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BackgroundEnzalutamide is an antiandrogen used to treat both metastatic and nonmetastatic prostate cancer. Here we present results from a phase 2 trial designed to determine the safety, tolerability, and efficacy of adding enzalutamide to standard androgen deprivation therapy with radiation therapy in high-risk localized or regional, nonmetastatic patients with prostate cancer.Methods and materialsEnrollment criteria included at least 2 of the following: stage cT3a/b, prostate specific antigen (PSA) ≥20 ng/mL, Gleason grade 8 to 10, ≥33% core involvement on biopsy, or pelvic lymph node involvement on computed tomography or magnetic resonance imaging. Patients with metastatic disease were excluded. All patients received 24 months of leuprolide and enzalutamide, and 5 weeks of intensity modulated radiation therapy followed by a brachytherapy boost. Adverse events (AE), PSA, testosterone, and basic laboratory tests were then followed for up to 36 months. Primary outcomes were safety and tolerability and PSA complete response rate (PSA-CR, defined as PSA ≤0.3). Secondary outcomes included time to biochemical recurrence (BCR; nadir+2 ng/mL).ResultsSixteen patients were enrolled; 2 were ineligible and 3 withdrew before starting treatment. Median age at enrollment was 69.0 years (interquartile range [IQR] 11.5). Median treatment duration was 24.0 months (IQR 11.9). Median follow-up time was 35.5 months (IQR 11.2), and 9 of 11 (81.8%) patients completed the 36 months of follow-up. One of 11 (9%) patients had grade 4 AE (seizure), and no grade 5 AE were reported. Four of 11 (36.4%) patients had grade 3 AE, such as erectile dysfunction and hot flashes. All patients achieved PSA-CR, and median time to PSA-CR was 4.2 months (IQR 1.4). At 24 months follow-up, 0 of 11 (0%) patients had a biochemical recurrence. At 36 months, 1 of 9 (11.1%) patient had a biochemical recurrence. Of note, this patient did not complete the full 24 months of enzalutamide and leuprolide due to AEs.ConclusionsEnzalutamide in combination with standard androgen deprivation therapy and radiation therapy was well-tolerated and effective warranting further study in a randomized controlled trial.

Purpose The purpose of this retrospective cohort study was to evaluate the effect of tumor location and other major factors on the risk of complications from stereotactic body radiation therapy (SBRT) in non-small cell lung cancer (NSCLC) patients with a history of thoracic surgery and/or radiation therapy. Methods Medical records of patients with recurrent or second primary NSCLC treated with SBRT between 2005 and 2015 were reviewed. All patients had prior thoracic surgery and/or radiation therapy and were treated with image-guided, robotic SBRT. Time to local failure and toxicity was evaluated by using cumulative incidence and competing risk regression analysis. Overall survival was estimated using the Kaplan-Meier method. Results Fifty-six patients with 74 tumors treated with SBRT were included for analysis. Of the 74 tumors, 19 (26%) were centrally located within 2 cm of the proximal bronchial tree. At a median follow-up of 27 months (range = 5–129), the 2-year cumulative incidence of LF was 13% for peripheral tumors and 16% for central tumors (p = 0.95). Neither prior thoracic surgery nor radiation therapy was associated with increased LF or toxicity. Among the 56 patients, eight (14%), three (5%), and one (2%) experienced grade 2, 3, and 4 complications following SBRT. Patients with a ≥ 50 pack-year smoking history were more likely to develop ≥ grade 2 toxicity (HR 5.3; 95% CI 1.4–19.9, p = 0.01). Central tumor location was associated with higher risk of toxicity (HR 3.4; 95% CI 1.1–10.5, p = 0.04) as was planning tumor volume > 30 mL (HR 4.3; 95% CI 1.1–16.3, p = 0.047). In a multivariable model, central location remained significant after adjusting for smoking history and planning tumor volume. Conclusions After prior thoracic surgery and/or radiation, SBRT retreatment for NSCLC provided durable local control and was well tolerated in most patients. Patients with a history of previously operated and/or radiated lung cancer with new central tumors, PTV volume > 30 mL, or smoking history ≥ 50 pack-years were at higher risk of complications from SBRT.

Dose calculation in treatment planning must account for tissue heterogeneity, especially for tumors within low-density lung tissues. While Monte Carlo (MC) calculation methods are the most accurate, Ray Tracing (RT) methods are also commonly employed. We evaluated dose calculation differences between the RT and MC algorithms in central and peripheral lung tumors treated with CyberKnife SBRT to determine which planning parameters may predict dose differences. We also examined clinical outcomes of local-regional control (LRC) and long-term treatment-related toxicity as a function of calculation method.A retrospective series of 70 patient plans (19 central and 51 peripheral lung lesions) treated between 2009 and 2011 were analyzed. Among those, 33 were primary lung cancer and 37 were metastatic lesions. Thirty-three treatment plans were developed with the RT method, and 37 plans used MC. Groups were recalculated with the reciprocal method for dose comparison. Parameters examined to quantify dose differences between the two algorithms included: dose delivered to 95% (D95) of the planning target volume (PTV), dose heterogeneity, and dose to organs at risk (OAR). Dose differences were analyzed as a function of target volume, distance to soft tissue, and fraction of target overlap with soft tissue. For the subset of primary lung tumors, LRC was assessed radiographically at a median follow-up of 19 months (mo) (range, 2 to 41 mo).Compared to MC, the RT algorithm largely overestimated the dose delivered to the PTV. The dose difference between RT and MC plans correlated to the volume of PTV overlapping with soft tissue; the smaller the overlap volume, the larger the dose differences between RT and MC. Compared to MC, the RT algorithm overestimated the dose delivered to 10% of the ipsilateral lung (D10%). Evidence of local progression was noted in only one of the 31 patients treated for primary lung malignancy. DFS and OS were not significantly different between RT and MC plans.There is a significant range of discordance between MC and RT dose calculations for SBRT treated peripheral lung tumors. While variation is correlated to target size and proximity to soft tissue, no single parameter can reliably predict dose differences. Ultimately, local control and long-term toxicity appear independent of the dose calculation method.

Purpose: To present the most updated American College of Radiology (ACR) Appropriateness Criteria formed by an expert panel on the appropriate delivery of external beam radiation to manage stage T1 and T2 prostate cancer (in the definitive setting and post-prostatectomy) and to provide clinical variants with expert recommendations based on accompanying Appropriateness Criteria for target volumes and treatment planning. Methods and materials: The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a panel of multidisciplinary experts. The guideline development and revision process includes an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In instances in which evidence is lacking or equivocal, expert opinion may supplement available evidence to recommend imaging or treatment. Results: The panel summarizes the most recent and relevant literature on the topic, including organ motion and localization methods, image guidance, and delivery techniques (eg, 3-dimensional conformal intensity modulation). The panel presents 7 clinical variants, including (1) a standard case and cases with (2) a distended rectum, (3) a large-volume prostate, (4) bilateral hip implants, (5) inflammatory bowel disease, (6) prior prostatectomy, and (7) a pannus extending into the radiation field. Each case outlines the appropriate techniques for simulation, treatment planning, image guidance, dose, and fractionation. Numerical rating and commentary is given for each treatment approach in each variant. Conclusions: External beam radiation is a key component of the curative management of T1 and T2 prostate cancer. By combining the most recent medical literature, these Appropriateness Criteria can aid clinicians in determining the appropriate treatment delivery and personalized approaches for individual patients.

There is a clear survival benefit to neoadjuvant chemoradiation prior to esophagectomy for patients with stages II-III esophageal cancer. A minimally invasive esophagectomy approach may decrease morbidity but is more challenging in a previously radiated field and therefore patients who undergo neoadjuvant chemoradiation may experience more postoperative complications.A prospective database of all esophageal cancer patients who underwent attempted hybrid minimally invasive Ivor Lewis esophagectomy was maintained between 2006 and 2015. The clinical characteristics, neoadjuvant treatments, perioperative complications, and survival outcomes were reviewed.Overall 30- and 90-day mortality rates were 0.8% (1/131) and 2.3% (3/131), respectively. The majority of patients 58% (76/131) underwent induction treatment without significant adverse impact on mortality, major complications, or hospital stay. Overall survival at 1, 3, and 5 years was 85.9%, 65.3%, and 53.9%. Five-year survival by pathologic stage was stage I 68.9%, stage II 54.0%, and stage III 29.6%.The hybrid minimally invasive Ivor Lewis esophagectomy approach results in low perioperative morbidity and mortality and is well tolerated after neoadjuvant chemoradiation. Good long-term overall survival rates likely resulted from combined concurrent neoadjuvant chemoradiation in the majority of patients, which did not impact the ability to safely perform the operation or postoperative complications rates. J. Surg. Oncol. 2016;114:838-847. © 2016 2016 Wiley Periodicals, Inc.

A unique capability of the CyberKnife system is dynamic target tracking. However, not all patients are eligible for this approach. Rather, their tumors are tracked statically using the vertebral column for alignment. When using static tracking, the internal target volume (ITV) is delineated on the four-dimensional (4D) CT scan and an additional margin is added to account for setup uncertainty [planning target volume (PTV)]. Treatment margins are difficult to estimate due to unpredictable variations in tumor motion and respiratory pattern during the course of treatment. The inability to track the target and detect changes in respiratory characteristics might result in geographic misses and local tumor recurrences. The purpose of this study is to develop a method to evaluate the adequacy of ITV-to-PTV margins for patients treated in this manner.Data from 24 patients with lesions in the upper lobe (n = 12), middle lobe (n = 3), and lower lobe (n = 9) were included in this study. Each patient was treated with dynamic tracking and underwent 4DCT scanning at the time of simulation. Data including the 3D coordinates of the target over the course of treatment were extracted from the treatment log files and used to determine actual target motion in the superior-inferior (S-I), anterior-posterior (A-P), and left-right (L-R) directions. Different approaches were used to calculate anisotropic and isotropic margins, assuming that the tumor moves as a rigid body. Anisotropic margins were calculated by separating target motion in the three anatomical directions, and a uniform margin was calculated by shifting the gross tumor volume contours in the 3D space and by computing the percentage of overlap with the PTV. The analysis was validated by means of a theoretical formulation.The three methods provided consistent results. A uniform margin of 4.5 mm around the ITV was necessary to assure 95% target coverage for 95% of the fractions included in the analysis. In the case of anisotropic margins, the expansion required in the S-I direction was larger (8.1 mm) than those in the L-R (4.9 mm) and A-P (4.5 mm) directions. This margin accounts for variations of target position within the same treatment fraction.The use of bony alignment for CyberKnife lung stereotactic body radiation therapy requires careful considerations, in terms of the potential for increased toxicity or local miss. Our method could be used by other centers to determine the adequacy of ITV-to-PTV margins for their patients.

The purpose of this article is to present an updated set of American College of Radiology consensus guidelines formed from an expert panel on the appropriate use of radiation therapy in postprostatectomy prostate cancer. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Recent and relevant literature reviewed by the panel led to establishment of criteria for appropriate use of radiation therapy in postprostatectomy prostate cancer. The discussion includes treatment technique, appropriate dose, field design, and the role of prostate-specific antigen (PSA). Ratings and commentary of the panel on multiple treatment parameters were used to reach consensus. Patients with high-risk pathologic features benefit from postprostatectomy radiation therapy.

The incidence of melanoma in US adults is approximately 1.5 per million, with 2% to 5% of patients developing metastatic disease. In children, melanoma is distinctly uncommon, and metastatic disease occurs even more seldom. This case report, the first of a patellar lesion as the initial presentation of metastatic melanoma in a pediatric patient, highlights use of patellectomy and intraoperative radiation therapy in obtaining palliative local control while avoiding periarticular functional morbidity.

To use an imaging beam line (IBL) to obtain the first megavoltage cone-beam computed tomography (MV CBCT) images of patients with a low atomic number (Z) target, and to compare these images to those taken of the same patients with the 6 MV flattened beam from the treatment beam line (TBL).The IBL, which produces a 4.2 MV unflattened beam from a carbon target, was installed on a linear accelerator in use for radiotherapy. Provision was made for switching between the IBL and TBL for imaging the same patient with beams from the low-Z and high-Z targets. Dose was quoted as monitor units times the dose per monitor unit for the standard calibration geometry. Images were acquired with institutional approval and patient consent with both the IBL and TBL on a series of 23 patients undergoing radiotherapy. Patients were imaged daily to weekly and aligned to the planning CT using the images. Doses were reduced over the course of treatment to determine the minimum doses required for alignment. Images were assessed offline.IBL MV CBCT images of prostate, head and neck, lung, and abdomen showed improvement in soft tissue contrast for the same dose as the TBL images. Bony anatomy, air cavities, and fiducial markers were sharper. CBCT with a dose of 1 cGy was sufficient for alignment of prostate and head and neck patients based on bony anatomy or implanted gold seeds, 2-4 cGy for lung, abdomen, and pelvis. Photon scatter in the patient had minimal effect on image quality. The metallic hip prosthesis in one patient showed reduced artifacts compared to diagnostic CT.The IBL has the advantage of improved image quality at the same dose, or reduced dose for the same image quality, over the TBL.

Hypofractionated stereotactic body radiotherapy (SBRT) has been tested for prostate cancer radiotherapy. This study aims to investigate the dosimetric effects of intrafraction prostate motion on the target and the normal structures for SBRT. For prostate cancer patients treated with an image-tracking CyberKnife system, the intrafraction prostate movements were recorded during 50-70 min treatment time. Based on the recorded intrafraction prostate movements, treatment plans were created for these cases using intensity modulated beams while scaling the average time patterns from the CyberKnife treatment to simulate hypofractionated intensity modulated radiotherapy (IMRT) delivery. The effect of delivery time on the intrafraction organ motion was investigated. For a nominal single fraction delivery of 9.5 Gy with IMRT, we found that the dosimetric effect of the intrafraction prostate movement is case dependent. For most cases, the dose volume histograms exhibited very small changes from the treatment plans that assumed no intrafractional prostate motion when the maximum intrafraction movements were within +/-5 mm. However, when sporadic prostate movements greater than 5 mm were present in any one direction, significant changes were found. For example, the V100, for the prostate could be reduced by more than 10% to less than 85% of the prostate volume coverage. If these large movements could be excluded by some active correction strategies, then the average V100% for the simulated plan could be restored to within approximately 2% of the ideal treatment plans. On average, the sporadic intrafraction motion has less dosimetric impact on the prolonged treatment delivery versus fast treatment delivery. For example, the average V100% for the clinical target volume was reduced from the original 95.1% to 92.1 +/- 3.7% for prolonged treatment, and to 91.3 +/- 5.4% when the treatment time was shortened by 50%. Due to the observed large sporadic prostate motions, we conclude that an on-line target motion monitoring and correction strategy is necessary to implement hypofractionated SBRT with intensity modulated beams for prostate cancer treatments.

Megavoltage cone-beam CT (MVCBCT), the recent addition to the family of in-room CT imaging systems for image-guided radiation therapy (IGRT), uses a conventional treatment unit equipped with a flat panel detector to obtain a three-dimensional representation of the patient in treatment position. MVCBCT has been used for more than two years in our clinic for anatomy verification and to improve patient alignment prior to dose delivery. The objective of this research is to evaluate the image acquisition dose delivered to patients for MVCBCT and to develop a simple method to reduce the additional dose resulting from routine MVCBCT imaging. Conventional CT scans of phantoms and patients were imported into a commercial treatment planning system (TPS: Phillips, Pinnacle) and an arc treatment mimicking the MVCBCT acquisition process was generated to compute the delivered acquisition dose. To validate the dose obtained from the TPS, a simple water-equivalent cylindrical phantom with spaces for MOSFETs and an ion chamber was used to measure the MVCBCT image acquisition dose. Absolute dose distributions were obtained by simulating MVCBCTs of 9 and 5 monitor units (MU) on pelvis and head and neck patients, respectively. A compensation factor was introduced to generate composite plans of treatment and MVCBCT imaging dose. The article provides a simple equation to compute the compensation factor. The developed imaging compensation method was tested on routinely used clinical plans for prostate and head and neck patients. The quantitative comparison between the calculated dose by the TPS and measurement points on the cylindrical phantom were all within 3%. The dose percentage difference for the ion chamber placed in the center of the phantom was only 0.2%. For a typical MVCBCT, the dose delivered to patients forms a small anterior-posterior gradient ranging from 0.6 to 1.2 cGy per MVCBCT MU. MVCBCT acquisitions in the pelvis and head and neck areas deliver slightly more dose than current portal imaging but render soft tissue information for positioning. Overall, the additional dose from daily 9 MU MVCBCTs of prostate patients is small compared to the treatment dose (4%). Dose-volume histograms of compensated plans for pelvis and head and neck patients imaged daily with MVCBCT showed no additional dose to the target and small increases at low doses. The results indicate that the dose delivered for MVCBCT imaging can be precisely calculated in the TPS and therefore included in the treatment plan. This allows simple plan compensations, such as slightly reducing the treatment dose, to minimize the total dose received by critical structures from daily positioning with MVCBCT. The proposed compensation factor reduces the number of MU per treatment beam per fraction. Both the number of fractions and the beam arrangement are kept unchanged. Reducing the imaging volume in the cranio-caudal direction can further reduce the dose delivered for MVCBCT. This is a useful feature to eliminate the imaging dose to the eyes or to focus on a specific region of interest for alignment.

This study assessed whether putative effectors of phosphatidylinositol3-kinase, including PTEN, protein kinase B (PKB), and p27(kip1), correlate with each other, with glioma histology, and with patient outcome.Components of the phosphatidylinositol 3-kinase signaling cascade were characterized in 25 glioblastoma multiforme (GBM) tumors, 8 grade II oligoastrocytomas, and 13 normal human brain specimens. The protein levels of PTEN and p27(kip1) were assessed by immunoblot analyses. PKB kinase activity was evaluated through the expression level of the phosphorylated (activated) PKB protein and the ability of PKB to phosphorylate a specific peptide substrate in vitro. Cox regression analyses between expression/activity variables and survival were performed across and within histology types. Actual value for expression/activity was used as a continuous variable. Survival time was displayed by Kaplan Meier.A strong inverse correlation was evident between PTEN levels and both phosphorylated PKB expression (P0.01) and PKB activity (P = 0.01). p27(kip1) levels did not correlate with PTEN expression or PKB activity. A significant association was evident between PTEN expression level and histology (P0.01). PTEN levels were highest in normal brain, lowest in GBM tumors, and intermediate in grade II oligoastrocytomas. PKB activity and phosphorylated PKB levels differed significantly among histologies, whereas p27(kip1) levels exhibited no association with histology. PTEN expression correlated significantly with survival time within the entire cohort (P0.01) and was associated with survival within the subgroup of GBM tumors (P = 0.11).Reduced PTEN expression is ubiquitous among GBM tumors and may play a role in the development of low-grade gliomas. PTEN inactivation in gliomas portends a particularly aggressive clinical behavior.