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Stereotactic body radiotherapy (SBRT) is a treatment option for early-stage lung cancer. The purpose of this study was to investigate the optimal dose distribution and prognostic factors for local control (LC) after SBRT for lung cancer. A total of 104 lung tumors from 100 patients who underwent SBRT using various treatment regimens were analyzed. Dose distributions were corrected to the biologically effective dose (BED). Clinical and dosimetric factors were tested for association with LC after SBRT. The median follow-up time was 23.8 months (range, 3.4–109.8 months) after SBRT. The 1- and 3-year LC rates were 95.7% and 87.7%, respectively. In univariate and multivariate analyses, pathologically confirmed squamous cell carcinoma (SQ), T2 tumor stage, and a Dmax < 125 Gy (BED10) were associated with worse LC. The LC rate was significantly lower in SQ than in non-SQ among tumors that received a Dmax < 125 Gy (BED10) (p = 0.016). However, there were no significant differences in LC rate between SQ and non-SQ among tumors receiving a Dmax ≥ 125 Gy (BED10) (p = 0.198). To conclude, SQ, T2 stage, and a Dmax < 125 Gy (BED10) were associated with poorer LC. LC may be improved by a higher Dmax of the planning target volume.

Introduction: Radiation Therapy Oncology Group (RTOG) report #0813 and 0915 recommends using D2cmand R50%as plan quality metrics for evaluation of normal tissue sparing in stereotactic body radiation therapy (SBRT) of lung lesion. This study introduces dose falloff gradient (DFG) as a tool for analyzing the dose beyond the planning target volume (PTV) extending into normal tissue structures. In ascertaining the impact of PTV size and SBRT planning techniques in DFG, this study questions the independence of the RTOG recommended metrics. Materials and Methods: In this retrospective study, 41 RapidArc lung SBRT plans with 2 or 3 complete or partial arcs were analyzed. PTV volumes ranged between 5.3 and 113 cm3 and their geographic locations were distributed in both lungs. 6MV, 6 MV-FFF, 10 MV, or 10 MV-FFF energies were used. RTOG-0915 metrics conformity index, homogeneity index, D2cm, R50%, and HDlocwere evaluated. DFG was computed from the mean and maximum dose in seven concentric 5 mm wide rings outside the PTV. DFG was investigated against the volume of normal lung irradiated by 50% isodose volume. Treatment plans with alternate energy and couch rotations were generated. Results: The dose falloff beyond PTV was modeled using a double exponential fit and evaluated for relationship with intermediate lung dose. Photon energy and beam configuration had a minimal impact on the dose falloff outside. The product of normalized D2cmand R50%was estimated to have a slowly varying value. Conclusions: Dose falloff outside PTV has been studied as a function of radial distance and ascertained by intermediate dose to normal lung. DFG can serve as a complementary plan quality metric.

To determine the therapeutic efficacy and safety of risk‐adapted stereotactic body radiation therapy (SBRT) schedules for patients with early‐stage central and ultra‐central inoperable non‐small cell lung cancer. From 2006 to 2015, 80 inoperable T1‐2N0M0 NSCLC patients were treated with two median dose levels: 60 Gy in six fractions (range, 48‐60 Gy in 4‐8 fractions) prescribed to the 74% isodose line (range, 58%‐79%) for central lesions (ie within 2 cm of, but not abutting, the proximal bronchial tree; n = 43), and 56 Gy in seven fractions (range, 48‐60 Gy in 5‐10 fractions) prescribed to the 74% isodose line (range, 60%‐80%) for ultra‐central lesions (ie abutting the proximal bronchial tree; n = 37) on consecutive days. Primary endpoint was overall survival (OS); secondary endpoints included progression‐free survival (PFS), tumor local control rate (LC), and toxicity. Median OS and PFS were 64.47 and 32.10 months (respectively) for ultra‐central patients, and not reached for central patients. Median time to local failure, regional failure, and any distant failures for central versus ultra‐central lesions were: 27.37 versus 26.07 months, 20.90 versus 12.53 months, and 20.85 versus 15.53 months, respectively, all P < .05. Multivariate analyses showed that tumor categorization (ultra‐central) and planning target volume ≥52.76 mL were poor prognostic factors of OS, PFS, and LC, respectively (all P < .05). There was one grade 5 toxicity; all other toxicities were grade 1‐2. Our results showed that ultra‐central tumors have a poor OS, PFS, and LC compared with central patients because of the use of risk‐adapted SBRT schedules that allow for equal and favorable toxicity profiles. There is great interest in defining risk‐adapted dose‐fractionation schedules for “ultra‐central” and “central” early‐stage NSCLC. Our results showed that compared with central lesions, ultra‐central tumors have worse OS, PFS, and LC following risk‐adapted SBRT dose‐fractionation regimens. Toxicity profiles of the two groups are similar, with almost no patients having grade 3 or higher toxicity.

With the widespread implementation of lung cancer screening, more and more patients are being diagnosed with multiple primary lung cancers (MPLCs). In the era of precision medicine, many controversies remain in differentiating MPLCs from intrapulmonary metastasis and the optimum treatment choice, especially in patients exhibiting similar histology. In this review, we summarize common diagnostic criteria and novel discrimination methods with a special emphasis on the emerging value of broad panel next-generation sequencing (NGS) for the diagnosis of MPLCs. We then discuss current advances regarding therapeutic approaches for MPLCs. Radical surgery is the main treatment modality, while stereotactic body radiotherapy (SBRT) is safe and feasible for early-stage MPLC patients with inoperable tumors. In addition, immunotherapy and targeted therapy, particularly epidermal growth factor receptor-tyrosine kinase inhibitors, are emerging therapeutic strategies that are still in their infancy. Characteristics of both genomic profiles and tumor microenvironment are currently being evaluated but warrant further exploration to facilitate the application of targeted systematic therapies in MPLC patients.

Background The internal target volume (ITV) approach and the mid-ventilation (MidV) concept are the two main respiratory motion-management strategies under free breathing. The purpose of this work was to compare the actual in-treatment target coverage during volumetric modulated arctherapy (VMAT) delivered through both ITV-based and MidV-based planning target volume (PTV) and to provide knowledge in choosing the optimal PTV for stereotactic body radiotherapy (SBRT) for lung lesions. Methods and materials Thirty-two lung cancer patients treated by a VMAT technique were included in the study. For each fraction, the mean time-weighted position of the target was localized by using a 4-dimensional cone-beam CT (4D-CBCT)-based image guidance procedure. The respiratory-correlated location of the gross tumor volume (GTV) during treatment delivery was determined for each fraction by using in-treatment 4D-CBCT images acquired concurrently with VMAT delivery (4D-CBCT in-treat ). The GTV was delineated from each of the ten respiratory phase-sorted 4D-CBCT in-treat datasets for each fraction. We defined target coverage as the average percentage of the GTV included within the PTV during the patient’s breathing cycle averaged over the treatment course. Target coverage and PTVs were reported for a MidV-based PTV (PTV MidV ) using dose-probabilistic margins and three ITV-based PTVs using isotropic margins of 5 mm (PTV ITV + 5mm ), 4 mm (PTV ITV + 4mm ) and 3 mm (PTV ITV + 3mm ). The in-treatment baseline displacements and target motion amplitudes were reported to evaluate the impact of both parameters on target coverage. Results Overall, 100 4D-CBCT in-treat images were analyzed. The mean target coverage was 98.6, 99.6, 98.9 and 97.2% for PTV MidV , PTV ITV + 5mm , PTV ITV + 4mm and PTV ITV + 3mm , respectively. All the PTV margins led to a target coverage per treatment higher than 95% in at least 90% of the evaluated cases. Compared to PTV ITV + 5mm , PTV MidV , PTV ITV + 4mm and PTV ITV + 3mm had mean PTV reductions of 16, 19 and 33%, respectively. Conclusion When implementing VMAT with 4D-CBCT-based image guidance, an ITV-based approach with a tighter margin than the commonly used 5 mm margin remains an alternative to the MidV-based approach for reducing healthy tissue exposure in lung SBRT. Compared to PTV MidV , PTV ITV + 3mm significantly reduced the PTV while still maintaining an adequate in-treatment target coverage.

Stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) leads to recurrence in approximately 18% of patients. We aimed to extract the radiomic features, with which we predicted clinical outcomes and to establish predictive models. Patients with primary non-metastatic NSCLC who were treated with SBRT between 2002 and 2022 were retrospectively reviewed. The 358 primary tumors were randomly divided into a training cohort of 250 tumors and a validation cohort of 108 tumors. Clinical features and 744 radiomic features derived from primary tumor delineation on pre-treatment computed tomography were examined as prognostic factors of survival outcomes by univariate and multivariate analyses in the training cohort. Predictive models of survival outcomes were established from the results of the multivariate analysis in the training cohort. The selected radiomic features and prediction models were tested in a validation cohort. We found that one radiomic feature showed a significant difference in overall survival (OS) in the validation cohort (p = 0.044) and one predicting model could estimate OS time (mean: 37.8 months) similar to the real OS time (33.7 months). In this study, we identified one radiomic factor and one prediction model that can be widely used.

Background Since the introduction of tumor tracking in radiotherapy, it is possible to ensure a precise irradiation of moving targets. To follow the tumor movement, most systems rely on the detection of implanted markers and correlation models between the internal and external patient movement. This study reports the clinical workflow and first results of the dynamic tumor tracking (DTT) performance for patients with liver carcinoma at the Vero SBRT system of the University Hospital Erlangen regarding the detection of the internal marker and the changes of the determined correlation models. Methods So far 13 liver patients were treated with DTT. For each patient, two fiducial markers (FM), which are monitored with X-rays during treatment, were implanted in the vicinity of the tumor. All patients received a fraction dose of 4–6 Gy with 8 to 12 fractions. Treatment and patient data is evaluated by processing the acquired log-files of the DTT treatment. Based on this, the marker detection and the changes of the correlation model between the internal and external movement is investigated. Results The median treatment time was 19:42 min. During treatment a median of 173 X-ray stereoscopic images were acquired. The marker detection was successful in 64.6% of the images. The FM detection is independent of the relative angle between the marker and the imager, but shows a dependency on the average intensity surrounding the FM position within the kV images. The number of correlation models needed during treatment increases in the presence of baseline shifts. The comparison of the correlation models shows large differences in the internal-external correlation between the different models acquired for one patient. Conclusion Thirteen liver patients were treated with DTT at the Vero SBRT system and the marker detection was analyzed. Furthermore, the importance of regularly monitoring the internal target motion could be shown, since the correlation between the internal and external motion changes considerably over the course of the treatment.

Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1), programmed cell death ligand-1 (PD-L1), and others have shown potent clinical efficacy and have revolutionized the treatment protocols of a broad spectrum of tumor types, especially non–small-cell lung cancer (NSCLC). Despite the substantial optimism of treatment with PD-1/PD-L1 inhibitors, there is still a large proportion of patients with advanced NSCLC who are resistant to the inhibitors. Preclinical and clinical trials have demonstrated that radiotherapy can induce a systemic antitumor immune response and have a great potential to sensitize refractory “cold” tumors to immunotherapy. Stereotactic body radiation therapy (SBRT), as a novel radiotherapy modality that delivers higher doses to smaller target lesions, has shown favorable antitumor effects with significantly improved local and distant control as well as better survival benefits in various solid tumors. Notably, research has revealed that SBRT is superior to conventional radiotherapy, possibly because of its more powerful immune activation effects. Thus, PD-1/PD-L1 inhibitors combined with SBRT instead of conventional radiotherapy might be more promising to fight against NSCLC, further achieving more favorable survival outcomes. In this review, we focus on the underlying mechanisms and recent advances of SBRT combined with PD-1/PD-L1 inhibitors with an emphasis on some future challenges and directions that warrant further investigation.

Hepatocellular carcinoma is the fourth leading cause of cancer-related death worldwide. Depending on the extent of disease and competing comorbidities for mortality, multiple liver-directed therapy options exist for the treatment of hepatocellular carcinoma. Advancements in radiation oncology have led to the emergence of stereotactic body radiation therapy as a promising liver-directed therapy, which delivers high doses of radiation with a steep dose gradient to maximize local tumor control and minimize radiation-induced treatment toxicity. In this study, we review the current clinical data as well as the unresolved issues and controversies regarding stereotactic body radiation therapy for hepatocellular carcinoma: (1) Is there a radiation dose–response relationship with hepatocellular carcinoma? (2) What are the optimal dosimetric predictors of radiation-induced liver disease, and do they differ for patients with varying liver function? (3) How do we assess treatment response on imaging? (4) How does stereotactic body radiation therapy compare to other liver-directed therapy modalities, including proton beam therapy? Based on the current literature discussed, this review highlights future possible research and clinical directions.

Increasing evidence demonstrates that radiation acts as an immune stimulus, recruiting immune mediators that enable anti-tumor responses within and outside the radiation field. There has been a rapid expansion in the number of clinical trials harnessing radiation to enhance antitumor immunity. If positive, results of these trials will lead to a paradigm shift in the use of radiotherapy. In this review, we discuss the rationale for trials combining radiation with various immunotherapies, provide an update of recent clinical trial results and highlight trials currently in progress. We also address issues pertaining to the optimal incorporation of immunotherapy with radiation, including sequencing of treatment, radiation dosing and evaluation of clinical trial endpoints.