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Tumor physiological changes during hypofractionated stereotactic body radiation therapy assessed using multi-parametric magnetic resonance imaging.

ABSTRACT: Radiation therapy is a primary treatment for non-resectable lung cancer and hypoxia is thought to influence tumor response. Hypoxia is expected to be particularly relevant to the evolving new radiation treatment scheme of hypofractionated stereotactic body radiation therapy (SBRT). As such, we sought to develop non-invasive tools to assess tumor pathophysiology and response to irradiation. We applied blood oxygen level dependent (BOLD) and tissue oxygen level dependent (TOLD) MRI, together with dynamic contrast enhanced (DCE) MRI to explore the longitudinal effects of SBRT on tumor oxygenation and vascular perfusion using A549 human lung cancer xenografts in a subcutaneous rat model. Intra-tumor heterogeneity was seen on multi-parametric maps, especially in BOLD, T2* and DCE. At baseline, most tumors showed a positive BOLD signal response (%ΔSI) and increased T2* in response to oxygen breathing challenge, indicating increased vascular oxygenation. Control tumors showed similar response 24 hours and 1 week later. Twenty-four hours after a single dose of 12 Gy, the irradiated tumors showed a significantly decreased T2* (-2.9±4.2 ms) and further decrease was observed (-4.0±6.0 ms) after 1 week, suggesting impaired vascular oxygenation. DCE revealed tumor heterogeneity, but showed minimal changes following irradiation. Rats were cured of the primary tumors by 3x12 Gy, providing long term survival, though with ultimate metastatic recurrence.

SUBMITTER: Zhou H

PROVIDER: S-EPMC5514922 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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:Background Little is known about the effectiveness of hypofractionated radiation therapy (HFRT) or stereotactic body radiation therapy (SBRT) for the treatment of patients with oligometastatic (OM) or oligoprogressive (OP) thymic malignancies. Methods We retrospectively reviewed Stage IV patients with OM or OP thymic malignancies treated with HFRT or SBRT between 2009–2021. We defined OM as 5 or fewer sites of metastatic disease and OP as 5 or fewer sites of metastatic disease increasing in radiological size at the time of radiation. Analysis of local failure (LF, defined as failure within a treated lesion) and distant failure (DF, defined as failure outside the treated lesion) was done at the treatment course level using univariate analysis Fine-Gray regression adjusted for clustering. Analysis of overall survival (OS) and progression-free survival (PFS) was done at the patient level utilizing only the first course of treatment for each patient. Results Our analysis included 50 patients with 92 treatment courses. Patients had thymoma (50%), thymic carcinoma (TC, 40%), or atypical thymic carcinoid (ATC, 10%). The median biologic effective dose (BED) was 51 Gy (range, 38–106 Gy). With a median follow-up of 36 months, the median OS and PFS were 50 and 6.5 months, respectively. Patients with TC or ATC had significantly worse PFS than those with thymoma [hazard ratio (HR) 2.37; 95% confidence interval (CI): 1.18–4.76, P=0.013], but similar OS (P=0.55) and LF (P=0.729). Treated thymoma lesions had a lower hazard of DF than TC/ATC lesions, but this was not statistically significant (HR 0.59; 95% CI: 0.34–1.03, P=0.065). Lesions treated to a BED higher than 60 Gy had lower hazards of LF and DF, although this was not statistically significant (HR 0.29; 95% CI: 0.05–1.68, P=0.166 and HR 0.58; 95% CI: 0.3–1.1, P=0.096, respectively). Conclusions In our analysis, patients with TC or ATC had worse PFS than those with thymoma. Treated thymoma and TC/ATC lesions had similar hazards of LF, indicating similar radiation sensitivity in thymic lesions regardless of histology. There was a trend towards increased local control with higher BED regimens, but this did not reach statistical significance. Overall, our analysis points to the need for clinical trials on HFRT/SBRT for the treatment of these rare malignancies.

Project description:PurposeTo determine the natural history of imaging findings seen on magnetic resonance imaging (MRI) of hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT). Although arterial hyperenhancement is a key feature of untreated HCC, our clinical experience suggested that tumors that never progressed could still show hyperenhancement. Therefore, we undertook a systematic study to test the hypothesis that persistent arterial phase hyperenhancement (APHE) after SBRT is an expected finding that does not suggest failure of treatment.Methods and materialsOne hundred forty-six patients undergoing SBRT for HCC between January 1, 2007, and December 31, 2015, were screened retrospectively using an institutional review board-approved prospectively maintained registry. Inclusion criteria were (1) HCC treated with SBRT, (2) multiphasic MRI ≤3 months before SBRT, (3) up to 1 year of follow-up MRI post-SBRT, and (4) cirrhosis. The exclusion criterion was ≤3 months of locoregional therapy to the liver segment containing the SBRT-treated HCC. Pre- and post-SBRT MRI from up to 3 years were analyzed in consensus by independent pairs of subspecialty-trained radiologists to determine the temporal evolution of major features for HCC and imaging findings in off-target parenchyma.ResultsSixty-two patients with 67 HCCs (Organ Procurement and Transplantation Network imaging criteria [OPTN] 5a [n = 26], OPTN 5b [n = 28], OPTN 5x [n = 7]; Liver Imaging Reporting Data System [LI-RAD]-M [n = 4] and LiRADs-4 [n = 2]) were studied. Tumor size either decreased (66% [44 of 67]) or remained unchanged (34% [23 of 67]) within the first 12 months. Post-SBRT APHE was common (58% [39 of 67]). When graded using modified Response Evaluation Criteria in Solid Tumors at 3 to 6 months, 25% (17 of 67) met criteria for complete response and 75% (50 of 67) met criteria for stable disease.ConclusionsSBRT is an effective locoregional treatment option for HCC. Persistent APHE is common and does not necessarily indicate viable neoplasm; thus, standard response assessment such as modified Response Evaluation Criteria should be used with caution, particularly in the early phases after SBRT therapy.

Project description:PurposeSpinal cord delineation is critical to the delivery of stereotactic body radiation therapy (SBRT). Although underestimating the spinal cord can lead to irreversible myelopathy, overestimating the spinal cord may compromise the planning target volume coverage. We compare spinal cord contours based on computed tomography (CT) simulation with a myelogram to spinal cord contours based on fused axial T2 magnetic resonance imaging (MRI).Methods and materialsEight patients with 9 spinal metastases treated with spinal SBRT were contoured by 8 radiation oncologists, neurosurgeons, and physicists, with spinal cord definition based on (1) fused axial T2 MRI and (2) CT-myelogram simulation images, yielding 72 sets of spinal cord contours. The spinal cord volume was contoured at the target vertebral body volume based on both images. The mixed-effect model assessed comparisons of T2 MRI- to myelogram-defined spinal cord in centroid deviations (deviations in the center point of the cord) through the vertebral body target volume, spinal cord volumes, and maximum doses (0.035 cc point) to the spinal cord applying the patient's SBRT treatment plan, in addition to in-between and within-subject variabilities.ResultsThe estimate for the fixed effect from the mixed model showed that the mean difference between 72 CT volumes and 72 MRI volumes was 0.06 cc and was not statistically significant (95% confidence interval, -0.034, 0.153; P = .1832). The mixed model showed that the mean dose at 0.035 cc for CT-defined spinal cord contours was 1.24 Gy lower than that of MRI-defined spinal cord contours and was statistically significant (95% confidence interval, -2.292, -0.180; P = .0271). Also, the mixed model indicated no statistical significance for deviations in any of the axes between MRI-defined spinal cord contours and CT-defined spinal cord contours.ConclusionsCT myelogram may not be required when MRI imaging is feasible, although uncertainty at the cord-to-treatment volume interface may result in overcontouring and hence higher estimated cord dose-maximums with axial T2 MRI-based cord definition.

Project description:ObjectiveThe aim of this study was to characterize response to photodynamic therapy (PDT) in a mouse cancer model using a multi-parametric quantitative MRI protocol and to identify MR parameters as potential biomarkers for early assessment of treatment outcome.MethodsCT26.WT colon carcinoma tumors were grown subcutaneously in the hind limb of BALB/c mice. Therapy consisted of intravenous injection of the photosensitizer Bremachlorin, followed by 10 min laser illumination (200 mW/cm2) of the tumor 6 h post injection. MRI at 7 T was performed at baseline, directly after PDT, as well as at 24 h, and 72 h. Tumor relaxation time constants (T1 and T2) and apparent diffusion coefficient (ADC) were quantified at each time point. Additionally, Gd-DOTA dynamic contrast-enhanced (DCE) MRI was performed to estimate transfer constants (Ktrans) and volume fractions of the extravascular extracellular space (ve) using standard Tofts-Kermode tracer kinetic modeling. At the end of the experiment, tumor viability was characterized by histology using NADH-diaphorase staining.ResultsThe therapy induced extensive cell death in the tumor and resulted in significant reduction in tumor growth, as compared to untreated controls. Tumor T1 and T2 relaxation times remained unchanged up to 24 h, but decreased at 72 h after treatment. Tumor ADC values significantly increased at 24 h and 72 h. DCE-MRI derived tracer kinetic parameters displayed an early response to the treatment. Directly after PDT complete vascular shutdown was observed in large parts of the tumors and reduced uptake (decreased Ktrans) in remaining tumor tissue. At 24 h, contrast uptake in most tumors was essentially absent. Out of 5 animals that were monitored for 2 weeks after treatment, 3 had tumor recurrence, in locations that showed strong contrast uptake at 72 h.ConclusionDCE-MRI is an effective tool for visualization of vascular effects directly after PDT. Endogenous contrast parameters T1, T2, and ADC, measured at 24 to 72 h after PDT, are also potential biomarkers for evaluation of therapy outcome.

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Tumor physiological changes during hypofractionated stereotactic body radiation therapy assessed using multi-parametric magnetic resonance imaging.

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