Stereotactic body radiotherapy versus conventional external beam radiotherapy in patients with painful spinal metastases: an open-label, multicentre, randomised, controlled, phase 2/3 trial.

BACKGROUND: Conventional external beam radiotherapy is the standard palliative treatment for spinal metastases; however, complete response rates for pain are as low as 10-20%. Stereotactic body radiotherapy delivers high-dose, ablative radiotherapy. We aimed to compare complete response rates for pain after stereotactic body radiotherapy or conventional external beam radiotherapy in patients with painful spinal metastasis. METHODS: This open-label, multicentre, randomised, controlled, phase 2/3 trial was done at 13 hospitals in Canada and five hospitals in Australia. Patients were eligible if they were aged 18 years and older, and had painful (defined as ≥2 points with the Brief Pain Inventory) MRI-confirmed spinal metastasis, no more than three consecutive vertebral segments to be included in the treatment volume, an Eastern Cooperative Oncology Group performance status of 0-2, a Spinal Instability Neoplasia Score of less than 12, and no neurologically symptomatic spinal cord or cauda equina compression. Patients were randomly assigned (1:1) with a web-based, computer-generated allocation sequence to receive either stereotactic body radiotherapy at a dose of 24 Gy in two daily fractions or conventional external beam radiotherapy at a dose of 20 Gy in five daily fractions using standard techniques. Treatment assignment was done centrally by use of a minimisation method to achieve balance for the stratification factors of radiosensitivity, the presence or absence of mass-type tumour (extraosseous or epidural disease extension, or both) on imaging, and centre. The primary endpoint was the proportion of patients with a complete response for pain at 3 months after radiotherapy. The primary endpoint was analysed in the intention-to-treat population and all safety and quality assurance analyses were done in the as-treated population (ie, all patients who received at least one fraction of radiotherapy). The trial is registered with ClinicalTrials.gov, NCT02512965. FINDINGS: Between Jan 4, 2016, and Sept 27, 2019, 229 patients were enrolled and randomly assigned to receive conventional external beam radiotherapy (n=115) or stereotactic body radiotherapy (n=114). All 229 patients were included in the intention-to-treat analysis. The median follow-up was 6·7 months (IQR 6·3-6·9). At 3 months, 40 (35%) of 114 patients in the stereotactic body radiotherapy group, and 16 (14%) of 115 patients in the conventional external beam radiotherapy group had a complete response for pain (risk ratio 1·33, 95% CI 1·14-1·55; p=0·0002). This significant difference was maintained in multivariable-adjusted analyses (odds ratio 3·47, 95% CI 1·77-6·80; p=0·0003). The most common grade 3-4 adverse event was grade 3 pain (five [4%] of 115 patients in the conventional external beam radiotherapy group vs five (5%) of 110 patients in the stereotactic body radiotherapy group). No treatment-related deaths were observed. INTERPRETATION: Stereotactic body radiotherapy at a dose of 24 Gy in two daily fractions was superior to conventional external beam radiotherapy at a dose of 20 Gy in five daily fractions in improving the complete response rate for pain. These results suggest that use of conformal, image-guided, stereotactically dose-escalated radiotherapy is appropriate in the palliative setting for symptom control for selected patients with painful spinal metastases, and an increased awareness of the need for specialised and multidisciplinary involvement in the delivery of end-of-life care is needed. FUNDING: Canadian Cancer Society and the Australian National Health and Medical Research Council.

Informal caregiver quality of life in a palliative oncology population.

PURPOSE: Many patients with advanced cancer receive primary supports from informal caregivers (IC). As patient health deteriorates, IC assume increasing responsibility, often accompanied by distress. We investigated the quality of life (QOL) of IC of patients referred to a palliative radiotherapy (PRT) program. METHODS: IC accompanying patients to a dedicated PRT clinic completed a survey based on the validated Caregiver Quality of Life Index-Cancer (CQOLC). Demographics, burden, and engagement in support services were evaluated. Summary statistics were calculated, and parameters were assessed for association with CQOLC scores by a generalized linear model. RESULTS: Two hundred one surveys were analyzed representing 197 unique patients. The mean age was 68.3 years, with predominantly lung (25.0%) and prostate (19.3%) malignancies. 24.4% had been in hospital/long-term care within the previous 7 days. IC were 60.8% female, and 60.6% were the patient's spouse. 69.5% lived with the patient and 38.3% were additionally employed. IC spent a daily mean of 6.6 h (SD 7) assisting with instrumental (72.5%) and basic (37.5%) activities of daily living. Mean CQOLC score was 82.1/140 (SD 20). 63.8% of IC had previously accessed support service(s), most commonly home care (37.2%) and pharmacy (29.1%). 55.9% indicated interest in services not yet accessed. Multivariate analysis revealed additional employment, cohabitation, poor patient performance status, and interest in accessing more support services significantly correlated with higher IC burden. CONCLUSIONS: Employing the CQOLC to screen IC of patients referred to a PRT program permits early identification of vulnerable IC to facilitate linkage with appropriate supports.

Is Radiation-Induced Cardiac Toxicity Reversible? Prospective Evaluation of Patients With Breast Cancer Enrolled in a Phase 3 Randomized Controlled Trial.

PURPOSE: Myocardial perfusion defects after breast radiation therapy (RT) correlate with volume of irradiated left ventricle (LV). We aimed to determine the relationship between myocardial perfusion, LV dosimetry, and grade ≥2 late cardiac events in patients with breast cancer undergoing adjuvant RT. METHODS AND MATERIALS: A randomized study evaluated the benefit of inverse-planned intensity modulated radiation therapy over forward-planned intensity modulated radiation therapy for radiation toxicity in breast cancer. A secondary endpoint was evaluating cardiac perfusion by single-photon emission computed tomography done at baseline, 6 months, 1 year, 2 years, and 5 years post-RT. We used receiver operating curve and regression analysis to identify association between perfusion, radiation dose-volumes, and the risk of late cardiac events. RESULTS: Of 181 patients who received adjuvant RT, 102 were patients with cancer in the left breast (called in this study the left-sided group) and 79 were patients with cancer in the right breast (called in this study the right-sided group). Median follow-up was 127 months (range, 19-160 months). A significant worsening of perfusion defects occurred after RT in the left-sided group, which improved by 1 year. Late cardiac events were found among 16 patients (17.2%) in the left-sided group and 4 patients (5.5%) in the right-sided group. Perfusion changes did not correlate with late cardiac events, but LV dose-volumes correlated with late cardiac events. Maintaining the LV volume receiving 5 Gy and 10 Gy to <42 cc and <38cc, respectively, can reduce the risk of radiation-related late cardiac events at 10 years to <5% over baseline. CONCLUSIONS: RT was associated with short-term perfusion defects that improved within 1 year and was not correlated with late cardiac events. The ventricular volumes receiving 5 Gy and 10 Gy were correlated with late cardiac events.

DREAM, a possible answer to the estrogen paradox of the Women's Health Initiative Trial.

Estrogen is thought to cause proliferation of all estrogen receptor positive (ER+) breast cancers. Paradoxically, in the Women's Health Initiative Trial, estrogen-only hormone replacement therapy reduced the incidence and mortality of low grade, ER+, HER2- breast cancer. We gave estradiol to 19 post-menopausal women with newly diagnosed low-grade, ER+, HER2- breast cancer in a prospective window of opportunity clinical trial and examined the changes in proliferation and gene expression before and after estradiol treatment. Ki67 decreased in 13/19 (68%) patients and 8/13 (62%) showed a decrease in Risk of Recurrence Score. We chose three prototypical estrogen responders (greatest decrease in ROR) and non-responders (no/minimal change in ROR) and applied a differential gene expression analysis to develop pre-treatment (PRESTO-30core) and post-treatment (PRESTO-45surg) gene expression profiles. The PRESTO-30core predicted adjuvant benefit in a published series of tamoxifen, the partial estrogen agonist. Of the 45 genes in the PRESTO-45surg, thirty contain the Cell cycle genes Homology Region (CHR) motif that binds the class B multi-vulva complex (MuvB) a member of the DREAM (Dimerization partner, retinoblastoma-like proteins, E2F, MuvB) complex responsible for reversible cell cycle arrest or quiescence. There was also near uniform suppression (89%) of the remaining DREAM genes consistent with estrogen induced activation of the DREAM complex to mediate cell cycle block after a short course of estrogens. To our knowledge, this is the first report to show estrogen modulation of DREAM genes and suggest involvement of DREAM pathway associated quiescence in endocrine responsive post-menopausal ER+ breast cancers.

Lung SBRT credentialing in the Canadian OCOG-LUSTRE randomized trial.

Purpose: To report on the Stereotactic Body Radiation Therapy (SBRT) credentialing experience during the Phase III Ontario Clinical Oncology Group (OCOG) LUSTRE trial for stage I non-small cell lung cancer. Methods: Three credentialing requirements were required in this process: (a) An institutional technical survey; (b) IROC (Imaging and Radiation Oncology Core) thoracic phantom end-to-end test; and (c) Contouring and completion of standardized test cases using SBRT for one central and one peripheral lung cancer, compared against the host institution as the standard. The main hypotheses were that unacceptable variation would exist particularly in OAR definition across all centres, and that institutions with limited experience in SBRT would be more likely to violate per-protocol guidelines. Results: Fifteen Canadian centres participated of which 8 were new, and 7 were previously established (≥2 years SBRT experience), and all successfully completed surveys and IROC phantom testing. Of 30 SBRT test plans, 10 required replanning due to major deviations, with no differences in violations between new and established centres (p = 0.61). Mean contouring errors were highest for brachial plexus in the central (C) case (12.55 ± 6.62 mm), and vessels in the peripheral (P) case (13.01 ± 12.55 mm), with the proximal bronchial tree (PBT) (2.82 ± 0.78 C, 3.27 ± 1.06 P) as another variable structure. Mean dice coefficients were lowest for plexus (0.37 ± 0.2 C, 0.37 ± 0.14 P), PBT (0.77 ± 0.06 C, 0.75 ± 0.09 P), vessels (0.69 ± 0.29 C, 0.64 ± 0.31 P), and esophagus (0.74 ± 0.04 C, 0.76 ± 0.04 P). All plans passed per-protocol planning target volume (PTV) coverage and maximum/volumetric organs-at-risk constraints, although variations existed in dose gradients within and outside the target. Conclusions: Clear differences exist in both contouring and planning with lung SBRT, regardless of centre experience. Such an exercise is important for studies that rely on high precision radiotherapy, and to ensure that implications on trial quality and outcomes are as optimal as possible.

Time domain principal component analysis for rapid, real-time 2D MRI reconstruction from undersampled data.

PURPOSE: A rapid real-time 2D accelerated method was developed for magnetic resonance imaging (MRI) using principal component analysis (PCA) in the temporal domain. This method employs a moving window of previous dynamic frames to reconstruct the current, real-time frame within this window. This technique could be particularly useful in real-time tracking applications such as in MR-guided radiotherapy, where low latency real-time reconstructions are essential. METHODS: The method was tested retrospectively on 15 fully-sampled data sets of lung patient data acquired on a 3T Philips Achieva system. High frequency data are incoherently undersampled, while the central low-frequency data are always acquired to characterize the temporal fluctuations through PCA. The undersampling pattern is derived in such a way that all of k-space is acquired within a pre-determined number of frames. The missing data in the current frame are then filled in by fitting the temporal characterizations to the acquired undersampled data, using a pre-determined number of PCs. A subset of six patients was used to test the contour ability of the images. Various accelerations between 3x and 8x were tested along with the optimal number of PCs for fitting. A comparison was also performed with previous work from our group proposed by Dietz et al. as well as with a standard low resolution acquisition. In order to determine how the method would perform at lower signal to noise ratio (SNR), noise levels of 2×, 4×, and 6× were added to the 3T data. Metrics such as normalised mean square error and Dice coefficient were used to measure the reconstruction image quality and contour ability. RESULTS: The proposed method demonstrated good temporal robustness as consistent metrics were detected for the duration of the imaging session. It was found that the optimal number of PCs for temporal fitting was dependent on the acceleration rate. For the data tested, five PCs were found to be optimal at the acceleration rates of 3× and 4×. This number decreases to three at accelerations of 5× and 6× and further decreases to two at an acceleration rate of 8×, likely due to greater instability with fewer acquired data points. The use of too many PCs for fitting increased the chances of noisy reconstruction which affected contourability. CONCLUSIONS: The proposed 2D real-time MR acceleration method demonstrated greater robustness in the metrics over time when compared with previous real-time PCA methods using metrics such as normalised mean squared error, peak SNR and structural similarity up to an acceleration of 8x. Improved temporal robustness of image structure contourability and accurate definition was also demonstrated using several metrics including the Dice coefficient. Reconstruction of raw acquired data can be performed at approximately 50 ms per frame using an Intel core i5 CPU. The method has the advantage of being very flexible in terms of hardware requirements as it can operate successfully on a single coil channel and does not require specialized computing power to implement in real-time.

Adjuvant breast radiotherapy, endocrine therapy, or both after breast conserving surgery in older women with low-risk breast cancer: Results from a population-based study.

BACKGROUND AND PURPOSE: The relative benefit of adjuvant radiotherapy (RT) alone in older women with low-risk early breast cancer (EBC) remains unclear. It is hypothesized that adjuvant RT-alone can improve outcomes of older patients with low-risk EBC, similar to endocrine therapy (ET) alone or combination of RT + ET. METHODS: In this population based study, we identified all women aged ≥70 with T1-2, N0, ER+ve, Her-2/neu-ve EBC treated with breast conserving surgery (BCS), followed by adjuvant treatments (RT-alone, ET-alone, or RT + ET combination) from 2005 to 2015. Primary outcome measures were recurrence-free survival (RFS), overall survival (OS), and breast cancer specific survival (BCSS). Treatment details were collected and Charlson Comorbidity Index (CCI) was calculated. RESULTS: A total of 1166 patients were identified. Median follow-up was 76.5 months. Adjuvant treatments: BCS only 130 (11%), RT 378 (32.5%), ET 161 (14%), and RT + ET 497 (42.5%). Less than 60% of women completed 5-years of ET. Compared to BCS alone, RT resulted in significant improvement in RFS (HR = 0.174; p < 0.001), similar to ET (HR = 0.414; p = 0.007) and RT + ET (HR = 0.236; p < 0.001). Determinants of OS were age, tumor grade, comorbidities, and adjuvant therapy. Increased comorbidity scores (0 vs. 1; 0 vs. ≥2) were associated with reduced OS (HR = 1.40; p = 0.013 and HR = 1.98; p < 0.001), without impact on RFS or BCSS. CONCLUSIONS: Adjuvant RT-alone is a reasonable alternative to ET or RT + ET for older women with biologically favorable EBC. No difference in RFS or BCSS was noted between RT, ET, and RT + ET. Comorbidity was independently associated with reduced overall survival.

The association between biological subtype and locoregional recurrence in newly diagnosed breast cancer.

We investigated the association between the risk of locoregional recurrence (LRR) and biological subtypes defined by hormonal receptors (HR) and HER-2 status in women with invasive breast cancer (BC). A total of 618 newly diagnosed BC patients were identified from a cancer registry within a single institution with standardized methods of tumor assessment for estrogen receptor (ER), progesterone receptor (PR), and HER-2. Patients were stratified based on surgical treatment, breast-conserving therapy (BCT) versus modified radical mastectomy (MRM), as well as biological subtypes: HR+/HER-2- (ER-positive or PR-positive, HER-2-negative), HR+/HER-2+ (ER-positive or PR-positive, HER-2-positive), HR-/HER-2+ (ER-negative and PR-negative, HER-2-positive) and TN (ER-negative, PR-negative and HER-2-negative). The association between clinicopathological factors, biological subtype and LRR was evaluated with univariate and multivariate Cox analysis. With a median follow-up of 4.8 years, the rate of LRR was 7.5%. On multivariate analysis, TN, tumor size ≥2 cm and lymph node (LN) positivity were associated with increased risk of LRR (P = 0.023, P = 0.048, and P = 0.0034, respectively). In BCT group, HR-/HER-2+ and LN positivity were associated with increased risk of LRR (HR 11.13; 95% CI 2.78-44.53; P = 0.0007 and HR 5.40; 95% CI 1.67-17.43; P = 0.0048, respectively). In MRM group, TN subtype and LN positivity were associated with increased risk of LRR (HR 4.72; 95% CI 1.53-14.52; P = 0.0069 and HR 3.23; 95% CI 1.44-7.29; P = 0.0047, respectively). Compared to HR+/HER-2-, HR-/HER-2+ treated by BCT and TN treated by MRM showed a significant decrease of 5-year LRR free survival (P = 0.0002 and P = 0.002, respectively). Tumor profiling using ER, PR, and HER-2 biomarkers is a promising tool to identify patients at high risk of LRR based on surgical treatment. Our findings suggest a different follow-up and locoregional treatment for patients with HR-/HER-2+ and TN subtypes.

Identification of a new microRNA expression profile as a potential cancer screening tool.

PURPOSE: Small non-coding microRNAs (miRNAs) are key components of cancer development and are considered as potential biomarkers for cancer diagnosis and treatment monitoring. This study investigated miRNA expression profiles of human cancer cells in order to develop a screening method for lung cancer. METHODS: A series of lung cancer related miRNAs (miR-21, miR-145, miR-155, miR-205, miR-210, miR-92, miR-17-5p, miR-143, miR-182, miR-372, let-7a) were selected as candidates for miRNA expression profiles of human lung cancer cell lines (A549, SK-mes-1). MicroRNA u6 was the endogenous control. Cancer cell lines for positive controls; breast MCF-7, prostate Du-145, and glioblastoma U118. The negative control was normal lung fibroblast cell line MRC-5. RT-PCR was performed on StepOnePlus (Applied Biosystem, USA). MiRNA expressions of malignant cells were compared with normal fibroblast cells as well as endogenous control (u6) using the thermal cycle at threshold. Assessment of miRNA expression profiles were then performed using agglomerative hierarchical cluster analysis software (SPSS13, USA). RESULTS: We demonstrated that miR-21, miR-182 and let7-5a were over-expressed, and miR-145 and miR-155 were under-expressed in all cancer cell lines. Combined with the cluster analysis we were able to clearly distinguish cell lines for normal fibroblasts, breast cancer, prostate cancer, glioblastoma, and lung cancer. CONCLUSION: There is potential utility of screening for lung cancer with miRNA expression profiles. Future work will focus on the sensitivity of such miRNA expression profiles in screening sputum for lung cancer, which can be performed in real time.

Single patient convolutional neural networks for real-time MR reconstruction: coherent low-resolution versus incoherent undersampling.

Accelerated MRI involves undersampling k-space, creating unwanted artifacts when reconstructing the data. While the strategy of incoherent k-space acquisition is proven for techniques such as compressed sensing, it may not be optimal for all techniques. This study compares the use of coherent low-resolution (coherent-LR) and incoherent undersampling phase-encoding for real-time 3D CNN image reconstruction. Data were acquired with our 3 T Philips Achieva system. A retrospective analysis was performed on six non-small cell lung cancer patients who received dynamic acquisitions consisting of 650 free breathing images using a bSSFP sequence. We retrospectively undersampled the data by 5x and 10x acceleration using the two phase-encoding schemes. A quantitative analysis was conducted evaluating the tumor segmentations from the CNN reconstructed data using the Dice coefficient (DC) and centroid displacement. The reconstruction noise was evaluated using the structural similarity index (SSIM). Furthermore, we qualitatively investigated the CNN reconstruction using prospectively undersampled data, where the fully sampled training data set is acquired separately from the accelerated undersampled data. The patient averaged DC, centroid displacement, and SSIM for the tumor segmentation at 5x and 10x was superior using coherent low-resolution undersampling. Furthermore, the patient-specific CNN can be trained in under 6 h and the reconstruction time was 54 ms per image. Both the incoherent and coherent-LR prospective CNN reconstructions yielded qualitatively acceptable images; however, the coherent-LR reconstruction appeared superior to the incoherent reconstruction. We have demonstrated that coherent-LR undersampling for real-time CNN image reconstruction performs quantitatively better for the retrospective case of lung tumor segmentation, and qualitatively better for the prospective case. The tumor segmentation mean DC increased for all six patients at 5x acceleration and the temporal (dynamic) variance of the segmentation was reduced. The reconstruction speed achieved for our current implementation was 54 ms, providing an acceptable frame rate for real-time on-the-fly MR imaging.

Should Stereotactic Radiosurgery Be Considered for Salvage of Intracranial Recurrence after Prophylactic Cranial Irradiation or Whole Brain Radiotherapy in Small Cell Lung Cancer? A Population-Based Analysis and Literature Review.

BACKGROUND: Prophylactic cranial irradiation (PCI) improves survival and prevents intracranial recurrence (IR) in limited stage (LS) and extensive stage (ES) small cell lung cancer (SCLC). However, despite PCI, IR affects 12%-45%, and limited data exist regarding salvage brain reirradiation (ReRT). We performed a population-based review of IR in SCLC. METHODS: Demographic, treatment, and outcome data of consecutive patients (N = 371) with SCLC assessed at a tertiary cancer centre (01/2013-12/2015) were abstracted, and summary statistics calculated. Kaplan-Meier estimates and univariate and multivariate analysis (MVA) via the Cox proportional hazard model were performed. RESULTS: Median age was 66.1 years, and 59.8% were Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Median survival was 24 months (95% CI 18.3-29.7 months) for LS (N = 103) and 7 months (95% CI 6.1-7.9 months) for ES (N = 268). 72 of 103 patients with LS and 97 of 214 of those with ES received PCI. 54 of 268 ES presented with brain metastases (BM) of whom 46 of 54 received whole brain RT (WBRT). 18.9% (32/169) recurred post-PCI (13 LS; 19 ES) and 30.4% (14/46) recurred after WBRT. Of those who recurred/progressed after cranial RT, 56.5% (26/46) had <5 BM, 39.1% had no extracranial disease, and 50% were ECOG 0-2. In retrospect, 17 of 46 would have been candidates for salvage stereotactic radiosurgery: 13 post-PCI and 4 post-WBRT. CONCLUSIONS: This cohort challenges commonly held beliefs that IR is always diffuse, associated with clinical deterioration, and synchronous with systemic failure. Approximately 1 in 3 SCLC patients with IR after PCI or WBRT appear clinically appropriate for salvage stereotactic radiosurgery.

Single patient convolutional neural networks for real-time MR reconstruction: a proof of concept application in lung tumor segmentation for adaptive radiotherapy.

Investigate 3D (spatial and temporal) convolutional neural networks (CNNs) for real-time on-the-fly magnetic resonance imaging (MRI) reconstruction. In particular, we investigated the applicability of training CNNs on a patient-by-patient basis for the purpose of lung tumor segmentation. Data were acquired with our 3 T Philips Achieva system. A retrospective analysis was performed on six non-small cell lung cancer patients who received fully sampled dynamic acquisitions consisting of 650 free breathing images using a bSSFP sequence. We retrospectively undersampled the six patient's data by 5× and 10× acceleration. The retrospective data was used to quantitatively compare the CNN reconstruction to gold truth data via the Dice coefficient (DC) and centroid displacement to compare the tumor segmentations. Reconstruction noise was investigated using the normalized mean square error (NMSE). We further validated the technique using prospectively undersampled data from a volunteer and motion phantom. The retrospectively undersampled data at 5× and 10× acceleration was reconstructed using patient specific trained CNNs. The patient average DCs for the tumor segmentation at 5× and 10× acceleration were 0.94 and 0.92, respectively. These DC values are greater than the inter- and intra-observer segmentations acquired by radiation oncologist experts as reported in a previous study of ours. Furthermore, the patient specific CNN can be trained in under 6 h and the reconstruction time was 65 ms per image. The prospectively undersampled CNN reconstruction data yielded qualitatively acceptable images. We have shown that 3D CNNs can be used for real-time on-the-fly dynamic image reconstruction utilizing both spatial and temporal data in this proof of concept study. We evaluated the technique using six retrospectively undersampled lung cancer patient data sets, as well as prospectively undersampled data acquired from a volunteer and motion phantom. The reconstruction speed achieved for our current implementation was 65 ms per image.

Evaluating performance of a user-trained MR lung tumor autocontouring algorithm in the context of intra- and interobserver variations.

PURPOSE: Real-time tracking of lung tumors using magnetic resonance imaging (MRI) has been proposed as a potential strategy to mitigate the ill-effects of breathing motion in radiation therapy. Several autocontouring methods have been evaluated against a "gold standard" of a single human expert user. However, contours drawn by experts have inherent intra- and interobserver variations. In this study, we aim to evaluate our user-trained autocontouring algorithm with manually drawn contours from multiple expert users, and to contextualize the accuracy of these autocontours within intra- and interobserver variations. METHODS: Six nonsmall cell lung cancer patients were recruited, with institutional ethics approval. Patients were imaged with a clinical 3 T Philips MR scanner using a dynamic 2D balanced SSFP sequence under free breathing. Three radiation oncology experts, each in two separate sessions, contoured 130 dynamic images for each patient. For autocontouring, the first 30 images were used for algorithm training, and the remaining 100 images were autocontoured and evaluated. Autocontours were compared against manual contours in terms of Dice's coefficient (DC) and Hausdorff distances (dH ). Intra- and interobserver variations of the manual contours were also evaluated. RESULTS: When compared with the manual contours of the expert user who trained it, the algorithm generates autocontours whose evaluation metrics (same session: DC = 0.90(0.03), dH  = 3.8(1.6) mm; different session DC = 0.88(0.04), dH  = 4.3(1.5) mm) are similar to or better than intraobserver variations (DC = 0.88(0.04), and dH  = 4.3(1.7) mm) between two sessions. The algorithm's autocontours are also compared to the manual contours from different expert users with evaluation metrics (DC = 0.87(0.04), dH  = 4.8(1.7) mm) similar to interobserver variations (DC = 0.87(0.04), dH  = 4.7(1.6) mm). CONCLUSIONS: Our autocontouring algorithm delineates tumor contours (<20 ms per contour), in dynamic MRI of lung, that are comparable to multiple human experts (several seconds per contour), but at a much faster speed. At the same time, the agreement between autocontours and manual contours is comparable to the intra- and interobserver variations. This algorithm may be a key component of the real time tumor tracking workflow for our hybrid Linac-MR device in the future.

Sliding window prior data assisted compressed sensing for MRI tracking of lung tumors.

PURPOSE: Hybrid magnetic resonance imaging and radiation therapy devices are capable of imaging in real-time to track intrafractional lung tumor motion during radiotherapy. Highly accelerated magnetic resonance (MR) imaging methods can potentially reduce system delay time and/or improves imaging spatial resolution, and provide flexibility in imaging parameters. Prior Data Assisted Compressed Sensing (PDACS) has previously been proposed as an acceleration method that combines the advantages of 2D compressed sensing and the KEYHOLE view-sharing technique. However, as PDACS relies on prior data acquired at the beginning of a dynamic imaging sequence, decline in image quality occurs for longer duration scans due to drifts in MR signal. Novel sliding window-based techniques for refreshing prior data are proposed as a solution to this problem. METHODS: MR acceleration is performed by retrospective removal of data from the fully sampled sets. Six patients with lung tumors are scanned with a clinical 3 T MRI using a balanced steady-state free precession (bSSFP) sequence for 3 min at approximately 4 frames per second, for a total of 650 dynamics. A series of distinct pseudo-random patterns of partial k-space acquisition is generated such that, when combined with other dynamics within a sliding window of 100 dynamics, covers the entire k-space. The prior data in the sliding window are continuously refreshed to reduce the impact of MR signal drifts. We intended to demonstrate two different ways to utilize the sliding window data: a simple averaging method and a navigator-based method. These two sliding window methods are quantitatively compared against the original PDACS method using three metrics: artifact power, centroid displacement error, and Dice's coefficient. The study is repeated with pseudo 0.5 T images by adding complex, normally distributed noise with a standard deviation that reduces image SNR, relative to original 3 T images, by a factor of 6. RESULTS: Without sliding window implemented, PDACS-reconstructed dynamic datasets showed progressive increases in image artifact power as the 3 min scan progresses. With sliding windows implemented, this increase in artifact power is eliminated. Near the end of a 3 min scan at 3 T SNR and 5× acceleration, implementation of an averaging (navigator) sliding window method improves our metrics by the following ways: artifact power decreases from 0.065 without sliding window to 0.030 (0.031), centroid error decreases from 2.64 to 1.41 mm (1.28 mm), and Dice coefficient agreement increases from 0.860 to 0.912 (0.915). At pseudo 0.5 T SNR, the improvements in metrics are as follows: artifact power decreases from 0.110 without sliding window to 0.0897 (0.0985), centroid error decreases from 2.92 mm to 1.36 mm (1.32 mm), and Dice coefficient agreements increases from 0.851 to 0.894 (0.896). CONCLUSIONS: In this work we demonstrated the negative impact of slow changes in MR signal for longer duration PDACS dynamic scans, namely increases in image artifact power and reductions of tumor tracking accuracy. We have also demonstrated sliding window implementations (i.e., refreshing of prior data) of PDACS are effective solutions to this problem at both 3 T and simulated 0.5 T bSSFP images.

Cardiac-sparing radiation therapy using positioning breast shell for patients with left-sided breast cancer who are ineligible for breath-hold techniques.

PURPOSE: Patients with left-sided breast cancer (LSBC) are at increased risk of cardiac morbidity from adjuvant breast radiation therapy (ABRT). Breath-hold (BH) techniques substantially reduce the radiation received by heart during radiation therapy for LSBC. However, a subset of patients with LSBC are ineligible for BH techniques due to an inability to breath-hold or because of other comorbidities. To reduce radiation to the heart, we routinely use a custom-made breast shell for the treatment of patients with LSBC who are ineligible for BH techniques. This study evaluates the dosimetric impact of using a breast shell for patients with LSBC undergoing ABRT. METHODS AND MATERIALS: Sixteen consecutive patients with LSBC who failed BH and underwent ABRT using a breast shell during the period of 2014 to 2016 were identified. Treatment was planned using field-in-field tangents with a prescribed dose of 42.5 Gy in 16 fractions. Comparisons between plans with and without a shell were made for each patient using a paired t test to quantify the sparing of organs at risk (OARs) and target coverage. RESULTS: There was no statistically significant difference in the planning target volume of breast coverage. A statistically significant improvement was observed in sparing the heart, left ventricle (LV), and ipsilateral lung (P-value < .001). Plans with the shell spared OARs better than the no-shell plans with a mean dose of 2.15 Gy versus 5.15 Gy (58.2% reduction) to the heart, 3.27 Gy versus 9.00 Gy (63.7% reduction) to the LV, and 5.16 Gy versus 7.95 Gy (35% reduction) to the ipsilateral lung. The irradiated volumes of OARs for plans with and without shell are 13.3 cc versus 59.5 cc (77.6% reduction) for the heart, 6.2 cc versus 33.2 cc (81.2% reduction) for the LV, and 92.8 cc versus 162.5 cc (42.9% reduction) for the ipsilateral lung. CONCLUSIONS: A positioning breast shell offers significant benefit in terms of sparing the heart for patients with LSBC who are ineligible for BH techniques. It also can be used as a simple cardiac-sparing alternative in centers without BH capability.

Dose-escalated Hypofractionated Intensity-modulated Radiation Therapy With Concurrent Chemotherapy for Inoperable or Unresectable Non-Small Cell Lung Cancer.

PURPOSE: The local control of inoperable non-small cell lung cancer (NSCLC) using standard radiotherapy (RT) doses is inadequate. Dose escalation is a potential strategy to improve the local control for patients with NSCLC; however, the optimal dose required for local control in this setting is unknown. METHODS AND MATERIALS: Patients with unresectable or inoperable stage II/III NSCLC with ECOG≤1 received 48 Gy in 20 daily fractions using intensity-modulated radiotherapy, followed by 1 of 3 boost dose levels: 16.8 Gy/7 (cumulative 2 Gy equivalent dose [EQD2]≅76 Gy/38), 20.0 Gy/7 (EQD2≅84 Gy/42), and 22.7 Gy/7 (EQD2≅92 Gy/46). Two cycles of cisplatin/etoposide chemotherapy were given concurrent with RT. The maximum tolerated dose was defined as the dose at which ≥30% experienced dose-limiting toxicity (any NCIC Common Terminology for Adverse Events V3.0 grade 3 or higher acute toxicity). RESULTS: Twelve patients completed treatment with a median follow-up of 22 months (range, 7 to 48). The median age was 72 (range, 54 to 80) and 50% of patients had adenocarcinoma. Five, 3, and 4 patients were treated on dose levels 1, 2, and 3, respectively. No dose-limiting toxicity was observed. One-year local progression-free survival and overall survival estimates were 81% and 58%, respectively. CONCLUSIONS: Hypofractionated intensity-modulated radiotherapy was well tolerated and provided meaningful local control for patients with locally advanced inoperable NSCLC. The maximum tolerated dose of RT in this setting lies beyond an EQD2 of 92 Gy/46 and further dose escalation in this setting is warranted.

Canadian Phase III Randomized Trial of Stereotactic Body Radiotherapy Versus Conventionally Hypofractionated Radiotherapy for Stage I, Medically Inoperable Non-Small-Cell Lung Cancer - Rationale and Protocol Design for the Ontario Clinical Oncology Group (OCOG)-LUSTRE Trial.

We describe a Canadian phase III randomized controlled trial of stereotactic body radiotherapy (SBRT) versus conventionally hypofractionated radiotherapy (CRT) for the treatment of stage I medically inoperable non-small-cell lung cancer (OCOG-LUSTRE Trial). Eligible patients are randomized in a 2:1 fashion to either SBRT (48 Gy in 4 fractions for peripherally located lesions; 60 Gy in 8 fractions for centrally located lesions) or CRT (60 Gy in 15 fractions). The primary outcome of the study is 3-year local control, which we hypothesize will improve from 75% with CRT to 87.5% with SBRT. With 85% power to detect a difference of this magnitude (hazard ratio = 0.46), a 2-sided α = 0.05 and a 2:1 randomization, we require a sample size of 324 patients (216 SBRT, 108 CRT). Important secondary outcomes include overall survival, disease-free survival, toxicity, radiation-related treatment death, quality of life, and cost-effectiveness. A robust radiation therapy quality assurance program has been established to assure consistent and high quality SBRT and CRT delivery. Despite widespread interest and adoption of SBRT, there still remains a concern regarding long-term control and risks of toxicity (particularly in patients with centrally located lesions). The OCOG-LUSTRE study is the only randomized phase III trial testing SBRT in a medically inoperable population, and the results of this trial will attempt to prove that the benefits of SBRT outweigh the potential risks.

Factors Associated With the Use of Radiation Therapy in Patients With Stage III Non-small Cell Lung Cancer in Alberta, Canada: A Population-based Study.

BACKGROUND: Cancer care in Alberta, Canada is publicly funded and provides patients with access to health care facilities and providers. The distribution of patients and health services across Alberta presents challenges to the delivery of cancer care, especially radiation therapy. In this study, we examined the association between patient and health system factors, the use of radiation therapy and survival outcomes in patients with stage III non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The provincial cancer registry was used to identify all patients who presented with clinical stage III NSCLC, diagnosed from 2005 to 2007, in Alberta. Patient characteristics, diagnostic method, treatment modality and treatment outcomes were collected from provincial health information systems for analyses. Factors influencing overall survival (OS) were analyzed using Cox proportional hazards models. RESULTS: Nine hundred twenty-nine patients were identified. Sixty-two percent of patients received radiation therapy (RT) as part of their initial cancer treatment and had a median OS of 1.04 vs. 0.34 years with a hazard ratio (HR) of 0.54. On multivariable analysis, patients who were less likely to receive any therapy were older, had higher comorbidity scores and were registered in community cancer centers without radiation therapy infrastructure. Patients registered in tertiary cancer centers had a higher likelihood of accessing multimodality treatment than patients in community centers, with a statistical significance of P<0.001 after correcting for age, gender, histology, substage, and comorbidity. INTERPRETATION: Improving access to radiotherapy treatment for patients presenting to non-radiation therapy centers at diagnosis has the potential to decrease variations in cancer care and improve cancer control outcomes in clinical stage III NSCLC.

SBRT Treatment of Metachronous Small-Cell and Non-Small-Cell Lung Carcinomas in a Patient with Severe COPD.

Stereotactic body radiotherapy (SBRT) has not been widely employed in the treatment of limited-stage (LS) small-cell lung cancer (SCLC), although SBRT finds particular utility in patients medically unfit to undergo surgical resection or radiotherapy with conventional fields. The authors present the case of a 61-year-old female smoker with severe chronic obstructive pulmonary disease (COPD), diagnosed incidentally with LS-SCLC. Concurrent chemoradiotherapy was contraindicated by her poor pulmonary function, and she was treated radically with four cycles of cisplatin and etoposide chemotherapy. This was followed by prophylactic cranial irradiation and consolidative SBRT (48 Gy in 4 fractions) to the residual tumour, which achieved a complete clinical response. Fifteen months following the patient's initial diagnosis, a metachronous Stage IA contralateral non-small cell lung cancer (NSCLC) was incidentally diagnosed and was treated with SBRT (48 Gy in 4 fractions). Although studies have established that the incidence of a second lung cancer is higher in patients with previous SCLC, this case is unique in that both primaries were treated with SBRT.

Outcomes in stage I non-small cell lung cancer following the introduction of stereotactic body radiotherapy in Alberta - A population-based study.

PURPOSE: To review outcomes of patients with stage I non-small cell lung cancer (NSCLC) following the introduction of stereotactic body radiation therapy (SBRT). METHODS: SBRT cases were linked to the cancer registry database along with clinical, treatment and health service parameters for n=2146 cases of stage I NSCLC diagnosed between 2005 and 2011. The pre-diagnosis Aggregated Clinical Risk Grouping score (ACRG3) was used as a proxy for pre-treatment patient comorbidity. A Cox regression model and the concordance statistic (C-statistic) were used to examine variables predicted for overall survival (OS). RESULTS: The SBRT utilization rate increased annually with superior OS to conventional RT (median survival [MS] of 39.4 VS. 23.5months, P<0.001) despite higher ACRG3 scores. Surgical patients were younger, had lower ACRG3, achieving MS of 69.6months. Regression analysis indicated both Surgery (hazard ratio [HR]=0.23, 95% CI: 0.18-0.28) and SBRT (HR=0.33, 95% CI: 0.21-0.51) remained most strongly associated with OS. ACRG3 (HR=0.79, P<0.001) and age (HR=0.83, P=0.03) were independently associated with OS. The OS model was associated with the C-statistic at 0.86, 95% CI: 0.81-0.90. CONCLUSION: In stage I NSCLC patients treated with surgery have the best survival. SBRT demonstrates improved OS compared to conventional RT. C-statistic result demonstrates discrimination of treatment selection factors on OS.