Daily Online Adaptive Radiation Therapy of Postoperative Endometrial and Cervical Cancer With PTV Margin Reduction to 5 mm: Dosimetric Outcomes, Acute Toxicity, and First Clinical Experience.

Purpose: This study evaluated the first clinical implementation of daily iterative cone beam computed tomography (iCBCT)-guided online adaptive radiation therapy (oART) in the postoperative treatment of endometrial and cervical cancer. Methods and Materials: Seventeen consecutive patients treated with daily iCBCT-guided oART were enrolled in this prospective study, with a reduced uniform 3-dimensional PTV margin of 5 mm. Treatment plans were designed to deliver 45 or 50.4 Gy in 1.8 Gy daily fractions to PTV. Pre- and posttreatment ultrasound and iCBCT scans were performed to record intrafractional bladder and rectal volume changes. The accuracy of contouring, oART procedure time, dosimetric outcomes, and acute toxicity were evaluated. Results: The average time from first iCBCT acquisition to completion of treatment was 22 minutes and 26 seconds. During this period, bladder volume increased by 44 cm3 using iCBCT contouring, whereas rectal volume remained stable (62.9 cm3 pretreatment vs 61.9 cm3 posttreatment). A total of 91.6% of influencers and 88.1% of CTVs required no or minor edits. The adapted plan was selected in all (434) fractions and significantly improved the dosimetry coverage for CTV and PTV, especially the vaginal PTV coverage by nearly 7% (P < .05). The adapted bladder Dmean was 104.61 cGy, and the rectum Dmean was 123.67 cGy, significantly lower than the scheduled plan of 108.24 and 128.19 cGy, respectively. The bone marrow and femur head left and right dosimetry were also improved with adaptation. Grade 2 acute gastrointestinal and genitourinary toxicities were 24% and 0, respectively. There was a grade 3 acute toxicity of decreased white blood cell count in 1 patient. Conclusions: Daily oART was associated with favorable dosimetry improvement and low acute toxicity, supporting its safety and efficacy for postoperative treatment of endometrial and cervical cancer. These results need to be validated in a larger prospective randomized controlled cohort.

Rebalancing TGF-ß/PGE2 breaks RT-induced immunosuppressive barriers by enhancing tumor-infiltrated dendritic cell homing.

A better understanding of how tumor microenvironments shape immune responses after radiotherapy (RT) is required to improve patient outcomes. This study focuses on the observation that dendritic cells (DCs) infiltrating irradiated cervical tumors are retained in transforming growth factor (TGF)-ß-abundant regions. We report that TGF-ß secretion from cervical cancer cells was increased by irradiation in a dose-dependent manner and that this significantly suppressed the expression of allostimulatory markers and Th1 cytokines in DCs. To investigate further, we blocked the TGF-ß signal in DCs and observed that RT had a dose-dependent immune-promoting effect, improving DC maturation. This suggested that proinflammatory mediators may also be induced by RT, but their effects were being counteracted by the simultaneously increased levels of TGF-ß. Prostaglandin E2 (PGE2), a proinflammatory molecule, was shown to be one such mediator. Adjusting the TGF-ß/PGE2 ratio by inhibiting TGF-ß rebooted RT-induced DC cytoskeletal organization by stimulating myosin light chain (MLC) phosphorylation. Consequently, the homing of intra-tumorally infiltrated DCs to tumor-draining lymph nodes was enhanced, leading to the induction of more robust cytotoxic T cells. Ultimately, rebalancing the TGF-ß/PGE2 ratio amplified the therapeutic effects of RT, resulting in increased intra-tumoral infiltration and activation of CD8+ T cells, and improved tumor control and overall survival rate in mice. DC depletion experiments verified that the improvement in tumor control is directly correlated with the involvement of DCs via the PGE2-MLC pathway. This study emphasizes the importance of maintaining a balanced cytokine environment during RT, particularly hypofractionated RT; and it is advisable to block TGF-ß while preserving PGE2 in the tumor microenvironment in order to better stimulate DC homing and DC -T priming.

Prospects for daily online adaptive radiotherapy for cervical cancer: Auto-contouring evaluation and dosimetric outcomes.

BACKGROUND: Training senior radiation therapists as "adapters" to manage influencers and target editing is critical in daily online adaptive radiotherapy (oART) for cervical cancer. The purpose of this study was to evaluate the accuracy and dosimetric outcomes of automatic contouring and identify the key areas for modification. METHODS: A total of 125 oART fractions from five postoperative cervical cancer patients and 140 oART fractions from five uterine cervical cancer patients treated with daily iCBCT-guided oART were enrolled in this prospective study. The same adaptive treatments were replanned using the Ethos automatic contours workflow without manual contouring edits. The clinical target volume (CTV) was subdivided into several separate regions, and the average surface distance dice (ASD), centroid deviation, dice similarity coefficient (DSC), and 95% Hausdorff distance (95% HD) were used to evaluate contouring for the above portions. Dosimetric results from automatic oART plans were compared to supervised oART plans to evaluate target volumes and organs at risk (OARs) dose changes. RESULTS: Overall, the paired CTV had high overlap rates, with an average DSC value greater than 0.75. The uterus had the largest consistency differences, with ASD, centroid deviation, and 95% HD being 2.67 ± 1.79 mm, 17.17 ± 12 mm, and 10.45 ± 5.68 mm, respectively. The consistency differences of the lower nodal CTVleft and nodal CTVright were relatively large, with ASD, centroid deviation, and 95% HD being 0.59 ± 0.53 mm, 3.6 ± 2.67 mm, and 5.41 ± 4.08 mm, and 0.59 ± 0.51 mm, 3.6 ± 2.54 mm, and 4.7 ± 1.57 mm, respectively. The automatic online-adapted plan met the clinical requirements of dosimetric coverage for the target volume and improved the OAR dosimetry. CONCLUSIONS: The accuracy of automatic contouring from the Ethos adaptive platform is considered clinically acceptable for cervical cancer, and the uterus, upper vaginal cuff, and lower nodal CTV are the areas that need to be focused on in training.

The Impact of Different Simulation Modalities on Target Volume Delineation in Breast-Conserving Radiotherapy.

PURPOSE: In the management of breast-conserving radiotherapy, computed tomography (CT) simulation is now commonly used to identify tumor bed while has difficulties defining precisely. We aimed to evaluate the impact of magnetic resonance (MR) and CT simulation on defining the postoperative tumor bed for breast-conserving radiotherapy in patients without the aid of surgical clips. METHODS: From August 2018 to March 2019, twenty patients with T1-2N0M0 breast cancer at our institution were enrolled. All the patients underwent breast-conserving surgery without implantation of surgical clips and were prepared to receive radiotherapy. CT and MR images were acquired on the same day for each patient. Three radiation oncologists independently assigned cavity visualization score (CVS) and delineated the tumor bed based on first the CT then the MR images. Interobserver variability was assessed by volumes, generalized conformity index (CIgen) and the distance between the centers of mass (dCOM). Differences in mean values for parameters were tested by paired t-test or one-way analysis of variance, as appropriate. RESULTS: First, the mean volumes of tumor bed derived from MR were 22%, 27% and 21% smaller than those based on CT images for each observer. In addition, the mean CIgen was significantly superior, and dCOM was smaller for MR than for CT images (CIgen: 0.59 vs 0.52, P= 0.008; dCOM: 1.30 cm vs 1.39 cm, P= 0.095). Moreover, the mean CVS was 3.23±1.34 and 2.43±0.92 for MR and CT images, respectively (P= 0.035). Last, a positive association was observed between the CVS and CIgen for both modalities (P< 0.01). CONCLUSION: Compared to CT, MR can improve the visualization of changes in the postoperative tumor bed. In addition, MR can yield a more precise definition of the tumor bed and improve the consistency of tumor bed contouring in patients without surgical clips.

Single High-Dose Radiation Enhances Dendritic Cell Homing and T Cell Priming by Promoting Reactive Oxygen Species-Induced Cytoskeletal Reorganization.

PURPOSE: Radiation therapy (RT) affects tumor-infiltrating immune cells, cooperatively driving tumor growth inhibition. However, there is still no absolute consensus on whether the homing ability of dendritic cells (DCs) is affected by direct x-ray irradiation. Most importantly, the underlying mechanisms are poorly understood. METHODS AND MATERIALS: Using noninvasive imaging, we systematically examined the dose effect of RT on the in vivo homing and distribution of bone marrow-derived DCs and elucidated the detailed mechanisms underlying these events. After exposure to 2, 5, 10, 15, and 20 Gy, DCs were analyzed for maturation, in vivo homing ability, and T cell priming. RESULTS: At ranges of 2 to 20 Gy, irradiation did not cause direct cellular apoptosis or necrosis, but it induced mitochondrial damage in DCs independent of dose. In addition, upregulation of CD40, CD80, CD86, CXCR4, and CCR7 were detected on irradiated DCs. Secretion of IL-1ß and IL-12p70 remained unchanged, whereas decreased secretion of IL-6 and promotion of tumor necrosis factor α secretion were observed. In particular, the homing ability of both the local residual and blood circulating DCs to lymphoid tissues was significantly higher in groups that received ≥5 Gy radiation than in the group that received 2 Gy. Furthermore, improved homing ability was associated with rearrangement of the cytoskeleton, which was regulated by reactive oxygen species accumulation through the RhoA/ROCK1 signaling pathway. Finally, more robust T cell activation was observed in mice inoculated with 20 Gy-treated DCs than in those inoculated with 2 Gy-irradiated DCs, and T cell activation also correlated with reactive oxygen species production. CONCLUSIONS: An RT dose ≥5 Gy has distinct advantages over 2 Gy in facilitating DC homing to lymph nodes and cross-priming T cells.

Hypofractionated electron-beam radiation therapy for keloids: retrospective study of 568 cases with 834 lesions.

We aimed to analyze the outcomes of hypofractionated high-energy electron beam radiotherapy for the treatment of keloids. From February 1998 to January 2012, 568 patients with a total of 834 keloids underwent radiotherapy: 826 lesions with postoperative radiotherapy, and 36 with skin-grafting. Lesion size was >5 cm in 335 keloids. An electron-beam of 6 or 7 MeV was used, with a total dose of 18 Gy (two fractions with a 1-week interval) covering the lesion with a 1-cm margin. The time between surgery and radiotherapy was 24-48 h. Skin-grafted patients underwent radiotherapy 10-15 days after the operation. The median follow-up was 40 months (range: 12-160 months). The local control rate was 88.25% (736/834). The relapse rate was 9.59% (80/834), and the time to relapse was 6-28 months (median: 12 months). Univariate analyses showed that gender, age, keloid size, keloid site, skin grafting, and operation-to-irradiation interval influenced the local control rate. Multivariate analysis showed that the relapse rate was correlated with gender (P = 0.048), age (P < 0.01), operation-to-irradiation interval (P < 0.01), keloid site (P < 0.01), surgical method (P = 0.04) and keloid size (P < 0.02). Adverse effects were observed in 9.83% (82/834). No radiation-induced cancers were observed. Hypofractionated high-energy electron beam radiotherapy for keloids yielded excellent outcomes, especially in cases without skin grafting. Early postoperative radiotherapy with limited hypofractionation could be a good choice for keloid treatment.

[An individualized approach combining local flaps with radiotherapy for the treatment of auricle keloid].

OBJECTIVE: To investigate an individualized approach to the treatment of auricle keloid to maintain the normal appearance of external ear and meanwhile reduce the recurrence. METHODS: Different local flaps were performed according to the location of the keloid in our approach. The auricle was divided into different anatomical regions and all the patients received local postoperative radiotherapy. RESULTS: Of 68 patients with auricle keloid received the individualized approach, 3 cases suffered delayed healing due to partial flap necrosis. The remaining patients were followed up for 8-21 months(mean:11.5 months) . Recurrence occurred in one patient(1.47%) . CONCLUSION: The individualized approach combining local flaps with radiotherapy in treating auricle keloid can effectively maintain the normal ear appearance with low recurrence rate.