Nzhde Agazaryan

Radiation Enhances Regulatory T Cell Representation

PURPOSE Immunotherapy could be a useful adjunct to standard cytotoxic therapies such as radiation in patients with micrometastatic disease, although successful integration of immunotherapy into treatment protocols will require further understanding of how standard therapies affect the generation of antitumor immune responses. This study was undertaken to evaluate the impact of radiation therapy (RT) on immunosuppressive T regulatory (Treg) cells. METHODS AND MATERIALS Treg cells were identified as a CD4(+)CD25(hi)Foxp3(+) lymphocyte subset, and their fate was followed in a murine TRAMP C1 model of prostate cancer in mice with and without RT. RESULTS CD4(+)CD25(hi)Foxp3(+) Treg cells increased in immune organs after local leg or whole-body radiation. A large part, but not all, of this increase after leg-only irradiation could be ascribed to radiation scatter and Treg cells being intrinsically more radiation resistant than other lymphocyte subpopulations, resulting in their selection. Their functional activity on a per-cell basis was not affected by radiation exposure. Similar findings were made with mice receiving local RT to murine prostate tumors growing in the leg. The importance of the Treg cell population in the response to RT was shown by systemic elimination of Treg cells, which greatly enhanced radiation-induced tumor regression. CONCLUSIONS We conclude that Treg cells are more resistant to radiation than other lymphocytes, resulting in their preferential increase. Treg cells may form an important homeostatic mechanism for tissues injured by radiation, and in a tumor context, they may assist in immune evasion during therapy. Targeting this population may allow enhancement of radiotherapeutic benefit through immune modulation.

Irradiation of the potential cancer stem cell niches in the adult brain improves progression-free survival of patients with malignant glioma

BackgroundGlioblastoma is the most common brain tumor in adults. The mechanisms leading to glioblastoma are not well understood but animal studies support that inactivation of tumor suppressor genes in neural stem cells (NSC) is required and sufficient to induce glial cancers. This suggests that the NSC niches in the brain may harbor cancer stem cells (CSCs), Thus providing novel therapy targets. We hypothesize that higher radiation doses to these NSC niches improve patient survival by eradicating CSCs.Methods55 adult patients with Grade 3 or Grade 4 glial cancer treated with radiotherapy at UCLA between February of 2003 and May of 2009 were included in this retrospective study. Using radiation planning software and patient radiological records, the SVZ and SGL were reconstructed for each of these patients and dosimetry data for these structures was calculated.ResultsUsing Kaplan-Meier analysis we show that patients whose bilateral subventricular zone (SVZ) received greater than the median SVZ dose (= 43 Gy) had a significant improvement in progression-free survival if compared to patients who received less than the median dose (15.0 vs 7.2 months PFS; P = 0.028). Furthermore, a mean dose >43 Gy to the bilateral SVZ yielded a hazard ratio of 0.73 (P = 0.019). Importantly, similarly analyzing total prescription dose failed to illustrate a statistically significant impact.ConclusionsOur study leads us to hypothesize that in glioma targeted radiotherapy of the stem cell niches in the adult brain could yield significant benefits over radiotherapy of the primary tumor mass alone and that damage caused by smaller fractions of radiation maybe less efficiently detected by the DNA repair mechanisms in CSCs.

An evaluation of gating window size, delivery method, and composite field dosimetry of respiratory-gated IMRT.

A respiratory gating system has been developed based on a commercial patient positioning system. The purpose of this study is to investigate the ability of the gating system to reproduce normal, nongated IMRT operation and to quantify the errors produced by delivering a nongated IMRT treatment onto a moving target. A moving phantom capable of simultaneous two-dimensional motion was built, and an analytical liver motion function was used to drive the phantom. Studies were performed to assess the effect of gating window size and choice of delivery method (segmented and dynamic multileaf collimation). Additionally, two multiple field IMRT cases were delivered to quantify the error in gated and nongated IMRT with motion. Dosimetric error between nonmoving and moving deliveries is related to gating window size. By reducing the window size, the error can be reduced. Delivery error can be reduced for both dynamic and segmented delivery with gating. For the implementation of dynamic IMRT delivery in this study, dynamic delivery was found to generate larger delivery errors than segmented delivery in most cases studied. For multiple field IMRT delivery, the largest errors were generated in regions where high field modulation was present parallel to the axis of motion. Gating was found to reduce these large errors to clinically acceptable levels.

Patient specific quality assurance for the delivery of intensity modulated radiotherapy

A patient specific quality assurance program has been developed to facilitate the clinical implementation of intensity modulated radiotherapy (IMRT) delivered using a micro‐multileaf collimator. The methodology includes several dosimetric tasks that are performed prior to the treatment of each patient. Film dosimetry is performed for each individual field and for the multifield composite plan. Individual field measurements are performed at a depth of 5 cm in a water equivalent slab phantom; export of dose calculations from the treatment planning system is similarly specified. For the composite distribution, parameters from the patient plan are applied to an IMRT phantom, and film is exposed in an axial orientation. Distributions are compared with the aid of software developed for the specific tasks. The measured and calculated dose distributions can be superimposed and positioned graphically using move, rotate, and mirror tools, as well as by specifying isocenter coordinates and using fiducial marks. Horizontal and vertical profiles are available for analysis. Dose difference, distance‐to‐agreement, and γ index, the minimum scaled multidimensional distance between a measurement and a calculation point determined in combined dose and physical distance space, are calculated along a specified isodose line and displayed. γ provides an excellent measure of disagreement between measurement and calculation for complex intensity distributions. We specify 3% dose difference and 3 mm distance as our scaling acceptability criteria. Absolute dosimetry for each composite plan is performed using an ionization chamber. To date, excellent agreement between measurements and calculations has been observed.

Image guided radiation therapy (IGRT) technologies for radiation therapy localization and delivery.

Image Guided Radiation Therapy (IGRT) Technologies for Radiation Therapy Localization and Delivery Jennifer De Los Santos, MD,* Richard Popple, PhD,* Nzhde Agazaryan, PhD,y John E. Bayouth, PhD,z Jean-Pierre Bissonnette, PhD,x Mary Kara Bucci, MD,k Sonja Dieterich, PhD,{ Lei Dong, PhD, Kenneth M. Forster, PhD,** Daniel Indelicato, MD,yy Katja Langen, PhD,zz Joerg Lehmann, PhD,{ Nina Mayr, MD,xx Ishmael Parsai, PhD,{{ William Salter, PhD, Michael Tomblyn, MD, MS,*** William T.C. Yuh, MD, MSEE,kk and Indrin J. Chetty, PhDyyy *Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama; yDepartment of Radiation Oncology, University of California Los Angeles, Los Angeles, California; zDepartment of Radiation Oncology, University of Iowa, Iowa City, Iowa; xDepartment of Radiation Physics, Princess Margaret Hospital, Toronto, Ontario, Canada; kAnchorage Radiation Therapy Center, Anchorage, Alaska; {Department of Radiation Oncology, University of California Davis, Sacramento, California; Scripps Proton Therapy Center, San Diego, California; **Department of Radiation Oncology, University of South Alabama, Mobile, Alabama; yyDepartment of Radiation Oncology, University of Florida Proton Therapy Institute, Jacksonville, Florida; zzDepartment of Radiation Oncology, MD Anderson Cancer Center Orlando, Orlando, Florida; Departments of xxRadiation Oncology and kkRadiology, Ohio State University, Columbus, Ohio; {{Department of Radiation Oncology, University of Toledo College of Medicine, Toledo, Ohio; Department of Radiation Oncology, Huntsman Cancer Hospital, Salt Lake City, Utah; ***Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida; and yyyDepartment of Radiation Oncology, Henry Ford Hospital and Health Centers, Detroit, Michigan

Evaluation of high ipsilateral subventricular zone radiation therapy dose in glioblastoma: a pooled analysis.

PURPOSE Cancer stem cells (CSCs) may play a role in the recurrence of glioblastoma. They are believed to originate from neural stem cells in the subventricular zone (SVZ). Because of their radioresistance, we hypothesized that high doses of radiation (>59.4 Gy) to the SVZ are necessary to control CSCs and improve progression-free survival (PFS) or overall survival (OS) in glioblastoma. METHODS AND MATERIALS 173 patients with glioblastoma pooled from 2 academic centers were treated with resection followed by chemoradiation therapy. The SVZ was segmented on computed tomography to calculate radiation doses delivered to the presumptive CSC niches. The relationships between high SVZ doses and PFS and OS were examined using Cox proportional hazards models. Five covariates were included to estimate their impact on PFS or OS: ipsilateral and contralateral SVZ doses, clinical target volume dose, age, and extent of resection. RESULTS Median PFS and OS were 10.4 and 19.6 months for the cohort. The mean ipsilateral SVZ, contralateral SVZ, and clinical target volume doses were 49.2, 35.2, and 60.1 Gy, respectively. Twenty-one patients who received high ipsilateral SVZ dose (>59.4 Gy) had significantly longer median PFS (12.6 vs 9.9 months, P=.042) and longer OS (25.8 vs 19.2 months, P=.173). On multivariate analysis, high radiation therapy doses to ipsilateral SVZ remained a statistically significant independent predictor of improved PFS but not of OS. The extent of surgery affected both PFS and OS on multivariate analysis. CONCLUSION High radiation therapy doses to ipsilateral CSC niches are associated with improved PFS in glioblastoma.

Stereotactic body radiation therapy and 3-dimensional conformal radiotherapy for stage I non-small cell lung cancer: A pooled analysis of biological equivalent dose and local control

PURPOSE To determine the relationship between tumor control probability (TCP) and biological effective dose (BED) for radiation therapy in medically inoperable stage I non-small cell lung cancer (NSCLC). METHODS AND MATERIALS Forty-two studies on 3-dimensional conformal radiation therapy (3D-CRT) and SBRT for stage I NSCLC were reviewed for tumor control (TC), defined as crude local control ≥ 2 years, as a function of BED. For each dose-fractionation schedule, BED was calculated at isocenter using the linear quadratic (LQ) and universal survival curve (USC) models. A scatter plot of TC versus BED was generated and fitted to the standard TCP equation for both models. RESULTS A total of 2696 patients were included in this study (SBRT: 1640; 3D-CRT: 1056). Daily fraction size was 1.2-4 Gy (total dose: 48-102.9) with 3D-CRT and 6-26 (total dose: 20-66) with SBRT. Median BED was 118.6 Gy (range, 68.5-320.3) and 95.6 Gy (range, 46.1-178.1) for the LQ and USC models, respectively. According to the LQ model, BED to achieve 50% TC (TCD50) was 61 Gy (95% confidence interval, 50.2-71.1). TCP as a function of BED was sigmoidal, with TCP ≥ 90% achieved with BED ≥ 159 Gy and 124 Gy for the LQ and USC models, respectively. CONCLUSIONS Dose-escalation beyond a BED 159 by LQ model likely translates into clinically insignificant gain in TCP but may result in clinically significant toxicity. When delivered with SBRT, BED of 159 Gy corresponds to a total dose of 53 Gy in 3 fractions at the isocenter.

The effects of tumor motion on planning and delivery of respiratory‐gated IMRT

The purpose of this study is to investigate the effects of object motion on the planning and delivery of IMRT. Two phantoms containing objects were imaged using CT under a variety of motion conditions. The effects of object motion on axial CT acquisition with and without gating were assessed qualitatively and quantitatively. Measurements of effective slice width and position for the CT scans were made. Mutual information image fusion was adapted for use as a quantitative measure of object deformation in CT images. IMRT plans were generated on the CT scans of the moving and gated object images. These plans were delivered with motion, with and without gating, and the delivery error between the moving deliveries and a nonmoving delivery was assessed using a scalable vector-based index. Motion during CT acquisition produces motion artifact, object deformation, and object mispositioning, which can be substantially reduced with gating. Objects that vary in cross section in the direction of motion exhibit the most deformation in CT images. Mutual information provides a useful quantitative estimate of object deformation. The delivery of IMRT in the presence of target motion significantly alters the delivered dose distribution in relation to the planned distribution. The utilization of gating for IMRT treatment, including imaging, planning, and delivery, significantly reduces the errors introduced by object motion.

Intraoperative Ultrasonography-Guided Positioning of Iodine 125 Plaque Brachytherapy in the Treatment of Choroidal Melanoma

PURPOSE To report intraoperative ultrasonography-guided positioning of iodine 125 (I(125)) plaques for brachytherapy of choroidal melanoma as a quality improvement measure. DESIGN Retrospective, single-center, consecutive case-cohort study. PARTICIPANTS One hundred fifty consecutive patients with choroidal melanoma. METHODS Patients with choroidal melanoma who were treated with I(125) plaque brachytherapy from January 2007 through January 2011 with at least 6 months of clinical follow-up were included. MAIN OUTCOME MEASURES Patient and tumor characteristics at diagnosis were tabulated. The need for plaque repositioning if intraoperative ultrasonography showed the plaque to be either not centered on the tumor or if there was less than 1.0 mm of plaque margin beyond the tumor border was recorded. The rate of local treatment failure and occurrence of distant metastasis were determined. RESULTS The average interval from surgery to last follow-up was 21.5 months. Fifty-four (36%) of 150 patients required plaque repositioning. Of tumors located in the macula, equator, and periphery, 15 (36.6%), 26 (36.6%), and 13 (34.2%) required repositioning. There was no case of local treatment failure during a mean follow-up of 21.5 months (range, 6-48 months). Clinical evidence of choroidal melanoma metastasis developed in 9 patients. The cumulative 2-year Kaplan-Meier rate of local treatment failure in the cohort was statistically lower compared with the Collaborative Ocular Melanoma Study, which did not require ultrasonography-guided plaque positioning. CONCLUSIONS Intraoperative ultrasonography identified the need to reposition I(125) plaques to achieve centration and plaque margin (>1.0 mm) beyond the tumor border in 36% of eyes. Neither tumor size nor tumor location correlated with the need to reposition the plaque. There was no case of local treatment failure during follow-up in this series. Correct plaque position is an essential component of quality outcomes in brachytherapy. Intraoperative ultrasonography reduces geographic errors in placement in eye plaque therapy and may help to reduce local treatment failure in choroidal melanoma.

Image-guided radiosurgery for spinal tumors : methods, accuracy and patient intrafraction motion

Image-guided frameless extracranial radiosurgery has become an established treatment option; however, without a frame to restrict patient movements, intrafraction field mispositioning becomes more probable. The primary aim of this study is to determine the intrafraction motion of spinal radiosurgery patients. This aim was approached in two steps. First, a phantom study demonstrated that the system can detect movements accurately within 0.1 mm and rotational changes within 0.2 degrees. Second, patient positioning and monitoring were carried out for a group of 15 patients with 20 treatment sites. For the patient pool in the study, vertebral anatomy movement was observed to vary as much as 3 mm between sequential measurements and could occur in as little as 5 min. These results suggest a need for intrafraction patient monitoring and correctional shifts, even for patients whose overall treatment times are expected to be relatively short. Small relative rotations with standard deviations of less than 1.5 degrees were observed. The small relative rotational movements observed do not, alone, justify patient monitoring using the image-guidance system during the treatments of generally small radiosurgical targets.