Abscopal Effect of Radiotherapy Enhanced with Immune Checkpoint Inhibitors of Triple Negative Breast Cancer in 4T1 Mammary Carcinoma Model.

Local radiotherapy (RT) is important to manage metastatic triple-negative breast cancer (TNBC). Although RT primarily reduces cancer cells locally, this control can be enhanced by triggering the immune system via immunotherapy. RT and immunotherapy may lead to an improved systemic effect, known as the abscopal effect. Here, we analyzed the antitumor effect of combination therapy using RT with an anti-programmed cell death-1 (PD-1) antibody in primary tumors, using poorly immunogenic metastatic mouse mammary carcinoma 4T1 model. Mice were injected subcutaneously into both flanks with 4T1 cells, and treatment was initiated 12 days later. Mice were randomly assigned to three treatment groups: (1) control (no treatment with RT or immune checkpoint inhibitor (ICI)), (2) RT alone, and (3) RT+ICI. The same RT dose was prescribed in both RT-alone and RT+ICI groups as 10Gy/fx in two fractions and delivered to only one of the two tumor burdens injected at both sides of flanks. In the RT+ICI group, 200 µg fixed dose of PD-1 antibody was intraperitoneally administered concurrently with RT. The RT and ICI combination markedly reduced tumor cell growth not only in the irradiated site but also in non-irradiated sites, a typical characteristic of the abscopal effect. This was observed only in radiation-sensitive cancer cells. Lung metastasis development was lower in RT-irradiated groups (RT-only and RT+ICI groups) than in the non-irradiated group, regardless of the radiation sensitivity of tumor cells. However, there was no additive effect of ICI on RT to control lung metastasis, as was already known regarding the abscopal effect. The combination of local RT with anti-PD-1 blockade could be a promising treatment strategy against metastatic TNBC. Further research is required to integrate our results into a clinical setting.

Comparison of Dose Distribution in Regional Lymph Nodes in Whole-Breast Radiotherapy vs. Whole-Breast Plus Regional Lymph Node Irradiation: An In Silico Planning Study in Participating Institutions of the Phase III Randomized Trial (KROG 1701).

The purpose of the current in silico planning study is to compare radiation doses of whole-breast irradiation (WBI) and whole-breast plus regional lymph node irradiation (WBI+RNI) administered to the regional lymph nodes (RLN) in pN1 breast cancer. Twenty-four participating institutions were asked to create plans of WBI and WBI+RNI for two dummy cases. To compare target coverage between the participants, an isodose line equal to 90% of the prescribed dose was converted to an isodose contour (contour90% iso). The relative nodal dose (RND) was obtained using the ratio of RLN dose to the target dose. The Fleiss's kappa values which represent inter-observer agreement of contour90% iso were over 0.68. For RNI, 6 institutions included axillary lymph node (ALN), supraclavicular lymph node (SCN), and internal mammary lymph node (IMN), while 18 hospitals included only ALN and SCN. The median RND between the WBI and WBI+RNI were as follows: 0.64 vs. 1.05 (ALN level I), 0.27 vs. 1.08 (ALN level II), 0.02 vs. 1.12 (ALN level III), 0.01 vs. 1.12 (SCN), and 0.54 vs. 0.82 (IMN). In all nodal regions, the RND was significantly lower in WBI than in WBI+RNI (p < 0.01). In this study, we could identify the nodal dose difference between WBI and WBI+RNI.

MRI-based radiotherapy planning method using rigid image registration technique combined with outer body correction scheme: a feasibility study.

An alternative pseudo CT generation method for magnetic resonance image (MRI)-based radiotherapy planning was investigated in the work. A pseudo CT was initially generated using the rigid image registration between the planning MRI and previously acquired diagnostic CT scan. The pseudo CT generated was then refined to have the same morphology with that of the referenced planning image scan by applying the outer body correction scheme. This method was applied to some sample of brain image data and the feasibility of the method was assessed by comparing dosimetry results with those from the current gold standard CT-based calculations. Validation showed that nearly the entire pixel doses calculated from pseudo CT were agreed well with those from actual planning CT within 2% in dosimetric and 1mm in geometric uncertainty ranges. The results demonstrated that the method suggested in the study was sufficiently accurate, and thus could be applicable to MRI-based brain radiotherapy planning.

Estimation of optimal margin for intrafraction movements during frameless brain radiosurgery.

PURPOSE: To examine the dosimetric effect of intrafraction movements occurred during image-guided frameless brain radiosurgery and to derive the optimal margin recipe to compensate the movement. METHODS: The patients' movements during image-guided radiosurgeries were measured using skull-tracking method incorporated in the CyberKnife system. The dosimetric changes with the movements were computed using the six different dynamic-arc treatment plans based on the dose-grid analysis method. The authors extensively searched the proper relationship between the dose variations and the intrafraction geometric errors. The optimal margin for intrafraction movement was estimated via statistical analysis of the dosimetric changes with 262 actual patients' data. RESULTS: The overall geometric effect of intrafraction movements was approximated as 1.0 r+0.2σ, where r and σ are the average and standard deviation of the movements, respectively. The authors computed the required margins to compensate the movements with various confidence levels and with various estimated times for completing the treatments. The computed optimal margins were calculated as 2.1, 3.2, and 4.2 mm at 90% confidence level when the authors assumed the estimated treatment times of 10, 20, and 30 min, respectively. CONCLUSIONS: The authors provide a quantitative relationship for dosimetric change with the intrafraction movement and derived appropriate margin recipes to ensure the prescribed dose delivery to targeted area for frameless brain radiosurgery.

Effect of early chemoradiotherapy in patients with limited stage small cell lung cancer.

PURPOSE: We evaluated the effect of early chemoradiotherapy on the treatment of patients with limited stage small cell lung cancer (LS-SCLC). MATERIALS AND METHODS: Between January 2006 and December 2011, thirty-one patients with histologically proven LS-SCLC who were treated with two cycles of chemotherapy followed by concurrent chemoradiotherapy and consolidation chemotherapy were retrospectively analyzed. The chemotherapy regimen was composed of etoposide and cisplatin. Thoracic radiotherapy consisted of 50 to 60 Gy (median, 54 Gy) given in 5 to 6.5 weeks. RESULTS: The follow-up period ranged from 5 to 53 months (median, 22 months). After chemoradiotherapy, 35.5% of the patients (11 patients) showed complete response, 61.3% (19 patients) showed partial response, 3.2% (one patient) showed progressive disease, resulting in an overall response rate of 96.8% (30 patients). The 1-, 2-, and 3-year overall survival (OS) rates were 66.5%, 41.0%, and 28.1%, respectively, with a median OS of 21.3 months. The 1-, 2-, and 3-year progression free survival (PFS) rates were 49.8%, 22.8%, and 13.7%, respectively, with median PFS of 12 months. The patterns of failure were: locoregional recurrences in 29.0% (nine patients), distant metastasis in 9.7% (three patients), and both locoregional and distant metastasis in 9.7% (three patients). Grade 3 or 4 toxicities of leukopenia, anemia, and thrombocytopenia were observed in 32.2%, 29.0%, and 25.8%, respectively. Grade 3 radiation esophagitis and radiation pneumonitis were shown in 12.9% and 6.4%, respectively. CONCLUSION: We conclude that early chemoradiotherapy for LS-SCLC provides feasible and acceptable local control and safety.