Radiation Therapy for Node-Negative Breast Cancer of 5 cm or Larger Tumors: A Multicenter Retrospective Analysis (KROG 20-03).

PURPOSE: To evaluate the role of postmastectomy radiation therapy (PMRT) in patients with node-negative breast cancer of 5cm or larger tumors undergoing mastectomy. MATERIALS AND METHODS: Medical records of 274 patients from 18 institutions treated with mastectomy between January 2000 and December 2016 were retrospectively reviewed. Among these, 202 patients underwent PMRT, while 72 did not. Two hundred and forty-one patients (88.0%) received systemic chemotherapy, and 172 (62.8%) received hormonal therapy. Patients receiving PMRT were younger, more likely to have progesterone receptor-positive tumors, and received adjuvant chemotherapy more frequently compared with those without PMRT (p <0.001, 0.018, and <0.001, respectively). Other characteristics were not significantly different between the two groups. RESULTS: With a median follow-up of 95 months (range, 1-249), there were 9 locoregional recurrences, and 20 distant metastases. The 8-year locoregional recurrence-free survival rates were 98.0% with PMRT and 91.3% without PMRT (p=0.133), and the 8-year disease-free survival (DFS) rates were 91.8% with PMRT and 73.9% without PMRT (p=0.008). On multivariate analysis incorporating age, histologic grade, lymphovascular invasion, hormonal therapy, chemotherapy, and PMRT, the absence of lymphovascular invasion and the receipt of PMRT were associated with improved DFS (p=0.025 and 0.009, respectively). CONCLUSION: Locoregional recurrence rate was very low in node-negative breast cancer of 5cm or larger tumors treated with mastectomy regardless of the receipt of PMRT. However, PMRT was significantly associated with improved DFS. Further investigation is needed to confirm these findings.

Effect of Postoperative Radiotherapy after Primary Tumor Resection in De Novo Stage IV Breast Cancer: A Multicenter Retrospective Study (KROG 19-02).

PURPOSE: This study aimed to investigate the impact of postoperative radiotherapy (PORT) in de novo metastatic breast cancer (dnMBC) patients undergoing planned primary tumor resection (PTR) and to identify the subgroup of patients who would most benefit from PORT. MATERIALS AND METHODS: This study enrolled 426 patients with dnMBC administered PTR alone or with PORT. The primary and secondary outcomes were overall and progression-free survival (OS and PFS), respectively. RESULTS: The median follow-up time was 53.7 months (range, 3.1 to 194.4). The 5-year OS and PFS rates were 73.2% and 32.0%, respectively. For OS, clinical T3/4 category, triple-negative breast cancer (TNBC), postoperative chemotherapy alone were significantly poor prognostic factors, and administration of PORT failed to show its significance. Regarding PFS, PORT was a favorable prognostic factor (hazard ratio, 0.64; 95% confidence interval, 0.50 to 0.82; p < 0.001), in addition to T1/2 category, ≤ 5 metastases, and non-TNBC. According to the multivariate analyses of OS in the PORT group, we divided the patients into three groups (group 1, T1/2 and non-TNBC [n=193]; group 2, T3/4 and non-TNBC [n=171]; and group 3, TNBC [n=49]), and evaluated the effect of PORT. Although PORT had no significance for OS in all subgroups, it was a significant factor for good prognosis regarding PFS in groups 1 and 2, not in group 3. CONCLUSION: PORT was associated with a significantly better PFS in patients with dnMBC who underwent PTR. Patients with clinical T1/2 category and non-TNBC benefited most from PORT, while those with TNBC showed little benefit.

Mutual Information-Based Non-Local Total Variation Denoiser for Low-Dose Cone-Beam Computed Tomography.

Conventional non-local total variation (NLTV) approaches use the weight of a non-local means (NLM) filter, which degrades performance in low-dose cone-beam computed tomography (CBCT) images generated with a low milliampere-seconds (mAs) parameter value because a local patch used to determine the pixel weights comprises noisy-damaged pixels that reduce the similarity between corresponding patches. In this paper, we propose a novel type of NLTV based on a combination of mutual information (MI): MI-NLTV. It is based on a statistical measure for a similarity calculation between the corresponding bins of non-local patches vs. a reference patch. The weight is determined in terms of a statistical measure comprising the MI value between corresponding non-local patches and the reference-patch entropy. The MI-NLTV denoising process is applied to CBCT images generated by the analytical reconstruction algorithm using a ray-driven backprojector (RDB). The MI-NLTV objective function is minimized based on the steepest gradient descent optimization to augment the difference between a real structure and noise, cleaning noisy pixels without significant loss of the fine structure and details that remain in the reconstructed images. The proposed method was evaluated using patient data and actual phantom measurement data acquired with lower mAs. The results show that integrating the RDB further enhances the MI-NLTV denoising-based analytical reconstruction algorithm to achieve a higher CBCT image quality when compared with those generated by NLTV denoising-based approach, with an average of 15.97% higher contrast-to-noise ratio, 2.67% lower root mean square error, 0.12% lower spatial non-uniformity, 1.14% higher correlation, and an average of 18.11% higher detectability index. These quantitative results indicate that the incorporation of MI makes the NLTV more stable and robust than the conventional NLM filter for low-dose CBCT imaging. In addition, achieving clinically acceptable CBCT image quality despite low-mAs projection acquisition can reduce the burden on common online CBCT imaging, improving patient safety throughout the course of radiotherapy.

Medical student education through flipped learning and virtual rotations in radiation oncology during the COVID-19 pandemic: a cross sectional research.

BACKGROUND: The COVID-19 pandemic has stripped many medical students worldwide of their right to quality education. In response, we developed hybrid courses involving aspects of both online and in-person teaching for radiation oncology medical student clerkship. METHODS: We entitled students to customize their own rotation schedule using Google Forms and developed a flipped learning online class, which consisted of at least one video clip on basic knowledge of radiation oncology per day (yonsei-radonc.com). Students were instructed to watch online videos before the next day's discussion session. Required components of the medical education program (e.g., target drawing, site visits to treatment facilities) were also prepared and conducted in accordance with the appropriate level of social distancing measures. Finally, we conducted questionnaire surveys after the completion of the week-long course and clerkship. RESULTS: From March to June 2020, 110 fourth-year medical students undertook a clinical module in our 1-week radiation oncology program course. Each day, students completed the flipped learning prior to meeting with the educator and then participated in the online discussion session and conference. All activities were well performed as scheduled. Students' motivation was high, as was their overall satisfaction with the course. The students were satisfied with the online contents, flipped learning strategy, and instructors. CONCLUSIONS: We successfully integrated open and virtual educational platforms to improve access to and satisfaction with student clerkship. In the future "new normal," minimized face-to-face learning interactions, such as flipped learning, should be actively utilized for medical and other students' education.