Concurrent Lapatinib With Brain Radiation Therapy in Patients With HER2+ Breast Cancer With Brain Metastases: NRG Oncology-KROG/RTOG 1119 Phase 2 Randomized Trial.

PURPOSE: Lapatinib plus whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) was hypothesized to improve the 12-week intracranial complete response (CR) rate compared with either option of radiation therapy (RT) alone for patients with brain metastases (BM) from human epidermal growth factor receptor 2-positive (HER2+) breast cancer. METHODS AND MATERIALS: This study included patients with HER2+ breast cancer with ≥1 measurable, unirradiated BM. Patients were randomized to WBRT (37.5 Gy/3 wk)/SRS (size-based dosing) ± concurrent lapatinib (1000 mg daily for 6 weeks). Secondary endpoints included objective response rate (ORR), lesion-specific response, central nervous system progression-free survival, and overall survival. RESULTS: From July 2012 to September 2019, 143 patients were randomized, with 116 analyzable for the primary endpoint. RT + lapatinib did not improve 12-week CR (0% vs 6% for RT alone, 1-sided P = .97), or ORR at 12 weeks. At 4 weeks, RT + lapatinib showed higher ORR (55% vs 42%). Higher graded prognostic assessment and ≤10 lesions were associated with higher 12-week ORR. Grade 3 and 4 adverse event rates were 8% and 0% for RT and 28% and 6% for RT + lapatinib. CONCLUSIONS: The addition of 6 weeks of concomitant lapatinib to WBRT/SRS did not improve the primary endpoint of 12-week CR rate or 12-week ORR. Adding lapatinib to WBRT/SRS showed improvement of 4-week ORR, suggesting a short-term benefit from concomitant therapy.

A MR-TRUS Registration Method for Ultrasound-Guided Prostate Interventions.

In this paper, we report a MR-TRUS prostate registration method that uses a subject-specific prostate strain model to improve MR-targeted, US-guided prostate interventions (e.g., biopsy and radiotherapy). The proposed algorithm combines a subject-specific prostate biomechanical model with a B-spline transformation to register the prostate gland of the MRI to the TRUS images. The prostate biomechanical model was obtained through US elastography and a 3D strain map of the prostate was generated. The B-spline transformation was calculated by minimizing Euclidean distance between the normalized attribute vectors of landmarks on MR and TRUS prostate surfaces. This prostate tissue gradient map was used to constrain the B-spline-based transformation to predict and compensate for the internal prostate-gland deformation. This method was validated with a prostate-phantom experiment and a pilot study of 5 prostate-cancer patients. For the phantom study, the mean target registration error (TRE) was 1.3 mm. MR-TRUS registration was also successfully performed for 5 patients with a mean TRE less than 2 mm. The proposed registration method may provide an accurate and robust means of estimating internal prostate-gland deformation, and could be valuable for prostate-cancer diagnosis and treatment.

A 3D Neurovascular Bundles Segmentation Method based on MR-TRUS Deformable Registration.

In this paper, we propose a 3D neurovascular bundles (NVB) segmentation method for ultrasound (US) image by integrating MR and transrectal ultrasound (TRUS) images through MR-TRUS deformable registration. First, 3D NVB was contoured by a physician in MR images, and the 3D MR-defined NVB was then transformed into US images using a MR-TRUS registration method, which models the prostate tissue as an elastic material, and jointly estimates the boundary deformation and the volumetric deformations under the elastic constraint. This technique was validated with a clinical study of 6 patients undergoing radiation therapy (RT) treatment for prostate cancer. The accuracy of our approach was assessed through the locations of landmarks, as well as previous ultrasound Doppler images of patients. MR-TRUS registration was successfully performed for all patients. The mean displacement of the landmarks between the post-registration MR and TRUS images was less than 2 mm, and the average NVB volume Dice Overlap Coefficient was over 89%. This NVB segmentation technique could be a useful tool as we try to spare the NVB in prostate RT, monitor NVB response to RT, and potentially improve post-RT potency outcomes.

Prostate CT segmentation method based on nonrigid registration in ultrasound-guided CT-based HDR prostate brachytherapy.

PURPOSE: The technological advances in real-time ultrasound image guidance for high-dose-rate (HDR) prostate brachytherapy have placed this treatment modality at the forefront of innovation in cancer radiotherapy. Prostate HDR treatment often involves placing the HDR catheters (needles) into the prostate gland under the transrectal ultrasound (TRUS) guidance, then generating a radiation treatment plan based on CT prostate images, and subsequently delivering high dose of radiation through these catheters. The main challenge for this HDR procedure is to accurately segment the prostate volume in the CT images for the radiation treatment planning. In this study, the authors propose a novel approach that integrates the prostate volume from 3D TRUS images into the treatment planning CT images to provide an accurate prostate delineation for prostate HDR treatment. METHODS: The authors' approach requires acquisition of 3D TRUS prostate images in the operating room right after the HDR catheters are inserted, which takes 1-3 min. These TRUS images are used to create prostate contours. The HDR catheters are reconstructed from the intraoperative TRUS and postoperative CT images, and subsequently used as landmarks for the TRUS-CT image fusion. After TRUS-CT fusion, the TRUS-based prostate volume is deformed to the CT images for treatment planning. This method was first validated with a prostate-phantom study. In addition, a pilot study of ten patients undergoing HDR prostate brachytherapy was conducted to test its clinical feasibility. The accuracy of their approach was assessed through the locations of three implanted fiducial (gold) markers, as well as T2-weighted MR prostate images of patients. RESULTS: For the phantom study, the target registration error (TRE) of gold-markers was 0.41 ± 0.11 mm. For the ten patients, the TRE of gold markers was 1.18 ± 0.26 mm; the prostate volume difference between the authors' approach and the MRI-based volume was 7.28% ± 0.86%, and the prostate volume Dice overlap coefficient was 91.89% ± 1.19%. CONCLUSIONS: The authors have developed a novel approach to improve prostate contour utilizing intraoperative TRUS-based prostate volume in the CT-based prostate HDR treatment planning, demonstrated its clinical feasibility, and validated its accuracy with MRIs. The proposed segmentation method would improve prostate delineations, enable accurate dose planning and treatment delivery, and potentially enhance the treatment outcome of prostate HDR brachytherapy.

Improved hippocampal dose with reduced margin radiotherapy for glioblastoma multiforme.

BACKGROUND: To dosimetrically evaluate the effect of reduced margin radiotherapy on hippocampal dose for glioblastoma multiforme (GBM) patients. METHODS: GBM patients enrolled on the Radiation Therapy Oncology Group (RTOG) 0825 trial at our institution were identified. Standard RTOG 0825 expansions were 2 cm + 3-5 mm from the gross tumor volume (GTV) to the clinical tumor volume (CTV) and from the CTV to the planning tumor volume (PTV), respectively. These same patients also had reduced margin tumor volumes generated with 8 mm (GTV to CTV) + 3 mm (CTV to PTV) expansions. Individual plans were created for both standard and reduced margin structures. The dose-volume histograms were statistically compared with a paired, two-tailed Student's t-test with a significance level of p < 0.05. RESULTS: A total of 16 patients were enrolled on RTOG 0825. The reduced margins resulted in statistically significant reductions in hippocampal dose at all evaluated endpoints. The hippocampal Dmax was reduced from a mean of 61.4 Gy to 56.1 Gy (8.7%), D40% was reduced from 49.9 Gy to 36.5 Gy (26.9%), D60% was reduced from 32.7 Gy to 18.7 Gy (42.9%) and the D80% was reduced from 27.3 Gy to 15.3 Gy (44%). CONCLUSIONS: The use of reduced margin PTV expansions in the treatment of GBM patients results in significant reductions in hippocampal dose. Though the exact clinical benefit of this reduction is currently unclear, this study does provide support for a future prospective trial evaluating the neurocognitive benefits of reduced margin tumor volumes in the treatment of GBM patients.

A New CT Prostate Segmentation for CT-Based HDR Brachytherapy.

High-dose-rate (HDR) brachytherapy has become a popular treatment modality for localized prostate cancer. Prostate HDR treatment involves placing 10 to 20 catheters (needles) into the prostate gland, and then delivering radiation dose to the cancerous regions through these catheters. These catheters are often inserted with transrectal ultrasound (TRUS) guidance and the HDR treatment plan is based on the CT images. The main challenge for CT-based HDR planning is to accurately segment prostate volume in CT images due to the poor soft tissue contrast and additional artifacts introduced by the catheters. To overcome these limitations, we propose a novel approach to segment the prostate in CT images through TRUS-CT deformable registration based on the catheter locations. In this approach, the HDR catheters are reconstructed from the intra-operative TRUS and planning CT images, and then used as landmarks for the TRUS-CT image registration. The prostate contour generated from the TRUS images captured during the ultrasound-guided HDR procedure was used to segment the prostate on the CT images through deformable registration. We conducted two studies. A prostate-phantom study demonstrated a submillimeter accuracy of our method. A pilot study of 5 prostate-cancer patients was conducted to further test its clinical feasibility. All patients had 3 gold markers implanted in the prostate that were used to evaluate the registration accuracy, as well as previous diagnostic MR images that were used as the gold standard to assess the prostate segmentation. For the 5 patients, the mean gold-marker displacement was 1.2 mm; the prostate volume difference between our approach and the MRI was 7.2%, and the Dice volume overlap was over 91%. Our proposed method could improve prostate delineation, enable accurate dose planning and delivery, and potentially enhance prostate HDR treatment outcome.

Clinical outcomes for a novel 6 degrees of freedom image guided localization method for frameless radiosurgery for intracranial brain metastases.

Stereotactic radiosurgery (SRS) is an accepted method of treatment for intracranial brain metastases with sub-millimeter accuracy. Frameless radiosurgery (FRS) is becoming an alternative to framed SRS due to its less invasive requirements. The purpose of this study is to describe the clinical outcomes and local patterns of failure for a novel 6 degrees of freedom CT guided method of localization for FRS of intracranial brain metastases. 42 patients underwent linear accelerator-based FRS to 94 intracranial brain metastases between 01/2009 and 07/2011. 78 and 22 % of treated sites were intact metastases and resection cavities, respectively. 55 % of patients had undergone prior brain radiotherapy (45 % SRS, 26 % whole brain radiation therapy). The 1 year actuarial local recurrence rate was 18 %, with a median imaging follow-up period of 13.2 months. Single fraction equivalent dose was the most important predictor of local recurrence. The 1 year actuarial first distant brain recurrence and total intracranial recurrence rate was 58 and 69 %, respectively. The crude radiographic radiation necrosis rate was 3 %. Of the 10 local recurrence events, 8 (80 %) were in-field only, 1 (10 %) was marginal only, and 1 (10 %) was both. The preponderance of in-field only patterns of failure suggests that geographic miss is not a major contributor to local recurrence using this novel localization method for FRS. The 1 year local control rate is comparable to other similar published series of framed and frameless radiosurgery.

Six degrees of freedom CBCT-based positioning for intracranial targets treated with frameless stereotactic radiosurgery.

Frameless radiosurgery is an attractive alternative to the framed procedure if it can be performed with comparable precision in a reasonable time frame. Here, we present a positioning approach for frameless radiosurgery based on in-room volumetric imaging coupled with an advanced six-degrees-of-freedom (6 DOF) image registration technique which avoids use of a bite block. Patient motion is restricted with a custom thermoplastic mask. Accurate positioning is achieved by registering a cone-beam CT to the planning CT scan and applying all translational and rotational shifts using a custom couch mount. System accuracy was initially verified on an anthropomorphic phantom. Isocenters of delineated targets in the phantom were computed and aligned by our system with an average accuracy of 0.2 mm, 0.3 mm, and 0.4 mm in the lateral, vertical, and longitudinal directions, respectively. The accuracy in the rotational directions was 0.1°, 0.2°, and 0.1° in the pitch, roll, and yaw, respectively. An additional test was performed using the phantom in which known shifts were introduced. Misalignments up to 10 mm and 3° in all directions/rotations were introduced in our phantom and recovered to an ideal alignment within 0.2 mm, 0.3 mm, and 0.4 mm in the lateral, vertical, and longitudinal directions, respectively, and within 0.3° in any rotational axis. These values are less than couch motion precision. Our first 28 patients with 38 targets treated over 63 fractions are analyzed in the patient positioning phase of the study. Mean error in the shifts predicted by the system were less than 0.5 mm in any translational direction and less than 0.3° in any rotation, as assessed by a confirmation CBCT scan. We conclude that accurate and efficient frameless radiosurgery positioning is achievable without the need for a bite block by using our 6DOF registration method. This system is inexpensive compared to a couch-based 6 DOF system, improves patient comfort compared to systems that utilize a bite block, and is ideal for the treatment of pediatric patients with or without general anesthesia, as well as of patients with dental issues. From this study, it is clear that only adjusting for 4 DOF may, in some cases, lead to significant compromise in PTV coverage. Since performing the additional match with 6 DOF in our registration system only adds a relatively short amount of time to the overall process, we advocate making the precise match in all cases.

Performance evaluation of Calypso 4D localization and kilovoltage image guidance systems for interfraction motion management of prostate patients.

Prostate cancer represents a model site for advances in understanding inter- and intrafraction motion for radiotherapy. In this study, we examined the correlation of the electromagnetic transponder system/Calypso 4D Localization System with conventional on-board imaging (OBI) using kilovoltage imaging. Initially using a quality assurance (QA) phantom and subsequently using data of seven patients, the vector distances between Calypso- and OBI-recorded shifts were compared using the t-test. For the 30 phantom measurements, the average differences between the measured Calypso offset and the calculated OBI shift were 0.4 +/- 0.4, 0.2 +/- 0.3, and 0.4 +/- 0.3 mm in the lateral, longitudinal, and vertical directions, respectively (p = 0.73, p = 0.91, and p = 0.99, respectively), and the average difference vector for all sessions was 0.8 +/- 0.4 mm. For the 259 patient measurements, the average differences between the measured Calypso offset and the calculated OBI shift were 0.7 +/- 0.5, 1.1 +/- 0.9, and 1.2 +/- 0.9 mm in the lateral, longitudinal, and vertical directions, respectively (p = 0.45, p = 0.28, and p = 0.56, respectively), and the average difference vector for all sessions was 2.1 +/- 1.0 mm. Our results demonstrated good correlation between Calypso and OBI. While other studies have explored the issue of Calypso/OBI correlation, our analysis is unique in our use of phantom validation and in our performing the patient analysis on an initial population prior to routine setup using Calypso without OBI. Implications for Calypso's role as a QA tool are discussed.

Performance evaluation of an automated image registration algorithm using an integrated kilovoltage imaging and guidance system.

Image-guided radiation therapy delivery may be used to assess the position of the tumor and anatomical structures within the body as opposed to relying on external marks. The purpose of this manuscript is to evaluate the performance of the image registration software for automatically detecting and repositioning a 3D offset of a phantom using a kilovoltage onboard imaging system. Verification tests were performed on both a geometric rigid phantom and an anthropomorphic head phantom containing a humanoid skeleton to assess the precision and accuracy of the automated positioning system. From the translation only studies, the average deviation between the detected and known offset was less than 0.75 mm for each of the three principal directions, and the shifts did not show any directional sensitivity. The results are given as the measurement with standard deviation in parentheses. The combined translations and rotations had the greatest average deviation in the lateral, longitudinal, and vertical directions. For all dimensions, the magnitude of the deviation does not appear to be correlated with the magnitude of the actual translation introduced. The On-Board Imager (OBI) system has been successfully integrated into a feasible online radiotherapy treatment guidance procedure. Evaluation of each patient's resulting automatch should be performed by therapists before each treatment session for adequate clinical oversight.