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Hypoxia in solid tumors is an important predictor of treatment resistance and poor clinical outcome. The significance of hypoxia in the development of resistance to radiotherapy has been recognized for decades and the search for hypoxia-targeting, radiosensitizing agents continues. This review summarizes the main hypoxia-related processes relevant for radiotherapy on the subcellular, cellular and tissue level and discusses the significance of hypoxia in radiation oncology, especially with regard to the current shift towards hypofractionated treatment regimens. Furthermore, we discuss the strategies to interfere with hypoxia for radiotherapy optimization, and we highlight novel insights into the molecular pathways involved in hypoxia that might be utilized to increase the efficacy of radiotherapy.

Background: Several immunotherapy (IT) agents are FDA approved for treatment of melanoma and non-small-cell lung cancer (NSCLC). The addition of stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT) to immunotherapy looks promising. A systematic review was conducted to evaluate the possible synergistic effects of immune checkpoints inhibitors (ICIs) and stereotactic radiation therapy in melanoma and NSCLC. Materials and methods: Pubmed databases from January 2010 to December 2020 were reviewed to identify English language studies reporting control of local and abscopal effect of the combination of ICI-SBRT/SRS in metastatic NSCLC and melanoma cancer. The inclusion criteria were followed according to PICO criteria. Results: Thirty-nine articles were included of the 2141 initial results. The reported rates for local control were 16.5–100% and 40–94% in brain and extracerebral metastases, respectively. Distant/abscopal response rates were 1–45% in extracerebral metastases. Abscopal effect could not be evaluated in brain metastases because it was not reported in studies. Treatments were well tolerated with few grade 4 toxicities and no grade 5. Conclusions: The combined treatment of ICI-SBRT/SRS achieves high local control and non-negligible abscopal response in patients with extracerebral metastases, with its benefit in cerebral metastases being more controversial. Clinical trials are needed to better characterize the potential synergism.

Background Stereotactic body radiotherapy (SBRT) is an emerging treatment option for liver metastases in patients unsuitable for surgery. We investigated factors associated with clinical outcomes for liver metastases treated with SBRT from a multi-center, international patient registry. Methods Patients with liver metastases treated with SBRT were identified in the RSSearch® Patient Registry. Patient, tumor and treatment characteristics associated with treatment outcomes were assessed. Dose fractionations were normalized to BED 10 . Overall survival (OS) and local control (LC) were evaluated using Kaplan Meier analysis and log-rank test. Results The study included 427 patients with 568 liver metastases from 25 academic and community-based centers. Median age was 67 years (31–91 years). Colorectal adenocarcinoma (CRC) was the most common primary cancer. 73% of patients received prior chemotherapy. Median tumor volume was 40 cm 3 (1.6–877 cm 3 ), median SBRT dose was 45 Gy (12–60 Gy) delivered in a median of 3 fractions [ 1 , 2 , 3 , 4 – 5 ]. At a median follow-up of 14 months (1–91 months) the median overall survival (OS) was 22 months. Median OS was greater for patients with CRC (27 mo), breast (21 mo) and gynecological (25 mo) metastases compared to lung (10 mo), other gastro-intestinal (GI) (18 mo) and pancreatic (6 mo) primaries ( p  < 0.0001). Smaller tumor volumes (< 40 cm 3 ) correlated with improved OS (25 months vs 15 months p  = 0.0014). BED 10  ≥ 100 Gy was also associated with improved OS (27 months vs 15 months p < 0.0001). Local control (LC) was evaluable in 430 liver metastases from 324 patients. Two-year LC rates was better for BED 10  ≥ 100 Gy (77.2% vs 59.6%) and the median LC was better for tumors < 40 cm 3 (52 vs 39 months). There was no difference in LC based on histology of the primary tumor. Conclusions In a large, multi-institutional series of patients with liver metastasis treated with SBRT, reasonable LC and OS was observed. OS and LC depended on dose and tumor volume, while OS varied by primary tumor. Future prospective trials on the role of SBRT for liver metastasis from different primaries in the setting of multidisciplinary management including systemic therapy, is warranted. Trial registration Clinicaltrials.gov: NCT01885299 .

In this commentary, we describe the potential of highly ablative doses utilizing Stereotactic Body Radiation Therapy (SBRT) in single or few fractions to enhance immune-responsiveness, how timing of this approach in combination with immune-checkpoint inhibitors may augment treatment-effect, and whether Personalized Ultrafractionated Stereotactic Adaptive Radiation Therapy (PULSAR) is an avenue for future advancement in the continued endeavor to foster a systemic effect of therapy beyond the radiation treatment field. The ablative potential of SBRT may support an increase in tumor-antigen presentation, enhancement of immune-stimulatory components, and an improvement in tumor-microenvironment immune cell infiltration. Furthermore, the latest advancement of ablative radiation delivery is PULSAR-based therapy, whereby ablative doses are delivered in pulses of treatment that may be several weeks apart, combined with adaptive treatment to tumor changes across time. The benefits of this novel approach include the ability to optimize direct tumor control by assessment of tumor size and location via dedicated imaging acquired prior to each delivered pulse, and further potentiation of immune recognition through combination with concurrent immune-checkpoint blockade.

Abstract BACKGROUND Vertebral compression fracture (VCF) is a challenging and not infrequent complication observed following spine stereotactic body radiation therapy (SBRT). OBJECTIVE To summarize the data from the multiple studies that have been published, addressing the risk and predictive factors for VCF post-SBRT. METHODS A systematic literature review was conducted. Studies were selected if they specifically addressed risk factors for post-SBRT VCF in their analyses. RESULTS A total of 11 studies were identified, reporting both the risk of VCF post-SBRT and an analysis of risk factors based on univariate and multivariate analysis. A total of 2911 spinal segments were treated with a crude VCF rate of 13.9%. The most frequently identified risk factors on multivariate analysis were: lytic disease (hazard ratio [HR] range, 2.76-12.2), baseline VCF prior to SBRT (HR range, 1.69-9.25), higher dose per fraction SBRT (HR range, 5.03-6.82), spinal deformity (HR range, 2.99-11.1), older age (HR range, 2.15-5.67), and more than 40% to 50% of vertebral body involved by tumor (HR range, 3.9-4.46). In the 9 studies that specifically reported on the use of post-SBRT surgical procedures, 37% of VCF had undergone an intervention (range, 11%-60%). CONCLUSION VCF is an important adverse effect following SBRT. Risk factors have been identified to guide the selection of high-risk patients. Evidence-based algorithms with respect to patient selection and intervention are needed.

Stereotactic radiotherapy with its forms of intracranial stereotactic radiosurgery (SRS), intracranial fractionated stereotactic radiotherapy (FSRT) and stereotactic body radiotherapy (SBRT) is today a guideline-recommended treatment for malignant or benign tumors as well as neurological or vascular functional disorders. The working groups for radiosurgery and stereotactic radiotherapy of the German Society for Radiation Oncology (DEGRO) and for physics and technology in stereotactic radiotherapy of the German Society for Medical Physics (DGMP) have established a consensus statement about the definition and minimal quality requirements for stereotactic radiotherapy to achieve best clinical outcome and treatment quality in the implementation into routine clinical practice.

PurposeSBRT demonstrated to increase survival in oligometastatic patients. Nevertheless, little is known regarding the natural history of oligometastatic disease (OMD) and how SBRT may impact the transition to the polymetastatic disease (PMD).Methods97 liver metastases in 61 oligometastatic patients were treated with SBRT. Twenty patients (33%) had synchronous oligometastases, 41 (67%) presented with metachronous oligometastases. Median number of treated metastases was 2 (range 1–5).ResultsMedian follow-up was 24 months. Median tPMC was 11 months (range 4–17 months). Median overall survival (OS) was 23 months (range 16–29 months). Cancer-specific survival predictive factors were having further OMD after SBRT (21 months versus 15 months; p = 0.00), and local control of treated metastases (27 months versus 18 months; p = 0.031). Median PFS was 7 months (range 4–12 months). Patients with 1 metastasis had longer median PFS as compared to those with 2–3 and 4–5 metastases (14.7 months versus 5.3 months versus 6.5 months; p = 0.041). At the last follow-up, 50/61 patients (82%) progressed, 16 of which (26.6%) again as oligometastatic and 34 (56%) as polymetastatic.ConclusionIn the setting of oligometastatic disease, SBRT is able to delay the transition to the PMD. A proportion of patients relapse as oligometastatic and can be eventually evaluated for a further SBRT course. Interestingly, those patients retain a survival benefit as compared to those who had PMD. Further studies are needed to explore the role of SBRT in OMD and to identify treatment strategies able to maintain the oligometastatic state.

Owing to the complex anatomical structure and biomechanics, the current standard palliative treatments for cervical spinal metastases are associated with a high risk of recurrence and complications. Stereotactic body radiotherapy (SBRT) can provide radical dose to tumors while protecting normal organs to the maximum extent. However, the efficacy and safety of SBRT for cervical spinal metastases is not well characterized. Data from 71 patients with cervical spine metastases who were treated with SBRT using CyberKnife between 2006 and 2021 were obtained from our prospectively maintained database. Primary endpoint was pain response at 12 weeks following SBRT completion; secondary endpoints included local control (LC), overall survival (OS), and adverse events. Standard‐risk patients were planned to receive 30 Gy (range 21–36) with median fractions of 3 (range 1–3) and high‐risk patients 35 Gy (range 24–50) with median fractions of 5 (range 4–5) according to the spinal cord and esophagus dose constraints. The median follow‐up time was 17.07 months (range 3.1–118.9). After 12 weeks of SBRT completion, 54 (98.2%) of 55 patients with baseline pain achieved pain response and 46 (83.6%) achieved complete pain response. LC rates were 93.1% and 90% at 1 year and 2 year, respectively. The 1‐year and 2‐year OS rates were 66.2% and 37.4%, respectively. Eight patients experienced grades 1–4 adverse events (six vertebral compression fracture [VCF], five of them had VCF before SBRT; and two hemiparesis). No grade 5 adverse events were observed. Therefore, risk‐adapted SBRT for cervical spine metastases achieved high pain control and LC rates with acceptable adverse events. Risk‐adapted SBRT for cervical spine metastases achieved high pain control and LC rates with acceptable adverse events. No grade 5 adverse events were observed. Importantly, these results were comparable regardless of spinal cord involvement.

Purpose The InTempo adaptive imaging system is an important component of the Accuray CyberKnife System, designed to enhance the system's ability to track and correct tumor motion during treatment. However, a limitation of this feature is the reduction of available nodes for treatment planning. The impact of a reduced number of nodes on the quality of InTempo‐based treatment plans has not previously been evaluated. This retrospective study aims to compare the dosimetry of CyberKnife plans with and without The InTempo path set for both prostate and lung stereotactic body radiotherapy (SBRT). Methods This study included twelve consecutive prostate SBRT patients and twenty selected lung SBRT patients. The selection criteria for the 20 lung patients were motivated by being able to construct a data set representative of common treatment tracking methods and dose prescriptions. To evaluate the impact of InTempo imaging, treatment plans were re‐optimized using the same optimization parameters and machine settings, except for the path set with the maximum number of nodes. To ensure a fair comparison, the study plans were prescribed using identical planning target volume coverage as the clinical treatment plans. Statistical analyses were performed using mean and standard deviation, dose metric plots, and a two‐sided Wilcoxon signed rank test with multiple testing correction to compare dose metrics between different path sets. Results No statistically significant differences were observed among the Prostate, Prostate_(S)hort, and their corresponding InTempo path sets in at least 8 of the 14 evaluated plan metrics, including prostate clinical tumor volume (CTV) V40Gy(%), conformity index, and homogeneity index. For example, the mean prostate CTV V40Gy (%) for the Prostate, Prostate_(S)hort, and their corresponding InTempo path sets was 90.8 ± 4.7, 89.4 ± 4.7, 90.2 ± 3.9, 91.0 ± 7.0, respectively. However, compared with the Prostate path set, the Prostate_(I)nTempo path set exhibited a statistically significant reduction in delivery time (p = 0.0010), number of beams, and bladder V18Gy (%), along with a statistically significant increase in the number of imaging beams (p = 0.0010). Additionally, Prostate_(S)hort demonstrated statistically significant reductions in delivery time and number of beams compared with the Prostate path set, while the number of imaging beams remained statistically equivalent. In contrast, the Reduced_(P)rostate and Reduced_(P)rostate_(I)nTempo sets consistently resulted in inferior dosimetric outcomes, with several plans deemed unoptimizable due to insufficient node availability. For lung SBRT, statistically significant differences were observed in delivery time and the number of imaging beams between plans with and without InTempo. However, no statistical differences were found in dose distribution metrics between these two lung groups. Conclusions InTempo‐compatible path sets do not significantly compromise plan quality for prostate or lung SBRT, provided adequate node availability. Specifically, the Prostate_(I)nTempo and Prostate_(S)hort path sets demonstrated a reduction in delivery time and an increase in adaptive imaging frequency compared with the Prostate path set. However, the Reduced_(P)rostate and Reduced_(P)rostate_(I)nTempo result in inferior plan quality and reduced deliverability and should be used with caution. These findings support the selective use of InTempo imaging in SBRT planning without sacrificing dosimetric integrity.

Abstract BACKGROUND Spine surgery is indicated for select patients with mechanical instability, pain, and/or malignant epidural spinal cord compression, with or without neurological compromise. Stereotactic body radiotherapy (SBRT) is an option for durable local control (LC) for metastatic spine disease. OBJECTIVE To determine factors associated with LC and progression-free survival (PFS) for patients receiving postoperative stereotactic spine radiosurgery. METHODS We analyzed consecutive patients from 2013 to 2019 treated with surgical intervention followed by SBRT. Surgical interventions included laminectomy and vertebrectomy. SBRT included patients treated with 1 to 5 fractions of radiosurgery. We analyzed LC, PFS, overall survival (OS), and toxicity. Univariate and multivariate analyses were performed. RESULTS A total of 63 patients were treated with a median follow-up of 12.5 mo. Approximately 75% of patients underwent vertebrectomy and 25% underwent laminectomy. One-year cumulative incidence of local failure was 19%. LC was significantly improved for patients receiving radiosurgery ≤40 d from surgery compared to that for patients receiving radiosurgery ≥40 d from surgery, 94% vs 75%, respectively, at 1 yr (P = .03). Patients who received preoperative embolization had improved LC with 1-yr LC of 88% vs 76% for those who did not receive preoperative embolization (P = .037). Significant predictors for LC on multivariate analysis were time from surgery to radiosurgery, higher radiotherapy dose, and preoperative embolization. The 1-yr PFS and OS was 56% and 60%, respectively. CONCLUSION Postoperative radiosurgery has excellent and durable LC for spine metastasis. An important consideration when planning postoperative radiosurgery is minimizing delay from surgery to radiosurgery. Preoperative embolization and higher radiotherapy dose were associated with improved LC warranting further study. Graphical Abstract Graphical Abstract