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Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy.

ABSTRACT: Cancer clinics currently use high-dose stereotactic body radiation therapy as a curative treatment for several kinds of cancers. However, the contribution of vascular endothelial cells to tumor response to radiation remains controversial. Using dual recombinase technology, we generated primary sarcomas in mice with targeted genetic mutations specifically in tumor cells or endothelial cells. We selectively mutated the proapoptotic gene Bax or the DNA damage response gene Atm to genetically manipulate the radiosensitivity of endothelial cells in primary soft tissue sarcomas. Bax deletion from endothelial cells did not affect radiation-induced cell death in tumor endothelial cells or sarcoma response to radiation therapy. Although Atm deletion increased endothelial cell death after radiation therapy, deletion of Atm from endothelial cells failed to enhance sarcoma eradication. In contrast, deletion of Atm from tumor cells increased sarcoma eradication by radiation therapy. These results demonstrate that tumor cells, rather than endothelial cells, are critical targets that regulate sarcoma eradication by radiation therapy. Treatment with BEZ235, a small-molecule protein kinase inhibitor, radiosensitized primary sarcomas more than the heart. These results suggest that inhibiting ATM kinase during radiation therapy is a viable strategy for radiosensitization of some tumors.

SUBMITTER: Moding EJ

PROVIDER: S-EPMC4360135 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy.

Moding Everett J EJ Castle Katherine D KD Perez Bradford A BA Oh Patrick P Min Hooney D HD Norris Hannah H Ma Yan Y Cardona Diana M DM Lee Chang-Lung CL Kirsch David G DG

Science translational medicine 20150301 278

Cancer clinics currently use high-dose stereotactic body radiation therapy as a curative treatment for several kinds of cancers. However, the contribution of vascular endothelial cells to tumor response to radiation remains controversial. Using dual recombinase technology, we generated primary sarcomas in mice with targeted genetic mutations specifically in tumor cells or endothelial cells. We selectively mutated the proapoptotic gene Bax or the DNA damage response gene Atm to genetically manipu ...[more]

PMID: 25761890

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Project description:BackgroundPrimary cardiac tumors are an extremely rare disease with limited prognosis. The treatment of choice is surgery. Other treatment options include chemotherapy and radiation therapy, which historically represented a palliative approach in patients who were not eligible for surgery. The development of hybrid MR-guided radiation therapy makes it possible to better visualize cardiac lesions and to apply high doses per fraction in sensible organs such as the heart.Case presentationPatients affected by inoperable primary cardiac sarcomas and treated at two different institutions were considered for this analysis and retrospectively analyzed. All patients were treated using a 0.35 T hybrid MR Linac system (MRIdian, ViewRay Inc., Mountain View, CA). In the present study we investigated the feasibility, early outcome and toxicity of MR-guided RT in primary cardiac sarcomas. Four consecutive non-metastasized patients who were treated between 05-09/2020 were analyzed. The cardiac sarcomas were mostly located in the right atrium (50%) and one patient presented with 3 epicardial lesions. All patients received MRgRT as a salvage treatment for recurrent cardiac sarcoma after initial surgery, after a mean interval of 12 months (range 1-29 months). Regarding the treatment characteristics, the mean GTV size was 22.9 cc (range 2.5-56.9 cc) and patients were treated with a mean GTV dose of 38.9 Gy (range 30.1-41.1 Gy) in 5 fractions. Regarding feasibility, all treatments were completed as planned and all patients tolerated the treatment very well and showed only mild grade 1 or 2 symptoms like fatigue, dyspnea or mild chest pain at early follow-up.ConclusionTo the best of our knowledge, in this retrospective analysis we present the first and largest series of patients presenting with primary cardiac sarcomas treated with online adaptive MRgRT. However, further studies are needed to evaluate the impact of this new methodology on the outcome of this very rare disease.

Project description:AimTo investigate the efficacy and safety of stereotactic body radiotherapy (SBRT) targeting the primary tumor for liver-only oligometastatic pancreatic cancer.MethodsWe compared the efficacy and safety of SBRT plus chemotherapy with chemotherapy alone in patients with liver-only oligometastatic pancreatic cancer. The populations were balanced by propensity score-weighted and propensity score-matched analyses based on baseline variables. The primary outcome was overall survival (OS). The secondary outcomes included progression free survival (PFS), local progression, metastatic progression and symptomatic local control.ResultsThis is a retrospective study of 89 pancreatic cancer patients with liver-only oligometastasis. Overall, 34 (38.2%) and 55 (61.8%) patients received SBRT plus chemotherapy and chemotherapy alone, respectively. After propensity score matching, 1-year OS rate was 34.0% (95%CI, 17.8-65.1%) in the SBRT plus chemotherapy group and 16.5% (95%CI, 5.9-46.1%) in chemotherapy alone group (P=0.115). The 6-month PFS rate was 29.4% (95%CI, 15.4-56.1) in SBRT plus chemotherapy and 20.6% (95%CI, 8.8-48.6) in chemotherapy alone group (P=0.468), respectively. Further subgroup analysis indicated that the addition of SBRT improved OS in patients with primary tumor located in the head of pancreas (stratified HR, 0.28; 95% CI, 0.09 to 0.90) or good performance status (stratified HR, 0.24; 95% CI, 0.07 to 0.86). In terms of disease control, SBRT delayed local progression of pancreas (P=0.008), but not distant metastatic progression (P=0.56). Besides, SBRT offered significant abdominal/back pain relief (P=0.016) with acceptable toxicities.ConclusionsThe addition of SBRT to chemotherapy in patients with liver-only oligometastatic pancreatic cancer improves the OS of those with primary tumor located in the head of pancreas or good performance status. In addition, it is a safe and effective method for local progression control and local symptomatic palliation in patients with metastatic pancreatic cancer.

Project description:IntroductionThe recent results from the Nordic-HILUS study indicate stereotactic body radiation therapy (SBRT) is associated with high-grade toxicity for ultracentral (UC) tumors. We hypothesized that magnetic resonance-guided SBRT (MRgSBRT) or hypofractionated radiation therapy (MRgHRT) enables the safe delivery of high-dose radiation to central and UC lung lesions.MethodsPatients with UC or central lesions were treated with MRgSBRT/MRgHRT with real-time gating or adaptation. Central lesions were defined as per the Radiation Therapy Oncology Group and UC as per the HILUS study definitions: (1) group A or tumors less than 1 cm from the trachea and/or mainstem bronchi; or (2) group B or tumors less than 1 cm from the lobar bronchi. The Kaplan-Meier estimate and log-rank test were used to estimate survival. Associations between toxicities and other patient factors were tested using the Mann-Whitney U test and Fisher's exact test.ResultsA total of 47 patients were included with a median follow-up of 22.9 months (95% confidence interval: 16.4-29.4). Most (53%) had metastatic disease. All patients had central lesions and 55.3% (n = 26) had UC group A. The median distance from the proximal bronchial tree was 6.0 mm (range: 0.0-19.0 mm). The median biologically equivalent dose (α/β = 10) was 105 Gy (range: 75-151.2). The most common radiation schedule was 60 Gy in eight fractions (40.4%). Most (55%) had previous systemic therapy, 32% had immunotherapy and 23.4% had previous thoracic radiation therapy. There were 16 patients who underwent daily adaptation. The 1-year overall survival was 82% (median = not reached), local control 87% (median = not reached), and progression-free survival 54% (median = 15.1 mo, 95% confidence interval: 5.1-25.1). Acute toxicity included grade 1 (26%) and grade 2 (21%) with only two patients experiencing grade 3 (4.3%) in the long term. No grade 4 or 5 toxicities were seen.ConclusionsPrevious studies noted high rates of toxicity after SBRT to central and UC lung lesions, with reports of grade 5 toxicities. In our cohort, the use of MRgSBRT/MRgHRT with high biologically effective doses was well tolerated, with two grade 3 toxicities and no grade 4/5.

Project description:PURPOSE:Analyze inter-fraction volumetric changes of lung tumors treated with stereotactic body radiation therapy (SBRT) and determine if the volume changes during treatment can be predicted and thus considered in treatment planning. METHODS AND MATERIALS:Kilo-voltage cone-beam CT (kV-CBCT) images obtained immediately prior to each fraction were used to monitor inter-fraction volumetric changes of 15 consecutive patients (18 lung nodules) treated with lung SBRT at our institution (45-54 Gy in 3-5 fractions) in the year of 2011-2012. Spearman's (?) correlation and Spearman's partial correlation analysis was performed with respect to patient/tumor and treatment characteristics. Multiple hypothesis correction was performed using False Discovery Rate (FDR) and q-values were reported. RESULTS:All tumors studied experienced volume change during treatment. Tumor increased in volume by an average of 15% and regressed by an average of 11%. The overall volume increase during treatment is contained within the planning target volume (PTV) for all tumors. Larger tumors increased in volume more than smaller tumors during treatment (q = 0.0029). The volume increase on CBCT was correlated to the treatment planning gross target volume (GTV) as well as internal target volumes (ITV) (q = 0.0085 and q = 0.0039 respectively) and could be predicted for tumors with a GTV less than 22 mL. The volume increase was correlated to the integral dose (ID) in the ITV at every fraction (q = 0.0049). The peak inter-fraction volume occurred at an earlier fraction in younger patients (q = 0.0122). CONCLUSIONS:We introduced a new analysis method to follow inter-fraction tumor volume changes and determined that the observed changes during lung SBRT treatment are correlated to the initial tumor volume, integral dose (ID), and patient age. Furthermore, the volume increase during treatment of tumors less than 22mL can be predicted during treatment planning. The volume increase remained significantly less than the overall PTV expansion, and radiation re-planning was therefore not required for the purpose of tumor control. The presence of the studied correlations suggests that the observed volumetric changes may reflect some underlying biologic process rather than random fluctuations.

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Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy.

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Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy.

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