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.

Metformin in Combination With Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer: The OCOG-ALMERA Randomized Clinical Trial.

IMPORTANCE: Unresected locally advanced non-small cell lung cancer (LA-NSCLC) shows poor survival outcomes even after aggressive concurrent chemoradiotherapy. Whether metformin, a diabetes agent that inhibits the mitochondria oxidative phosphorylation chain, could improve radiotherapy and chemotherapy response in LA-NSCLC remains to be studied. OBJECTIVE: To examine whether metformin, given concurrently with chemoradiotherapy and as consolidation treatment, could improve outcomes in patients with LA-NSCLC. DESIGN, SETTING, AND PARTICIPANTS: The Ontario Clinical Oncology Group Advanced Lung Cancer Treatment With Metformin and Chemoradiotherapy (OCOG-ALMERA) study was a multicenter phase 2 randomized clinical trial. Patients were stratified for stage IIIA vs IIIB LA-NSCLC and use of consolidation chemotherapy. The trial was designed to enroll 96 patients with unresected LA-NSCLC who did not have diabetes. The trial was conducted from September 24, 2014, to March 8, 2019. INTERVENTIONS: Patients were randomized to platinum-based chemotherapy, concurrent with chest radiotherapy (60-63 Gy), with or without consolidation chemotherapy or the same treatment plus metformin, 2000 mg/d, during chemoradiotherapy and afterward for up to 12 months. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients who experienced a failure event (ie, locoregional disease progression, distant metastases, death, and discontinuation of trial treatment or planned evaluations for any reason within 12 months). Proportions were compared using a 2-sided Fisher exact test. Conventional progression-free and overall survival were estimated using the Kaplan-Meier method. Adverse events were graded with Common Terminology Criteria for Adverse Events, version 4.03. All randomized patients were included in an intention-to-treat analysis. RESULTS: The trial was stopped early due to slow accrual. Between 2014 and 2019, 54 patients were randomized (26 in experimental arm and 28 in control arm). Participants included 30 women (55.6%); mean (SD) age was 65.6 (7.6) years. Treatment failure was detected in 18 patients (69.2%) receiving metformin within 1 year vs 12 (42.9%) control patients (P = .05). The 1-year progression-free survival rate was 34.8% (95% CI, 16.6%-53.7%) in the metformin arm and 63.0% (95% CI, 42.1%-78.1%) in the control arm (hazard ratio, 2.42; 95% CI, 1.14-5.10) The overall survival rates were 47.4% (95% CI, 26.3%-65.9%) in the metformin arm and 85.2% (95% CI, 65.2%-94.2%) in the control arm (hazard ratio, 3.80; 95% CI, 1.49-9.73). More patients in the experimental arm vs control arm (53.8% vs 25.0%) reported at least 1 grade 3 or higher adverse event. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the addition of metformin to chemoradiotherapy was associated with worse treatment efficacy and increased toxic effects compared with combined modality therapy alone. Metformin is not recommended in patients with LA-NSCLC who are candidates for chemoradiotherapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02115464.

A method for optimizing planning target volume margins for patients receiving lung stereotactic body radiotherapy.

Lung stereotactic-body radiotherapy (SBRT) places additional requirements on targeting accuracy over standard approaches. In treatment planning, a tumour volume is geometrically expanded and the resulting planning target volume (PTV) is covered with the prescribed dose. This ensures full dose delivery despite various uncertainties encountered during treatment. We developed a retrospective technique for optimizing the PTV expansion for a patient population. The method relies on deformable image registration (DIR) of the planning CT to a treatment cone-beam CT (CBCT). The resulting transformation is used to map the planned target onto the treatment geometry, allowing the computation of the achieved target/PTV overlap. Basic validation of the method was performed using an anthropomorphic respiratory motion phantom. A self-validation technique was also implemented to allow estimation of the DIR error for the data being analyzed. Our workflow was used to retrospectively optimize PTV margin for 25 patients treated over 93 fractions. Targets for these patients were contoured on 4D CT images. SBRT delivery followed CBCT acquisition and a couch correction. A post-treatment CBCT was also acquired in some cases. Our basic validation demonstrated that the DIR-based technique is capable of transforming target volumes from planning CTs to treatment CBCTs with sub-mm accuracy. Our clinical analysis showed that the minimum percentages of target volumes covered for 3, 4, and 5 mm PTV margins were 92.1, 97.6, and 99.2, respectively. Analyzing data acquired before and just after treatment demonstrated that margins exceeding 5 mm did not significantly improve coverage. Finally, a 5 mm PTV margin achieved ⩾95% target volume coverage with ⩾95% probability. Our technique is accurate, automated, self-validating, and incorporates complex ITV shapes/deformations to allow PTV margin optimization. The analysis of clinical data indicates a 5 mm PTV margin is optimal for our process. This approach is generalizable to other disease sites and treatment strategies.

Measurement of skin surface dose distributions in radiation therapy using poly(vinyl alcohol) cryogel dosimeters.

In external beam radiation therapy (EBRT), skin dose measurement is important to evaluate dose coverage of superficial target volumes. Treatment planning systems (TPSs) are often inaccurate in this region of the patient, so in vivo measurements are necessary for skin surface dose estimation. In this work, superficial dose distributions were measured using radiochromic translucent poly(vinyl alcohol) cryogels. The cryogels simultaneously served as bolus material, providing the necessary buildup to achieve the desired superficial dose. The relationship between dose to the skin surface and dose measured with the bolus was established using a series of oblique irradiations with gantry angles ranging from 0° to 90°. EBT-2 Gafchromic film was placed under the bolus, and the ratio of bolus-film dose was determined ranging from 0.749 ± 0.005 to 0.930 ± 0.002 for 0° and 90° gantry angles, respectively. The average ratio over 0-67.5° (0.800 ± 0.064) was used as the single correction factor to convert dose in bolus to dose to the skin surface. The correction factor was applied to bolus measurements of skin dose from head and neck intensity-modulated radiation therapy (IMRT) treatments delivered to a RANDO phantom. The resulting dose distributions were compared to film measurements using gamma analysis with a 3%/3 mm tolerance and a 10% threshold. The minimum gamma pass rate was 95.2% suggesting that the radiochromic bolus may provide an accurate estimation of skin surface dose using a simple correction factor. This study demonstrates the suitability of radiochromic cryogels for superficial dose measurements in megavoltage photon beams.

A Novel Neoadjuvant Therapy for Operable Locally Invasive Non-Small-Cell Lung Cancer. Phase I Study of Neoadjuvant Stereotactic Body Radiotherapy. LINNEARRE I (NCT02433574).

BACKGROUND: Despite improved staging and surgical techniques, the rate of incomplete resection (R1) of non-small-cell lung cancer (NSCLC) has not significantly decreased. Patients with R1 resection have worse survival compared with those with complete resection (R0). Stereotactic body radiotherapy (SBRT) is a rapid and convenient radiotherapy treatment that delivers high-dose radiotherapy to tumors with high precision while sparing normal organs. Although its efficacy in treating small lung tumors is documented, its use as neoadjuvant therapy for locally advanced (LA) NSCLC has not been examined. We hypothesized that a short course of preoperative SBRT is feasible and can be delivered safely as a neoadjuvant therapy in patients at risk for incomplete resection. METHODS: In this phase I study, 20 patients with cT3 to 4, N0 to 1, M0 NSCLC at risk for incomplete resection will be treated with neoadjuvant SBRT followed by surgery and adjuvant chemotherapy. Four groups of 5 patients will be treated with escalating doses (35, 40, 45, and 50 Gy) in 10 daily fractions. The primary outcome is feasibility (ie, the ability to complete SBRT and surgery as planned; within 7 weeks). Secondary outcomes include acute and late adverse events; R0, R1, and R2 rates; and secondary surrogates of feasibility and safety. RELEVANCE: This study is an important first step in introducing a new therapeutic modality to patients with LA NSCLC that could improve surgical outcomes in the future. If neoadjuvant SBRT is found to be feasible and safe for LA NSCLC, its effect in achieving R0 resection could be investigated in randomized trials.

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.

Automatic image guidance for prostate IMRT using low dose CBCT.

PURPOSE: Varian's On-Board Imager is a linac-integrated cone-beam CT (CBCT) system used at the authors' institution to acquire images prior to delivering each fraction of prostate intensity modulated radiotherapy. The images are used to determine a couch shift that realigns the tumor with the position obtained in the planning CT. However, this manual image-guided radiotherapy (IGRT) technique is operator dependent, time consuming, offers limited degrees of freedom, and requires significant imaging dose over the course of treatment. To overcome these problems, the authors propose two fully automatic IGRT techniques that require significantly less imaging dose. METHODS: Dose is reduced by lowering the x-ray tube mA s during CBCT acquisition at the cost of increasing image noise. In "forward" IGRT, the CBCT image is automatically registered to the planning CT to obtain the necessary couch shift. The "reverse" technique offers additional degrees of freedom as it involves nonrigid registration of the planning CT to the CBCT. Both techniques were evaluated using images of an anthropomorphic phantom with simulated motion and by retrospectively analyzing data from ten prostate cancer patients. RESULTS: IGRT error for the phantom data at 100% relative imaging dose was 8.2 +/- 3.7, 3.5 +/- 1.2,, and 2.1 +/- 0.6 mm for setup only, forward, and reverse techniques, respectively. For patient images acquired at 100% relative imaging dose, the errors were 5.4 +/- 1.7, 5.0 +/- 1.6, 5.0 +/- 2.0, and 4.0 +/- 1.6 mm for setup only, manual forward (performed clinically), automatic forward, and reverse IGRT, respectively. Furthermore, imaging dose could be reduced to 20% without a significant loss in image guidance accuracy. CONCLUSIONS: The presented image guidance methods are accurate while requiring only 20% of the standard imaging dose. The combination of low dose, automation, and accuracy enables frequent corrections during treatment, possibly leading to reduced margins and improved treatment outcomes.

Subject-specific models for image-guided cardiac surgery.

Three-dimensional visualization for planning and guidance is still not routinely available for minimally invasive cardiac surgery (MICS). This can be addressed by providing the surgeon with subject-specific geometric models derived from 3D preoperative images for planning of port locations or to rehearse the procedure. For guidance purposes, these models can also be registered to the subject using intraoperative images. In this paper, we present a method for extracting subject-specific heart geometry from preoperative MR images. The main obstacle we face is the low quality of clinical data in terms of resolution, signal-to-noise ratio, and presence of artefacts. Instead of using these images directly, we approach the problem in three steps: (1) generate a high quality template model, (2) register the template with the preoperative data, and (3) animate the result over the cardiac cycle. Validation of this approach showed that dynamic subject-specific models can be generated with a mean error of 3.6+/-1.1 mm from low resolution target images (6 mm slices). Thus, the models are sufficiently accurate for MICS training and procedure planning. In terms of guidance, we also demonstrate how the resulting models may be adapted to the operating room using intraoperative ultrasound imaging.

Towards a biomechanics-based technique for assessing myocardial contractility: an inverse problem approach.

This work presents the initial development and implementation of a novel 3D biomechanics-based approach to measure the mechanical activity of myocardial tissue, as a potential non-invasive tool to assess myocardial function. This technique quantifies the myocardial contraction forces developed within the ventricular myofibers in response to electro-physiological stimuli. We provide a 3D finite element formulation of a contraction force reconstruction algorithm, along with its implementation using magnetic resonance (MR) data. Our algorithm is based on an inverse problem solution governed by the fundamental continuum mechanics principle of conservation of linear momentum, under a first-order approximation of elastic and isotropic material conditions. We implemented our technique using a subject-specific ventricle model obtained by extracting the left ventricular anatomical features from a set of high-resolution cardiac MR images acquired throughout the cardiac cycle using prospective electrocardiographic gating. Cardiac motion information was extracted by non-rigid registration of the mid-diastole reference image to the remaining images of a 4D dataset. Using our technique, we reconstructed dynamic maps that show the contraction force distribution superimposed onto the deformed ventricle model at each acquired frame in the cardiac cycle. Our next objective will consist of validating this technique by showing the correlation between the presence of low contraction force patterns and poor myocardial functionality.

Towards subject-specific models of the dynamic heart for image-guided mitral valve surgery.

Surgeons need a robust interventional system capable of providing reliable, real-time information regarding the position and orientation of the surgical targets and tools to compensate for the lack of direct vision and to enhance manipulation of intracardiac targets during minimally-invasive, off-pump cardiac interventions. In this paper, we describe a novel method for creating dynamic, pre-operative, subject-specific cardiac models containing the surgical targets and surrounding anatomy, and how they are used to augment the intra-operative virtual environment for guidance of valvular interventions. The accuracy of these pre-operative models was established by comparing the target registration error between the mitral valve annulus characterized in the pre-operative images and their equivalent structures manually extracted from 3D US data. On average, the mitral valve annulus was extracted with a 3.1 mm error across all cardiac phases. In addition, we also propose a method for registering the pre-operative models into the intra-operative virtual environment.

On enhancing planning and navigation of beating-heart mitral valve surgery using pre-operative cardiac models.

In an effort to reduce morbidity during minimally-invasive cardiac procedures, we have recently developed an interventional technique targeted towards off-pump cardiac interventions. To compensate for the absence of direct visualization, our system employs a virtual reality environment for image guidance, that integrates pre-operative information with real-time intra-operative imaging and surgical tool tracking. This work focuses on enhancing intracardiac visualization and navigation by overlaying pre-operative cardiac models onto the intra-operative virtual space, to display surgical targets within their specific anatomical context. Our method for integrating pre-operative data into the intra-operative environment is accurate within 5.0 mm. Thus, we feel that our virtually-augmented surgical space is accurate enough to improve spatial orientation and intracardiac navigation.

Dose reduction for cardiac CT using a registration-based approach.

Two reasons for the recent rise in radiation exposure from CT are increases in its clinical applicability and the desire to maintain high SNR while acquiring smaller voxels. To address this emerging dose problem, several strategies for reducing patient exposure have already been proposed. One method employed in cardiac imaging is ECG-driven modulation of the tube current between 100% at one time point in the cardiac cycle and a reduced fraction at the remaining phases. In this paper, we describe how images obtained during such acquisition can be used to reconstruct 4D data of consistent high quality throughout the cardiac cycle. In our approach, we assume that the middiastole (MD) phase is imaged with full dose. The MD image is then independently registered to lower dose images (lower SNR) at other frames, resulting in a set of transformations. Finally, the transformations are used to warp the MD frame through the cardiac cycle to generate the full 4D image. In addition, the transformations may be interpolated to increase the temporal sampling or to generate images at arbitrary time points. Our approach was validated using various data obtained with simulated and scanner-implemented dose modulation. We determined that as little as 10% of the total dose was required to reproduce full quality images with a 1 mm spatial error and an error in intensity values on the order of the image noise. Thus, our technique offers considerable dose reductions compared to standard imaging protocols, with minimal effects on the quality of the final data.

Towards a biomechanical-based method for assessing myocardial tissue viability.

This work presents the first steps towards the development and implementation of a novel 3D biomechanical-based method for assessing the viability of myocardial tissue, with particular interest for its application in myocardial infarction (MI) diagnosis. This assessment technique quantifies the myocardial contraction forces developed within the ventricular myofibrils in response to the electrophysiological stimulus. In this manuscript we provide a 3D finite element (FE) formulation of a contraction force reconstruction algorithm based on an inverse problem solution of linear elasticity, along with its implementation using clinical data. This algorithm has been applied to patient-specific models obtained by extracting anatomical features from high-resolution, high-contrast magnetic resonance (MR) cardiac images. The input consists of motion information extracted by nonrigid registration of the mid-diastole reference image to the remaining images of the 4D data set, acquired using ECG-gating throughout the cardiac cycle. The result consists of a display-map of the contraction force distribution superimposed on the anatomical ventricle model, which allows the clinician to identify regions of low contractility in the myocardium.

Real-time fusion of endoscopic views with dynamic 3-D cardiac images: a phantom study.

Minimally invasive robotically assisted cardiac surgical systems currently do not routinely employ 3-D image guidance. However, preoperative magnetic resonance and computed tomography (CT) images have the potential to be used in this role, if appropriately registered with the patient anatomy and animated synchronously with the motion of the actual heart. This paper discusses the fusion of optical images of a beating heart phantom obtained from an optically tracked endoscope, with volumetric images of the phantom created from a dynamic CT dataset. High quality preoperative dynamic CT images are created by first extracting the motion parameters of the heart from the series of temporal frames, and then applying this information to animate a high-quality heart image acquired at end systole. Temporal synchronization of the endoscopic and CT model is achieved by selecting the appropriate CT image from the dynamic set, based on an electrocardiographic trigger signal. The spatial error between the optical and virtual images is 1.4 +/- 1.1 mm, while the time discrepancy is typically 50-100 ms. Index Terms-Image guidance, image warping, minimally invasive cardiac surgery, virtual endoscopy, virtual reality.

Validation of dynamic heart models obtained using non-linear registration for virtual reality training, planning, and guidance of minimally invasive cardiac surgeries.

Current minimally invasive techniques for beating heart surgery are associated with three major limitations: the shortage of realistic and safe training methods, the process of selecting port locations for optimal target coverage from X-rays and angiograms, and the sole use of the endoscope for instrument navigation in a dynamic and confined 3D environment. To supplement the current surgery training, planning and guidance methods, we continue to develop our Virtual Cardiac Surgery Planning environment (VCSP) -- a virtual reality, patient-specific, thoracic cavity model derived from 3D pre-procedural images. In this work, we create and validate dynamic models of the heart and its components. A static model is first generated by segmenting one of the image frames in a given 4D data set. The dynamics of this model are then extracted from the remaining image frames using a non-linear, intensity-based registration algorithm with a choice of six different similarity metrics. The algorithm is validated on an artificial CT image set created using an excised porcine heart, on CT images of canine subjects, and on MR images of human volunteers. We found that with the appropriate choice of similarity metric, our algorithm extracts the motion of the epicardial surface in CT images, or of the myocardium, right atrium, right ventricle, aorta, left atrium, pulmonary arteries, vena cava and epicardial surface in MR images, with a root mean square error in the 1 mm range. These results indicate that our method of modeling the motion of the heart is easily adaptable and sufficiently accurate to meet the requirements for reliable cardiac surgery training, planning, and guidance.