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.

Intraoperative radiation therapy induces immune response activity after pancreatic surgery.

BACKGROUND: Pancreatic cancer has highly aggressive features, such as local recurrence that leads to significantly high morbidity and mortality and recurrence after successful tumour resection. Intraoperative radiation therapy (IORT), which delivers targeted radiation to a tumour bed, is known to reduce local recurrence by directly killing tumour cells and modifying the tumour microenvironment. METHODS: Among 30 patients diagnosed with pancreatic cancer, 17 patients received IORT immediately after surgical resection. We investigated changes in the immune response induced by IORT by analysing the peritoneal fluid (PF) and blood of patients with and without IORT treatment after pancreatic cancer surgery. Further, we treated three pancreatic cell lines with PF to observe proliferation and activity changes. RESULTS: Levels of cytokines involved in the PI3K/SMAD pathway were increased in the PF of IORT-treated patients. Moreover, IORT-treated PF inhibited the growth, migration, and invasiveness of pancreatic cancer cells. Changes in lymphocyte populations in the blood of IORT-treated patients indicated an increased immune response. CONCLUSIONS: Based on the characterisation and quantification of immune cells in the blood and cytokine levels in the PF, we conclude that IORT induced an anti-tumour effect by activating the immune response, which may prevent pancreatic cancer recurrence. CLINICAL TRIAL REGISTRATION: NCT03273374 .

Magnetic resonance imaging-based validation of the 2018 FIGO staging system in patients treated with definitive radiotherapy for locally advanced cervix cancer.

OBJECTIVE: To validate the revised 2018 International Federation of Gynecologic and Obstetrics (FIGO) staging system in patients who underwent diagnostic magnetic resonance imaging (MRI) and radiotherapy (RT) for locally advanced cervix cancer. METHODS: We analyzed 677 patients who were diagnosed with pelvic MRI and treated with definitive (chemo-)RT for locally advanced cervix cancer (stage IB2/IIA2-IVA or N+) between 1992 and 2018. Patients were classified according to 2009 and 2018 FIGO staging, and survival outcomes were compared. We developed a nomogram to improve prediction of progression-free survival (PFS). RESULTS: Pelvic and paraaortic lymph nodes were positive in 331 (48.9%) and 78 (11.5%) patients, respectively. At a median follow-up of 77.9 months, the 5-year PFS was 83.5%, 65.2%, 71.0%, 60.6%, 37.6% and 38.9% for IB, IIA, IIB, IIIA, IIIB and IVA according to FIGO 2009 and 88.9%, 60.0%, 73.8%, 66.7%, 36.3%, 68.9%, 43.6%, and 38.9% for IB, IIA, IIB, IIIA, IIIB, IIIC1, IIIC2, and IVA according to FIGO 2018, respectively. Survival of stage IIIC cervix cancer depended on the local extent of the tumor: the 5-year PFS of T1, T2, and T3 stages were 80.3%, 73.9%, and 45.5% for IIIC1 and 100%, 44.9%, and 23.4% for IIIC2. Histology, tumor size, node metastasis, FIGO 2009, and treatment modality were independent prognostic factors in the Cox regression analysis, and the nomogram incorporating these factors outperformed FIGO 2009 and FIGO 2018 (AUC 0.718 vs. 0.616 vs. 0.594). CONCLUSIONS: FIGO 2018 revision was associated with heterogenous outcomes among stage III cervix cancer patients. Our nomogram can assist the FIGO system in predicting PFS after definitive RT.

Redefining Eligibility by Analyzing Canceled Intraoperative Radiotherapy as a Boost for Patients Undergoing Breast-Conserving Treatment.

BACKGROUND: Intraoperative radiotherapy (IORT) with a 50-kV x-ray is used for a tumor bed boost during breast-conserving surgery. This study evaluated the anatomicosurgical factors associated with cancellation of planned IORT. METHODS: Patient eligibility for the study included age of 20 years or older, compatibility for lumpectomy, and ductal carcinoma in situ or stages 1-3 invasive carcinoma. All the patients underwent magnetic resonance imaging (MRI) and multidisciplinary team evaluations. Resection margins were assessed by frozen pathology. Pre- and intraoperative variables were compared between the IORT and IORT-cancellation groups. RESULTS: A total of 434 patients underwent surgeries for IORT between August 2014 and December 2017. For 90 of these patients, IORT was canceled because of repeated positive margins leading to a large cavity or total mastectomy (n = 27), insufficient cavity-skin distance (n = 14), satellite lesions leading to a large cavity or total mastectomy (n = 12), MRI findings of a large primary tumor or uncertain margins leading to a large cavity (n = 6), cavity geometry unsuitable for IORT (n = 6), subareolar tumor extension (n = 6), tumor abutting the pectoralis muscle (n = 3), patient refusal (n = 5), intraoperative confirmation of bilateral breast cancer (n = 3) or benign pathology (n = 3), device malfunction (n = 3), or scheduling difficulty (n = 2). A tumor larger than 2 cm (P = 0.014) and the presence of satellite lesions (P = 0.014) were independent predictors of IORT cancellation. CONCLUSIONS: Surgical procedures resulting in large cavities were the leading cause of IORT cancellation. Multidisciplinary evaluations using MRI were critical for completion of IORT procedures.

A phase II study of intraoperative radiotherapy using a low-energy x-ray source for resectable pancreatic cancer: a study protocol.

BACKGROUND: The current standard treatment for resectable pancreatic cancer is surgical resection followed by adjuvant chemotherapy. Local recurrence rates are high even after curative resection; thus, the long-term outcome of locally advanced pancreatic cancer remains poor. Intraoperative radiotherapy (IORT) uses a low-energy x-ray source to deliver a single fraction of high-dose radiation to the tumor bed during a surgical procedure, while effectively sparing the surrounding normal tissues. IORT has the potential to improve the efficacy of radiation therapy for pancreatic cancer. METHODS/DESIGN: This prospective, one-armed, phase II study will investigate the role of IORT in improving local control in patients with resectable pancreatic adenocarcinoma. The patients will receive surgery and IORT of 10 Gy prescribed at a 5-mm depth of the tumor bed, followed by adjuvant gemcitabine chemotherapy according to the current standard of care. The aim is to enroll 42 patients. DISCUSSION: The primary endpoint of this trial is to evaluate the feasibility of IORT and the local recurrence rate after one year. The secondary endpoints include the acute and late toxicities, and disease-free survival and overall survival rates. TRIAL REGISTRATION: The trial was prospectively registered at Clinicaltrials.gov NCT03273374 on September 6, 2017.

Improved oncologic outcome with chemoradiotherapy followed by surgery in unresectable intrahepatic cholangiocarcinoma.

PURPOSE: To investigate the ability of chemoradiotherapy (CRT) to down-stage unresectable intrahepatic cholangiocarcinoma (IHCC) to resectable lesions, as well as the factors associated with achieving such down-staging. METHODS: The study cohort comprised 120 patients diagnosed with stage I-IVA IHCC between 2001 and 2012. Of these patients, 56 underwent surgery and 64 received CRT as their initial treatment. The rate of curative resections for patients who received CRT was assessed, and the locoregional failure-free survival (LRFFS) and overall survival (OS) rates of these patients were compared to those of patients who underwent CRT alone. RESULTS: Median follow-up was 36 months. A partial response after CRT was observed in 25% of patients, whereas a biologic response (a >70% decrease of CA19-9) was observed in 35%. Eight patients (12.5%) received curative resection after CRT and showed significantly improved LRFFS and OS compared to those treated with CRT alone (3-year LRFFS: 50 vs. 15.7%, respectively, p = 0.03; 3­year OS: 50 vs. 11.2%, respectively, p = 0.012); these rates were comparable to those of patients who received initial surgery. Factors associated with curative surgery after CRT were gemcitabine administration, higher radiotherapy dose (biological effective dose ≥55 Gy with α/ß = 10), and a >70% reduction of CA19-9. CONCLUSION: Upfront CRT could produce favorable outcomes by converting unresectable lesions to resectable tumors in selected patients. Higher radiotherapy doses and gemcitabine-based chemotherapy yielded a significant reduction of CA19-9 after CRT; patients with these characteristics had a greater chance of curative resection and improved OS.

Aggressive Local Ablative Radiotherapy Mitigates Progression Risk in Oligometastatic Lung Adenocarcinoma.

PURPOSE: This study aimed to determine the role of local ablative radiotherapy (LART) in oligometastatic/oligoprogressive lung adenocarcinoma. MATERIALS AND METHODS: Patients (n=176) with oligometastatic lung adenocarcinoma treated with LART were identified, and those treated with LART at the initial diagnosis of synchronous oligometastatic disease (OMD group) or treated with LART when they presented with repeat oligoprogression (OPD group) were included. RESULTS: In the OMD group (n=54), the 1- and 3-year progression-free survival (PFS) were 50.9% and 22.5%, respectively, whereas the 1- and 3-year overall survival in the OPD group were 75.9% and 58.1%, respectively. Forty-one patients (75.9%) received LART at all gross disease sites. Tyrosine kinase inhibitor (TKI) use and all-metastatic site LART were significant predictors of higher PFS (p=0.018 and p=0.046, respectively). In patients treated with TKIs at the time of LART (n=23) and those treated with all-metastatic site LART, the 1-year PFS was 86.7%, while that of patients not treated with all-metastatic site LART was 37.5% (p=0.006). In the OPD group (n=122), 67.2% of the patients (n=82) maintained a systemic therapy regimen after LART. The cumulative incidence of changing systemic therapy was 39.6%, 62.9%, and 78.5% at 6 months, 1 year, and 2 years after LART, respectively. CONCLUSION: Aggressive LART can be an option to improve survival in patients with oligometastatic disease. Patients with synchronous oligometastatic disease receiving TKI and all-metastatic site LART may have improved PFS. In patients with repeat oligoprogression, LART might potentially extend survival by delaying the need to change the systemic treatment regimen.

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.

Dosimetric Comparison of CPAP and DIBH for Left-sided Breast Cancer Radiation Therapy.

Purpose: Despite the increasing interest in using continuous positive airway pressure (CPAP) in radiation therapy (RT), direct comparisons with the more widely used deep inspiration breath-hold (DIBH) have been limited. This planning study aimed to offer comprehensive geometric and dosimetric evidence by comparing CPAP and DIBH-based RT plans. Materials and Methods: A retrospective data set of 35 patients with left-sided breast cancer with planning computed tomography scans under three breathing conditions (free breathing (FB), CPAP with 10 cmH2O pressure, and DIBH) was collected. Volumetric arc therapy plans aimed for 95% dose coverage to 95% of the planning target volume with a maximum dose below 107%. A comparative dosimetric analysis among the three plans was conducted. Additionally, geometric differences were assessed by calculating the minimum distance between the heart and the clinical target volume (CTV) in each planning computed tomography. Results: CPAP and DIBH plans demonstrated comparable mean heart doses (1.05 Gy), which were significantly lower than the FB plan (1.34 Gy). The maximum dose to the left anterior descending artery was smallest in the CPAP plan (4.44 Gy), followed by DIBH (4.73 Gy) and FB (7.33 Gy) plans. Other organ-at-risk doses for CPAP and DIBH were similar, with mean contralateral breast doses of 2.27 and 2.21 Gy, mean ipsilateral lung doses of 4.09 and 4.08 Gy, V20 at 6.11% and 6.31%, and mean contralateral lung doses of 0.94 and 0.92 Gy, respectively. No significant difference was found in the minimum heart-to-CTV distance between CPAP and DIBH. DIBH exhibited the greatest lung volume (3908 cc), followed by CPAP (3509 cc), and FB(2703 cc). Conclusions: The comparison between CPAP and DIBH shows their similarity in both geometric and dosimetric aspects, providing strong evidence for CPAP's effectiveness and feasibility in RT. This suggests its potential as an alternative to DIBH for patients with left-sided breast cancer.

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.

Neural network based ensemble model to predict radiation induced lymphopenia after concurrent chemo-radiotherapy for non-small cell lung cancer from two institutions.

The use of adjuvant Immune Checkpoint Inhibitors (ICI) after concurrent chemo-radiation therapy (CCRT) has become the standard of care for locally advanced non-small cell lung cancer (LA-NSCLC). However, prolonged radiotherapy regimens are known to cause radiation-induced lymphopenia (RIL), a long-neglected toxicity that has been shown to correlate with response to ICIs and survival of patients treated with adjuvant ICI after CCRT. In this study, we aim to develop a novel neural network (NN) approach that integrates patient characteristics, treatment related variables, and differential dose volume histograms (dDVH) of lung and heart to predict the incidence of RIL at the end of treatment. Multi-institutional data of 139 LA-NSCLC patients from two hospitals were collected for training and validation of our suggested model. Ensemble learning was combined with a bootstrap strategy to stabilize the model, which was evaluated internally using repeated cross validation. The performance of our proposed model was compared to conventional models using the same input features, such as Logistic Regression (LR) and Random Forests (RF), using the Area Under the Curve (AUC) of Receiver Operating Characteristics (ROC) curves. Our suggested model (AUC=0.77) outperformed the comparison models (AUC=0.72, 0.74) in terms of absolute performance, indicating that the convolutional structure of the network successfully abstracts additional information from the differential DVHs, which we studied using Gradient-weighted Class Activation Map. This study shows that clinical factors combined with dDVHs can be used to predict the risk of RIL for an individual patient and shows a path toward preventing lymphopenia using patient-specific modifications of the radiotherapy plan.

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.

Prognostic impact of radiotherapy-induced-lymphopenia in patients treated with breast-conservative surgery.

We investigated a prognostic impact of radiotherapy-induced lymphopenia (RIL) in breast cancer patients treated with breast-conservative surgery (BCS). We included 531 breast cancer patients who were treated with BCS and adjuvant radiotherapy. None of these received (neo)adjuvant chemotherapy. Pre- and post- absolute lymphocyte counts (ALC) were reviewed before and after radiotherapy. The primary endpoint was to evaluate recurrence-free survival (RFS) according to the pre-to-post ALC ratio. Binary logistic regression model was used to identify risk factors for RIL. Either continuous or categorical (> 2.4) pre-to-post ALC ratio was associated with RFS. In 531 patients receiving whole breast irradiation (WBI) and regional nodal irradiation (RNI), RFS was significantly reduced in the patients with high pre-to-post ALC ration (> 2.4). In multivariable analysis, low pre-to-post post ALC ratio was significantly related to decreased RFS in the multivariable analysis (HR 2.293, 95% CIs 1.110-4.735, P = 0.025). In 452 patients treated with WBI alone, high pre-to-post ALC ratio was still significantly associated with decreased RFS in the multivariable analysis (HR 2.708, 95% CIs 1.016-7.218, P = 0.046). In binary logistic regression analysis, RNI was only significant risk factor for clinically meaningful RIL. Our findings show that a markedly decrease in ALC during radiotherapy has a negative prognostic impact.

Risk of on-treatment lymphopenia is associated with treatment outcome and efficacy of consolidation immunotherapy in patients with non-small cell lung cancer treated with concurrent chemoradiotherapy.

BACKGROUND AND PURPOSE: The ability of the effective dose to immune cells (EDIC) and the pre-radiotherapy (RT) absolute lymphocyte count (ALC) to predict lymphopenia during RT, treatment outcomes, and efficacy of consolidation immunotherapy in patients with locally advanced non-small cell lung cancer was investigated. METHODS AND MATERIALS: Among 517 patients treated with concurrent chemoradiotherapy, EDIC was calculated using the mean doses to the lungs, heart, and total body. The patients were grouped according to high and low EDIC and pre-RT ALC, and the correlations with radiation-induced lymphopenia and survival outcomes were determined. RESULTS: Altogether, 195 patients (37.7%) received consolidation immunotherapy. The cutoff values of EDIC and pre-RT ALC for predicting severe lymphopenia were 2.89 Gy and 2.03 × 109 cells/L, respectively. The high-risk group was defined as EDIC ≥ 2.89 Gy and pre-RT ALC < 2.03 × 109 cells/L, while the low-risk group as EDIC < 2.89 Gy and pre-RT ALC ≥ 2.03 × 109 cells/L, and the rest of the patients as the intermediate-risk group. The incidences of severe lymphopenia during RT in the high-, intermediate-, and low-risk groups were 90.1%, 77.1%, and 52.3%, respectively (P < 0.001). The risk groups could independently predict both progression-free (P < 0.001) and overall survival (P < 0.001). The high-risk group showed a higher incidence of locoregional and distant recurrence (P < 0.001). Consolidation immunotherapy showed significant survival benefit in the low- and intermediate-risk groups but not in the high-risk group. CONCLUSIONS: The combination of EDIC and pre-RT ALC predicted severe lymphopenia, recurrence, and survival. It may potentially serve as a biomarker for consolidation immunotherapy.

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).

Association of neutrophil-to-lymphocyte ratio, radiotherapy fractionation/technique, and risk of development of distant metastasis among patients with locally advanced rectal cancer.

BACKGROUND: We investigated the prognostic impact of the neutrophil-to-lymphocyte ratio (NLR) in patients with locally advanced rectal cancer (LARC) and whether modifiable factors in radiotherapy (RT) influenced the NLR. METHODS: Data of 1386 patients who were treated with neoadjuvant RT and concurrent or sequential chemotherapy for LARC between 2006 and 2019 were evaluated. Most patients (97.8%) were treated with long-course RT (LCRT; 50-50.4 Gy in 25-28 fractions) using three-dimensional conformal radiotherapy (3D-CRT) (n = 851) or helical tomotherapy (n = 504), and 30 patients underwent short-course RT (SCRT; 25 Gy in 5 fractions, followed by XELOX administration for 6 weeks). Absolute neutrophil and lymphocyte counts were obtained at initial diagnosis, before and during the preoperative RT course, and after preoperative concurrent chemoradiotherapy. The primary endpoint was distant metastasis-free survival (DMFS). RESULTS: The median follow-up time was 61.3 (4.1-173.7) months; the 5-year DMFS was 80.1% and was significantly associated with the NLR after RT but not before. A post-RT NLR ≥ 4 independently correlated with worse DMFS (hazard ratio, 1.42; 95% confidence interval, 1.12-1.80), along with higher ypT and ypN stages. Post-RT NLR (≥ 4) more frequently increased following LCRT (vs. SCRT, odds ratio [OR] 2.77, p = 0.012) or helical tomotherapy (vs. 3D-CRT, OR 1.29, p < 0.001). CONCLUSIONS: Increased NLR after neoadjuvant RT is associated with increased distant metastasis risk and poor survival outcome in patients with LARC. Moreover, high NLR following RT is directly related to RT fractionation, delivery modality, and tumor characteristics. These results are hypothesis-generating only, and confirmatory studies are required.

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.

Patient-Specific Quality Assurance Using a 3D-Printed Chest Phantom for Intraoperative Radiotherapy in Breast Cancer.

This study aims to confirm the usefulness of patient-specific quality assurance (PSQA) using three-dimensional (3D)-printed phantoms in ensuring the stability of IORT and the precision of the treatment administered. In this study, five patient-specific chest phantoms were fabricated using a 3D printer such that they were dosimetrically equivalent to the chests of actual patients in terms of organ density and shape around the given target, where a spherical applicator was inserted for breast IORT treatment via the INTRABEAM™ system. Models of lungs and soft tissue were fabricated by applying infill ratios corresponding to the mean Hounsfield unit (HU) values calculated from CT scans of the patients. The two models were then assembled into one. A 3D-printed water-equivalent phantom was also fabricated to verify the vendor-provided depth dose curve. Pieces of an EBT3 film were inserted into the 3D-printed customized phantoms to measure the doses. A 10 Gy prescription dose based on the surface of the spherical applicator was delivered and measured through EBT3 films parallel and perpendicular to the axis of the beam. The shapes of the phantoms, CT values, and absorbed doses were compared between the expected and printed ones. The morphological agreement among the five patient-specific 3D chest phantoms was assessed. The mean differences in terms of HU between the patients and the phantoms was 2.2 HU for soft tissue and -26.2 HU for the lungs. The dose irradiated on the surface of the spherical applicator yielded a percent error of -2.16% ± 3.91% between the measured and prescribed doses. In a depth dose comparison using a 3D-printed water phantom, the uncertainty in the measurements based on the EBT3 film decreased as the depth increased beyond 5 mm, and a good agreement in terms of the absolute dose was noted between the EBT3 film and the vendor data. These results demonstrate the applicability of the 3D-printed chest phantom for PSQA in breast IORT. This enhanced precision offers new opportunities for advancements in IORT.

Association between Skeletal Muscle Loss and the Response to Neoadjuvant Chemotherapy for Breast Cancer.

There are no means to predict patient response to neoadjuvant chemotherapy (NAC); the impact of skeletal muscle loss on the response to NAC remains undefined. We investigated the association between response to chemotherapy and skeletal muscle loss in breast cancer patients. Patients diagnosed with invasive breast cancer who were treated with NAC, surgery, and radiotherapy were analyzed. We quantified skeletal muscle loss using pre-NAC and post-NAC computed tomography scans. The response to treatment was determined using the Response Evaluation Criteria in Solid Tumors. We included 246 patients in this study (median follow-up, 28.85 months). The median age was 48 years old (interquartile range 42-54) and 115 patients were less than 48 years old (46.7%). Patients showing a complete or partial response were categorized into the responder group (208 patients); the rest were categorized into the non-responder group (38 patients). The skeletal muscle mass cut-off value was determined using a receiver operating characteristic curve; it showed areas under the curve of 0.732 and 0.885 for the pre-NAC and post-NAC skeletal muscle index (p < 0.001 for both), respectively. Skeletal muscle loss and cancer stage were significantly associated with poor response to NAC in locally advanced breast cancer patients. Accurately measuring muscle loss to guide treatment and delaying muscle loss through various interventions would help enhance the response to NAC and improve clinical outcomes.

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.