Julian Perks

Comparison of peripheral dose from image-guided radiation therapy (IGRT) using kV cone beam CT to intensity-modulated radiation therapy (IMRT)

PURPOSE The growing use of IMRT with volumetric kilovoltage cone-beam computed tomography (kV-CBCT) for IGRT has increased concerns over the additional (typically unaccounted) radiation dose associated with the procedures. Published data quantify the in-field dose of IGRT and the peripheral dose from IMRT. This study adds to the data on dose outside the target area by measuring peripheral CBCT dose and comparing it with out-of-field IMRT dose. MATERIALS AND METHODS Measurements of the CBCT peripheral dose were made in an anthropomorphic phantom with TLDs and were compared to peripheral dose measurements for prostate IMRT, determined with MOSFET detectors. RESULTS Doses above 1cGy (per scan) were found outside the CBCT imaged volume, with 0.2cGy at 25 cm from the central axis. IMRT peripheral dose was 1cGy at 20 cm and 0.4cGy at 25 cm (per fraction). CONCLUSIONS An appreciable dose can be found beyond the edge of the IGRT field; of similar order of magnitude as peripheral dose from IMRT (mGy), and approximately half the dose delivered to the same point from the IMRT treatment (0.2cGy c.f. 0.4cGy 25 cm from the isocenter). This shows that peripheral dose, as well as the in-field dose from CBCT, needs to be taken into account when considering long term care of radiation oncology patients.

Evaluation of the Planning Target Volume in the Treatment of Head and Neck Cancer With Intensity-Modulated Radiotherapy: What Is the Appropriate Expansion Margin in the Setting of Daily Image Guidance?

PURPOSE To compare patterns of disease failure among patients treated with intensity-modulated radiotherapy (IMRT) in conjunction with daily image-guided radiotherapy (IGRT) for head and neck cancer, according to the margins used to expand the clinical target volume (CTV) to create a planning target volume (PTV). METHODS AND MATERIALS Two-hundred and twenty-five patients were treated with IMRT for squamous cell carcinoma of the head and neck. Daily IGRT scans were acquired using either kilovoltage or megavoltage volumetric imaging prior to each delivered fraction. The first 95 patients were treated with IMRT with 5-mm CTV-to-PTV margins. The subsequent 130 patients were treated using 3-mm PTV expansion margins. RESULTS Two-year estimates of overall survival, local-regional control, and distant metastasis-free survival were 76%, 78%, and 81%, respectively. There were no differences with respect to any of these endpoints among patients treated with 5-mm and 3-mm PTV expansion margins (p > 0.05, all). The 2-year local-regional control rate for patients treated with IMRT with 5-mm and 3-mm PTV margins was 78% and 78%, respectively (p = 0.96). Spatial evaluation revealed no differences in the incidences of marginal failures among those treated with 5-mm and 3-mm PTV margins. CONCLUSIONS The use of 3-mm PTV expansion margins appears adequate and did not increase local-regional failures among patients treated with IMRT for head and neck cancer. These data demonstrate the safety of PTV reduction of less than 5 mm and support current protocols recommending this approach in the setting of daily IGRT.

Commissioning experience with cone-beam computed tomography for image-guided radiation therapy.

This paper reports on the commissioning of an Elekta cone‐beam computed tomography (CT) system at one of the first U.S. sites to install a “regular,” off‐the‐shelf Elekta Synergy (Elekta, Stockholm, Sweden) accelerator system. We present the quality assurance (QA) procedure as a guide for other users. The commissioning had six elements: (1) system safety, (2) geometric accuracy (agreement of megavoltage and kilovoltage beam isocenters), (3) image quality, (4) registration and correction accuracy, (5) dose to patient and dosimetric stability, and (6) QA procedures. The system passed the safety tests, and agreement of the isocenters was found to be within 1 mm. Using a precisely moved skull phantom, the reconstruction and alignment algorithm was found to be accurate within 1 mm and 1 degree in each dimension. Of 12 measurement points spanning a 9×9×15‐cm volume in a Rando phantom (The Phantom Laboratory, Salem, NY), the average agreement in the x, y, and z coordinates was 0.10 mm, −0.12 mm, and 0.22 mm [standard deviations (SDs): 0.21 mm, 0.55 mm, 0.21 mm; largest deviations: 0.6 mm, 1.0 mm, 0.5 mm] respectively. The larger deviation for the y component can be partly attributed to the CT slice thickness of 1 mm in that direction. Dose to the patient depends on the machine settings and patient geometry. To monitor dose consistency, air kerma (output) and half‐value layer (beam quality) are measured for a typical clinical setting. Air kerma was 6.3 cGy (120 kVp, 40 mA, 40 ms per frame, 360‐degree scan, S20 field of view); half value layer was 7.1 mm aluminum (120 kV, 40 mA). We suggest performing items 1, 2, and 3 monthly, and 4 and 5 annually. In addition, we devised a daily QA procedure to verify agreement of the megavoltage and kilovoltage isocenters using a simple phantom containing three small steel balls. The frequency of all checks will be reevaluated based on data collected during about 1 year. PACS number: 87.53.Xd

Failure Mode and Effect Analysis for Delivery of Lung Stereotactic Body Radiation Therapy

PURPOSE To improve the quality and safety of our practice of stereotactic body radiation therapy (SBRT), we analyzed the process following the failure mode and effects analysis (FMEA) method. METHODS The FMEA was performed by a multidisciplinary team. For each step in the SBRT delivery process, a potential failure occurrence was derived and three factors were assessed: the probability of each occurrence, the severity if the event occurs, and the probability of detection by the treatment team. A rank of 1 to 10 was assigned to each factor, and then the multiplied ranks yielded the relative risks (risk priority numbers). The failure modes with the highest risk priority numbers were then considered to implement process improvement measures. RESULTS A total of 28 occurrences were derived, of which nine events scored with significantly high risk priority numbers. The risk priority numbers of the highest ranked events ranged from 20 to 80. These included transcription errors of the stereotactic coordinates and machine failures. CONCLUSION Several areas of our SBRT delivery were reconsidered in terms of process improvement, and safety measures, including treatment checklists and a surgical time-out, were added for our practice of gantry-based image-guided SBRT. This study serves as a guide for other users of SBRT to perform FMEA of their own practice.

Patterns-of-Care for Thoracic Stereotactic Body Radiotherapy among Practicing Radiation Oncologists in the United States

Introduction: Radiation oncologists were surveyed to assess practice patterns in the use of stereotactic body radiotherapy (SBRT) for lung cancer. Methods: A customized patterns-of-care survey, consisting of 18 questions and two clinical scenarios, was e-mailed to 136 academic radiation oncologists and 768 community practitioners to evaluate the technical basis and delivery parameters associated with SBRT. Results: A total of 117 surveys were evaluable. The cited delivery techniques included: static noncoplanar beams (48%), intensity-modulated radiotherapy (41%), rotational intensity-modulated radiotherapy (47%), dynamic conformal arcs (7%), and small-beam delivery with fiducial tracking (24%), with 46% using multiple techniques. The immobilization methods included: stereotactic frame (10%), alpha cradle or vacuum-lock system (52%), wingboard (3%), stereotactic frame with an alpha cradle or vacuum-lock system (11%); combination of devices (14%), or no immobilization (9%). Abdominal compression was used by 51% and respiratory gating by 31%. For a peripheral T1N0 tumor, the preferred doses included: 25 to 34 Gy in one fraction (1%); 54 to 60 Gy in three fractions (56%), 48 to 50 Gy in four fractions (18%), and 50 to 60 Gy in five fractions (25%). For a centrally located T1N0 tumor, 58% recommended SBRT outside a clinical protocol, with recommended doses ranging from 40 to 60 Gy in three to 10 fractions. The recommended interval to first surveillance imaging ranged from 6 weeks or lesser (32%) to 25 weeks or more (2%). Conclusions: Considerable variation exists for thoracic SBRT with regard to dose selection, fractionation, immobilization, planning, management of central lesions, and surveillance. Ongoing prospective evaluation is recommended to identify best practices and provide continual process improvement.

CDK1-mediated SIRT3 activation enhances mitochondrial function and tumor radioresistance

Tumor adaptive resistance to therapeutic radiation remains a barrier for further improvement of local cancer control. SIRT3, a member of the sirtuin family of NAD+-dependent protein deacetylases in mitochondria, promotes metabolic homeostasis through regulation of mitochondrial protein deacetylation and plays a key role in prevention of cell aging. Here, we demonstrate that SIRT3 expression is induced in an array of radiation-treated human tumor cells and their corresponding xenograft tumors, including colon cancer HCT-116, glioblastoma U87, and breast cancer MDA-MB231 cells. SIRT3 transcriptional activation is due to SIRT3 promoter activation controlled by the stress transcription factor NF-κB. Posttranscriptionally, SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by cyclin B1–CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3. Cells expressing Thr150Ala/Ser159Ala-mutant SIRT3 show a reduction in mitochondrial protein lysine deacetylation, Δψm, MnSOD activity, and mitochondrial ATP generation. The clonogenicity of Thr150Ala/Ser159Ala-mutant transfectants is lower and significantly decreased under radiation. Tumors harboring Thr150Ala/Ser159Ala-mutant SIRT3 show inhibited growth and increased sensitivity to in vivo local irradiation. These results demonstrate that enhanced SIRT3 transcription and posttranslational modifications in mitochondria contribute to adaptive radioresistance in tumor cells. CDK1-mediated SIRT3 phosphorylation is a potential effective target to sensitize tumor cells to radiotherapy. Mol Cancer Ther; 14(9); 2090–102. ©2015 AACR.

Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies

Purpose: Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term “rebound immune suppression,” limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy. Experimental Design: We examined the efficacy and immunologic effects of a novel triple therapy consisting of local radiotherapy, intratumoral CpG, and systemic IDO blockade in murine models and a pilot canine clinical trial. Results: In murine models, we observed marked increase in intratumoral IDO expression after treatment with radiotherapy, CpG, or other immunotherapies. The addition of IDO blockade to radiotherapy + CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment. This triple combination induced systemic antitumor effects, decreasing metastases, and improving survival in a CD8+ T-cell–dependent manner. We evaluated this novel triple therapy in a canine clinical trial, because spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intratumoral immunosuppression, and induced robust systemic antitumor effects. Conclusions: These results suggest that IDO maintains immune suppression in the tumor after therapy, and IDO blockade promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation. Clin Cancer Res; 22(17); 4328–40. ©2016 AACR.

Glass rod detectors for small field, stereotactic radiosurgery dosimetric audit.

This paper demonstrates the feasibility of using glass rod detectors for quality assurance audit of radiosurgery units. Five radiosurgery units (3 Gamma Knife model C, 1 Gamma Knife model U and 1 Cyberknife) located in California participated in the study. At each center glass rod detectors were used to measure a number of dosimetric parameters including relative collimator output factor and absolute dose rate. The Gamma Knife data obtained is in excellent agreement with the commissioning data generated by the manufacturer for each unit and the Cyberknife data is in general agreement with the data published by other centers. In particular the output factor of the 4 mm Gamma Knife helmet factor, a subject of abundant debate, was measured in the range 0.863-0.872 with an accuracy of better than 1% across the four participating centers. It is hoped that this pilot study will facilitate a nationwide postal audit of stereotactic radiosurgery units.

Skin dose effects of postmastectomy chest wall radiation therapy using brass mesh as an alternative to tissue equivalent bolus

PURPOSE The use of brass mesh as a bolus is relatively uncommon in postmastectomy chest wall radiation therapy (PMRT). This study aimed to characterize the skin dose effects of using 2-mm fine brass mesh as an alternative to the traditional tissue-equivalent bolus during chest wall PMRT. METHODS AND MATERIALS Data were collected from patients who received PMRT using brass mesh at the University of California Davis Department of Radiation Oncology between January 2008 and June 2011. Several patient characteristics including age, body habitus, and ethnicity were analyzed along with several disease and treatment characteristics to determine whether or not they had an impact on the skin reaction observed during radiation treatment. Additionally, in vivo surface dose measurements were obtained for 16 of the 48 patients (33%). RESULTS Forty-eight female patients aged 28-83 received PMRT using brass mesh. As expected, the severity of skin toxicity increased with subsequent doses of radiation with all patients beginning treatment with no skin reaction (National Cancer Institute scores [NCIS] = 0) and the majority of patients completing treatment with either faint to moderate erythema (n = 19, 40%, NCIS = 1) or moderate to brisk erythema (n = 23, 48%, NCIS = 2). In vivo dosimetry analysis revealed surface doses between 81% and 122% of the prescribed dose, with an average of 99% of the prescribed radiation dose and standard deviation of 10% being delivered. CONCLUSIONS For postmastectomy chest wall radiation therapy, brass mesh is an effective alternative to tissue-equivalent bolus. The brass mesh achieved moderate erythema in the majority of patients at the end of treatment and the surface dose was validated using in vivo dosimetry.

Comparison of IMRT techniques in the radiotherapeutic management of head and neck cancer: is tomotherapy "better" than step-and-shoot IMRT?

Currently, the most common method of delivering intensity-modulated radiotherapy (IMRT) is through step-and-shoot, segmental multi-leaf collimator (SMLC)-based techniques. Although rotational delivery methods such as helical tomotherapy (HT) have been proposed as offering advantages in the treatment of head and neck cancer, a lack of clinical data exists on its potential utility. This study compared dosimetric, clinical, and quality-of-life endpoints among 149 patients treated by HT and SMLC-IMRT for head and neck cancer. Dosimetric analysis revealed that the use of HT resulted in significant improvements with respect to mean dose (23.5 versus 27.9 Gy, p = 0.03) and V30 (30.1 versus 43.9 Gy, p = 0.01) to the contralateral (spared) parotid gland. However, the incidence of grade 3+ xerostomia in the late setting was 10% and 8% among patients treated by HT and SMLC-IMRT, respectively (p = 0.46). There were no significant differences in any of the quality of life endpoints among patients treated by HT and SMLC-IMRT (p > 0.05, for all). Acknowledging the biases inherent in this retrospective analysis, we found that the dosimetric advantages observed with HT compared to SMLC-IMRT failed to translate into significant improvements in clinical outcome. Prospective studies are needed to further evaluate how HT may affect the therapeutic ratio.